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Critical Review

Quaternary Ammonium Compounds: A Chemical Class of Emerging Concern
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Environmental Science & Technology

Cite this: Environ. Sci. Technol. 2023, 57, 20, 7645–7665
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https://doi.org/10.1021/acs.est.2c08244
Published May 8, 2023

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Abstract

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Quaternary ammonium compounds (QACs), a large class of chemicals that includes high production volume substances, have been used for decades as antimicrobials, preservatives, and antistatic agents and for other functions in cleaning, disinfecting, personal care products, and durable consumer goods. QAC use has accelerated in response to the COVID-19 pandemic and the banning of 19 antimicrobials from several personal care products by the US Food and Drug Administration in 2016. Studies conducted before and after the onset of the pandemic indicate increased human exposure to QACs. Environmental releases of these chemicals have also increased. Emerging information on adverse environmental and human health impacts of QACs is motivating a reconsideration of the risks and benefits across the life cycle of their production, use, and disposal. This work presents a critical review of the literature and scientific perspective developed by a multidisciplinary, multi-institutional team of authors from academia, governmental, and nonprofit organizations. The review evaluates currently available information on the ecological and human health profile of QACs and identifies multiple areas of potential concern. Adverse ecological effects include acute and chronic toxicity to susceptible aquatic organisms, with concentrations of some QACs approaching levels of concern. Suspected or known adverse health outcomes include dermal and respiratory effects, developmental and reproductive toxicity, disruption of metabolic function such as lipid homeostasis, and impairment of mitochondrial function. QACs’ role in antimicrobial resistance has also been demonstrated. In the US regulatory system, how a QAC is managed depends on how it is used, for example in pesticides or personal care products. This can result in the same QACs receiving different degrees of scrutiny depending on the use and the agency regulating it. Further, the US Environmental Protection Agency’s current method of grouping QACs based on structure, first proposed in 1988, is insufficient to address the wide range of QAC chemistries, potential toxicities, and exposure scenarios. Consequently, exposures to common mixtures of QACs and from multiple sources remain largely unassessed. Some restrictions on the use of QACs have been implemented in the US and elsewhere, primarily focused on personal care products. Assessing the risks posed by QACs is hampered by their vast structural diversity and a lack of quantitative data on exposure and toxicity for the majority of these compounds. This review identifies important data gaps and provides research and policy recommendations for preserving the utility of QAC chemistries while also seeking to limit adverse environmental and human health effects.

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Introduction

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Quaternary ammonium compounds (QACs; also referred to as quats) comprise hundreds of chemicals and mixtures. QACs serve many different functions, primarily as antimicrobials, surfactants, preservatives, antistatic and softening agents, and dispersants. They are often found in cleaning products, hand sanitizers, personal care products, many kinds of wipes (surface, baby, hand, and disinfecting wipes), and various pesticidal products (Table 1 and Supporting Information Table S1). QACs are frequently incorporated into polymers and used in a variety of applications, including in personal care products (Table S1). QACs are also bonded to surfaces as antimicrobial treatments, including textiles, (1,2) biomedical instruments, (3) and high-touch surfaces in public spaces. (4,5)
Table 1. Common Subclasses of QACs and Associated Productsa
a

Structures of some of these subclasses are shown in Figure S1. QAC product types are excerpts from the larger product Table S1. Chemical functions are derived from product ingredient information on manufacturer websites, EPA’s CompTox Dashboard, (25) general understanding of QAC uses and applications as described above, and the Handbook of Applied Surface and Colloid Chemistry, Vol. 1. (26) Abbreviations by others: *, Benzalkonium chloride as BAC (see further discussion in the text); **, chloride salt of DADMAC C10:C10 as DDAC.

QACs consist of a central ammonium group with a permanent positive charge (see Figure S1) typically bonded to alkyl and aromatic substituents. The boundaries of the class of QACs, and even subclasses of QACs, are not well-defined and encompass an extremely broad array of chemicals. The nature of the bonded substituents and the length of the alkyl chain affect QAC function, performance, environmental fate, and toxicity. QACs used in cleaning and disinfecting products tend to have shorter alkyl chain lengths (C8–C16) than those used in personal care products, which can have alkyl chains as long as 22 carbons. (6) While comprehensive data on the different uses of QACs are lacking, information on approximately 800 QACs used in Canadian commerce was recently made public. (7) Many QACs are high production volume chemicals in the US (>1 million pounds produced or imported annually). (8)
The use of QACs as antimicrobials has increased substantially in response to the COVID-19 pandemic. (9,10) A number of antimicrobial QACs are registered with the US Environmental Protection Agency (EPA) as being effective against common pathogens. (11) QACs are in ∼50% of the products on EPA’s List N of disinfectants effective against SARS-CoV-2, (12) which is likely an important driver of the increase in use. QACs are also on EPA’s List Q of Disinfectants for Emerging Viral Pathogens. (13,14) Large-scale fogging and spraying of products containing QACs occurs as a COVID-19 control measure, despite the World Health Organization and US Centers for Disease Control and Prevention discouraging these practices as ineffective and potentially harmful. (15,16) Additionally, use of certain QACs has increased in recent years because they are frequent replacements for the 19 active ingredients, including triclosan and triclocarban, banned from use in over-the-counter hand and body washes by the US Food and Drug Administration (FDA) in 2016. (17) While QACs can kill or inactivate a number of different microorganisms in controlled laboratory settings, which is often presumed to be beneficial and marketed to create an impression of cleanliness, evidence of QAC effectiveness in reducing transmission of infectious disease in real world settings and applications, such as the field of healthcare, is limited. (18,19) In addition, no high-quality evidence shows that antimicrobials bonded to surfaces reduce healthcare acquired infections. (20)
Despite widespread use and environmental releases of QACs to the environment, most QACs have not undergone rigorous regulatory assessment for potential adverse human and ecological health effects. In fact, the most basic parameters needed to assess their potential for harm, such as quantitative data on uses and volumes, physicochemical properties, exposure, and toxicity, are lacking for the majority of these compounds. For example, QAC production volume information is difficult to obtain, and environmental releases usually do not have to be reported nor are they routinely monitored in environmental media such as sludge, biosolids, or drinking or surface waters. Also, QACs are not included in the US federal biomonitoring efforts, (21) and the lack of ingredient transparency in many applications makes it difficult to properly characterize the major exposure sources.
The purpose of this review is to summarize what is known about QACs, including environmental properties, occurrence, and ecological effects; human exposure, metabolic fate, and health effects; and antimicrobial resistance. We also briefly describe chemical management strategies in the US. We conclude by identifying the most pressing knowledge gaps and recommending research and policy actions to address these chemicals of emerging concern.

QAC Nomenclature

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The nomenclature for QACs is complex and variable. Table 1 shows several subclasses of QACs commonly described in environmental studies, including benzylalkyldimethyl ammonium compounds (BACs), alkyltrimethyl ammonium compounds (ATMACs), and dialkyldimethyl ammonium compounds (DADMACs) (22−24) (Figure S1 depicts the structure of these subclasses). Table 1 also includes alkyldimethyl ethylbenzyl ammonium compounds (EBACs), alkylpyridinium compounds, and other QACs not often included in environmental studies but found in consumer products (see also Table S1).
An example of the inconsistencies in QAC nomenclature is benzalkonium chloride, which has been abbreviated by others as BAC─the definition of BACs in this work (benzylalkyldimethyl ammonium compounds) is broader. The EPA FIFRA program uses slightly different nomenclature for this subclass, calling it alkyl dimethyl benzyl ammonium chloride (ADBAC). Benzalkonium chloride and ADBACs are all mixtures with varying alkyl chain lengths, typically ranging from C8 to C18 (C12 to C14 have the highest biocidal activity (5)), but the proportion of each chain length within the mixture varies (12,27) and is often unspecified (see Table S1). While in some instances benzalkonium chlorides may be listed as an inactive ingredient on eye drop packaging, n-alkyl (C14, 60%; C16, 30%; C12, 5%; C18, 5%) dimethyl benzyl ammonium chloride may be used to describe the active ingredient listed on a disinfectant package. Further, in environmental studies this may be listed simply as C12- to C18-BACs (i.e., BAC C12–C18). This inconsistent QAC nomenclature leads to confusion and complicates efforts to effectively survey the uses and scientific literature of these compounds. This lack of consistency also makes it difficult for consumers to identify which products contain QACs, even when their use is disclosed.
In this work, we use the abbreviations shown in Table 1 and indicate the number of carbons in the alkyl side chain(s) when known (e.g., BAC C12 or DADMAC C12:C12), or “C-undefined” when unknown. The colon indicates multiple alkyl chain lengths on the same compound (DADMAC C12:C12), while a dash indicates a range of chain lengths (DADMAC C12:C12–C18:C18).
In 1988, the EPA proposed grouping QACs registered for use in pesticidal products into four groups based on chemical structure. (28) These groupings, however, are not widely used in the scientific literature and do not address possible within-group differences (e.g., persistence or toxicity) due to chain lengths nor do they reflect the enormous diversity of structures of QACs. The QACs described in Table 1 predominantly fall into EPA’s Group I (alkyl or hydroxyalkyl straight chain QACs) and Group II (nonhalogenated benzyl substituted QACs). Group III refers to di- and trichlorobenzyl substituted QACs, while Group IV encompasses QACs with unusual substituents (charged heterocyclic ammonium compounds). Grouping strategies based solely on structure run the risk of assessing a less harmful QAC and inferring safety for the entire group. Utilizing grouping strategies that consider variables such as alkyl chain length, function (e.g., antimicrobial or not), sensitization potential, common mixtures, and coexposures, and that address the entire class of QACs, would greatly aid in prioritizing immediate actions on the most harmful members of this large and broadly used class of chemicals of emerging concern.

Chemical Properties and Environmental Occurrence

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As mentioned previously, QACs have a permanently charged central ammonium ion, although nondissociated salts may exist, including within products and possibly even on surfaces. Compiled experimental and calculated data (29,30) generally indicate high water solubility, low volatility, and low to moderate hydrophobicity (log Kow < 4) for some QACs. Theoretical predictions (30) suggest high hydrophobicity (log Kow > 9) for QACs with multiple aryl or alkyl groups with more than ten carbons, but experimental measurements to confirm these extreme values are currently lacking. Properties of QACs control their fate and occurrence in the multimedia environment: The high water solubility and low hydrophobicity render smaller QACs abundant in wastewater and water; the permanent positive charges facilitate the sorption of QACs to negatively charged solids, especially phyllosilicate clay minerals that are abundant in soil and sediment; (31) and the low volatility limits volatilization loss after indoor applications and contributes to QAC persistence on indoor surfaces.
QAC persistence varies with compound structure and environmental conditions. While QACs are relatively susceptible to aerobic biodegradation and indirect photolysis, (32) the strong affinity of QACs for sorption to particles and solids limits the importance of these processes. Earlier work on other chemicals indicates that sorption to nonaqueous phases remarkably lowers bioavailability of chemicals and thereby suppresses biodegradation. (33) Additionally, reported nonlinear adsorption isotherms indicate that QACs may bind to organic particles more strongly at low concentrations. (34)
Chemical persistence is an important factor in prioritizing chemicals of concern. Current regulatory frameworks often define chemical persistence based on half-lives in surface media (water, soil, sediment, etc.), typically with thresholds on the order of months under conditions that may be idealized for biodegradation (i.e., highly oxygenated, acclimated bacteria, etc.), but these thresholds can vary considerably (35) and may not be reflective of environmental conditions relevant to QACs. Some QACs, particularly those with longer side chains such as DADMAC C18:C18, (23) likely meet regulatory criteria for persistence, depending on the criteria used and studies allowed for consideration. While other QACs may not meet criteria for persistence in water set by existing chemical regulatory frameworks, in some instances they approach the current thresholds. (36) However, QACs’ strong affinity for sorption in nonaqueous phases, together with their permanent charges, may reduce the rate of biodegradation, leading to longer than expected half-lives (on the order of years) (23,37) once sorbed to soil and sediment and, thus, meeting the criteria of persistence. (38,39)
In addition, persistence in indoor environments is of particular concern as it increases the potential for exposure, especially for susceptible populations such as children, and because of the role that QACs may play in antimicrobial resistance. Indoors, QACs partition into polar and weakly polar condensed phases, such as carpet, flooring, indoor aerosols, and settled dust. Indoor fate and transport modeling indicates that QACs can substantially partition into the thin layer of organic films on various indoor surfaces and thus be protected from rapid heterogeneous oxidation. (29) Removal of dust and organic films seems to be the main mechanism for the loss of QACs indoors, (29) which often takes days or weeks and thus enables a long presence of QACs indoors. Extended duration of antimicrobials may be a desired feature but can also be problematic for substances of concern due to increased opportunities for exposure. A better understanding of the persistence of QACs in both indoor and ambient environmental settings is needed.
Detection and quantification of QACs is key to assessing their environmental fate. Colorimetric assays have been used for 70 years, and more recent assays use ion association complexes or derivatization, the latter having limits of quantification in the tens of nanomolar. (40−42) While these methods are capable of detecting total QACs, triple quadrupole or high-resolution mass spectrometry is required for the detection and quantification of individual analytes. (37,43−45) The wide variety of chain lengths and hydrophobicity of QACs influence their interaction with the materials (e.g., solid phase extraction cartridges) used for the preconcentration and cleanup of samples. Thus, for a given method, recoveries for different QACs will vary widely. Finding a single method that can effectively recover compounds with C2 to C22 chain lengths is an ongoing challenge.
Given the wide variety of QAC uses, there are various pathways from source to the environment (Figure 1). (22) Most usage occurs in indoor environments and leads to QACs entering wastewater treatment plants via the sewage system. Both industrial and residential/commercial discharges are significant sources of QACs in wastewater. (37,46)

Figure 1

Figure 1. QAC exposure routes from products and other sources, via pathways indoors and outdoors.

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QACs persist through wastewater treatment. Levels in wastewater effluent are reported in tens of μg/L, (22,37,47) and are associated with the occurrence of QACs in downstream surface water and sediments. Wastewater influent levels are 10-fold higher, and specific waste streams may have concentrations in the mg/L range. (22,24,37,47−49) While typical levels of QACs in influent are not expected to interfere with treatment processes by inhibiting biological nitrification (the conversion of ammonia to nitrate), (22,48) inhibition could occur sporadically due to concentrated discharge or high usage in specific processes or industries. In aerated biological wastewater treatment systems, QAC removal results from both adsorption to sludge and microbial degradation. (49,50)
Levels in sludge and biosolids as high as 500 mg/kg (dry weight) have been measured. (47,51−53) The presence of QACs in soils could arise from amendment with QAC-containing biosolids, as well as from direct use as surfactants in pesticide/herbicide formulations. QACs have also been detected in soil irrigated with municipal wastewater. (54) The levels and persistence of QACs in soils remain largely unexplored. (24,55) Aerosolized usage of QACs outdoors (e.g., disinfection of outdoor surfaces, agricultural applications) and transport of dust particles are additional pathways by which these compounds could move in the outdoor environment.
Long-term monitoring data are currently insufficient to assess trends in QAC levels in wastewater effluents, biosolids, or sludges. Trends are a function of changes in usage rates and wastewater treatment effectiveness. Recent preliminary results showed an increase of some QAC disinfectants in untreated wastewater (56) and wastewater sludge samples (57) during the early stages of the COVID-19 pandemic.
Wastewater discharges can lead to the presence of QACs in downstream aquatic ecosystems. A recent review of environmental occurrence of QACs (BACs C12–C18, DADMACs C10:C10–C18:C18, ATMACs C12–C18) indicated frequent observations in surface waters from Europe, Asia, and North America, with concentrations of individual compounds generally less than 1 μg/L. (47) Broader data are available for aquatic sediment (BACs C8–C18, DADMACs C8:C10–C18:C18, ATMACs C10–C18); (47) Mohapatra et al. suggested that, for BACs, C12 was generally observed at the greatest abundance, while, for DADMACs and ATMACs, abundance was greater for those compounds with longer alkyl chain length. All water and sediment studies reviewed were conducted before the pandemic. Notably, ATMACs C20 and C22, which are used extensively in hair products, were not reviewed, although they have been shown to be present in sediment at relatively high concentrations. (44)
In aquatic environments, sediment cores can be used to reconstruct long-term temporal trends in QAC contamination, due to the affinity of these compounds for both inorganic and organic particles and their persistence in this matrix. QACs have been examined in sediment cores from lakes in Minnesota, (37) as well as urban estuaries including Jamaica Bay in New York, (23,44) San Francisco Bay in California, (58) the Pearl River Estuary in China, and Tokyo Bay in Japan. (59) Overall, sediment core data indicate the appearance of BACs, DADMACs, and ATMACs in the 1950s, with peak discharges in urban areas typically occurring within the 1960s through 1980s. Declines often follow treatment upgrades at wastewater facilities. Temporal trends specific to individual QACs may reflect changes in use and formulation of consumer products. Examples include greater use of disinfecting and antibacterial products, and reformulation of fabric softeners and hair care products. (23,44)

Ecological Risks

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Bioavailability of QACs in aquatic ecosystems is modified by their affinity for organic and mineral particles, with studies suggesting that toxicity is primarily driven by exposure to dissolved concentrations. (60,61) Available ecotoxicity data and recent reviews generally indicate QACs may pose risks to biota. (22,24,47,55,62,63) More data are available for biocides, including BACs and shorter chain DADMACs (e.g., C10:C10), due to regulatory requirements. Toxicity varies with algal species and QAC structure, (55) with BACs and DADMACs generally considered highly toxic to freshwater and estuarine/marine algae. Fifty percent effective concentrations (EC50s) are as low as 14 μg/L for BAC C12–C16 (64) and 11 μg/L for DADMAC C10:C10, (65) and lowest and no observed concentrations (LOECs/NOECs) are as low as 1 μg/L for BACs and DADMACs. (55)
For aquatic invertebrates, Daphnia magna (D. magna) is particularly sensitive, with lowest reported acute EC50s for BAC C12–C16 and DADMAC C10:C10 of 5.8 μg/L (64) and 18 μg/L, (65) respectively. LOECs and NOECs as low as 0.006 μg/L have been reported for aquatic invertebrates subjected to chronic exposures to BACs. (55) However, chronic toxicity thresholds for D. magna are generally similar to acute toxicity thresholds, suggesting a nonspecific mode of action. (66,67) Although QACs are persistent in aquatic sediment, chronic toxicity data for larval Chironomus tentans, a freshwater midge, indicate relatively low sediment toxicity (adverse effects expected at >100 mg/kg dry weight for BAC C12–C16 and DADMAC C10:C10). (66,67)
Studies of fish indicate many QACs are moderately to highly toxic, depending on species and end point. A review of acute toxicity data in freshwater fish species reveals 50% lethal concentrations (LC50s) as low as 64 μg/L for BACs and 1 μg/L for DADMACs, (55) and sublethal effects can occur at exposures below LC50s. (68) For regulatory purposes, however, higher LC50s of 280 μg/L (fathead minnow, Pimephales promelas) and 190 μg/L (zebra fish, Brachydanio rerio) are used for BAC C12–C16 and DADMAC C10:C10, respectively. (65−67,69) Chronic toxicity tests indicate NOECs of 32 μg/L for both of these QACs. (65−67,69) Very few studies are available for estuarine or marine species. (62,65−67,69)
QAC concentrations in aquatic ecosystems are approaching protective toxicity thresholds, such as predicted no effect concentrations (PNECs) calculated using single-species studies like those described above. European regulatory assessments for biocidal applications of BACs (C12–C16) and DADMACs (C10:C10) list PNECs of 0.415 and 1.1 μg/L, respectively. (66,67) Reported monitoring data, thoroughly compiled in a recent review, indicate surface water concentrations exceed the PNEC for BACs in some locations, but not for DADMACs. (24,47,68) For ATMACs, the European Chemicals Agency (ECHA) lists a range of freshwater and marine PNECs depending on chain length. For example, ATMAC C16 has freshwater and marine PNECs of 0.42 μg/L and 0.042 μg/L, respectively; (66,67) limited available freshwater monitoring data suggest concentrations do not exceed freshwater thresholds. (47,70)
Preliminary evidence suggests QAC mixtures are likely to have additive aquatic toxicity, though synergistic or antagonistic behavior has been observed for some QAC combinations. Hora et al. calculated a simplified, general PNEC for QACs of 0.10 μg/L using the geometric mean of all available D. magna acute toxicity EC50 values for BACs, DADMACs, and ATMACs and a protective assessment factor of 1000. (22) Comparison of this PNEC to average reported surface water concentrations of ∼0.07 μg/L for single QAC compounds and ∼0.28 μg/L for summed QACs suggests potential risks associated with current and future concentrations. To inform robust risk evaluation for aquatic ecosystems, key data gaps to address include chronic toxicity data, studies of mixture toxicity, and comprehensive exposure measurements, especially for wastewater effluent dominated systems. Specific data gaps have been noted for EBACs, APyrCs, and benzethonium chloride. (22,37)
Data on QAC exposure and toxicity to terrestrial organisms are even more limited. (24) Repeated applications of wastewater-derived biosolids or QAC-containing agricultural products may result in QAC accumulation in soils; however, limited bioavailability reduces overall risk to biota. (22,68)

Human Exposure

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Exposure Routes

Humans can be exposed to QACs via several routes including dermal, hand-to-mouth, inhalation/ingestion of contaminated dust, and inhalation of aerosolized QACs (Figure 1). Acute high-level exposure is typically accidental. For example, exposure to QAC concentrates can cause dermal corrosion and burns (71−73) and children and dementia patients have experienced sometimes fatal oral exposure. (74) The primary focus of this review is chronic exposure resulting from the manufacture and use of QAC-containing products. For example, if not wiped off after disinfection, QACs can stay on surfaces, which would lead to postapplication exposure. In the latter case, exposure routes include touching disinfected hard surfaces, unintended hand-to-mouth contact (e.g., ingestion of both surface residues and dust-bound QACs), (75) and dermal absorption of chemicals present on hands after surface-to-hand contact. Li et al. (29) modeled human exposure to 14 QACs after their application to indoor hard surfaces. Assuming the applied disinfectants are not wiped off after disinfection, hand-to-mouth contact was found to contribute most (>90%) to postapplication exposure. For shorter chain QACs (e.g., BAC C8), dermal absorption also matters but is not the primary exposure route (contributes less than 10% of postapplication exposure). (29) Based on their affinity for materials like cotton and rayon, (76) significant residues of QACs are likely to remain on textile surfaces long after application. (77,78)
Some QACs easily adsorb to airborne particles and dust. Zheng et al. (45) measured 19 QACs (BACs, DADMACs, and ATMACs) in residential dust collected before and during the COVID-19 pandemic. QACs were detected in >90% of the samples collected during the pandemic at concentrations ranging from 1.95 to 531 μg/g (median 58.9 μg/g). The total QAC concentrations in these samples were significantly higher than in samples collected before the pandemic (median 36.3 μg/g) and strongly correlated with disinfection frequency in homes. Similarity in the profiles of QACs in dust and disinfecting products used in these homes suggested that these products are an important source of QACs in house dust.
Lebouf et al. (79) reported high concentrations of some QACs (including BAC C12–C16, benzethonium chloride up to 5.31 μg/m3) in the air shortly after spraying a QAC-containing product. Zheng et al. (80) found that background QAC concentrations (including several BACs, DADMACs, and ATMACs) in residential indoor air (with no direct spraying in the sampled area) can reach up to 4.36 μg/m3. ATMACs (common in personal care products, including air fresheners; Table S1) were the most abundant QACs in the latter samples, contributing 78% to the total QAC concentrations. The abundance of ATMACs in air can be explained by their relatively lower octanol–air partition coefficients (log KOA 8.17–11.8), compared to BACs and DADMACs (log KOA 11.0–18.2). These findings suggest that inhalation could be important for more volatile QACs. Food and water are other possible sources of exposure as QACs are used widely for sanitation in food production, processing, and services; and they can be found in surface water. (81,82)

Highly Exposed Populations

Workers who manufacture cleaning products and those in occupations that use QAC-containing cleaning and disinfection products, such as housekeeping, domestic cleaning, facilities maintenance, health care, hospitality, food services, and food production and processing, are more highly exposed than the general population. Medical equipment preparers, housekeepers, floor strippers/waxers, endoscopy technicians, nurses, and dental assistants report commonly spending over an hour per shift using QAC-containing products. (83) Women are more highly exposed to cleaning and disinfecting products both at home and work. (84−86)
Teachers, students, childcare providers, and children in daycares may also have elevated exposures, as industrial cleaners and sanitizers are commonly used in these settings. (87) School staff and their students used disinfectants extensively during the COVID-19 pandemic, in some cases unsafely and without instruction on proper handling and use. (88) Sanitizers and disinfectants are also commonly used in correctional facilities and detention centers. Troubling exposures in these settings were reported during the pandemic. (89,90)
Among the general population, children may experience greater exposure to QACs than adults. Li et al. (29) modeled the daily uptake of 14 QACs (ATMAC C16, BACs C8–C18, EBACs C12–C14, DADMACs C8:C8–C10:C10, benzethonium chloride) by children (aged 3), teenagers (aged 14), and adults (aged 25) resulting from indoor hard surface disinfection. The results indicate that children have 14–55 times higher daily uptake of these QACs compared to teenagers and adults due to their more frequent hand-to-mouth contact.

Biomonitoring Data

Exposure to QACs is not currently monitored by the National Health and Nutrition Examination Survey (NHANES). (21) In 2021, QACs were added to the California Environmental Contaminant Biomonitoring Program’s list of priority chemicals, but to date no data have been collected. (84−86,91)
What we know about human exposure to QACs is mostly from academic studies. QACs have been detected in blood from the general population, with higher levels observed during the pandemic. Hrubec et al. (92) measured five QACs (BACs C10–C16, DADMAC C10:C10) in human plasma collected prior to the COVID-19 pandemic and reported up to 80% detection frequency with total QAC concentrations ranging from 0.01 to 58.7 ng/mL (median 1.9 ng/mL). Zheng et al. (80) analyzed human serum from 222 Indiana residents collected before and during the COVID-19 pandemic. Fifteen QACs (ATMACs C12–C18, BACs C8–C18, DADMACs C8:C8–C10:C10 and C14:C14–C18:C18) were detected in up to 97% of the samples. The total QAC concentrations in samples collected during the pandemic were significantly higher than those measured in blood collected before the pandemic (medians 6.04 ng/mL vs 3.41 ng/mL, a 77% increase). ATMACs were the most abundant QAC group in both sample groups and contributed 50–66% of the QAC concentrations. The prevalence of ATMACs in blood is similar to that in indoor air, suggesting that inhalation could be an exposure pathway leading to buildup in blood. In addition, oxidative metabolites of BACs were detected in human urine (93) and were consistent with published work on BAC metabolism by human hepatic cytochrome P450. (94)
QACs have also been found in breast milk, suggesting that breastfeeding could be an important exposure pathway for nursing infants. Zheng et al. (95) identified 13 QACs (ATMACs C8–C18, BACs C10–C18, and DADMACs C8:C8–C10:C10) in breast milk collected from women in the US. The median total QAC concentration in breast milk was 1.5 ng/mL, and the most abundant QACs included BACs C12–C16 and ATMACs C14–C18.

Metabolic Fate

Absorption, distribution, metabolism, and excretion (ADME) of QACs in humans is poorly understood. However, based on the available data in human and animal studies, we have summarized the proposed ADME routes in Figure 2.

Figure 2

Figure 2. Proposed ADME routes for QACs based on in vitro and in vivo data on some subgroups of QACs in humans and animals.

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Absorption

Several acute incidents of high-level exposure indicate that QACs are readily detectable in human blood following oral ingestion. (96−102) In one case of oral BAC poisoning, (102) BACs C12, C14, and C16 were still present in blood (115, 123, and 16 ng/mL, respectively) when the individual died 18 days postingestion, but these BACs were undetectable in urine. Another case involving substantially higher oral BAC exposures and levels in blood also found that parent BACs were undetectable in urine. (100) These cases of acute exposure suggest that QACs may be orally absorbed and persist in humans, and indicate that renal secretion is poor.
A dermal penetration study funded by QAC manufacturers Lonza and Henkel detected only trace amounts of BACs (low- to sub-nM) in plasma after extensive hand washing with 0.13% BAC antiseptic wash. (103) Thus, an intact skin layer appears to be an effective barrier to dermal uptake of certain QACs under hand washing conditions.
While cases of QAC ingestion in humans have demonstrated oral bioavailability, the absorption mechanisms and specific bioavailability values of QACs have not been studied in humans. In rats, Kim et al. (104) observed that oral bioavailability of a model QAC compound (tributylmethyl ammonium) increased with dose from 17% up to 35%. The dose-dependent bioavailability is attributed to saturation of intestinal P-glycoprotein (P-gp) efflux at higher doses. (104,105) Furthermore, P-gp gene knockout mice displayed enhanced persistence of intravenously (IV)-dosed QACs. (106) In rats dosed orally with cetyltrimethylammonium (ATMAC C16) or BACs (C12 and C14), (107,108) time courses show intestinal absorption occurs over several hours, with these QACs persisting beyond 24 h in blood and tissues. Rats that aspirated BAC material into their lungs experienced efficient and rapid absorption as evidenced by several-fold higher levels of BACs in blood and tissues relative to rats dosed orally. These animal studies establish moderate oral bioavailability of QACs, with inhalation leading to greater exposure, which is likely due to efficient absorption in the lung and the bypassing of the first-pass metabolism in the liver.

Transport and Excretion

Studies performed mainly on model QAC compounds (typically tetraalkyl ammonium compounds) suggest that several transporters, including P-glycoprotein (P-gp), organic cation transporters (OCTs), and thiamine transporters (ThTRs), may contribute to QAC disposition in the human body. While QACs were found to be poor P-gp substrates, the ion pair complexes between model tetraalkyl QACs and bile acids are efficiently transported by P-gp. (109,110) P-gp at the bile canalicular membrane of hepatocytes may facilitate hepatobiliary QAC excretion. Additionally, various QACs are excellent substrates of OCTs. (110−112) Involvement of OCT transport in the disposition of QACs may explain the hepatobiliary excretion (OCT1), renal accumulation (OCT2), and accumulation in the heart (OCT1/3) in animals as discussed below. ThTRs transport dietary vitamin B1 (thiamine), which also contains a quaternary nitrogen. Benzethonium and ATMAC C16 were recently shown to interact with ThTR-2, (113) the transporter primarily involved in intestinal absorption and renal proximal tubular reabsorption of thiamine. Further study is needed to determine the role of these transporters in QAC disposition with the highest priority given to the QACs with emerging human exposure data (ATMACs, BACs, DADMACs, etc.), and eventually extending broadly to the wide range of QACs of toxicological interest.
QACs in circulation may bind plasma proteins, such as albumin and α-1-acid glycoprotein; (80,114−116) however, plasma half-lives of BACs C12, C14, and C16, dosed via IV bolus to rats, are somewhat brief (1.8–3.7 h) and volumes of distribution are high (5.6–6.7 L/kg), suggesting that partitioning into tissues is favored over retention in plasma. IV-administered BACs accumulated in heart, lung, spleen, and kidney, which was consistent with earlier findings by Xue et al. (101,108) No parent BACs were detected in urine, confirming urine is not a preferred excretory pathway for the parent BACs. Additional studies are needed on the tissue distribution and excretion routes of other QACs.
IV administration of QACs to bile-cannulated rats established that higher molecular weight (MW) QACs (>200) are preferentially excreted from the liver into bile. (117,118) Commercial disinfecting QACs generally have MW values >300, so it can be reasonably assumed that QACs in the body are mostly excreted into bile regardless of the administration routes. Rats given a single IV dose of 14C-radiolabeled BACs excreted 45–55% of radioactivity to feces (likely through bile) and 20–30% to urine (possibly as metabolites), with 30–35% remaining in tissues/carcass at 7 days postadministration. (119−121)

Metabolism

Seguin et al. reported metabolism of BACs C10, C12, C14, and C16 by human cytochrome P450s (CYPs), the main xenobiotic metabolizing enzymes. (94) CYP2D6 and several CYP4F isoforms produced the major oxidative metabolites of BACs. Significantly, a series of oxidized BAC metabolites were found in human urine samples, further confirming human exposure to QACs and their metabolism by CYPs (unpublished data). (91) Expanded identification and incorporation of polar human QAC metabolites excreted into urine and feces in biomonitoring studies will allow for an enhanced understanding of human QAC exposures.
A study conducted in rats by Luz et al. found that oral dosing of 14C-radiolabeled BACs (C12, C14, and C16) or DADMAC (C10:C10) resulted in 88–98% recovery of radioactivity in feces, wherein substantial fractions (1/3 for BACs or 1/2 for DADMAC) presented as oxidized metabolites. (119−121) While Luz et al. (119) proposed that “. . .microbes in the intestinal tract are likely responsible for metabolism. . .”, oxidation reactions are not typically associated with xenobiotic metabolism by gut microbiota, (122) likely because the luminal space of the intestine is hypoxic. Conversely, recent evidence confirming the metabolism of BACs C10–C16 by CYPs (94) suggests that lipophilic QACs are likely susceptible to oxidation by CYPs. Furthermore, oxidized BAC metabolites were observed in the brain, liver, and blood of mice fed a BAC-containing diet, indicating intestinal absorption. (123) However, intestinal metabolism and absorption may vary among species and should be further elucidated. As both parent QACs and metabolites can be excreted via biliary and intestinal transport, fecal samples would be suitable for biomonitoring of QACs and QAC metabolites.

Bioaccumulation

Zheng et al., (80) determined the bioaccumulation potentials of 18 QACs (ATMACs, BACs, and DADMACs) with alkyl chain lengths of C8–C18 in an in vitro–in vivo extrapolation model using the results of human hepatic metabolism and serum protein binding experiments. The in vitro clearance rates determined for these QACs decreased with increased length of the alkyl chain, similarly to the findings reported by Seguin et al. (94) Generally, ATMACs were metabolized at slower rates than BACs and DADMACs. Bioaccumulation of QACs was further confirmed through the analysis of blood (sera) samples (n = 222). The QACs with slower predicted in vivo clearance rates were detected at higher levels in serum. The lowest predictions of in vivo clearance rates (0.114–0.505 mL/h/g liver, respectively) were determined for ATMACs C12–C16, and these compounds were found at relatively high concentrations in analyzed blood samples.

Health Effects

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Studies in which specific end points and health effects are identified are shown in Table S2.

Dermal, Respiratory, and Immune Effects

The immune system plays a central role in mediating many dermal and respiratory effects observed following QAC exposures. Hypersensitivity is an excessive immune response to allergens that also can be accompanied by chronic inflammation. Skin irritation can involve both inflammatory and hypersensitivity responses. These underlying immunological responses of hypersensitivity, irritation, and inflammation, may be common mechanisms driving dermal, respiratory, and other types of immune-specific and immune-related effects of QACs described below.

Dermal Effects

Skin irritation, sensitization, and dermatitis associated with QAC exposure have been reported in some human studies. Various studies have found that exposure to quaternium 15, a formaldehyde-releasing preservative used in personal care products, is linked with allergic contact dermatitis. (124−126) A study in patients with suspected allergic contact dermatitis found 5.5% with positive skin sensitization reactions to the chloride salt of BAC C-undefined, but infrequent reactions to quaternium 15. (127) A review of patients tested for allergic contact dermatitis concluded that the chloride salt of BAC C-undefined is a skin irritant and sensitizer. (128) A study of patients with suspected contact sensitization to occupationally used disinfectants concluded that clinically relevant sensitization to the chloride salt of DADMAC C10:C10 is rare. (129)
Cases of allergic contact dermatitis linked with some QAC exposures have been reported, including the chloride salt of APyrC C16 in latex gloves; (130) quaternium 15 in a lotion, (131) hair products, (132) and electroencephalography skin preparation gel; (133) and N,N-didecyl-N-methylpoly(oxyethyl) ammonium propionate in a dental clinic disinfectant. (134) Robinson et al. (135) described cases of a rare skin condition in children who were exposed to the chloride salt of BAC C-undefined via clothing washed with an antibacterial laundry rinse aid.
In animal studies, the National Institute for Occupational Safety and Health found that mice dermally exposed to the chloride and bromide salts of DADMAC C10:C10 displayed both skin irritation and allergic sensitization. (136,137) The researchers identified an immune basis for the response observed in mice exposed to the chloride salt of DADMAC C10:C10. (138) Immune response gene expression was altered in the skin tissue of mice exposed to the chloride salts of DADMAC C10:C10 or BAC C-undefined. (139)
ECHA and EPA risk assessments of the chloride salts of BACs C12–C16 (66,69) and the chloride salt of DADMAC C10:C10 (65,67) have not classified these compounds as skin sensitizers. (119) Further research is needed on exposure potential and dermal effects of other QACs that are in personal care products (e.g., polyquaternium compounds, the chloride salt of ATMAC C22) and therefore likely or intended to contact the skin.

Respiratory Effects

Exposure to some QACs is associated with work-related asthma and other possible respiratory effects. The Association of Occupational and Environmental Clinics has identified the chloride salts of some BACs and DADMAC C10:C10 as sensitizer-induced asthmagens, or substances known to cause asthma newly acquired from a workplace exposure. (140) Studies conducted among hospital staff, (141) staff in other sectors, (142) and case reports (143−146) have found exposure to QAC-containing disinfectants and cleaning products to be linked to work-related asthma. Bellier et al. (147) described a study in which subjects were exposed via inhalation to a QAC diluted in water. Of four QACs tested, subjects reacted most frequently to the chloride salt of DADMAC C10:C10. These authors suggested that QACs may induce work-related asthma through a specific immunological response-sensitizing mechanism and that irritation could also play a role. There are challenges in characterizing human exposure to QAC-containing products (e.g., data gaps in quantitative exposure measurements, use of multiple types of QAC-containing products), and in mechanistically linking these exposures with asthma. (148,149)
In a prospective cohort study of female nurses in the US, high-level exposures to disinfectants and cleaning products, including QAC-containing items, were significantly associated with increased risk of chronic obstructive pulmonary disease, independent of asthma and smoking status. (86)
Respiratory effects have also been reported in animal studies. Mice exposed to aerosols of various QACs (the chloride salt of BAC C-undefined, the bromide salt of ATMAC C16, the bromide salt of DADMAC C18:C18, and the chloride salt of APyrC C16) had reduced lung tidal volume and increased respiratory rate. The exposures to the chloride salts of BAC C-undefined and APyrC C16 also gave rise to pulmonary inflammation. (150) Studies of rats exposed to the aerosolized chloride salt of BAC C-undefined have reported effects such as pulmonary cell damage and inflammation, (151) and nasal cavity and lung irritation. (152) Increased markers of pulmonary inflammation were observed in mice exposed to the chloride salt of DADMAC C10:C10 via intra-tracheal instillation. (153)
ECHA reported that although no experimental data were available, the chloride salts of BACs C12–C16 and the chloride salt of DADMAC C10:C10 are not expected to be respiratory sensitizers. (66,67,119)
More information on the specific QACs used in disinfecting sprays and foggers, perfumes, and air fresheners would help determine which QACs should be evaluated for their ability to be inhaled. Biomonitoring data from individuals who regularly use these sprayed products would aid in quantifying the extent of work-related exposures. Inhalation toxicology studies of respirable QACs are essential for understanding their potential respiratory and pulmonary effects.

Immune Effects

A pilot study examining the immune response to QAC exposure in humans reported that 80% of participants had blood residues of BACs C12–C16 and DADMAC C10:C10 and a dose-dependent increase in inflammatory cytokine concentrations. (92) While the clinical significance of this increased inflammation remains to be determined, blood of some individuals from this study had QACs at levels associated with adverse effects in experimental animal studies.
Abdelhamid et al. (154) evaluated ambient exposure to BACs C12–C16 and DADMAC C10:C10 in a mouse model of autoimmunity. Using MRL/lpr mice, models of Systemic Lupus Erythematosus were used to evaluate several immune end points, including markers of innate and adaptive immunity. The authors found that rather than exacerbating autoimmune markers, QAC exposure in this model attenuated signs of autoimmunity. Other measured markers, however, indicated that neutrophils, cells of innate immunity, may have hindered expansion of autoreactive T cells and/or exacerbated T cell apoptosis. Neutrophils in this model possessed a phenotype often seen in patients who experience sepsis, and combined with other findings, led Abdelhamid et al. (154) to conclude that in this model, QAC exposure was immunosuppressive.
Immune effects of QAC exposure so far are primarily limited to descriptive observational measures. Studies assessing functional outcomes such as antigen-specific antibody responses, cell-mediated cytotoxicity, or host resistance would help delineate effects of QACs on a challenged immune system.

Reproduction and Development

Reproductive Effects

Reproductive toxicity in mice was accidentally discovered when unexpected infertility was traced back to use of a vivarium cleaning product. A 6 month breeding trial in mice exposed orally to a commercial cleaning product containing BACs C12–C16 and DADMAC C10:C10 demonstrated infertility and decreased fecundity. (155) Follow-up studies identified similar effects in mice orally dosed with a mixture of purified BACs C12–C16 and DADMAC C10:C10 formulated similarly to the commercial product, or with ambient exposure to the commercial product used in the mouse room. (156) Adverse outcomes were dose-dependent and included longer time to first litter, increased pregnancy interval, and fewer total litters. (155) Reproductive effects were identified for both males and females. (156) Female outcomes included increased time between estrus cycles, reduced ovulation and implantation, and increased postimplantation losses. Male outcomes included decreased sperm concentration and motility. (156) A different study using CD rats failed to find reproductive effects, (157) but the rat study did not assess a mixture similar to the commercial cleaning product, only the BAC (C12–C16) and DADMAC (C10:C10) separately. The rat study also did not assess sperm concentration and mobility or estrous/ovulation.
The potential for reproductive toxicity of QACs is highlighted in a patent from 1975 titled “Method for the Control of Fertility’’ (158) that presents studies demonstrating that dietary administration of QACs to dogs and rats is embryocidal, ovicidal, and/or spermicidal. The patent included any QAC salt with a structure of a central positively charged nitrogen with four substituents and a variety of anions. Notably, BACs are an active spermicidal ingredient in some sponges, vaginal creams, and capsules currently sold in some countries; (159) BAC and APyrC C16 bind to the estrogen receptor to exert antiestrogenic effects. (160) No human epidemiologic studies on reproduction or development were identified in our review.

Developmental Effects

Exposure to a commercial cleaning product containing BACs C12–C16 and DADMAC C10:C10 impaired embryo development, caused neural tube defects (NTDs), and increased embryonic death in mice. (161) Effects were similar for pregnant mice exposed ambiently to the commercial cleaning product containing BACs C12–C16 and DADMAC C10:C10 used to clean the vivarium, or a mixture of purified BACs C12–C16 and DADMAC C10:C10 formulated similarly to the commercial product. NTDs were observed regardless of the timing of exposure (continuous, prebreeding period, or the window of embryo vulnerability for neural tube closure) and regardless of whether it was the male or female parent that was exposed. Up to 20% of embryos in a litter were affected, a 1000-fold increase over the background rate for the mouse strain. Multiple defects were occasionally seen in an individual embryo at different neural tube closure sites. NTDs are not typically lethal but exposure increased both early embryo death (resorptions) and late term fetal deaths, suggesting the mixture may affect more than the developing nervous system. Effects on the placenta may play a role, as the placental size was generally not proportional to the size of the fetus (e.g., large fetuses with small placentas and small fetuses with large placentas─conditions that can affect fetal viability).
Another study reported limited developmental toxicity with reductions in pup body weights at the highest dose but no effect on litter size. (157) The study used CD rats as opposed to mice and fed either BAC (C12–C16) or DADMAC (C10:C10) rather than as a mixture similar to the commercial cleaning product. The study did not evaluate other end points such as NTD formation or placental development. Hrubec et al. found the occurrence of NTDs in rat embryos to be considerably lower than in mice, (161) indicating that rats may be more resistant to developmental toxicity. Replicating the Hrubec et al. study in rats would help elucidate whether rats are indeed more resistant.

Biochemical Effects

Cholesterol and Lipid Homeostasis

Cholesterol plays important roles in embryonic and neural development. (162−164) Alterations in cholesterol biosynthesis lead to various developmental disorders. (165) In 2016, Herron et al. found that BACs significantly inhibit cholesterol biosynthesis at low nM concentrations in neuroblastoma cells. (166) Specifically, shorter chain BACs, such as BAC C10 and C12, potently inhibit 3b-hydroxysterol-Δ7-reductase (DHCR7), the last step of the cholesterol biosynthetic pathway, while longer chain BACs (C14 and C16) likely inhibit an earlier unidentified step. The same activities were also observed in a 3D culture of neural progenitor cells. (167) However, in an in vivo study on neonatal mice born to dams fed a BAC-containing diet, inhibition of DHCR7 was not observed in the neonatal brains, (123) likely due to the low concentrations (around 1 nM) of BACs observed in the neonatal tissues. In contrast, an overall decreased level of total sterols was observed in either BAC C12 or BAC C16 (BAC C14 not tested in this study) exposed mouse brains, suggesting an inhibition of cholesterol biosynthesis at a step before the formation of the first sterol, lanosterol. Furthermore, upregulation of cholesterol biosynthesis genes was observed, which was consistent with the inhibition of cholesterol biosynthesis by individual BACs. In the same study, the authors found that diglycerides, triglycerides, ceramides, and hexosylceramides were also significantly affected by BACs. In another study by the same group, (94) ω- and (ω – 1)-hydroxylated metabolites of BAC C10 displayed greatly reduced potency in inhibiting DHCR7, suggesting CYP metabolism is potentially detoxifying.
In a study by Hrubec et al. examining the correlation between QAC levels in human blood and several biological measurements, some sterols were significantly correlated with certain QAC levels. (92) In particular, DADMAC C10:C10 was highly correlated with lanosterol, zymosterol, desmosterol, and 8-dehydrocholesterol. Although the sample size is small, the strong preliminary data justify a large-scale human study to examine relationships between QAC exposure and toxicological end points.

Mitochondrial Bioenergetics

Mitochondria are the major source of energy in the form of ATP in animals including humans. Apart from energy generation, mitochondria perform many biochemical reactions critical for cellular and tissue homeostasis. Along with the better understanding of the role of mitochondria in physiological and pathological states, (168) recent decades have seen a sharp rise in reports recognizing pharmaceuticals, (169) and environmental pollutants such as QACs (160,170) as previously unidentified mitochondrial toxicants.
Chemically, most QACs can be classified as lipophilic cations that can accumulate into a negatively charged mitochondrial matrix. Evidence of direct inhibition of mitochondrial oxidative phosphorylation comes from multiple in vitro studies involving several QACs (BACs C10–C18, APyrC C16, and tetraoctyl ammonium). (160,171,172) Inácio et al. (173) evaluated several types of QACs (ATMAC C10, APyrC C12, and BAC C12) individually and demonstrated that, at lower concentrations, QACs (ATMAC C10) inhibit mitochondrial oxidative phosphorylation at complex I in vitro which precedes their surfactant action and concluded from the study that inhibition of mitochondrial oxidative phosphorylation by QACs is the most likely mechanism underlying the antimicrobial effects of QACs. No study, however, has explicitly related mitochondrial inhibition to antimicrobial activity. Additionally, chain length can play an important role in mitochondrial toxicity of QACs. When tested in mitochondrial toxicity assay, BAC C8 did not show any mitochondrial inhibition, whereas BAC C12, C14, and C16 were all mitochondrially toxic. The individual BACs (C12, C14, and C16), however, were less potent inhibitors of mitochondrial oxidative phosphorylation in vitro compared to the mixture (unpublished data). Consistent with these studies, a pyridinium-based gemini QAC (two pyridinium-based QACs in one compound) inhibited respiration in a yeast model at an approximately 2.5-fold lower concentration than the concentrations causing membrane damage. (174,175) Notably, in an acute time frame, QAC-based disinfectants predominantly show surfactant aka membrane dissolving effects on bacteria due to their high concentrations of QACs. The long-term antibacterial effects of these products may be due to their mitochondrial inhibitory property at lower concentrations, which has not been completely studied yet. In another study, Inácio et al. (176) demonstrated that there is a differential sensitivity to APyrC C12 between bacteria and mammalian cells with bacteria being more sensitive. This differential sensitivity suggests that there could be a “therapeutic window” for the QACs; i.e., there is a possibility to safely use the QACs for general disinfection purposes without adversely affecting mammalian cells. However, the practical application of this differential sensitivity needs to be explored in the context of persistence in the environment and chronic reexposure, which may lead to increased antimicrobial resistance.
Research indicates that APyrC C16, (160) and ATMAC C10 (173) inhibit mitochondrial respiration in vitro. Datta et al. (160) observed antiestrogenic activity of APyrC C16 in vitro and hypothesized that it is mediated through effects on mitochondrial function. ATMAC C10 induced the generation of intracellular reactive oxygen species, particularly superoxide anion (173) which is consistent with impairment of the mitochondrial respiratory chain. The consequences of mitochondrial inhibition by QACs in both microbes and mammalian cells need further elucidation to determine the role it plays in the antimicrobial effects and other deleterious effects in the mammalian system.

Predictive Toxicology

In vitro and predictive toxicology studies can be important data sources for QACs that have little or no publicly available health effect information. These methodologies likely will be relied upon more heavily by regulatory bodies like the EPA to reduce and replace vertebrate animal testing. (177) The EPA’s Chemistry Dashboard (25) contains some QAC bioactivity data from ToxCast/Tox21 assays. (178) Of approximately 100 unique QAC CASRNs searched, 29 had ToxCast/Tox21 bioactivity information; 21 of these QACs were active in at least 100 assays. Some examples of the diversity of QAC bioactivities reported at subcytotoxic concentrations include ATMAC C12 effects on G protein-coupled receptor binding and altered cell proliferation, ATMAC C18 impacts on altered gene expression, and DADMAC C16:C16 effects on CYP expression, enzyme activity, and cell morphology. The use of new approach methodologies such as quantitative structure–activity relationships and ToxCast/Tox21 testing may be helpful for grouping and prioritization of the most harmful QACs. However, assessing the utility of these methods with regard to QACs is beyond the scope of this review.

Antimicrobial Resistance

Antimicrobial chemicals, including disinfectants and antibiotic drugs, have an important role in preventing and curing infections, but their efficacy is jeopardized by the evolution of antimicrobial resistance. Indeed, there were nearly 5 million deaths associated with antimicrobial resistance in 2019. (179) In addition to human and veterinary medicine, an increasing body of evidence points to the use of disinfectants and cleaning products as a contributor to antimicrobial resistance. (47,180,181) For example, tolerance to BAC was described in the Gram-negative opportunistic pathogen Serratia marcescens as early as the 1950s., (46,181,182)
At concentrations lethal to microorganisms, QACs are purported to either dissolve cell membranes or inactivate cytoplasmic enzymes. (47,183) At sublethal concentrations, however, conditions favor the survival of some microorganisms over others, particularly those with resistance.
Certain microorganisms can form coatings, e.g., spores, which effectively protect against QACs. (184) Resistance conferred by features of the outermost layer of the cell (i.e., spore coat, cell wall, or outer membrane) is termed “intrinsic”. (185) Accordingly, disinfectant tolerance is generally highest in spores, followed by Gram-negative bacteria and finally Gram-positive bacteria. This pattern holds true for QACs. For example, surfaces embedded with BAC C12–C16 are relatively ineffective against spores, (186) and hospital surfaces cleaned with an unspecified QAC were enriched for Gram-negatives compared to surfaces cleaned with bleach. (187)
In addition to intrinsic resistance, microorganisms can acquire resistance through mutation and horizontal gene transfer. Acquired resistance develops in response to exposure, particularly at sublethal concentrations, and spreads with increasing application. (182) as shown in various organisms via a variety of mechanisms. (47,181,188)
Members of the genus Pseudomonas are of particular interest when it comes to antimicrobial resistance, as they are widespread in the environment and include one of the most nefarious drug-resistant pathogens: Pseudomonas aeruginosa (P. aeruginosa). One reason P. aeruginosa is so difficult to treat is its rich arsenal of efflux pumps, which can extrude multiple antimicrobials, including QACs, as well as antibiotic drugs. (189) Tolerance of QACs, and particularly BACs, has been repeatedly observed. (190,191) In Pseudomonas, tolerance has been attributed to lipid production or changes in membrane lipid composition, (183) increase in phospholipids and fatty and neutral lipids, (191,192) modification of cell surface charge, and efflux. (193) In P. aeruginosa, BACs C-undefined induced aggregation, (192) which has important implications for population-level behaviors, e.g., biofilm formation. While BACs are equally as effective against P. aeruginosa in planktonic and biofilm forms, (194) biofilm formation may limit the efficacy of other disinfecting strategies if not preceded by cleaning to remove the biofilm. In some cases, increased tolerance to BACs was associated with a change in resistance to other QAC C12–C14 or C-undefined, (195,196) disinfectants, or clinically relevant antibiotics. (196)
The presence of other organisms in the environment may enhance survival in the face of disinfectant stress. In dual-species biofilms, the presence of Lysteria monocytogenes (L. monocytogene) provided a protective effect for Pseudomonas putida (P. putida) from treatment with sublethal concentrations of BAC C-undefined, which preferentially killed the L. monocytogenes. (197) Also, the presence of Pseudomonas fluorescens enhanced resistance (198) to a mixture of QACs (BACs C-undefined, DADMACs C8:C8–C10:C10) in Salmonella enterica in dual-species biofilms. (199) Salmonella species are particularly relevant for food production, where QACs are also often used as disinfectants; however, nearly three-quarters of Salmonella isolated from swine slaughterhouses were resistant to unspecified QACs. (200) In multispecies biofilms, sublethal concentrations of BACs C-undefined select for Pseudomonas and Bacillus species. (201) Thus, tolerance is not only a function of the intrinsic properties of the organism or the presence of acquired traits but also the presence of other microorganisms in the environment.
Despite being widespread in the environment, studies of the impact of QACs on antimicrobial resistance in situ are rare. However, a recent study demonstrated that exposure of soil microbial communities to BAC C12 increased both the absolute and relative abundance of several antimicrobial resistance genes. (202) Critically, this enrichment was most pronounced at 1 and 10 mg/kg. This concentration range is directly relevant to BAC concentrations observed in sediment (0.008 to 5.325 mg/kg; C12–C18) and sludge (14.568 mg/kg; C10–C16). (46)
Finally, above and beyond resistance, microorganisms may also gain the ability to use an antimicrobial as a source of nutrients or energy. Indeed, organisms closely related to Pseudomonas nitroreducens and P. putida are implicated in assimilatory BAC degradation. (203) This phenomenon not only benefits the degrading organisms but may also confer protection to others in the community due to the bystander effect.
Whether through intrinsic or acquired mechanisms, or due to indirect effects of other microorganisms, antimicrobial resistance is a critical problem. A substantial body of evidence points to QACs as exacerbating this problem, notably in drug-resistant pathogens of concern, e.g., P. aeruginosa. (47) Following the COVID-19 pandemic, an increase in antibiotic resistance was observed. (204) This phenomenon was likely caused by a confluence of factors, of which the increased use of QAC-based disinfectants may be one. Exposure of bacteria to disinfectants is expected to result in an increase in resistance, both to QACs and clinically relevant antibiotics. (205) Problems associated with tolerance range from disinfection failure, to cross-resistance to medically relevant antibiotic drugs (e.g., through multidrug efflux). (46,189)

QAC Management in the U.S

The degree of US governmental oversight of QACs depends on how a specific compound is used. The EPA regulates QAC-containing products marketed with pesticidal claims under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA). Chemical risk assessments under FIFRA use a structure-based grouping approach in which a selected model compound is assessed (e.g., for the BAC group, the model compound is BAC C12–C16, CAS Reg. No. 68424-85-124, and for the DADMAC group, DADMAC C10:C10, CAS Reg. No. 7173-51-5 is used). (199) Inferences are then made from these model compounds to the larger group. One problem with this approach is that basing groups solely on structure runs the risk of assessing a less harmful QAC and inferring safety for the entire group. Studies described above indicate differences in toxicity between QACs that are structurally similar but differ by a few carbons. Examples of other variables that could be used to group QACs are alkyl chain length, function (e.g., antimicrobial or not), sensitization potential, common mixtures, and coexposures. These variables may be more useful in identifying the most hazardous QACs with the highest exposure potential. The FIFRA grouping approach also applies only to pesticides and does not address the many frequently used QACs with possible bioactive properties and high potential for exposure and environmental release.
EPA has also addressed some QACs through their Safer Choice Program, specifically the Safer Chemical Ingredient List (SCIL) that identifies products with ingredients deemed safer for human health and the environment. SCIL lists several QACs as ingredients of the lowest concern within the functional class of surfactants. (205) Unfortunately, while the SCIL criteria are publicly available, (206) the chemical-specific health and environmental hazard information is not, making it difficult to determine the degree to which these QACs have been assessed, particularly for hazard end points identified in this review.
EPA’s Toxic Substances Control Act (TSCA) governs chemicals in products not regulated by other agencies or programs (generally everything except food additives, drugs, cosmetics, and pesticides). This includes many QACs used in products listed in Table S1. Chemicals regulated under TSCA are subject to less rigorous risk assessment requirements than those managed under FIFRA. (206,207) Access to information about QACs also varies depending on how the QAC is used. While manufacturers who make pesticidal claims need to have their labeling information (i.e., active ingredient concentrations, consumer warnings, information about how to obtain directions on proper use) reviewed and approved by the EPA under FIFRA, many of the products listed in Table S1 (e.g., hair conditioners, fabric softeners) that utilize the same QACs for other purposes or without making pesticidal claims can be sold without providing the same type of information to the end user. Additionally, QAC uses in many applications (e.g., surface coatings and durable products) usually do not have to be disclosed─this makes it difficult to identify which products contain QACs. A more consistent approach to availability of information and the rigor of assessment for the entire class of QACs is warranted.
Chemicals used in pharmaceuticals, cosmetics, or food additives are regulated by their respective FDA programs. As noted above, QACs were frequent replacement chemicals in over-the-counter hand and body washes after the 2016 FDA ban of 19 active ingredients, including triclosan and triclocarban, for these uses. (17) The ban was based on a lack of additional benefit compared with non-antibacterial soap and water, and insufficient evidence of their safety. The original version of the FDA rule also included benzalkonium chloride and benzethonium chloride, but they were removed from the final rule to allow manufacturers more time to submit data on their safety and effectiveness. The FDA has granted several extensions to submit data, which have been publicly reported through 2020, (208) but has yet to make a ruling on these two QACs. A 2018 study concluded that benzalkonium chloride and benzethonium chloride are more toxic than triclosan and triclocarban to the environmental model organisms nematodes and zebrafish and that they should not be considered safer alternatives in this respect. (209) Given the seven year delay and the growing evidence of adverse environmental and human health impacts, including QACs role in antimicrobial resistance, if FDA lacks evidence of added benefit, they should proceed to finalizing their ruling as soon as possible.
Both the EPA and FDA use hazard and risk data to estimate risks associated with chemicals within their jurisdictions. Regulatory risk assessments are typically limited to data from guideline studies conducted by the regulated community. Such studies have been criticized for assessing end points that are not sensitive enough to detect many adverse health outcomes associated with chemical exposure. (210) Relevant academic studies described throughout this work, including those demonstrating adverse effects at ambient levels of QAC exposure, and exposure assessments predicting risks to children are not systematically incorporated into decision making. (29)
In recent years, a number of jurisdictions in the US and the EU have taken actions regarding QACs. For example, BACs are no longer approved for use in consumer hand and body washes in the EU. (211) Quaternium 15 is banned from cosmetics in the EU (212) and will be banned from cosmetics and personal care products manufactured or sold in California beginning in 2025. (213) Also, in 2021, QACs were added to the California Environmental Contaminant Biomonitoring Program’s list of priority chemicals. (214) In 2021, the Massachusetts Toxics Use Reduction Institute Science Advisory Board recommended listing BACs and DADMACs as toxic or hazardous substances. If adopted, this listing will require annual use reporting and reduction planning by businesses. (215) These recent actions signal growing concern about the use and potential for exposure to certain QACs and whether human and ecological health are sufficiently protected under current policies and regulations.
The fact that there is already widespread exposure and growing evidence of adverse environmental and human health impacts of QACs suggests that source control to reduce exposure should be considered, for example, through the essential-use approach. (206) The essential-use approach states that chemicals of concern should only be used where their function is necessary for health and safety, or is critical for the functioning of society, and no safer alternatives exist. This approach has been used in various contexts beginning with the 1987 Montreal Protocol to phase out certain ozone-depleting substances (e.g., chlorofluorocarbons). (216) It is also currently being applied to per- and polyfluoroalkyl substances in European REACH regulations. (217) Examples of potential non-essential uses of QACs include odor and static prevention, some surfactant and emulsifier uses, and antimicrobial treatments in furniture. (218,219) Where their use might be essential, such as for disinfection, safer alternatives can often be identified. (220) For example the Design for the Environment program, which helps purchasers find antimicrobial products that meet both the EPA antimicrobial registration requirements and safer ingredient standards, lists the following safer alternatives for certain uses: hydrogen peroxide, citric acid, ethanol, and lactic acid. (221) Eliminating QAC uses that are not required for health and safety or where safer alternatives exist could quickly reduce human exposure as well as releases to the environment.

Recommendations

QAC use is increasing, without high-quality evidence of their effectiveness in reducing transmission of infectious disease in many settings and applications. (18) Meanwhile, greater indoor usage is consistent with higher indoor exposure, which is a concern given the recent discovery of adverse health outcomes in laboratory animals at relatively low (ambient) exposure concentrations. Increased production and usage is anticipated to result in higher QAC concentrations in wastewater, which is a pathway for broader environmental exposure and potential risks to biota. This is especially concerning given that some environmental concentrations already exceed protective aquatic toxicity thresholds. Furthermore, excessive use of QACs likely contributes to the global problem of antimicrobial resistance.
This review supports the need for a comprehensive research and policy agenda to expand our understanding of QACs while simultaneously taking action to protect human and ecological health. Toward this end, we make the following recommendations:

General Research Recommendations

  • Research a broader suite of QACs, beyond the relatively few currently studied compounds, including QACs not registered as antimicrobials.

  • Continue to develop and improve analytical methods for QACs in different sample matrices (e.g., dust, air, water, sediment/soil, blood, urine, feces, breast milk).

  • Conduct studies on common mixtures of QACs, including in environmental media, humans, wildlife, or products, and their possible health effects, to establish protective concentrations and environmental thresholds.

Environmental Research Recommendations

  • Conduct comprehensive monitoring of wastewater influent, effluent and biosolids, as well as impacted surface waters, to better understand the fate and transport of QACs in the environment and potential sources and exposure pathways for biota.

  • Perform experimental and theoretical research on the physicochemical properties, environmental and biological behavior, and fate and transport of a wide array of QACs. In particular the persistence of QACs in soil/sediment needs to be better understood.

Human Health Research Recommendations

  • Conduct quantitative exposure surveys and collect comprehensive biomonitoring data on QACs and QAC metabolites in blood, urine, and feces (e.g., in the general public through NHANES and in highly exposed populations via National Institute for Occupational Safety and Health (NIOSH) or the Nurses’ Health Study. (222) The State of California may be ideally positioned to convene such a study given that QACs are on Biomonitoring California’s list of priority chemicals.

  • Study QACs in indoor environments to better characterize human exposure (dermal, inhalation, and ingestion) directly from products and through routes such as household air and dust. In particular, better understanding of the indoor persistence of QACs of varying chain lengths is needed.

  • Conduct additional research on metabolic fate to better understand how QACs are absorbed, distributed, metabolized and excreted by the human body and how these differ from model species such as rats and mice.

  • Carry out human epidemiological and animal toxicity studies of respiratory, immune, reproductive, developmental, and other sensitive end points to replicate and expand on current findings in animal models.

Policy Recommendations

  • Include QACs on lists of contaminants of emerging concern used for reporting, monitoring, assessment, etc. This should also include QACs not registered as antimicrobials but used in large quantities or detected in the environment (see Table S1).

  • Regulate QACs consistently across different uses and agencies and consider exposure from multiple sources when evaluating allowable concentrations, formulations, and conditions of use.

  • Require full disclosure of the exact QACs used in all products, their functions (including for non-antimicrobial use such as material preservation or odor control), and production volumes. Achieving full transparency from manufacturers will likely require legislative or regulatory changes and collaboration across all relevant government agencies.

  • Develop a generally agreed upon definition of the entire class of QACs, perhaps with the help of the National Academies of Science and Medicine, to better understand the scope of the problem and support research and policy initiatives. This should include establishment of naming conventions that specify alkyl chain length, possible subgroups, and identification of QACs likely to have antimicrobial activity.

  • Reevaluate the 1988 EPA grouping strategies to better characterize and prioritize QACs for further research and management. An effort should be made to include all QACs, not just substances regulated under FIFRA. In addition to structure, other potentially relevant methods to group QACs should also be considered, such as alkyl chain length, function (e.g., antimicrobial or not), sensitization potential, common mixtures, and coexposures. New approach methodologies such as quantitative structure–activity relationships and ToxCast/Tox21 may be helpful in this effort.

  • Revisit QACs on the EPA Safer Chemical Ingredient List to ensure that they have been assessed for end points of concern identified for other QACs. As part of this process, health and environmental hazard data used for such assessments should be publicly available.

  • Finalize the FDA assessments regarding safety and effectiveness of benzalkonium chloride and benzethonium chloride in over-the-counter hand and body washes.

  • Establish a more rigorous process to incorporate academic findings in investigations of health or environmental hazards of QACs carried out by regulatory agencies. This research should be used to direct the regulated community to expand their research to include sensitive end points, QACs of varying chain lengths, and suspected adverse health effects of commonly used mixtures (e.g., BACs and DADMACs).

  • Immediately address the known threat of antimicrobial resistance. The medical field recommends that antibiotics be prescribed only when necessary and educates the public about proper use. Similar efforts to eliminate non-essential uses of antimicrobial QACs in consumer products are warranted. An example would be product labeling requirements such as “To reduce the public health threat of antimicrobial resistance, use this product only when disinfection is necessary and not for general cleaning”. Manufacturers should also be discouraged from implying a health benefit of QAC use in coatings and other durable product treatments without supporting evidence that these treatments are effective in reducing the transmission of infectious diseases.

QACs are a very large and diverse class of chemicals. Until we better understand possible differences among subgroups, it would be prudent to assume that all QACs could pose some level of risk. This is justified given the known impacts of antimicrobial resistance, biomonitoring data indicating their presence in humans, and recent data on adverse health outcomes. To effectively manage risks in a timely manner, the entire class of QACs should be addressed. For example, identifying and removing unnecessary uses of QACs, pointing to existing safer alternatives for essential uses, and incentivizing innovation of safer alternatives can prevent harm. We believe the research presented in this review supports such actions to preserve human and ecological health.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.est.2c08244.

  • (Table S2) Adverse health effects associated with specific QACs in humans and rodent models; (Figure S1) example structures and associated acronyms for some of the most well-studied subclasses of QACs (PDF)

  • Table S1 showing examples of QACs used in a variety of formulated consumer products (XLSX)

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Author Information

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  • Corresponding Author
  • Authors
    • William A. Arnold - University of Minnesota, Minneapolis, Minnesota 55455, United States;  Orcidhttps://orcid.org/0000-0003-0814-5469
    • Arlene Blum - Green Science Policy Institute, Berkeley, California 94709, United States;  University of California, Berkeley, California 94720, United States
    • Jennifer Branyan - California Department of Toxic Substances Control, Sacramento, California 95814, United States
    • Thomas A. Bruton - California Department of Toxic Substances Control, Sacramento, California 95814, United States;  Orcidhttps://orcid.org/0000-0002-4090-6021
    • Courtney C. Carignan - Michigan State University, East Lansing, Michigan 48824, United States;  Orcidhttps://orcid.org/0000-0002-5500-0222
    • Gino Cortopassi - University of California, Davis, California 95616, United States
    • Sandipan Datta - University of California, Davis, California 95616, United States;  Present Address: California Department of Toxic Substances Control, Sacramento, CA 95814, USA
    • Jamie DeWitt - East Carolina University, Greenville, North Carolina 27834, United States
    • Anne-Cooper Doherty - California Department of Toxic Substances Control, Sacramento, California 95814, United States
    • Rolf U. Halden - Arizona State University, Tempe, Arizona 85287, United States;  Orcidhttps://orcid.org/0000-0001-5232-7361
    • Homero Harari - Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
    • Erica M. Hartmann - Northwestern University, Evanston, Illinois 60208, United States;  Orcidhttps://orcid.org/0000-0002-0966-2014
    • Terry C. Hrubec - Edward Via College of Osteopathic Medicine, Blacksburg, Virginia 24060, United States
    • Shoba Iyer - California Office of Environmental Health Hazard Assessment, Oakland, California 94612, United States;  Present Address: San Francisco Environment Department, San Francisco, CA 94103, USA
    • Jonas LaPier - Green Science Policy Institute, Berkeley, California 94709, United States
    • Dingsheng Li - University of Nevada, Reno, Nevada 89557, United States;  Orcidhttps://orcid.org/0000-0002-8432-4023
    • Li Li - University of Nevada, Reno, Nevada 89557, United States;  Orcidhttps://orcid.org/0000-0002-5157-7366
    • Jorge G. Muñiz Ortiz - US Public Health Service, Rockville, Maryland 20582, United States
    • Amina Salamova - Indiana University, Atlanta, Georgia 30322, United States;  Orcidhttps://orcid.org/0000-0003-2174-030X
    • Ted Schettler - Science and Environmental Health Network, Bolinas, California 94924, United States
    • Ryan P. Seguin - University of Washington, Seattle, Washington 98195, United States
    • Anna Soehl - Green Science Policy Institute, Berkeley, California 94709, United States
    • Rebecca Sutton - San Francisco Estuary Institute, Richmond, California 94804, United States
    • Libin Xu - University of Washington, Seattle, Washington 98195, United States;  Orcidhttps://orcid.org/0000-0003-1021-5200
    • Guomao Zheng - Southern University of Science and Technology, Shenzhen, Guangdong 518055, China;  Orcidhttps://orcid.org/0000-0002-5235-9950
  • Notes
    Disclaimer. The views expressed are those of the authors and do not necessarily represent those of the Office of Environmental Health Hazard Assessment, the Department of Toxic Substances Control, the California Environmental Protection Agency, the State of California, the United States Government, or any Federal Government Agency.
    The authors declare the following competing financial interest(s): R.U.H. is co-founder of AquaVitas, LLC, an Arizona State University (ASU) startup company that works in the intellectual space touched upon by this study. R.U.H. is also the founder of ASU Foundation's OneWaterOneHealth, a nonprofit project providing wastewater-based health assessments to underserved US communities for assessing human exposure to harmful chemical and biological agents.

Acknowledgments

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The authors acknowledge the following funding sources that supported the research and writing of this manuscript: US National Science Foundation CBET 2051313 (W.A.A.); charitable contributions to the Green Science Policy Foundation (A.B., C.F.K., J.L., and A.S.); USDA National Institute of Food and Agriculture, Hatch Project MICL02565 (C.C.); NIEHS P30ES023513 pilot award (G.C. and S.D.); J. M. Kaplan Fund’s OneWaterOneHealth Project Award 30009070 (R.U.H.); NIEHS 1R01ES027890 (H.H.); US National Science Foundation CBET 2043156 (E.M.H.); The Alfred P. Sloan Foundation Grant 2019-12356 (E.M.H.); The Passport Foundation (T.C.H.); NIEHS T32-ES007032 (R.P.S.), R01ES031927 (R.P.S. and L.X.), and P30ES007033 pilot grant (L.X.); Regional Monitoring Program for Water Quality in San Francisco Bay (R.S.); National Natural Science Foundation of China 22206071 (G.Z.). We are extremely grateful to Hannah Ray and Seth Rojello Fernández for their assistance in preparing the manuscript. We also thank Sara Hoover, Martha Sandy, and Vince Cogliano for reviewing the manuscript prior to submission. R.S. thanks Dr. Ezra Miller for constructive feedback regarding QAC ecotoxicology.

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    United States Environmental Protection Agency. List N Tool: COVID-19 Disinfectants. https://cfpub.epa.gov/wizards/disinfectants/ (accessed 2023-02-02).
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    Mpox: Applying What We Know About Biological Agents to Prepare for Emerging Public Health Threats. Science Matters, United States Environmental Protection Agency, July 19, 2022. https://www.epa.gov/sciencematters/monkeypox-applying-what-we-know-about-biological-agents-prepare-emerging-public (accessed 2022-09-23).
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    Disinfectants for Emerging Viral Pathogens (EVPs): List Q. Pesticide Registration, United States Environmental Protection Agency. https://www.epa.gov/pesticide-registration/disinfectants-emerging-viral-pathogens-evps-list-q#search (accessed 2022-09-23).
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    World Health Organization. Cleaning and Disinfection of Environmental Surfaces in the Context of COVID-19: Interim Guidance, 15 May 2020; World Health Organization: Geneva, 2020. https://apps.who.int/iris/handle/10665/332096 (2022-06-07).
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    Center for Disease Control and Prevention. Clarification Statement. Environmental Fogging (December 2009). Guideline for Disinfection and Sterilization in Healthcare Facilities , 2008.https://www.cdc.gov/infectioncontrol/guidelines/disinfection/updates.html#anchor_1554393533 (accessed 2023-02-02).
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    Food and Drug Administration. Safety and Effectiveness of Consumer Antiseptics; Topical Antimicrobial Drug Products for Over-the-Counter Human Use. Federal Register , 2016; pp 61106– 61130. https://www.federalregister.gov/documents/2016/09/06/2016-21337/safety-and-effectiveness-of-consumer-antiseptics-topical-antimicrobial-drug-products-for (accessed 2022-06-17).
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    Gebel, J.; Exner, M.; French, G.; Chartier, Y.; Christiansen, B.; Gemein, S.; Goroncy-Bermes, P.; Hartemann, P.; Heudorf, U.; Kramer, A.; Maillard, J.-Y.; Oltmanns, P.; Rotter, M.; Sonntag, H.-G. The Role of Surface Disinfection in Infection Prevention. GMS Hyg. Infect. Control 2013, 8 (1), Doc10
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    Disinfection and Sterilization. Center for Disease Control and Prevention. https://www.cdc.gov/infectioncontrol/guidelines/disinfection/index.html (accessed 2023-02-02).
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    Muller, M. P.; MacDougall, C.; Lim, M. Antimicrobial Surfaces to Prevent Healthcare-Associated Infections: A Systematic Review. J. Hosp. Infect. 2016, 92 (1), 7– 13,  DOI: 10.1016/j.jhin.2015.09.008
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    Antimicrobial surfaces to prevent healthcare-associated infections: a systematic review
    Muller M P; MacDougall C; Lim M
    The Journal of hospital infection (2016), 92 (1), 7-13 ISSN:.
    Contamination of the healthcare environment with pathogenic organisms contributes to the burden of healthcare-associated infection (HCAI). Antimicrobial surfaces are designed to reduce microbial contamination of healthcare surfaces. We aimed to determine whether antimicrobial surfaces prevent HCAI, transmission of antibiotic-resistant organisms (AROs), or microbial contamination, we conducted a systematic review of the use of antimicrobial surfaces in patient rooms. Outcomes included HCAI, ARO, and quantitative microbial contamination. Relevant databases were searched. Abstract review, full text review, and data abstraction were performed in duplicate. Risk of bias was assessed using the Cochrane Effective Practice and Organization Care (EPOC) Group risk of bias assessment tool and the strength of evidence determined using Grading of Recommendations Assessment, Development and Evaluation (GRADE). Eleven studies assessed the effect of copper (N = 7), silver (N = 1), metal-alloy (N = 1), or organosilane-treated surfaces (N = 2) on microbial contamination. Copper surfaces demonstrated a median (range) reduction of microbial contamination of <1 log10 (<1 to 2 log10). Two studies addressed HCAI/ARO incidence. An RCT of copper surfaces in an ICU demonstrated 58% reduction in HCAI (P = 0.013) and 64% reduction in ARO transmission (P = 0.063) but was considered low-quality evidence due to improper randomization and incomplete blinding. An uncontrolled before-after study evaluating copper-impregnated textiles in a long-term care ward demonstrated 24% reduction in HCAI but was considered very-low-quality evidence based on the study design. Copper surfaces used in clinical settings result in modest reductions in microbial contamination. One study of copper surfaces and one of copper textiles demonstrated reduction in HCAI, but both were at high risk of bias.
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    Centers for Disease Control and Prevention (CDC). National Report on Human Exposure to Environmental Chemicals, CDC, U.S. Department of Health and Human Services, https://www.cdc.gov/exposurereport/ (accessed 2022-02-02).
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    Hora, P. I.; Pati, S. G.; McNamara, P. J.; Arnold, W. A. Increased Use of Quaternary Ammonium Compounds during the SARS-CoV-2 Pandemic and Beyond: Consideration of Environmental Implications. Environ. Sci. Technol. Lett. 2020, 7, 622,  DOI: 10.1021/acs.estlett.0c00437
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    22
    Increased Use of Quaternary Ammonium Compounds during the SARS-CoV-2 Pandemic and Beyond: Consideration of Environmental Implications
    Hora, Priya I.; Pati, Sarah G.; McNamara, Patrick J.; Arnold, William A.
    Environmental Science & Technology Letters (2020), 7 (9), 622-631CODEN: ESTLCU; ISSN:2328-8930. (American Chemical Society)
    Quaternary ammonium compds. (QACs) are active ingredients in over 200 disinfectants currently recommended by the U.S. EPA for use to inactivate the SARS-CoV-2 (COVID-19) virus. The amts. of these compds. used in household, workplace, and industry settings has very likely increased, and usage will continue to be elevated given the scope of the pandemic. QACs have been previously detected in wastewater, surface waters, and sediments, and effects on antibiotic resistance have been explored. Thus, it is important to assess potential environmental and engineering impacts of elevated QAC usage, which may include disruption of wastewater treatment unit operations, proliferation of antibiotic resistance, formation of nitrosamine disinfection byproducts, and impacts on biota in surface waters. The threat caused by COVID-19 is clear, and a reasonable response is elevated use of QACs to mitigate spread of infection. Exploration of potential effects, environmental fate, and technologies to minimize environmental releases of QACs, however, is warranted.
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  23. 23
    Li, X.; Doherty, A. C.; Brownawell, B.; Lara-Martin, P. A. Distribution and Diagenetic Fate of Synthetic Surfactants and Their Metabolites in Sewage-Impacted Estuarine Sediments. Environ. Pollut. 2018, 242, 209– 218,  DOI: 10.1016/j.envpol.2018.06.064
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    23
    Distribution and diagenetic fate of synthetic surfactants and their metabolites in sewage-impacted estuarine sediments
    Li, Xiaolin; Doherty, Anne Cooper; Brownawell, Bruce; Lara-Martin, Pablo A.
    Environmental Pollution (Oxford, United Kingdom) (2018), 242 (Part_A), 209-218CODEN: ENPOEK; ISSN:0269-7491. (Elsevier Ltd.)
    Surfactants are high prodn. vol. chems. used in numerous domestic and industrial applications and, after use, the most abundant org. contaminants in wastewater. Their discharge might jeopardize the receiving aquatic ecosystems, including sediments, where they tend to accumulate. This is the first comprehensive study on their distribution and fate in this environmental compartment as we performed simultaneous anal. of the three main classes of surfactants and some of their transformation products (SPC, NP, NPEC, and PEG). Surface sediments and dated cores were collected from Jamaica Bay, a heavily sewage-impacted estuary in New York City. Cationic surfactants were found at the highest concns., with DTDMAC accounting for between 52 and 90% of the total sum of target compds. Two sub-surface surfactant peaks in the mid-1960s and late 1980s coinciding with known STP upgrades. Except for DADMAC, C22ATMAC, and PEG, which showed a continuous increase towards top of cores. In-situ degrdn. was studied by comparing sediment core samples taken 12 years apart (1996 and 2008) and revealed a net decrease in PEG and specific surfactants accompanied by growing concns. of metabolites . DTDMAC, DADMAC, and LAS, however, remained stable over this period, suggesting recalcitrant behavior under the anaerobic conditions in Jamaica Bay sediments. Chronol. of major synthetic surfactants are illustrated in the dated sediment cores, as well as their different diagenetic fates.
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  24. 24
    Zhang, C.; Cui, F.; Zeng, G. M.; Jiang, M.; Yang, Z. Z.; Yu, Z. G.; Zhu, M. Y.; Shen, L. Q. Quaternary Ammonium Compounds (QACs): A Review on Occurrence, Fate and Toxicity in the Environment. Sci. Total Environ. 2015, 518–519, 352– 362,  DOI: 10.1016/j.scitotenv.2015.03.007
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    24
    Quaternary ammonium compounds (QACs): A review on occurrence, fate and toxicity in the environment
    Zhang, Chang; Cui, Fang; Zeng, Guang-ming; Jiang, Min; Yang, Zhong-zhu; Yu, Zhi-gang; Zhu, Meng-ying; Shen, Liu-qing
    Science of the Total Environment (2015), 518-519 (), 352-362CODEN: STENDL; ISSN:0048-9697. (Elsevier B.V.)
    A review. Quaternary ammonium compds. (QACs) are widely applied in household and industrial products. Most uses of QACs can be expected to lead to their release to wastewater treatment plants (WWTPs) and then dispersed into various environmental compartments through sewage effluent and sludge land application. Although QACs are considered to be aerobically biodegradable, the degrdn. is affected by its chem. structures, dissolved oxygen concn., complexing with anionic surfactants, etc. High abundance of QACs has been detected in sediment and sludge samples due to its strong sorption and resistance to biodegrdn. under anoxic/anaerobic conditions. QACs are toxic to a lot of aquatic organisms including fish, daphnids, algae, rotifer and microorganisms employed in wastewater treatment systems. And antibiotic resistance has emerged in microorganisms due to excessive use of QACs in household and industrial applications. The occurrence of QACs in the environment is correlated with anthropogenic activities, such as wastewater discharge from WWTPs or single source polluters, and sludge land application. This article also reviews the anal. methods for detn. of QACs in environmental compartments including surface water, wastewater, sewage sludge and sediments.
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  25. 25
    Williams, A. J.; Grulke, C. M.; Edwards, J.; McEachran, A. D.; Mansouri, K.; Baker, N. C.; Patlewicz, G.; Shah, I.; Wambaugh, J. F.; Judson, R. S.; Richard, A. M. The CompTox Chemistry Dashboard: A Community Data Resource for Environmental Chemistry. J. Cheminform. 2017, 9 (1), 61,  DOI: 10.1186/s13321-017-0247-6
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    The CompTox Chemistry Dashboard: a community data resource for environmental chemistry
    Williams Antony J; Grulke Christopher M; Edwards Jeff; Mansouri Kamel; Patlewicz Grace; Shah Imran; Wambaugh John F; Judson Richard S; Richard Ann M; McEachran Andrew D; Mansouri Kamel; Mansouri Kamel; Baker Nancy C
    Journal of cheminformatics (2017), 9 (1), 61 ISSN:1758-2946.
    Despite an abundance of online databases providing access to chemical data, there is increasing demand for high-quality, structure-curated, open data to meet the various needs of the environmental sciences and computational toxicology communities. The U.S. Environmental Protection Agency's (EPA) web-based CompTox Chemistry Dashboard is addressing these needs by integrating diverse types of relevant domain data through a cheminformatics layer, built upon a database of curated substances linked to chemical structures. These data include physicochemical, environmental fate and transport, exposure, usage, in vivo toxicity, and in vitro bioassay data, surfaced through an integration hub with link-outs to additional EPA data and public domain online resources. Batch searching allows for direct chemical identifier (ID) mapping and downloading of multiple data streams in several different formats. This facilitates fast access to available structure, property, toxicity, and bioassay data for collections of chemicals (hundreds to thousands at a time). Advanced search capabilities are available to support, for example, non-targeted analysis and identification of chemicals using mass spectrometry. The contents of the chemistry database, presently containing ~ 760,000 substances, are available as public domain data for download. The chemistry content underpinning the Dashboard has been aggregated over the past 15 years by both manual and auto-curation techniques within EPA's DSSTox project. DSSTox chemical content is subject to strict quality controls to enforce consistency among chemical substance-structure identifiers, as well as list curation review to ensure accurate linkages of DSSTox substances to chemical lists and associated data. The Dashboard, publicly launched in April 2016, has expanded considerably in content and user traffic over the past year. It is continuously evolving with the growth of DSSTox into high-interest or data-rich domains of interest to EPA, such as chemicals on the Toxic Substances Control Act listing, while providing the user community with a flexible and dynamic web-based platform for integration, processing, visualization and delivery of data and resources. The Dashboard provides support for a broad array of research and regulatory programs across the worldwide community of toxicologists and environmental scientists.
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    Lyon, L. A. Handbook of Applied Surface and Colloid Chemistry. Volumes 1 and 2 Edited by Krister Holmberg (Chalmers University of Technology). John Wiley & Sons: West Sussex. 2002. Xii + 1110 Pp. $600.00. ISBN 0–471–49083–0. J. Am. Chem. Soc. 2002, 124 (50), 15143– 15144,  DOI: 10.1021/ja025281k
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    Handbook of Applied Surface and Colloid Chemistry. Volumes 1 and 2, edited by Krister Holmberg (Chalmers University of Technology)
    Lyon, L. Andrew
    Journal of the American Chemical Society (2002), 124 (50), 15143-15144CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    There is no expanded citation for this reference.
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    Office of Prevention, Pesticides and Toxic Substances (7510C), United States Environmental Protection Agency (EPA). Reregistration Eligibility Decision for Alkyl Dimethyl Benzyl Ammonium Chloride (ADBAC), EPA739-R-06-009; EPA, 2006 (accessed 2022-06-19).
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    United States Environmental Protection Agency. Pesticide Registration Notice 88-2: Clustering of Quaternary Ammonium Compounds. February 26, 1988. https://www.epa.gov/sites/default/files/2015-09/documents/pr88-2.pdf (accessed 2023-02-02).
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    Li, D.; Sangion, A.; Li, L. Evaluating Consumer Exposure to Disinfecting Chemicals against Coronavirus Disease 2019 (COVID-19) and Associated Health Risks. Environ. Int. 2020, 145, 106108,  DOI: 10.1016/j.envint.2020.106108
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    Evaluating consumer exposure to disinfecting chemicals against coronavirus disease 2019 (COVID-19) and associated health risks
    Li, Dingsheng; Sangion, Alessandro; Li, Li
    Environment International (2020), 145 (), 106108CODEN: ENVIDV; ISSN:0160-4120. (Elsevier Ltd.)
    Disinfection of surfaces has been recommended as one of the most effective ways to combat the spread of novel coronavirus (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19). However, overexposure to disinfecting chems. may lead to unintended human health risks. Here, using an indoor fate and chem. exposure model, we est. human exposure to 22 disinfecting chems. on the lists recommended by various governmental agencies against COVID-19, resulting from contact with disinfected surfaces and handwashing. Three near-field exposure routes, i.e., mouthing-mediated oral ingestion, inhalation, and dermal absorption, are considered to calc. the whole-body uptake doses and blood concns. caused by single use per day for three age groups (3, 14, and 24-yr-old). We also assess the health risks by comparing the predicted whole-body uptake doses with in vivo toxicol. data and the predicted blood concns. with in vitro bioactivity data. Our results indicate that both the total exposure and relative contribution of each exposure route vary considerably among the disinfecting chems. due to their diverse physicochem. properties. 3-yr-old children have consistent higher exposure than other age groups, esp. in the scenario of contact with disinfected surfaces, due to their more frequent hand contact and mouthing activities. Due to the short duration of handwashing, we do not expect any health risk from the use of disinfecting chems. in handwashing. In contrast, exposure from contact with disinfected surfaces may result in health risks for certain age groups esp. children, even the surfaces are disinfected once a day. Interestingly, risk assessments based on whole-body uptake doses and in vivo toxicol. data tend to give higher risk ests. than do those based on blood concns. and in vitro bioactivity data. Our results reveal the most important exposure routes for disinfecting chems. used in the indoor environment; they also highlight the need for more accurate data for both chem. properties and toxicity to better understand the risks assocd. with the increased use of disinfecting chems. in the pandemic.
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    Zhao, Y. H.; Abraham, M. H. Octanol/Water Partition of Ionic Species, Including 544 Cations. J. Org. Chem. 2005, 70 (7), 2633– 2640,  DOI: 10.1021/jo048078b
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    Octanol/Water Partition of Ionic Species, Including 544 Cations
    Zhao, Yuan H.; Abraham, Michael H.
    Journal of Organic Chemistry (2005), 70 (7), 2633-2640CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
    Partition coeffs. of single ions in the octanol/water system (log Poct) have been assigned on the (Ph4As+, Ph4P+) = Ph4B- assumption. The log Poct values of Cl-, Br-, and I- ions are then used to obtain the partition coeffs. of cations from partition coeffs. of the neutral combination of anion and cation. Partition coeffs. of 544 cations derived from 585 org. salts from the MedChem database have been studied. The contributions of the aliph. charge N+ and arom. charge n+ in these cations have been investigated. The results show that the contributions of N+ and n+ in different homologous series are affected by the attached functional groups and are not const., although the effect of the central cation is const. along any given homologous series. The latter can be accounted for qual. and semiquant. by the electrostatic theory of ionic solvation of Abraham and Liszi. A no. of regression equations have been established between partition coeffs. of ions and partition coeffs. of the corresponding neutral species. These equations can be used to est. octanol/water partition coeffs. for addnl. cations to about 0.5 log unit.
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  31. 31
    Droge, S. T. J.; Goss, K.-U. Sorption of Organic Cations to Phyllosilicate Clay Minerals: CEC-Normalization, Salt Dependency, and the Role of Electrostatic and Hydrophobic Effects. Environ. Sci. Technol. 2013, 47 (24), 14224– 14232,  DOI: 10.1021/es403187w
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    Sorption of Organic Cations to Phyllosilicate Clay Minerals: CEC-Normalization, Salt Dependency, and the Role of Electrostatic and Hydrophobic Effects
    Droge, Steven T. J.; Goss, Kai-Uwe
    Environmental Science & Technology (2013), 47 (24), 14224-14232CODEN: ESTHAG; ISSN:0013-936X. (American Chemical Society)
    Sorption to the phyllosilicate clay minerals Illite, kaolinite, and bentonite has been studied for a wide variety of org. cations using a flow-through method with fully aq. medium as the eluent. Linear isotherms were obsd. at concns. below 10% of the cation-exchange capacity (CEC) for Illite and kaolinite and below 1 mmol/kg (<1% CEC) for bentonite. Sorption to clays was strongly influenced by the electrolyte compn. of the eluent but with a consistent trend for a diverse set of compds. on all clays, thus allowing for empirical correction factors. When sorption affinities for a given compd. to a given clay are normalized to the CEC of the clay, the differences in sorption affinities between clays are reduced to less than 0.5 log units for most compds. Although CEC-normalized sorption of quaternary ammonium compds. to clay was up to 10-fold higher than CEC-normalized sorption to soil org. matter, CEC-normalized sorption for most compds. was comparable between clays and soil org. matter. The clay fraction is thus a potentially relevant sorption phase for org. cations in many soils. The sorption data for org. cations to clay showed several regular trends with mol. structure but also showed quite a few systematic effects that we cannot explain. A model on the basis of the mol. size and charge d. at the ionized nitrogen is used here as a tool to obtain benchmark values that elucidate the effect of specific polar moieties on the sorption affinity.
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  32. 32
    Oh, S.; Kurt, Z.; Tsementzi, D.; Weigand, M. R.; Kim, M.; Hatt, J. K.; Tandukar, M.; Pavlostathis, S. G.; Spain, J. C.; Konstantinidis, K. T. Microbial Community Degradation of Widely Used Quaternary Ammonium Disinfectants. Appl. Environ. Microbiol. 2014, 80 (19), 5892– 5900,  DOI: 10.1128/AEM.01255-14
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    Microbial community degradation of widely used quaternary ammonium disinfectants
    Oh, Seungdae; Kurt, Zohre; Tsementzi, Despina; Weigand, Michael R.; Kim, Minjae; Hatt, Janet K.; Tandukar, Madan; Pavlostathis, Spyros G.; Spain, Jim C.; Konstantinidis, Konstantinos T.
    Applied and Environmental Microbiology (2014), 80 (19), 5892-5900, 10 pp.CODEN: AEMIDF; ISSN:1098-5336. (American Society for Microbiology)
    Benzalkonium chlorides (BACs) are disinfectants widely used in a variety of clin. and environmental settings to prevent microbial infections, and they are frequently detected in nontarget environments, such as aquatic and engineered biol. systems, even at toxic levels. Therefore, microbial degrdn. of BACs has important ramifications for alleviating disinfectant toxicity in nontarget environments as well as compromising disinfectant efficacy in target environments. However, how natural microbial communities respond to BAC exposure and what genes underlie BAC biodegrdn. remain elusive. Our previous metagenomic anal. of a river sediment microbial community revealed that BAC exposure selected for a low-diversity community, dominated by several members of the Pseudomonas genus that quickly degraded BACs. To elucidate the genetic determinants of BAC degrdn., we conducted time-series metatranscriptomic anal. of this microbial community during a complete feeding cycle with BACs as the sole carbon and energy source under aerobic conditions. Metatranscriptomic profiles revealed a candidate gene for BAC dealkylation, the first step in BAC biodegrdn. that results in a product 500 times less toxic. Subsequent biochem. assays and isolate characterization verified that the putative amine oxidase gene product was functionally capable of initiating BAC degrdn. Our anal. also revealed cooperative interactions among community members to alleviate BAC toxicity, such as the further degrdn. of BAC dealkylation byproducts by organisms not encoding amine oxidase. Collectively, our results advance the understanding of BAC aerobic biodegrdn. and provide genetic biomarkers to assess the crit. first step of this process in nontarget environments. The metatranscriptome data used in this study were deposited in GenBank under the accession nos. SRR955467 (B0h), SRR955468 (B0.5 h-1), SRR955469 (B0.5 h-2), SRR955498 (B0.5 h-3), SRR955499 (B12 h), and SRR955500 (B48 h).
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    Kickham, P.; Otton, S. V.; Moore, M. M.; Ikonomou, M. G.; Gobas, F. A. P. C. Relationship between Biodegradation and Sorption of Phthalate Esters and Their Metabolites in Natural Sediments. Environ. Toxicol. Chem. 2012, 31 (8), 1730– 1737,  DOI: 10.1002/etc.1903
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    Relationship between biodegradation and sorption of phthalate esters and their metabolites in natural sediments
    Kickham, Peter; Otton, S. Victoria; Moore, Margo M.; Ikonomou, Michael G.; Gobas, Frank A. P. C.
    Environmental Toxicology and Chemistry (2012), 31 (8), 1730-1737CODEN: ETOCDK; ISSN:0730-7268. (Wiley-Blackwell)
    Regulatory evaluations of com. chems. in Canada, the US, the European Union, and other countries aim to identify biodegrdn. rates of chems. in natural soils and sediments. However, commonly used biodegrdn. testing methods are limited in their capacity to det. biodegrdn. rates under natural environmental conditions. As a result, widely varying biodegrdn. rates have been reported for many very hydrophobic substances. This variability causes difficulties in regulatory evaluations, potentially leading to chem. misclassification. The authors developed a model of the relation between biodegrdn., sorption, and hydrophobicity, and tested the model in expts. that measured the biodegrdn. rates of a range of di-phthalate esters (DPEs) and mono-phthalate esters (MPEs) in natural sediments. The results indicate that DPEs and MPEs have the inherent capacity to be quickly degraded by microbes in sediments at a common rate, but that DPE biodegrdn. rates in natural sediments decrease with increasing phthalate ester sorption to sediments. The results show that inherently biodegradable substances that are subject to a high degree of sorption can be expected to exhibit long half-lives in natural sediments. The model provides a potential methodol. for assessing biodegrdn. rates in natural sediments from inherent biodegrdn. rates measured in screening tests by accounting for chem. sorption. The present study indicates that a reduced rate of biodegrdn. is due to a reduced fraction of freely dissolved chem. concn. in the interstitial water, and that the environmental significance of sorption-reduced biodegrdn. rates needs to be viewed in the context of risk in chem. evaluations.
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    Brownawell, B. J.; Chen, H.; Collier, J. M.; Westall, J. C. Adsorption of Organic Cations to Natural Materials. Environ. Sci. Technol. 1990, 24 (8), 1234– 1241,  DOI: 10.1021/es00078a011
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    Environmental Science and Technology (1990), 24 (8), 1234-41CODEN: ESTHAG; ISSN:0013-936X.
    The factors that control the extent of adsorption of amphiphilic org. cations on environmental and pristine surfaces were studied. The sorbents were kaolinite, montmorillonite, 2 aquifer materials, and a soil; the solns. contained various concns. of NaCl and CaCl2 at various pH values. The distribution ratio of dodecylpyridinium was strongly dependent on the nature and concn. of the inorg. cations in soln., but virtually independent of soln. pH. The adsorption isotherms were distinctly nonlinear, even at very low surface concns. of org. cations. A multisite adsorption model was developed to describe adsorption over a wide range of dodecylpyridinium, NaCl, and CaCl2 concns. Two types of adsorption reactions were significant: exchange of pyridinium with a alkali-metal cation, and adsorption of pyridinium with Cl- counterion.
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    Hora, P. I.; Arnold, W. A. Photochemical Fate of Quaternary Ammonium Compounds in River Water. Environ. Sci. Process. Impacts 2020, 22 (6), 1368– 1381,  DOI: 10.1039/D0EM00086H
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    Photochemical fate of quaternary ammonium compounds in river water
    Hora, Priya I.; Arnold, William A.
    Environmental Science: Processes & Impacts (2020), 22 (6), 1368-1381CODEN: ESPICZ; ISSN:2050-7895. (Royal Society of Chemistry)
    Quaternary ammonium compds. (QACs) are not completely removed during wastewater treatment and are frequently detected in surface waters and sediments. The photochem. transformation of QACs has not been thoroughly investigated as a potential degrdn. pathway affecting their fate in the environment. Kinetic studies of common QACs with and without arom. groups under simulated and natural sunlight conditions were performed with model sensitizers and dissolved org. matter to est. photochem. half-lives in the aquatic environment. All QACs investigated react with hydroxyl radicals at diffusion-controlled rates (∼2.9 x 109 to 1.2 x 1010 M-1 s-1). Benzethonium reacted via direct photolysis (ΦBZT,outdoor = 1.7 x 10-2 (mol Ei-1)). Benzethonium also reacted with the triplet excited state model sensitizer 2-acetylnaphthalene, but evidence suggests this reaction pathway is unimportant in natural waters due to faster quenching of the triplet 2-acetylnaphthalene by oxygen. Reactivity with singlet oxygen for the QACs was minimal. Overall, reactions with hydroxyl radicals will dominate over direct photolysis due to limited spectral overlap of sunlight emission and QAC absorbance. Photolysis half-lives are predicted to be 12 to 94 days, indicating slow abiotic degrdn. in surface water.
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    Pati, S. G.; Arnold, W. A. Comprehensive Screening of Quaternary Ammonium Surfactants and Ionic Liquids in Wastewater Effluents and Lake Sediments. Environ. Sci. Process. Impacts 2020, 22 (2), 430– 441,  DOI: 10.1039/C9EM00554D
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    Comprehensive screening of quaternary ammonium surfactants and ionic liquids in wastewater effluents and lake sediments
    Pati Sarah G; Arnold William A
    Environmental science. Processes & impacts (2020), 22 (2), 430-441 ISSN:.
    Quaternary ammonium compounds (QACs) are widely applied as surfactants and biocides in cleaning and personal-care products. Because of incomplete removal during wastewater treatment, QACs are present in wastewater effluents, with which they are discharged into natural waters, where they accumulate in sediments. To assess the levels of QACs in aquatic environments, a liquid chromatography high-resolution mass spectrometry method using both target and suspect screening was developed. The water and sediment sample preparation, measurement, and data analysis workflow were optimized for 22 target compounds with a wide range of hydrophobicity, including ionic liquids that have potential use as solvents and QACs common in personal-care and sanitizing products. In wastewater effluents, average concentrations of all target and suspect QACs combined ranged from 0.4 μg L-1 to 6.6 μg L-1. Various homologs of benzylalkyldimethylammonium (BAC) and dialkyldimethylammonium (DADMAC) as well as the ionic liquid butylpyridinium and 15 suspect QACs were detected in at least one wastewater effluent sample. A spatial profile of sediment samples in a lake demonstrated potential inputs from both municipal wastewater effluent and agricultural sources for BACs. In sediment cores, two distinct trends of temporal QAC accumulation were observed. In lakes with large watersheds and mixed domestic and industrial wastewater sources (Lake Pepin and Duluth Harbor), peak concentrations of QACs were found at depths corresponding to deposition in the 1980s and decreases after this time are attributed to improved wastewater treatment and source control. In a smaller lake with predominantly domestic wastewater inputs (Lake Winona), concentrations of QACs increased slowly over time until today.
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    Auerbach, M. Germicidal Quaternary Ammonium Salts in Dilute Solution A Colorimetric Assay Method. Ind. Eng. Chem. Anal. Ed. 1943, 15 (8), 492– 493,  DOI: 10.1021/i560120a006
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    Germicidal quaternary ammonium salts in dilute solution. A colorimetric assay method
    Auerbach, M. E.
    Industrial and Engineering Chemistry, Analytical Edition (1943), 15 (), 492-3CODEN: IENAAD; ISSN:0096-4484.
    Since in a colorimetric method for the detn. of some germicidal quaternary compds. in dil. solns. inorganic alkalies and the common primary, secondary, and tertiary amines do not interfere, an extension of the general method is suggested for the detn. of alkaloids (cations) with bromothymol blue as dye anion, and for the detn. of some colored sulfonic acids (anions) with quaternary ammonium cations.
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    Li, S.; Zhao, S. Spectrophotometric Determination of Cationic Surfactants with Benzothiaxolyldiazoaminoazobenzene. Anal. Chim. Acta 2004, 501 (1), 99– 102,  DOI: 10.1016/j.aca.2003.09.014
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    Spectrophotometric determination of cationic surfactants with benzothiaxolyldiazoaminoazobenzene
    Li, Shuting; Zhao, Shulin
    Analytica Chimica Acta (2004), 501 (1), 99-102CODEN: ACACAM; ISSN:0003-2670. (Elsevier Science B.V.)
    A novel spectrophotometric method for the detn. of cationic surfactants (CS) by using a new reagent benzothiaxolyldiazoaminoazobenzene (BTDAB) is developed. In 0.06-0.10 M NaOH, CS such as cetyltrimethylammonium bromide (CTMAB) and cetylpyridinium chloride (CPC) react with BTDAB to form a violet-red 1:2 (CS:BTDAB) ion assocn. complex in the presence of Triton X-100. This ion assoc. exhibits an absorption max. at 580 nm with an apparent molar absorptivity of 4.1 × 104 l mol-1 cm-1. Beer's law is obeyed for CTMAB or CPC in the concn. range 0-100 μg per 25 mL of soln. The proposed method based on the above color reaction is simple and rapid, and there is no use of toxic org. solvents. It was applied to the detn. of trace CS in industrial wastewater with satisfactory results.
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    Woods-Chabane, G. C.; Glover, C. M.; Marti, E. J.; Dickenson, E. R. V. A Novel Assay to Measure Tertiary and Quaternary Amines in Wastewater: An Indicator for NDMA Wastewater Precursors. Chemosphere 2017, 179, 298– 305,  DOI: 10.1016/j.chemosphere.2017.03.045
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    A novel assay to measure tertiary and quaternary amines in wastewater: An indicator for NDMA wastewater precursors
    Woods-Chabane, Gwen C.; Glover, Caitlin M.; Marti, Erica J.; Dickenson, Eric R. V.
    Chemosphere (2017), 179 (), 298-305CODEN: CMSHAF; ISSN:0045-6535. (Elsevier Ltd.)
    This study examd. the potential of using a novel bulk amine assay as an approxn. for the tertiary and quaternary amine load in wastewaters and surface water samples, and this approxn. was compared to N-nitrosodimethylamine (NDMA) formation potential using chloramines. An existing colorimetric method was examd. and optimized for the detection of amines in environmental water samples. The method consists of liq.-liq. extn. followed by a catalyzed reaction to form a yet-undefined product that is known to be both a strong chromophore and fluorophore. Previous work verified that this reaction was effectively catalyzed by a no. of compds. contg. tertiary and quaternary amine moieties. Many tertiary and quaternary compds. are also efficient producers of NDMA under chloramination conditions, and a linear correlation was consequently derived from the bulk amine signals vs. NDMA formation potential in various wastewater samples (R2 = 0.74; n = 24; p-value < 0.05). The results provide evidence that approx. 2% of the tertiary and quaternary amines measured can form NDMA and an estd. 0.01-1.3% of nitrogen in dissolved org. nitrogen originates from these bulk amines. The normalization of NDMA concn. by the amine measurement revealed that ozone effectively destroyed those tertiary and quaternary amine structures more likely to form NDMA in treated wastewater samples. This bulk amine assay illustrates that proxy measurements of tertiary and quaternary amines can be linked to the NDMA formation potential of a given sample, and this approach may prove useful as a characterizing tool for NDMA precursors in wastewater.
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    Li, X.; Brownawell, B. J. Analysis of Quaternary Ammonium Compounds in Estuarine Sediments by LC-ToF-MS: Very High Positive Mass Defects of Alkylamine Ions as Powerful Diagnostic Tools for Identification and Structural Elucidation. Anal. Chem. 2009, 81 (19), 7926– 7935,  DOI: 10.1021/ac900900y
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    Analysis of Quaternary Ammonium Compounds in Estuarine Sediments by LC-ToF-MS: Very High Positive Mass Defects of Alkylamine Ions as Powerful Diagnostic Tools for Identification and Structural Elucidation
    Li, Xiaolin; Brownawell, Bruce J.
    Analytical Chemistry (Washington, DC, United States) (2009), 81 (19), 7926-7935CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
    A sensitive and robust method of anal. for quaternary ammonium compds. (QACs) in marine sediments is presented. Methods for extn., sample purifn., and HPLC-time-of-flight MS anal. were optimized, providing solns. to problems assocd. with anal. of QACs, such as dialkyldimethylammonium (DADMAC) and benzalkonium (BAC) compds. experienced previously. Recognized in this study are the exceptionally high pos. mass defects characteristic of alkylammonium or protonated alkylamine ions. No alternative and chem. viable elemental formulas exist within 25.2 mDa when the no. of double bond equiv. is low, effectively allowing facile discrimination of this compd. class in complex mixts. Accurate mass measurements of diagnostic collision-induced dissocn. fragment ions and heavy isotope peaks were obtained and also seen to be uniquely heavy compared to other elemental formulas. The ability to resolve masses of alkylamine fragment ions is much greater than for the mol. ions of BACs and many other chems., opening up a range of potential applications. The power of utilizing a combination of approaches is illustrated with the identification of nontargeted DADMAC C8:C8 and C8:C10, 2 widely used biocides previously unreported in environmental samples. Concns. of QACs in sewage-impacted estuarine sediments (≤74 μg/g) were higher than concns. of other org. contaminants measured in the same or nearby samples, suggesting that further study is needed.
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    Lara-Martín, P. A.; Li, X.; Bopp, R. F.; Brownawell, B. J. Occurrence of Alkyltrimethylammonium Compounds in Urban Estuarine Sediments: Behentrimonium As a New Emerging Contaminant. Environ. Sci. Technol. 2010, 44 (19), 7569– 7575,  DOI: 10.1021/es101169a
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    Occurrence of Alkyltrimethylammonium Compounds in Urban Estuarine Sediments: Behentrimonium As a New Emerging Contaminant
    Lara-Martin, Pablo A.; Li, Xiaolin; Bopp, Richard F.; Brownawell, Bruce J.
    Environmental Science & Technology (2010), 44 (19), 7569-7575CODEN: ESTHAG; ISSN:0013-936X. (American Chemical Society)
    The distribution of alkyltrimethylammonium compds. (ATMAC), cationic surfactants used in a wide variety of applications, has been detd. in sediments from Jamaica Bay (NY). Total concns. in surficial sediments collected between 1998 and 2008 were 361-6750 ng/g. The highest values were found in samples from a deeper basin directly affected by treated wastewater discharges. Behentrimonium, a mixt. dominated by a homolog with 22 C atoms in its alkyl chain (ATMAC 22), was identified for the 1st time using time-of-flight mass spectrometry and accounted for ∼80% of the total ATMAC in recent sediment samples. Analyses of a dated sediment core and subsequent surface grab samples revealed an exponential increase in concn. over the last 3 decades with a doubling time of 3.9 yr. Similar temporal trends were seen in surface samples from other sites in Jamaica Bay and Newton Creek (NY), another site greatly influenced by wastewater discharges. This dramatic increase in ATMAC 22 reflects greater use of behentrimonium and likely replacement of other products contg. other ATMAC homologues in personal care products. Further monitoring is recommended to assess the environmental risk and fate of this persistent emerging contaminant.
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    Zheng, G.; Filippelli, G. M.; Salamova, A. Increased Indoor Exposure to Commonly Used Disinfectants during the COVID-19 Pandemic. Environ. Sci. Technol. Lett. 2020, 7 (10), 760– 765,  DOI: 10.1021/acs.estlett.0c00587
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    Increased Indoor Exposure to Commonly Used Disinfectants during the COVID-19 Pandemic
    Zheng, Guomao; Filippelli, Gabriel M.; Salamova, Amina
    Environmental Science & Technology Letters (2020), 7 (10), 760-765CODEN: ESTLCU; ISSN:2328-8930. (American Chemical Society)
    Quaternary ammonium compds. (QACs or "quats") make up a class of chems. used as disinfectants in cleaning and other consumer products. While disinfection is recommended for maintaining a safe environment during the COVID-19 pandemic, the increased use of QACs is concerning as exposure to these compds. has been assocd. with adverse effects on reproductive and respiratory systems. We have detd. the occurrence of 19 QACs in residential dust collected before and during the COVID-19 pandemic. QACs were detected in >90% of the samples collected during the pandemic at concns. ranging from 1.95 to 531μg/g (n = 40; median of 58.9μg/g). The total QAC concns. in these samples were significantly higher than in samples collected before the COVID-19 pandemic (p < 0.05; n = 21; median of 36.3μg/g). Higher QAC concns. were found in households that generally disinfected more frequently (p < 0.05). Disinfecting products commonly used in these homes were analyzed, and the QAC profiles in dust and in products were similar, suggesting that these products can be a significant source of QACs. Our findings indicate that indoor exposure to QACs is widespread and has increased during the pandemic.
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    Barber, O. W.; Hartmann, E. M. Benzalkonium Chloride: A Systematic Review of Its Environmental Entry through Wastewater Treatment, Potential Impact, and Mitigation Strategies. Crit. Rev. Environ. Sci. Technol. 2022, 52 (15), 2691– 2719,  DOI: 10.1080/10643389.2021.1889284
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    Benzalkonium chloride and A systematic review of its environmental entry through wastewater treatment, potential impact, and mitigation strategies
    Barber, Olivia Williams; Hartmann, Erica M.
    Critical Reviews in Environmental Science and Technology (2022), 52 (15), 2691-2719CODEN: CRETEK; ISSN:1064-3389. (Taylor & Francis, Inc.)
    A review Benzalkonium chloride is a concern because of its widespread use combined with environmental impacts. It has been found throughout the built and natural environment in wastewater influent, effluent, biosolids, surface water and groundwater. Once benzalkonium chloride enters the environment, it can be lethal to aquatic organisms and invoke antimicrobial resistance. Resistance is a particular concern in the food industry, where benzalkonium chloride is used as a disinfectant. Disinfectants are used liberally against biofilms, which require far higher lethal concns. than planktonic cells and create resistance reservoirs. While the use of benzalkonium chloride in hospitals is justified with careful use, placing it in consumer products such as hand wash is only increasing the likelihood of environmental release. The widespread use of benzalkonium chloride and how we treat the portion that enters wastewater treatment must be reevaluated to create a safer, healthier environment.
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    Mohapatra, S.; Yutao, L.; Goh, S. G.; Ng, C.; Luhua, Y.; Tran, N. H.; Gin, K. Y.-H. Quaternary Ammonium Compounds of Emerging Concern: Classification, Occurrence, Fate, Toxicity and Antimicrobial Resistance. J. Hazard. Mater. 2023, 445, 130393,  DOI: 10.1016/j.jhazmat.2022.130393
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    Quaternary ammonium compounds of emerging concern: Classification, occurrence, fate, toxicity and antimicrobial resistance
    Mohapatra, Sanjeeb; Yutao, Lin; Goh, Shin Giek; Ng, Charmaine; Luhua, You; Tran, Ngoc Han; Gin, Karina Yew-Hoong
    Journal of Hazardous Materials (2023), 445 (), 130393CODEN: JHMAD9; ISSN:0304-3894. (Elsevier B.V.)
    A review. Amplified hygiene and precautionary measures are of utmost importance to control the spread of COVID-19 and future infection; however, these changes in practice are projected to trigger a rise in the purchase, utilization and hence, discharge of many disinfectants into the environment. While alc.-based, hydrogen peroxide-based, and chlorine-based compds. have been used widely, quaternary ammonium compds. (QACs) based disinfectants are of significant concern due to their overuse during this pandemic. This review presents the classification of disinfectants and their mechanism of action, focusing on QACs. Most importantly, the occurrence, fate, toxicity and antimicrobial resistance due to QACs are covered in this paper. Here we collated evidence from multiple studies and found rising trends of concern, including an increase in the mass load of QACs at a wastewater treatment plant (WWTP) by 331% compared to before the COVID-19 pandemic, as well as an increases in the concn. of 62% in residential dust, resulting in high concns. of QACs in human blood and breast milk and suggesting that these could be potential sources of persistent QACs in infants. In addn. to increased toxicity to human and aquatic life, increased use of QACs and accelerated use of antibiotics and antimicrobials during the COVID-19 pandemic could multiply the threat to antimicrobial resistance.
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    Yang, J.; Tezel, U.; Li, K.; Pavlostathis, S. G. Prolonged Exposure of Mixed Aerobic Cultures to Low Temperature and Benzalkonium Chloride Affect the Rate and Extent of Nitrification. Bioresour. Technol. 2015, 179, 193– 201,  DOI: 10.1016/j.biortech.2014.12.030
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    Prolonged exposure of mixed aerobic cultures to low temperature and benzalkonium chloride affect the rate and extent of nitrification
    Yang, Jeongwoo; Tezel, Ulas; Li, Kexun; Pavlostathis, Spyros G.
    Bioresource Technology (2015), 179 (), 193-201CODEN: BIRTEB; ISSN:0960-8524. (Elsevier Ltd.)
    The combined effect of benzalkonium chloride (BAC) and prolonged exposure to low temp. on nitrification was investigated. Ammonia oxidn. at 22-24 °C by an enriched nitrifying culture was inhibited at increasing BAC concns. and ceased at 15 mg BAC/L. The non-competitive inhibition coeff. was 1.5 ± 0.9 mg BAC/L. Nitrification tests were conducted without and with BAC at 5 mg/L using an aerobic, mixed heterotrophic/nitrifying culture maintained at a temp. range of 24-10 °C. Maintaining this culture at 10 °C for over one month in the absence of BAC, resulted in slower nitrification kinetics compared to those measured when the culture was first exposed to 10 °C. BAC was degraded by the heterotrophic population, but its degrdn. rate decreased significantly as the culture temp. decreased to 10 °C. These results confirm the neg. impact of quaternary ammonium compds. on the nitrification process, which is further exacerbated by prolonged, low temp. conditions.
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    Östman, M.; Fick, J.; Tysklind, M. Detailed Mass Flows and Removal Efficiencies for Biocides and Antibiotics in Swedish Sewage Treatment Plants. Sci. Total Environ. 2018, 640–641, 327– 336,  DOI: 10.1016/j.scitotenv.2018.05.304
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    Detailed mass flows and removal efficiencies for biocides and antibiotics in Swedish sewage treatment plants
    Ostman Marcus; Fick Jerker; Tysklind Mats
    The Science of the total environment (2018), 640-641 (), 327-336 ISSN:.
    Antimicrobial compounds, such as biocides and antibiotics, are widely used in society with significant quantities of these chemicals ending up in sewage treatment plants (STPs). In this study, mass flows and removal efficiency in different treatment steps at three Swedish STPs were evaluated for eleven different biocides and antibiotics. Mass flows were calculated at eight different locations (incoming wastewater, water after the first sedimentation step, treated effluent, primary sludge, surplus sludge, digested sludge, dewatered digested sludge and reject water). Samples were collected for a total of nine days over three weeks. The STPs were able to remove 53->99% of the antimicrobial compounds and 0-64% were biodegraded on average in the three STPs. Quaternary ammonium compounds were removed from the wastewater >99%, partly through biodegradation, but 38-96% remained in the digested sludge. Chlorhexidine was not biodegraded but was efficiently removed from the wastewater to the sludge. The biological treatment step was the most important step for the degradation of the studied compounds, but also removed several compounds through the surplus sludge. Compounds that were inefficiently removed included benzotriazoles, trimethoprim and fluconazole. The study provides mass flows and removal efficiencies for several compounds that have been seldom studied.
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    Clara, M.; Scharf, S.; Scheffknecht, C.; Gans, O. Occurrence of Selected Surfactants in Untreated and Treated Sewage. Water Res. 2007, 41 (19), 4339– 4348,  DOI: 10.1016/j.watres.2007.06.027
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    Occurrence of selected surfactants in untreated and treated sewage
    Clara, M.; Scharf, S.; Scheffknecht, C.; Gans, O.
    Water Research (2007), 41 (19), 4339-4348CODEN: WATRAG; ISSN:0043-1354. (Elsevier Ltd.)
    Several surfactants were monitored in treated and untreated sewage in 9 municipal wastewater treatment plants (WWTPs) in western Austria. The 9 sampled WWTPs cover a wide variety referring to size and applied treatment technol. The study focused on linear alkylbenzenesulfonate (LAS), quaternary ammonia compds. (QAC), nonylphenol (NP), octylphenol (OP), nonylphenolmono- (NP1EO) and -diethoxylates (NP2EO). Whereas LAS, NP, OP and NP1,2EO were analyzed sep. in the liq. phase and in the solid phase, the QACs were measured in the total sample. Total influent concns. of LAS were 2.4-6.7 mg/L whereas total effluent concns. were 11-50 μg/L. Whichever the type of treatment, a clear removal during treatment was obsd. Solid liq. distribution coeffs. Kd were calcd. for untreated sewage. The calcd. Kd values were 1300-3900 L/Kg. OP was of minor importance with total influent concns. <1 μg/L. NP and NP1,2EO were present in all analyzed influents in concns. 1-35 μg/L. Effluent concns. were notably lower than the measured influent concns. Kd values for NP were 500-6600 L/Kg, for NP1EO 800-2700 L/Kg and for NP2EO 100-1800 L/Kg. From the QACs several alkyl benzyl (BAC), dialkyl (DDAC) and trialkyl (ATAC) ammonium chlorides with varying alkyl chain lengths were analyzed. Highest total concns. in the influents to the WWTPs were obsd. for the BAC-C12 and the ATAC-C16 homologues. Effluent concns. were notably lower compared to influent concns., indicating removal by adsorption and/or biodegrdn. The influence of the removal by adsorption increased with increasing alkyl chain length.
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    Martínez-Carballo, E.; González-Barreiro, C.; Sitka, A.; Kreuzinger, N.; Scharf, S.; Gans, O. Determination of Selected Quaternary Ammonium Compounds by Liquid Chromatography with Mass Spectrometry. Part II. Application to Sediment and Sludge Samples in Austria. Environ. Pollut. 2007, 146 (2), 543– 547,  DOI: 10.1016/j.envpol.2006.07.016
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    Determination of selected quaternary ammonium compounds by liquid chromatography with mass spectrometry. Part II. Application to sediment and sludge samples in Austria
    Martinez-Carballo, Elena; Gonzalez-Barreiro, Carmen; Sitka, Andrea; Kreuzinger, Norbert; Scharf, Sigrid; Gans, Oliver
    Environmental Pollution (Amsterdam, Netherlands) (2007), 146 (2), 543-547CODEN: ENPOEK; ISSN:0269-7491. (Elsevier B.V.)
    Soxhlet extn. and high-performance liq. chromatog. (HPLC) coupled to tandem mass spectrometry detection (MS/MS) was used for the detn. of selected quaternary ammonium compds. (QACs) in solid samples. The method was applied for the detn. of alkyl benzyl, dialkyl, and trialkyl quaternary ammonium compds. in sediment and sludge samples in Austria. The overall method quantification limits range from 0.6 to 3 μg/kg for sediments and from 2 to 5 μg/kg for sewage sludges. Mean recoveries between 67 and 95% were achieved. In general sediments were esp. contaminated by C12 chain benzalkonium chloride (BAC-C12) as well as by the long C-chain dialkyldimethylammonium chloride (DDAC-C18) with a max. concn. of 3.6 mg/kg and 2.1 mg/kg, resp. Maxima of 27 mg/kg for DDAC-C10, 25 mg/kg for BAC-C12 and 23 mg/kg for BAC-C14 were detd. for sludge samples. The sums of the 12 selected target compds. range from 22 mg/kg to 103 mg/kg in the sludge samples. The presence of quaternary ammonium surfactants in sediment and sludge samples is reported for the first time in Austria.
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    Ruan, T.; Song, S.; Wang, T.; Liu, R.; Lin, Y.; Jiang, G. Identification and Composition of Emerging Quaternary Ammonium Compounds in Municipal Sewage Sludge in China. Environ. Sci. Technol. 2014, 48 (8), 4289– 4297,  DOI: 10.1021/es4050314
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    Identification and Composition of Emerging Quaternary Ammonium Compounds in Municipal Sewage Sludge in China
    Ruan, Ting; Song, Shanjun; Wang, Thanh; Liu, Runzeng; Lin, Yongfeng; Jiang, Guibin
    Environmental Science & Technology (2014), 48 (8), 4289-4297CODEN: ESTHAG; ISSN:0013-936X. (American Chemical Society)
    Quaternary ammonium compds. (QACs) have raised considerable attention due to their wide com. applications and recent discovery of unknown persistent analogs in aq. environment. The occurrence and distribution of alkyltrimethylammonium (ATMAC), benzylakyldimethylethylammonium (BAC) and dialkyldimethylammonium (DADMAC) homologs were studied in fifty-two municipal sewage sludge samples. ATMAC C10-18, BAC C8-18 and paired DADMAC C8:8-C18:18 as well as emerging homologs such as ATMAC-20, 22 and mixed DADMAC-16:18 and 14:16 were present. Also, paired DADMAC-20:20 and mixed DADMAC-14:18, 18:20 were identified for the 1st time by nontarget qual. strategies. A triple quadruple mass spectrometer quantification method was also initially verified with the aid of lab. synthesized stds. for the anal. of the mixed DADMACs with no certificated com. stds. currently available. The total concns. of ATMACs, BACs and DADMACs were at 0.38-293, 0.09-191 and 0.64-344 μg/g dry wt., resp., and particularly, mixed DADMACs constituted 39 ± 7% of total DADMAC concns. The concns. and profiles of individual homologs further suggested different QAC applications and fate in China. Significant correlations were also found among the concns. of various QAC homologs as well as wastewater treatment plant (WWTP) characteristics (total org. carbon contents and daily treatment vols.).
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  53. 53
    Wolters, B.; Hauschild, K.; Blau, K.; Mulder, I.; Heyde, B. J.; Sørensen, S. J.; Siemens, J.; Jechalke, S.; Smalla, K.; Nesme, J. Biosolids for Safe Land Application: Does Wastewater Treatment Plant Size Matters When Considering Antibiotics, Pollutants, Microbiome, Mobile Genetic Elements and Associated Resistance Genes?. Environmental Microbiology. 2022, 24, 1573– 1589,  DOI: 10.1111/1462-2920.15938
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    Biosolids for safe land application: does wastewater treatment plant size matters when considering antibiotics, pollutants, microbiome, mobile genetic elements and associated resistance genes?
    Wolters, Birgit; Hauschild, Kristin; Blau, Khald; Mulder, Ines; Heyde, Benjamin Justus; Soerensen, Soeren J.; Siemens, Jan; Jechalke, Sven; Smalla, Kornelia; Nesme, Joseph
    Environmental Microbiology (2022), 24 (3), 1573-1589CODEN: ENMIFM; ISSN:1462-2912. (Wiley-Blackwell)
    Soil fertilization with wastewater treatment plant (WWTP) biosolids is assocd. with the introduction of resistance genes (RGs), mobile genetic elements (MGEs) and potentially selective pollutants (antibiotics, heavy metals, disinfectants) into soil. Not much data are available on the parallel anal. of biosolid pollutant contents, RG/MGE abundances and microbial community compn. In the present study, DNA extd. from biosolids taken at 12 WWTPs (two large-scale, six middle-scale and four small-scale plants) was used to det. the abundance of RGs and MGEs via quant. real-time PCR and the bacterial and archaeal community compn. was assessed by 16S rRNA gene amplicon sequencing. Concns. of heavy metals, antibiotics, the biocides triclosan, triclocarban and quaternary ammonium compds. (QACs) were measured. Strong and significant correlations were revealed between several target genes and concns. of Cu, Zn, triclosan, several antibiotics and QACs. Interestingly, the size of the sewage treatment plant (inhabitant equiv.) was neg. correlated with antibiotic concns., RGs and MGEs abundances and had little influence on the load of metals and QACs or the microbial community compn. Biosolids from WWTPs with anaerobic treatment and hospitals in their catchment area were assocd. with a higher abundance of potential opportunistic pathogens and higher concns. of QACs.
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    Heyde, B. J.; Anders, A.; Siebe, C.; Siemens, J.; Mulder, I. Quaternary Alkylammonium Disinfectant Concentrations in Soils Rise Exponentially after Long-Term Wastewater Irrigation. Environ. Res. Lett. 2021, 16 (6), 064002,  DOI: 10.1088/1748-9326/abf0cf
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    Quaternary alkylammonium disinfectant concentrations in soils rise exponentially after long-term wastewater irrigation
    Heyde, Benjamin Justus; Anders, Anja; Siebe, Christina; Siemens, Jan; Mulder, Ines
    Environmental Research Letters (2021), 16 (6), 064002CODEN: ERLNAL; ISSN:1748-9326. (IOP Publishing Ltd.)
    Quaternary alkylammonium compds. (QAACs) are used as disinfectants and surfactants worldwide, with their usage currently increasing as a result of the COVID-19 pandemic. QAACs are released into the environment with manure, sewage sludge and wastewater. The fate of QAACs in soils is poorly understood, although QAACs are inflicted in the selection of antibiotic-resistant bacteria. We studied the temporal accumulation of QAACs in soils of the Mezquital Valley that have been irrigated with Mexico City wastewater from 0 to 88 years. Concns. of 16 QAACs, including alkyltrimethylammonium compds. (ATMACs), dialkyldimethylammonium compds. (DADMACs) and benzylalkyldimethylethylammonium compds. (BACs), were detd. using HPLC-MS/MS after ultrasonic extn. The most abundant QAAC-homologues in the soils were BACs > ATMACs > DADMACs. The concns. of QAACs increased linearly and slowly during the first years of irrigation (.sum.QAAC: 2-23 μg kg-1), but after 40 years of wastewater irrigation we obsd. an exponential increase in QAAC concns. (up to 155 μg kg-1). QAACs accumulate in soils of the Mezquital Valley during long-term wastewater irrigation. In contrast to pharmaceuticals, no apparent 'steady state' concn. is reached after decades of wastewater irrigation.
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    DeLeo, P. C.; Huynh, C.; Pattanayek, M.; Schmid, K. C.; Pechacek, N. Assessment of Ecological Hazards and Environmental Fate of Disinfectant Quaternary Ammonium Compounds. Ecotoxicol. Environ. Saf. 2020, 206, 111116,  DOI: 10.1016/j.ecoenv.2020.111116
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    Assessment of ecological hazards and environmental fate of disinfectant quaternary ammonium compounds
    DeLeo, Paul C.; Huynh, Carolyn; Pattanayek, Mala; Schmid, Katherine Clark; Pechacek, Nathan
    Ecotoxicology and Environmental Safety (2020), 206 (), 111116CODEN: EESADV; ISSN:0147-6513. (Elsevier B.V.)
    A review. Disinfectant quaternary ammonium compds. (Quats) have diverse uses in a variety of consumer and com. products, particularly cleaning products. With the emergence of the COVID-19 pandemic, they have become a primary tool to inactivate the SARS-CoV-2 virus on surfaces. Disinfectant Quats have very low vapor pressure, and following the use phase of the products in which they are found, disposal is typically "down-the-drain" to wastewater treatment systems. Consequently, the potential for the greatest environmental effect is to the aquatic environment, from treated effluent, and potentially to soils, which might be amended with wastewater biosolids. Among the earliest used and still common disinfectant Quats are the alkyl di-Me benzyl ammonium chloride (ADBAC) compds. and the dialkyl di-Me ammonium chloride (DDAC) compds. They are cationic surfactants often found in consumer and com. surface cleaners. Because of their biocidal properties, disinfectant Quats are heavily regulated for human and environmental safety around the world. Consequently, there is a robust database of information regarding the ecol. hazards and environmental fate of ADBAC and DDAC; however, some of the data presented are from unpublished studies that have been submitted to and reviewed by regulatory agencies (i.e., EPA and European Chems. Agency) to support antimicrobial product registration. We summarize the available environmental fate data and the acute and chronic aquatic ecotoxicity data for freshwater species, including algae, invertebrates, fish, and plants using peer-reviewed literature and unpublished data submitted to and summarized by regulatory agencies. The lower limit of the range of the ecotoxicity data for disinfectant Quats tends to be lower than that for other surface active agents, such as nonionic or anionic surfactants. However, ecotoxicity is mitigated by environmental fate characteristics, the data for which we also summarize, including high biodegradability and a strong tendency to sorb to wastewater biosolids, sediment, and soil. As a result, disinfectant Quats are largely removed during wastewater treatment, and those residues discharged in treated effluent are likely to rapidly bind to suspended solids or sediments, thus mitigating their toxicity.
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    Alygizakis, N.; Galani, A.; Rousis, N. I.; Aalizadeh, R.; Dimopoulos, M.-A.; Thomaidis, N. S. Change in the Chemical Content of Untreated Wastewater of Athens, Greece under COVID-19 Pandemic. Sci. Total Environ. 2021, 799, 149230– 149230,  DOI: 10.1016/j.scitotenv.2021.149230
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    Change in the chemical content of untreated wastewater of Athens, Greece under COVID-19 pandemic
    Alygizakis, Nikiforos; Galani, Aikaterini; Rousis, Nikolaos I.; Aalizadeh, Reza; Dimopoulos, Meletios-Athanasios; Thomaidis, Nikolaos S.
    Science of the Total Environment (2021), 799 (), 149230CODEN: STENDL; ISSN:0048-9697. (Elsevier B.V.)
    COVID-19 pandemic spread rapidly worldwide with unanticipated effects on mental health, lifestyle, stability of economies and societies. Although many research groups have already reported SARS-CoV-2 surveillance in untreated wastewater, only few studies evaluated the implications of the pandemic on the use of chems. by influent wastewater anal. Wide-scope target and suspect screening were used to monitor the effects of the pandemic on the Greek population through wastewater-based epidemiol. Composite 24 h influent wastewater samples were collected from the wastewater treatment plant of Athens during the 1st lockdown and analyzed by liq. chromatog. mass spectrometry. A wide range of compds. was investigated (11,286), including antipsychotic drugs, illicit drugs, tobacco compds., food additives, pesticides, biocides, surfactants, and industrial chems. Mass loads of chem. markers were estd. and compared with the data obtained under non-COVID-19 conditions (campaign 2019). The findings revealed increases in surfactants (+196%), biocides (+152%), cationic quaternary ammonium surfactants (used as surfactants and biocides) (+331%), whereas the most important decreases were estd. for tobacco (-33%) and industrial chems. (-52%). The introduction of social-restriction measures by the government affected all aspects of life.
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    Nason, S.; Lin, E.; Eitzer, B.; Koelmel, J.; Peccia, J. Changes in Sewage Sludge Chemical Signatures During a COVID-19 Community Lockdown, Part 1: Traffic, Drugs, Mental Health, and Disinfectants. Environ. Toxicol. Chem. 2022, 41, 1179,  DOI: 10.1002/etc.5217
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    Changes in Sewage Sludge Chemical Signatures During a COVID-19 Community Lockdown, Part 1: Traffic, Drugs, Mental Health, and Disinfectants
    Nason, Sara L.; Lin, Elizabeth; Eitzer, Brian; Koelmel, Jeremy; Peccia, Jordan
    Environmental Toxicology and Chemistry (2022), 41 (5), 1179-1192CODEN: ETOCDK; ISSN:0730-7268. (Wiley-Blackwell)
    The early months of the COVID-19 pandemic and the assocd. shutdowns disrupted many aspects of daily life and thus caused changes in the use and disposal of many types of chems. While records of sales, prescriptions, drug overdoses, and so forth provide data about specific chem. uses during this time, wastewater and sewage sludge anal. can provide a more comprehensive overview of chem. changes within a region. We analyzed primary sludge from a wastewater-treatment plant in Connecticut, USA, collected March 19 to June 30, 2020. This time period encompassed the 1st wave of the pandemic, the initial statewide stay at home order, and the 1st phase of reopening. We used liq. chromatog.-high-resoln. mass spectrometry and targeted and suspect screening strategies to identify 78 chems. of interest, which included pharmaceuticals, illicit drugs, disinfectants, UV filters, and others. We analyzed trends over time for the identified chems. using linear trend analyses and multivariate comparisons. We found trends related directly to the pandemic (e.g., hydroxychloroquine, a drug publicized for its potential to treat COVID-19, had elevated concns. in the week following the implementation of the US Emergency Use Authorization), as well as evidence for seasonal changes in chem. use (e.g., increases for 3 UV-filter compds.). Though wastewater surveillance during the pandemic has largely focused on measuring severe acute respiratory syndrome-coronavirus-2 RNA concns., chem. anal. can also show trends that are important for revealing the public and environmental health effects of the pandemic.
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    Arnold, W. A. Presentation to the March 8, 2021 Scientific Guidance Panel Meeting. Biomonitoring California Scientific Guidance Panel Meeting , March 2021. https://www.biomonitoring.ca.gov/es/downloads/william-arnold-presentation-march-8-2021-scientific-guidance-panel-meeting (accessed 2022-10-19).
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    Dai, X.; Wang, C.; Lam, J. C. W.; Yamashita, N.; Yamazaki, E.; Horii, Y.; Chen, W.; Li, X. Accumulation of Quaternary Ammonium Compounds as Emerging Contaminants in Sediments Collected from the Pearl River Estuary, China and Tokyo Bay, Japan. Mar. Pollut. Bull. 2018, 136, 276– 281,  DOI: 10.1016/j.marpolbul.2018.09.027
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    Accumulation of quaternary ammonium compounds as emerging contaminants in sediments collected from the Pearl River Estuary, China and Tokyo Bay, Japan
    Dai, Xi; Wang, Cuicui; Lam, James C. W.; Yamashita, Nobuyoshi; Yamazaki, Eriko; Horii, Yuichi; Chen, Weifang; Li, Xiaolin
    Marine Pollution Bulletin (2018), 136 (), 276-281CODEN: MPNBAZ; ISSN:0025-326X. (Elsevier Ltd.)
    In this work, the distribution of quaternary ammonium compds. (QACs) in two dated sediment cores, collected from the Pearl River Estuary (PRE) and Tokyo Bay (TB), were investigated to understand the historical input of QACs and their diagenetic behavior in urban estuarine environments. The vertical variation profiles of QAC concns. showed that benzylalkyldimethyl ammonium compds. (BACs) and dialkyldimethyl ammonium compds. (DADMACs) were widely used during 1970s and 1980s both in China and Japan. The declining environmental concns. of QACs suggested a compositional change of commodities and the effectiveness of emission control strategies. For the individual QAC homologues, BAC homologues decreased significantly over time, while DADMAC compns. remained relatively stable. The differences in concn. and compn. profiles of BACs and DADMACs in the sediment cores provided useful information on the patterns of use of QACs in China and Japan, as well as their diagenetic behaviors in the sediments.
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    Chen, Y.; Geurts, M.; Sjollema, S. B.; Kramer, N. I.; Hermens, J. L.; Droge, S. T. Acute Toxicity of the Cationic Surfactant C12-Benzalkonium in Different Bioassays: How Test Design Affects Bioavailability and Effect Concentrations. Environ. Toxicol. Chem. 2014, 33 (3), 606– 615,  DOI: 10.1002/etc.2465
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    Acute toxicity of the cationic surfactant C12-benzalkonium in different bioassays: How test design affects bioavailability and effect concentrations
    Chen, Yi; Geurts, Marc; Sjollema, Sascha B.; Kramer, Nynke I.; Hermens, Joop L. M.; Droge, Steven T. J.
    Environmental Toxicology and Chemistry (2014), 33 (3), 606-615CODEN: ETOCDK; ISSN:0730-7268. (Wiley-Blackwell)
    Using an ion-exchange-based solid-phase microextn. (SPME) method, the freely dissolved concns. of C12-benzalkonium were measured in different toxicity assays, including (1) immobilization of Daphnia magna in the presence or absence of dissolved humic acid; (2) mortality of Lumbriculus variegatus in the presence or absence of a suspension of Organization for Economic Co-Operation and Development (OECD) sediment; (3) photosystem II inhibition of green algae Chlorella vulgaris; and (4) viability of in vitro rainbow trout gill cell line (RTgill-W1) in the presence or absence of serum proteins. Furthermore, the loss from chem. adsorption to the different test vessels used in these tests was also detd. The C12-benzalkonium sorption isotherms to the different sorbent phases were established as well. The authors' results show that the freely dissolved concn. is a better indicator of the actual exposure concn. than the nominal or total concn. in most test assays. Daphnia was the most sensitive species to C12-benzalkonium. The acute Daphnia and Lumbriculus tests both showed no enhanced toxicity from possible ingestion of sorbed C12-benzalkonium in comparison with water-only exposure, which is in accordance with the equil. partitioning theory. Moreover, the present study demonstrates that commonly used sorbent phases can strongly affect bioavailability and obsd. effect concns. for C12-benzalkonium. Even stronger effects of decreased actual exposure concns. resulting from sorption to test vessels, cells, and sorbent phases can be expected for more hydrophobic cationic surfactants. Environ Toxicol Chem 2014;33:606-615. © 2013 SETAC.
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    van Wijk, D.; Gyimesi-van den Bos, M.; Garttener-Arends, I.; Geurts, M.; Kamstra, J.; Thomas, P. Bioavailability and Detoxification of Cationics: I. Algal Toxicity of Alkyltrimethyl Ammonium Salts in the Presence of Suspended Sediment and Humic Acid. Chemosphere 2009, 75 (3), 303– 309,  DOI: 10.1016/j.chemosphere.2008.12.047
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    Bioavailability and detoxification of cationics: I. Algal toxicity of alkyltrimethyl ammonium salts in the presence of suspended sediment and humic acid
    van Wijk, Dolf; Gyimesi-van den Bos, Mirjam; Garttener-Arends, Irmgard; Geurts, Marc; Kamstra, Jorke; Thomas, Paul
    Chemosphere (2009), 75 (3), 303-309CODEN: CMSHAF; ISSN:0045-6535. (Elsevier Ltd.)
    We investigated the role of sorption in reducing bioavailability and consequently the measured toxicity of monoalkyl tri-Me ammonium salts (MAQ) under environmental conditions. The obsd. toxicity of MAQ in the presence of various types of sorbents was tested on algae. Decreased toxicity was found in the presence of all particulate sorbents tested, i.e. montmorillonite, silica, different sediments and for dissolved humic acid. Silica had a minor effect on the obsd. toxicity, whereas the clay mineral montmorillonite detoxified very effectively. The detoxification by several real-world sediments being mixts. of sand and clay was in-between silica and montmorillonite. Humic acid detoxified most effectively on wt. basis. Polynomial relationships (QSARs') were established for algal toxicity of MAQ in the presence of montmorillonite, silica and humic acid with carbon chain length as descriptor. Freundlich sorption isotherms for MAQ C16 for a clay sediment, montmorillonite, silica and for algae confirmed their relative detoxification in toxicity tests. Humic acid significantly reduced bioavailability and obsd. toxicity of quaternary ammonium salts. Sorption of pos. charged amines to suspended sediment is effectively controlled by its silt/clay fraction, not by the org. fraction. Purchased defined quality montmorillonite can serve as model sorbent in std. tests mimicking the clay fraction of natural suspended matter. It enables to study the effect of bioavailability on toxicity in a standardised way. The QSARs developed for ecotoxicity of MAQ in the presence of suspended matter and humic acid enable quant. incorporation of bioavailability in effect assessment. This increases realism in risk assessments of these fatty amine derivs.
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    Jackson, M.; Eadsforth, C.; Schowanek, D.; Delfosse, T.; Riddle, A.; Budgen, N. Comprehensive Review of Several Surfactants in Marine Environments: Fate and Ecotoxicity. Environ. Toxicol. Chem. 2016, 35 (5), 1077– 1086,  DOI: 10.1002/etc.3297
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    Comprehensive review of several surfactants in marine environments: Fate and ecotoxicity
    Jackson, Mathew; Eadsforth, Charles; Schowanek, Diederik; Delfosse, Thomas; Riddle, Andrew; Budgen, Nigel
    Environmental Toxicology and Chemistry (2016), 35 (5), 1077-1086CODEN: ETOCDK; ISSN:0730-7268. (Wiley-Blackwell)
    A review is given. Surfactants are a com. important group of chems. widely used on a global scale. Despite high removal efficiencies during wastewater treatment, their high consumption vols. mean that a certain fraction will always enter aquatic ecosystems, with marine environments being the ultimate sites of deposition. Consequently, surfactants have been detected within marine waters and sediments. However, aquatic environmental studies have mostly focused on the freshwater environment, and marine studies are considerably underrepresented by comparison. The paper provides a summary of current marine environmental fate (monitoring, biodegrdn., and bioconcn.) and effects data of 5 key surfactant groups: linear alkylbenzene sulfonates, alc. ethoxysulfates, alkyl sulfates, alc. ethoxylates, and ditallow di-Me ammonium chloride. Monitoring data are currently limited, esp. for alc. ethoxysulfates and alkyl sulfates. Biodegrdn. was shown to be considerably slower under marine conditions, whereas ecotoxicity studies suggest that marine species are approx. equally as sensitive to these surfactants as freshwater species. Marine bioconcn. studies are almost nonexistent. Current gaps within the literature are presented, thereby highlighting research areas where addnl. marine studies should focus. Environ Toxicol Chem 2016;9999:1-10. © 2015 SETAC.
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    Jardak, K.; Drogui, P.; Daghrir, R. Surfactants in Aquatic and Terrestrial Environment: Occurrence, Behavior, and Treatment Processes. Environ. Sci. Pollut. Res. Int. 2016, 23 (4), 3195– 3216,  DOI: 10.1007/s11356-015-5803-x
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    Surfactants in aquatic and terrestrial environment: occurrence, behavior, and treatment processes
    Jardak K; Drogui P; Daghrir R
    Environmental science and pollution research international (2016), 23 (4), 3195-216 ISSN:.
    Surfactants belong to a group of chemicals that are well known for their cleaning properties. Their excessive use as ingredients in care products (e.g., shampoos, body wash) and in household cleaning products (e.g., dishwashing detergents, laundry detergents, hard-surface cleaners) has led to the discharge of highly contaminated wastewaters in aquatic and terrestrial environment. Once reached in the different environmental compartments (rivers, lakes, soils, and sediments), surfactants can undergo aerobic or anaerobic degradation. The most studied surfactants so far are linear alkylbenzene sulfonate (LAS), quaternary ammonium compounds (QACs), alkylphenol ethoxylate (APEOs), and alcohol ethoxylate (AEOs). Concentrations of surfactants in wastewaters can range between few micrograms to hundreds of milligrams in some cases, while it reaches several grams in sludge used for soil amendments in agricultural areas. Above the legislation standards, surfactants can be toxic to aquatic and terrestrial organisms which make treatment processes necessary before their discharge into the environment. Given this fact, biological and chemical processes should be considered for better surfactants removal. In this review, we investigate several issues with regard to: (1) the toxicity of surfactants in the environment, (2) their behavior in different ecological systems, (3) and the different treatment processes used in wastewater treatment plants in order to reduce the effects of surfactants on living organisms.
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    European Chemicals Agency. Assessment Report Alkyl (C12–16) Dimethylbenzyl Ammonium Chloride. Directive 98/8/EC Concerning the Placing Biocidal Products on the Market: Inclusion of Active Substances in Annex I to Directive 98/8/EC , June 2015. https://echa.europa.eu/documents/10162/b9030b10-c8af-211b-456a-4f4b11d509b7 (accessed 2022-10-20).
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    Kreuzinger, N.; Fuerhacker, M.; Scharf, S.; Uhl, M.; Gans, O.; Grillitsch, B. Methodological Approach towards the Environmental Significance of Uncharacterized Substances ─ Quaternary Ammonium Compounds as an Example. Desalination 2007, 215 (1), 209– 222,  DOI: 10.1016/j.desal.2006.10.036
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    Methodological approach towards the environmental significance of uncharacterized substances - quaternary ammonium compounds as an example
    Kreuzinger, Norbert; Fuerhacker, Maria; Scharf, Sigrid; Uhl, Maria; Gans, Oliver; Grillitsch, Britta
    Desalination (2007), 215 (1-3), 209-222CODEN: DSLNAH; ISSN:0011-9164. (Elsevier B.V.)
    The European Commission has presented a list of priority substances in addn. to the Water Framework Directive (WFD) adopted in Dec. 2000. The list of priority substances is a matter of continuous review hence other relevant substances identified as hazardous can be implemented for regulation. In that regard a group of potential hazardous substances, quaternary ammonium compds. (QAC) is selected for further study and assessment, as QAC are widely used as disinfectants, biocides, and detergents among a variety of other applications. This paper provides information on a general interdisciplinary approach for assessing the potential significance of chem. substances hitherto not described in a coherent way considering QACs as example. Benzalkonium chlorides (BAC) and dialkyldimethylammonium chlorides (DDAC) were selected as key compds. because of their product and application profiles, as well as their ecotoxicol. properties. For basic environmental risk evaluation, QAC usage pattern, emissions from single source polluters, the fate in wastewater treatment plants, concns. in surface water and sediments, as well as ecotoxicol. effective concns. were analyzed in this study. Based on substrate characteristics and use pattern relevant single source polluters were identified and emission concns. as well as loads discharged into the sewerage were detd. Effluents from hospitals and laundries but also from wellness resorts showed high effluent concns. compared to municipal wastewater. To describe the fate of QACs during wastewater treatment, adsorption and degrdn. behavior were detd. The effect of QACs on biol. processes, esp. nitrification was assessed. Partition coeff. values (log kOC) for QACs were detd. between 4.35 for DDAC-C10 and 5.69 for DDAC-C18 indicating the high adsorption potential of those substances to the activated sludge in the wastewater treatment plants. Results for BAC-C12-18 were in the same range. Concns. for nitrification inhibition in wastewater treatment plants lay above concns. found in municipal wastewater but in the range of concns. discharged by single source polluters.
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    Ding, W.-H.; Tsai, P.-C. Determination of Alkyltrimethylammonium Chlorides in River Water by Gas Chromatography/Ion Trap Mass Spectrometry with Electron Impact and Chemical Ionization. Anal. Chem. 2003, 75 (8), 1792– 1797,  DOI: 10.1021/ac020536y
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    Determination of Alkyltrimethylammonium Chlorides in River Water by Gas Chromatography/Ion Trap Mass Spectrometry with Electron Impact and Chemical Ionization
    Ding, Wang-Hsien; Tsai, Pei-Chuan
    Analytical Chemistry (2003), 75 (8), 1792-1797CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
    This work describes a modified method to analyze alkyltrimethylammonium chlorides (ATMACs) in river water samples. The proposed method involves adding solid KI to H2O sample (pH adjusted to 10.0) as a counterion to enhance the extn. of ATMAC residues by CH2Cl2 liq.-liq. extn. The iodide-ATMA+ ion pairs were demethylated to their corresponding nonionic alkyldimethylamines (ADMAs) by thermal decompn. in a GC injection port. The corresponding ADMAs were then identified and quantitated by gas chromatog./ion trap mass spectrometry (GC/MS) in electron impact and low-pressure pos. ion chem. ionization (PICI) modes. A relatively high abundance of ADMAs was detected at a demethylation temp. >300° in the injection port. The proposed method is precise and sensitive in ATMACs anal. and allows quantitation at ≤0.01 μg/L in 500 mL of the H2O samples. The enhanced selectivity of quasi-mol. ion chromatograms of C12-C18-ADMA, obtained using MeOH PICI-MS, enables ATMAC residues to be identified at trace levels in environmental samples. Recovery of the ATMACs in various spiked H2O samples ranged from 70 to 94% while relative std. deviation ranged from 3 to 12%. The concns. of total measured ATMAC residues in river water samples ranged from nondetectable to 1.24 μg/L.
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    Cutaneous necrosis due to cetrimide application
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    Cetrimide burn in an infant
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    Chang, A.; Schnall, A. H.; Law, R.; Bronstein, A. C.; Marraffa, J. M.; Spiller, H. A.; Hays, H. L.; Funk, A. R.; Mercurio-Zappala, M.; Calello, D. P.; Aleguas, A.; Borys, D. J.; Boehmer, T.; Svendsen, E. Cleaning and Disinfectant Chemical Exposures and Temporal Associations with COVID-19 - National Poison Data System, United States, January 1, 2020-March 31, 2020. MMWR Morb. Mortal. Wkly. Rep. 2020, 69 (16), 496– 498,  DOI: 10.15585/mmwr.mm6916e1
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    Cleaning and disinfectant chemical exposures and temporal associations with COVID-19 - national poison data system, United States, January 1, 2020-March 31, 2020
    Chang, Arthur; Schnall, Amy H.; Law, Royal; Bronstein, Alvin C.; Marraffa, Jeanna M.; Spiller, Henry A.; Hays, Hannah L.; Funk, Alexandra R.; Mercurio-Zappala, Maria; Calello, Diane P.; Aleguas, Alfred; Borys, Douglas J.; Boehmer, Tegan; Svendsen, Erik
    Morbidity and Mortality Weekly Report (2020), 69 (16), 496-498CODEN: MMWRC7; ISSN:1545-861X. (Centers for Disease Control and Prevention)
    To assess whether there might be a possible assocn. between COVID-19 cleaning recommendations from public health agencies and the media and the no. of chem. exposures reported to the National Poison Data System (NPDS), CDC and the American Assocn. of Poison Control Centers surveillance team compared the no. of exposures reported for the period Jan.-March 2020 with the no. of reports during the same 3-mo period in 2018 and 2019. Fifty-five poison centers in the United States provide free, 24-h professional advice and medical management information regarding exposures to poisons, chems., drugs, and medications. Call data from poison centers are uploaded in near real-time to NPDS. During Jan.-March 2020, poison centers received 45,550 exposure calls related to cleaners (28,158) and disinfectants (17,392), representing overall increases of 20.4% and 16.4% from Jan.-March 2019 (37,822) and Jan.-March 2018 (39,122), resp. Although NPDS data do not provide information showing a definite link between exposures and COVID-19 cleaning efforts, there appears to be a clear temporal assocn. with increased use of these products. The daily no. of calls to poison centers increased sharply at the beginning of March 2020 for exposures to both cleaners and disinfectants.
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    Li, L.; Hughes, L.; Arnot, J. A. Addressing Uncertainty in Mouthing-Mediated Ingestion of Chemicals on Indoor Surfaces, Objects, and Dust. Environ. Int. 2021, 146, 106266,  DOI: 10.1016/j.envint.2020.106266
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    Addressing uncertainty in mouthing-mediated ingestion of chemicals on indoor surfaces, objects, and dust
    Li, Li; Hughes, Lauren; Arnot, Jon A.
    Environment International (2021), 146 (), 106266CODEN: ENVIDV; ISSN:0160-4120. (Elsevier Ltd.)
    In indoor environments, humans ingest chems. present as surface residues and bound to settled particles (dust), through mouthing hands (hand-to-mouth transfer) and objects (object-to-mouth transfer). Here, we introduce a novel modeling approach in support of systematic investigation into the mouthing-mediated ingestion of chems. present in indoor environments. This model explicitly considers the indoor dynamics of dust and chems., building on mechanistic links with physicochem. properties of chems., features of the indoor environment, and human activity patterns. The evaluation of this model demonstrates that it satisfactorily reproduces chem. hand loadings and exposure data reported in the literature. We then use the evaluated model to investigate the response of mouthing-mediated ingestion to chem. partitioning between the gas phase and solid phases, expressed as the octanol-air partition coeff. (KOA). Assuming a unit emission rate to the indoor environment, we find that low-volatility chems. (with a KOA greater than 109) are more efficiently enriched in hand skin, resulting in higher mouthing-mediated ingestion than other compds. For individuals living in a room with a typical level of dustiness, more than half of the chem. mass found in their hands comes from dust transfer, whereas more than half of the chem. mass ingested is the fraction present as residues on hands. We also use the new model to explore how the mouthing-mediated ingestion of chems. is dependent on factors describing the indoor environment and human behavior. The model predicts that less frequent cleaning leads to higher accumulation of dust on indoor surfaces, thereby transferring more chems. to hands and mouth in each contact. Introducing more dust into the room, but maintaining the same cleanup frequency, increases the dustiness of indoor surfaces, which promotes the transfer of relatively volatile chems. (with a KOA lower than 109) to hands and mouth but decreases the transfer of chems. with low volatility. More frequent hand contact with indoor surfaces increases both the hand loading and mouthing-mediated ingestion of chems., but the increases are more remarkable for adults than children because the higher surface contact frequency of children "sats." hand loadings. An increase in handwashing frequency lowers the hand loading and mouthing-mediated ingestion of chems. and this mitigating process is more prominent for relatively volatile chems. The new evaluated modeling approach can facilitate the prediction of mouthing-mediated ingestion for various age groups and the model predictions can be used to aid future fate and (bio)monitoring studies focusing on indoor contamination.
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    Investigations on adsorption of benzalkonium chloride U.S.P. by skin, gloves, and sponges
    KUNDSIN R B; WALTER C W
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    There is no expanded citation for this reference.
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    Dewey, H. M.; Jones, J. M.; Keating, M. R.; Budhathoki-Uprety, J. Increased Use of Disinfectants During the COVID-19 Pandemic and Its Potential Impacts on Health and Safety. ACS Chem. Health Saf. 2022, 29, 27,  DOI: 10.1021/acs.chas.1c00026
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    Increased Use of Disinfectants During the COVID-19 Pandemic and Its Potential Impacts on Health and Safety
    Dewey, Hannah M.; Jones, Jaron M.; Keating, Mike R.; Budhathoki-Uprety, Januka
    ACS Chemical Health & Safety (2022), 29 (1), 27-38CODEN: ACHSC5; ISSN:1878-0504. (American Chemical Society)
    A review. The COVID-19 pandemic has called for the increased use of disinfectants worldwide in public facilities, transportation, hospitals, nursing homes, wastewater treatment facilities, and even common households to mitigate virus burden. Active ingredients in common disinfectants recommended for use against COVID-19 viruses include chems. such as quaternary ammonium compds. (QACs), hydrogen peroxide, bleach (sodium hypochlorite), and alcs. These disinfecting chems. differ in their structures, properties, modes of action, environmental behaviors, and effects on human health upon exposure. Humans can be exposed to disinfecting chems. mainly through dermal absorption, inhalation, and ingestion. The total exposure and relative contribution of each exposure route vary considerably among the disinfectants. QACs have been linked to occupational illnesses such as asthma and an increased risk of chronic obstructive pulmonary disease (COPD), whereas excess use of bleach, hydrogen peroxide, or alc.-based disinfectants can cause respiratory damage and has been linked to an increased risk of developing and controlling asthma. Recent studies showed that the presence of QACs in human blood has been assocd. with changes in health biomarkers such as an increase in inflammatory cytokines, decreased mitochondrial function, and disruption of cholesterol homeostasis in a dose-dependent manner. Therefore, repeated human exposure to disinfectants during the pandemic has raised questions on exposure-related long-term health risks and occupational safety. Furthermore, in lieu of a lack of adequate knowledge and public awareness, these chems. have been frequently used on porous surfaces, including fabrics/textiles and consumer plastics and even for disinfecting cloth facemasks, on which disinfectant chem. residues may persist for longer duration, causing potential degrdn. of plastic materials, releasing additives, and shedding microplastics. In addn., the increased use of these disinfectant chems. and the subsequent discharge into wastewater may cause adverse impacts on aquatic ecosystems, accumulation on vegetables, and contamination of the food chain via wastewater irrigation and sludge application. This article provides a well-rounded understanding of the most common disinfectants and reviews modes of action of those disinfectants, their interactions with aquatic and terrestrial environments, the exposure to humans, and potential impacts to human health and safety.
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    LeBouf, R. F.; Virji, M. A.; Ranpara, A.; Stefaniak, A. B. Air and Surface Sampling Method for Assessing Exposures to Quaternary Ammonium Compounds Using Liquid Chromatography Tandem Mass Spectrometry. Ann. Work Exposures Health 2017, 61 (6), 724– 736,  DOI: 10.1093/annweh/wxx037
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    Air and surface sampling method for assessing exposures to quaternary ammonium compounds using liquid chromatography tandem mass spectrometry
    LeBouf, Ryan F.; Virji, Mohammed Abbas; Ranpara, Anand; Stefaniak, Aleksandr B.
    Annals of Work Exposures and Health (2017), 61 (6), 724-736CODEN: AWEHAR; ISSN:2398-7316. (Oxford University Press)
    This method was designed for sampling select quaternary ammonium (quat) compds. in air or on surfaces followed by anal. using ultraperformance liq. chromatog. tandem mass spectrometry. Target quats were benzethonium chloride, didecyldimethylammonium bromide, benzyldimethyldodecylammonium chloride, benzyldimethyltetradecylammonium chloride, and benzyldimethylhexadecylammonium chloride. For air sampling, polytetrafluoroethylene (PTFE) filters are recommended for 15-min to 24-h sampling. For surface sampling, Pro-wipe 880 (PW) media was chosen. Samples were extd. in 60:40 acetonitrile:0.1% formic acid for 1 h on an orbital shaker. Method detection limits range from 0.3 to 2 ng/mL depending on media and analyte. Matrix effects of media are minimized through the use of multiple reaction monitoring vs. selected ion recording. Upper confidence limits on accuracy meet the National Institute for Occupational Safety and Health 25% criterion for PTFE and PW media for all analytes. Using PTFE and PW analyzed with multiple reaction monitoring, the method quantifies levels among the different quats compds. with high precision (<10% relative std. deviation) and low bias (<11%). The method is sensitive enough with very low method detection limits to capture quats on air sampling filters with only a 15-min sample duration with a max. assessed storage time of 103 days before sample extn. This method will support future exposure assessment and quant. epidemiol. studies to explore exposure-response relationships and establish levels of quats exposures assocd. with adverse health effects.
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    Zheng, G.; Webster, T. F.; Salamova, A. Quaternary Ammonium Compounds: Bioaccumulation Potentials in Humans and Levels in Blood before and during the Covid-19 Pandemic. Environ. Sci. Technol. 2021, 55 (21), 14689– 14698,  DOI: 10.1021/acs.est.1c01654
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    Quaternary Ammonium Compounds: Bioaccumulation Potentials in Humans and Levels in Blood before and during the Covid-19 Pandemic
    Zheng, Guomao; Webster, Thomas F.; Salamova, Amina
    Environmental Science & Technology (2021), 55 (21), 14689-14698CODEN: ESTHAG; ISSN:1520-5851. (American Chemical Society)
    Quaternary ammonium compds. (QACs) are commonly used in a variety of consumer, pharmaceutical, and medical products. In this study, bioaccumulation potentials of 18 QACs with alkyl chain lengths of C8-C18 were detd. in the in vitro-in vivo extrapolation (IVIVE) model using the results of human hepatic metab. and serum protein binding expts. The slowest in vivo clearance rates were estd. for C12-QACs, suggesting that these compds. may preferentially build up in blood. The bioaccumulation of QACs was further confirmed by the anal. of human blood (sera) samples (n = 222). Fifteen out of the 18 targeted QACs were detected in blood with the ΣQAC concns. reaching up to 68.6 ng/mL. The blood samples were collected during two distinct time periods: before the outbreak of the COVID-19 pandemic (2019; n = 111) and during the pandemic (2020, n = 111). The ΣQAC concns. were significantly higher in samples collected during the pandemic (median 6.04 ng/mL) than in those collected before (median 3.41 ng/mL). This is the first comprehensive study on the bioaccumulation and biomonitoring of the three major QAC groups and our results provide valuable information for future epidemiol., toxicol., and risk assessment studies targeting these chems.
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    Bundesinstitut für Risikobewertung. Health Assessment of Benzalkonium Chloride Residues in Food . BfR Opinion No. 032, 2012 (accessed 2022-10-19).
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    Arp, H. P. Preliminary Assessment of Substances Registered under REACH That Could Fulfil the Proposed PMT/vPvM Criteria, Technical Note 20160426-TN-01; Hale, S., Ed.; Norwegian Geotechnical Institute (NGI), 2018 (accessed 2022-07-17).
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    Saito, R.; Virji, M. A.; Henneberger, P. K.; Humann, M. J.; LeBouf, R. F.; Stanton, M. L.; Liang, X.; Stefaniak, A. B. Characterization of Cleaning and Disinfecting Tasks and Product Use among Hospital Occupations. Am. J. Ind. Med. 2015, 58 (1), 101– 111,  DOI: 10.1002/ajim.22393
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    Characterization of cleaning and disinfecting tasks and product use among hospital occupations
    Saito Rena; Virji M Abbas; Henneberger Paul K; Humann Michael J; LeBouf Ryan F; Stanton Marcia L; Liang Xiaoming; Stefaniak Aleksandr B
    American journal of industrial medicine (2015), 58 (1), 101-11 ISSN:.
    BACKGROUND: Healthcare workers have an elevated prevalence of asthma and related symptoms associated with the use of cleaning/disinfecting products. The objective of this study was to identify and characterize cleaning/disinfecting tasks and products used among hospital occupations. METHODS: Workers from 14 occupations at five hospitals were monitored for 216 shifts, and work tasks and products used were recorded at five-minute intervals. The major chemical constituents of each product were identified from safety data sheets. RESULTS: Cleaning and disinfecting tasks were performed with a high frequency at least once per shift in many occupations. Medical equipment preparers, housekeepers, floor strippers/waxers, and endoscopy technicians spent on average 108-177 min/shift performing cleaning/disinfecting tasks. Many occupations used products containing amines and quaternary ammonium compounds for >100 min/shift. CONCLUSIONS: This analysis demonstrates that many occupations besides housekeeping incur exposures to cleaning/disinfecting products, albeit for different durations and using products containing different chemicals.
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    Svanes, D.; Bertelsen, R. J.; Lygre, S. H. L.; Carsin, A. E.; Antó, J. M.; Forsberg, B.; García-García, J. M.; Gullón, J. A.; Heinrich, J.; Holm, M.; Kogevinas, M.; Urrutia, I.; Leynaert, B.; Moratalla, J. M.; Le Moual, N.; Lytras, T.; Norbäck, D.; Nowak, D.; Olivieri, M.; Pin, I.; Probst-Hensch, N.; Schlünssen, V.; Sigsgaard, T.; Skorge, T. D.; Villani, S.; Jarvis, D.; Zock, J. P.; Svanes, C. Cleaning at Home and at Work in Relation to Lung Function Decline and Airway Obstruction. Am. J. Respir. Crit. Care Med. 2018, 197 (9), 1157– 1163,  DOI: 10.1164/rccm.201706-1311OC
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    Cleaning at Home and at Work in Relation to Lung Function Decline and Airway Obstruction
    Svanes Oistein; Bertelsen Randi J; Svanes Oistein; Lygre Stein H L; Skorge Trude D; Svanes Cecilie; Carsin Anne E; Anto Josep M; Kogevinas Manolis; Lytras Theodore; Zock Jan P; Carsin Anne E; Carsin Anne E; Forsberg Bertil; Garcia-Garcia Jose M; Gullon Jose A; Heinrich Joachim; Nowak Dennis; Holm Mathias; Urrutia Isabel; Leynaert Benedicte; Leynaert Benedicte; Moratalla Jesus M; Le Moual Nicole; Le Moual Nicole; Lytras Theodore; Norback Dan; Olivieri Mario; Pin Isabelle; Probst-Hensch Nicole; Probst-Hensch Nicole; Schlunssen Vivi; Sigsgaard Torben; Schlunssen Vivi; Villani Simona; Jarvis Debbie; Svanes Cecilie
    American journal of respiratory and critical care medicine (2018), 197 (9), 1157-1163 ISSN:.
    RATIONALE: Cleaning tasks may imply exposure to chemical agents with potential harmful effects to the respiratory system, and increased risk of asthma and respiratory symptoms among professional cleaners and in persons cleaning at home has been reported. Long-term consequences of cleaning agents on respiratory health are, however, not well described. OBJECTIVES: This study aimed to investigate long-term effects of occupational cleaning and cleaning at home on lung function decline and airway obstruction. METHODS: The European Community Respiratory Health Survey (ECRHS) investigated a multicenter population-based cohort at three time points over 20 years. A total of 6,235 participants with at least one lung function measurement from 22 study centers, who in ECRHS II responded to questionnaire modules concerning cleaning activities between ECRHS I and ECRHS II, were included. The data were analyzed with mixed linear models adjusting for potential confounders. MEASUREMENTS AND MAIN RESULTS: As compared with women not engaged in cleaning (ΔFEV1 = -18.5 ml/yr), FEV1 declined more rapidly in women responsible for cleaning at home (-22.1; P = 0.01) and occupational cleaners (-22.4; P = 0.03). The same was found for decline in FVC (ΔFVC = -8.8 ml/yr; -13.1, P = 0.02; and -15.9, P = 0.002; respectively). Both cleaning sprays and other cleaning agents were associated with accelerated FEV1 decline (-22.0, P = 0.04; and -22.9, P = 0.004; respectively). Cleaning was not significantly associated with lung function decline in men or with FEV1/FVC decline or airway obstruction. CONCLUSIONS: Women cleaning at home or working as occupational cleaners had accelerated decline in lung function, suggesting that exposures related to cleaning activities may constitute a risk to long-term respiratory health.
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    Marbac, M.; Sedki, M.; Boutron-Ruault, M.-C.; Dumas, O. Patterns of Cleaning Product Exposures Using a Novel Clustering Approach for Data with Correlated Variables. Ann. Epidemiol. 2018, 28 (8), 563– 569, e6  DOI: 10.1016/j.annepidem.2018.05.004
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    Patterns of cleaning product exposures using a novel clustering approach for data with correlated variables
    Marbac Matthieu; Sedki Mohammed; Boutron-Ruault Marie-Christine; Dumas Orianne
    Annals of epidemiology (2018), 28 (8), 563-569.e6 ISSN:.
    PURPOSE: Clustering methods may be useful in epidemiology to better characterize exposures and account for their multidimensional aspects. In this context, application of clustering models allowing for highly dependent variables is of particular interest. We aimed to characterize patterns of domestic exposure to cleaning products using a novel clustering model allowing for highly dependent variables. METHODS: To identify domestic cleaning patterns in a large population of French women, we used a mixture model of dependency blocks. This novel approach specifically models within-class dependencies, and is an alternative to the latent class model, which assumes conditional independence. Analyses were conducted in 19,398 participants of the E3N study (women aged 61-88 years) who completed a questionnaire regarding household cleaning habits. RESULTS: Seven classes were identified, which differed with the frequency of cleaning tasks (e.g., dusting/sweeping/hoovering) and use of specific products (e.g., bleach, sprays). The model also grouped the variables into conditionally independent blocks, providing a summary of the main dependencies among the variables. CONCLUSIONS: The mixture model of dependency blocks, a useful alternative to the latent class model, may have broader application in epidemiology, in particular, in the context of exposome research and growing need for data-reduction methods.
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  86. 86
    Dumas, O.; Varraso, R.; Boggs, K. M.; Quinot, C.; Zock, J.-P.; Henneberger, P. K.; Speizer, F. E.; Le Moual, N.; Camargo, C. A., Jr Association of Occupational Exposure to Disinfectants With Incidence of Chronic Obstructive Pulmonary Disease Among US Female Nurses. JAMA Network Open 2019, 2 (10), e1913563  DOI: 10.1001/jamanetworkopen.2019.13563
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    Holm, S. M.; Leonard, V.; Durrani, T.; Miller, M. D. Do We Know How Best to Disinfect Child Care Sites in the United States? A Review of Available Disinfectant Efficacy Data and Health Risks of the Major Disinfectant Classes. Am. J. Infect. Control 2019, 47 (1), 82– 91,  DOI: 10.1016/j.ajic.2018.06.013
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    87
    Do we know how best to disinfect child care sites in the United States? A review of available disinfectant efficacy data and health risks of the major disinfectant classes
    Holm Stephanie M; Leonard Victoria; Durrani Timur; Miller Mark D
    American journal of infection control (2019), 47 (1), 82-91 ISSN:.
    BACKGROUND: Children in child care settings have a high infectious burden. They are frequently exposed to sanitizing and disinfecting agents, whose toxicities have not been studied in these settings. Current guidance on the preferred disinfection agents for child care is vague. METHODS: This article combines 2 different sources of information: the Environmental Protection Agency registration data on the efficacy of hospital-grade disinfectants and a review of the research on the toxicities of the most common of these disinfectants to summarize information that could be used for more evidence-based early care and education disinfection regulations and guidelines. RESULTS: Coverage of these organisms varied both between disinfectant classes (defined by active ingredient), as well as within classes. The 3 most common active ingredients in the database-quaternary ammonias, bleaches, and hydrogen peroxides-had 251, 63, and 31 products, respectively. Quaternary ammonias and bleaches are both known asthmagens, with the potential for toxic gas release when mixed. Quaternary ammonias may also cause reproductive toxicity. Disinfectant-grade peroxides have relatively low inhalational toxicity. CONCLUSIONS: A clear rationale is needed to establish policies for determining preferable disinfection products for use in child care settings, based on efficacy against relevant pathogens, toxicity, ease of use, and cost. When other factors are equal, the use of peroxide-based disinfectant products is recommended to minimize inhalational toxicity.
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    Hilbert, T. J.; Brancato, C.; Carter, K.; Westneat, S.; Bush, H. M.; Haynes, E. N. Disinfectant Use by K-12 School Staff to Combat SARS-CoV-2. Am. J. Infect. Control 2021, 49 (11), 1432– 1434,  DOI: 10.1016/j.ajic.2021.08.023
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    88
    Disinfectant use by K-12 school staff to combat SARS-CoV-2
    Hilbert, Timothy J.; Brancato, Candace; Carter, Kelsey; Westneat, Susan; Bush, Heather M.; Haynes, Erin N.
    American Journal of Infection Control (2021), 49 (11), 1432-1434CODEN: AJICDC; ISSN:0196-6553. (Elsevier Inc.)
    K-12 school staff from Indiana, Kentucky and Ohio were asked about their use of disinfectants to mitigate the spread of COVID-19 in schools. Survey participants (n = 1,555) reported frequent use of disinfectants, often using unknown products, and were provided little to no training on safe and effective use. Participant concerns included student involvement in disinfection, inadequate ventilation, surface contact time, and potential health effects.
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  89. 89
    Castillo, A. Prison Company Violated Federal Pesticide Law in Misuse of Disinfectant inside Immigration Detention Center. Los Angeles Times , March 21, 2021. https://www.latimes.com/california/story/2021-03-22/prison-company-violated-federal-pesticide-law-in-misuse-of-disinfectant-inside-immigration-detention-center (accessed 2022-10-19).
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    Phelan, M. Immigrants in U.S. Detention Exposed to Hazardous Disinfectants Every Day. Scientific American , September 17, 2021. https://www.scientificamerican.com/article/immigrants-in-u-s-detention-exposed-to-hazardous-disinfectants-every-day/ (accessed 2023-03-19).
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    Agenda. Biomonitoring California Scientific Guidance Panel Meeting, Biomonitoring California Scientific Guidance Panel, March 8, 2021. https://biomonitoring.ca.gov/events/biomonitoring-california-scientific-guidance-panel-meeting-march-2021#:~:text=March%208%2C%202021%3A%2010%3A,join%20by%209%3A55%20am.&text=All%20times%20shown%20below%20are%20approximate%20and%20subject%20to%20changehttps://biomonitoring.ca.gov/events/biomonitoring-california-scientific-guidance-panel-meeting-march-2021#:~:text=March%208%2C%202021%3A%2010%3A,join%20by%209%3A55%20am.&text=All%20times%20shown%20below%20are%20approximate%20and%20subject%20to%20change (accessed 2023-03-19).
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    Hrubec, T. C.; Seguin, R. P.; Xu, L.; Cortopassi, G. A.; Datta, S.; Hanlon, A. L.; Lozano, A. J.; McDonald, V. A.; Healy, C. A.; Anderson, T. C.; Musse, N. A.; Williams, R. T. Altered Toxicological Endpoints in Humans from Common Quaternary Ammonium Compound Disinfectant Exposure. Toxicol. Rep. 2021, 8, 646– 656,  DOI: 10.1016/j.toxrep.2021.03.006
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    92
    Altered toxicological endpoints in humans from common quaternary ammonium compound disinfectant exposure
    Hrubec, Terry C.; Seguin, Ryan P.; Xu, Libin; Cortopassi, Gino A.; Datta, Sandipan; Hanlon, Alexandra L.; Lozano, Alicia J.; McDonald, Valerie A.; Healy, Claire A.; Anderson, Tyler C.; Musse, Najaha A.; Williams, Richard T.
    Toxicology Reports (2021), 8 (), 646-656CODEN: TROEF9; ISSN:2214-7500. (Elsevier B.V.)
    Humans are frequently exposed to Quaternary Ammonium Compds. (QACs). QACs are ubiquitously used in medical settings, restaurants, and homes as cleaners and disinfectants. Despite their prevalence, nothing is known about the health effects assocd. with chronic low-level exposure. Chronic QAC toxicity, only recently identified in mice, resulted in developmental, reproductive, and immune dysfunction. Cell based studies indicate increased inflammation, decreased mitochondrial function, and disruption of cholesterol synthesis. If these findings translate to human toxicity, multiple physiol. processes could be affected. This study tested whether QAC concns. could be detected in the blood of 43 human volunteers, and whether QAC concns. influenced markers of inflammation, mitochondrial function, and cholesterol synthesis. QAC concns. were detected in 80% of study participants. Blood QACs were assocd. with increase in inflammatory cytokines, decreased mitochondrial function, and disruption of cholesterol homeostasis in a dose dependent manner. This is the first study to measure QACs in human blood, and also the first to demonstrate statistically significant relationships between blood QAC and meaningful health related biomarkers. Addnl., the results are timely in light of the increased QAC disinfectant exposure occurring due to the SARS-CoV-2 pandemic. This study found that 80% of study participants contained QACs in their blood; and that markers of inflammation, mitochondrial function, and sterol homeostasis varied with blood QAC concn.
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    Xu, L. Reviewing QACs for Biomonitoring: Metabolism, Analytical Considerations, and Effects on Cholesterol Homeostasis , 2021.
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    Seguin, R. P.; Herron, J. M.; Lopez, V. A.; Dempsey, J. L.; Xu, L. Metabolism of Benzalkonium Chlorides by Human Hepatic Cytochromes P450. Chem. Res. Toxicol. 2019, 32 (12), 2466– 2478,  DOI: 10.1021/acs.chemrestox.9b00293
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    94
    Metabolism of Benzalkonium Chlorides by Human Hepatic Cytochromes P450
    Seguin, Ryan P.; Herron, Josi M.; Lopez, Vanessa A.; Dempsey, Joseph L.; Xu, Libin
    Chemical Research in Toxicology (2019), 32 (12), 2466-2478CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)
    Benzalkonium chlorides (BACs) are widely used as disinfectants in cleaning products, medical products, and the food processing industry. Despite a wide range of reported toxicities, limited studies have been conducted on the metab. of these compds. in animal models and none in human-derived cells or tissues. In this work, we report on the metab. of BACs in human liver microsomes (HLM) and by recombinant human hepatic cytochrome P 450 (CYP) enzymes. BAC metab. in HLM was NADPH-dependent and displayed apparent half-lives that increased with BAC alkyl chain length (C10 < C12 < C14 < C16), suggesting enhanced metabolic stability of the more lipophilic, longer chain BACs. Metabolites of d7-benzyl labeled BAC substrates retained all deuteriums and there was no evidence of N-dealkylation. MS/MS fragmentation of BAC metabolites confirmed oxidn. occurs on the alkyl chain region. Major metabolites of C10-BAC were identified as ω-hydroxy-, (ω-1)-hydroxy-, (ω,ω-1-diol-, ω-1)-ketone-, and ω-carboxylic acid-C10-BAC by LC-MS comparison with synthetic stds. In a screen of hepatic CYP isoforms, recombinant CYP2D6, CYP4F2, and CYP4F12 consumed substantial quantities of BAC substrates and produced the major microsomal metabolites. The use of potent pan-CYP4 inhibitor HET0016, the specific CYP2D6 inhibitor quinidine, or both confirmed major contributions of CYP4- and CYP2D6-mediated metab. in the microsomal disappearance of BACs. Kinetic characterization of C10-BAC metabolite formation in HLM demonstrated robust Michaelis-Menten kinetic parameters for ω-hydroxylation (Vmax = 380 pmol/min/mg, Km = 0.69μM) and (ω-1)-hydroxylation (Vmax = 126 pmol/min/mg, Km = 0.13μM) reactions. This work illustrates important roles for CYP4-mediated ω-hydroxylation and CYP2D6/CYP4-mediated (ω-1)-hydroxylation during the hepatic elimination of BACs, an environmental contaminant of emerging concern. Furthermore, we demonstrate that CYP-mediated oxidn. of C10-BAC mitigates the potent inhibition of cholesterol biosynthesis exhibited by this short-chain BAC. Furthermore, we demonstrate that CYP-mediated oxidn. of C10-BAC mitigates the potent inhibition of cholesterol biosynthesis exhibited by this short-chain BAC.
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    Zheng, G.; Schreder, E.; Sathyanarayana, S.; Salamova, A. The First Detection of Quaternary Ammonium Compounds in Breast Milk: Implications for Early-Life Exposure. J. Expo. Sci. Environ. Epidemiol. 2022, 32, 682,  DOI: 10.1038/s41370-022-00439-4
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    95
    The first detection of quaternary ammonium compounds in breast milk: Implications for early-life exposure
    Zheng, Guomao; Schreder, Erika; Sathyanarayana, Sheela; Salamova, Amina
    Journal of Exposure Science & Environmental Epidemiology (2022), 32 (5), 682-688CODEN: JESEBS; ISSN:1559-0631. (Nature Portfolio)
    Abstr.: Background: Quaternary ammonium compds. (QACs), commonly used in cleaning, disinfecting, and personal care products, have recently gained worldwide attention due to the massive use of disinfectants during the COVID-19 pandemic. However, despite extensive use of these chems., no studies have focused on the anal. of QACs in human milk, a major route of exposure for infants. [graphic not available: see fulltext] Objective: Our objectives were to identify and measure QACs in breast milk and evaluate early-life exposure to this group of compds. for nursing infants. Methods: Eighteen QACs, including 6 benzylalkyldimethyl ammonium compds. (BACs, with alkyl chain lengths of C8-C18), 6 dialkyldimethyl ammonium compds. (DDACs, C8-C18), and 6 alkyltrimethyl ammonium compds. (ATMACs, C8-C18), were measured in breast milk samples collected from U. S. mothers. Daily lactational intake was estd. based on the detd. concns. for 0-12 mo old nursing infants. Results: Thirteen of the 18 QACs were detected in breast milk and 7 of them were found in more than half of the samples. The total QAC concns. (ΣQAC) ranged from 0.33 to 7.4 ng/mL (median 1.5 ng/mL). The most abundant QAC was C14-BAC with a median concn. of 0.45 ng/mL. The highest median ΣQAC estd. daily intake (EDI) was detd. for <1-mo old infants based on the av. (using the median concn.) and high (using the 95th percentile concn.) exposure scenarios (230 and 750 ng/kg body wt./day, resp.). Significance: Our findings provide the first evidence of the detection of several QACs in breast milk and identify breastfeeding as an exposure pathway to QACs for nursing infants. Impact statement: Our findings provide the first evidence of QAC occurrence in breast milk and identify breastfeeding as one of the exposure pathways to QACs for nursing infants.
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    Adelson, L.; Sunshine, I. Fatal Poisoning due to a Cationic Detergent of the Quaternary Ammonium Compound Type. Am. J. Clin. Pathol. 1952, 22 (7), 656– 661,  DOI: 10.1093/ajcp/22.7.656
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    Fatal poisoning due to a cationic detergent of the quaternary ammonium compound type
    Adelson, Lester; Sunshine, Irving
    American Journal of Clinical Pathology (1952), 22 (), 656-61CODEN: AJCPAI; ISSN:0002-9173.
    This is the first reported case of fatal human poisoning due to the ingestion of cationic detergent. The toxic agent was less than 1 oz. of an alc. soln. of Syntho-San, a 10% soln. of methyldodecylbenzyltrimethylammonium chloride. The lethal effect is probably the result of a combined inhibition of cholinesterase and intracellular oxidative enzymes. Exptl. investigation with white rats demonstrated that alc. (whiskey) increases the toxic effect of the detergent.
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    Wilson, J. T.; Burr, I. M. Benzalkonium Chloride Poisoning in Infant Twins. Am. J. Dis. Child. 1975, 129 (10), 1208– 1209,  DOI: 10.1001/archpedi.1975.02120470054015
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    Benzalkonium chloride poisoning in infant twins
    Wilson J T; Burr I M
    American journal of diseases of children (1960) (1975), 129 (10), 1208-9 ISSN:0002-922X.
    Infant twins sustained severe circumoral and pharyngeal burns from a concentrated solution of benzalkonium (Zephiran) chloride prescribed for treatment of candidiasis. This report emphasizes the unnecessary hazard accompanying use of a potentially toxic drug-especially when prepared in error by the pharmacist-when a safer drug (nystatin) is available for treatment of oral candidiasis. Risks from use of a prescription drug for other than the intended patient are also highlighted by this episode of poisoning.
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    van Berkel, M.; de Wolff, F. A. Survival after Acute Benzalkonium Chloride Poisoning. Hum. Toxicol. 1988, 7 (2), 191– 193,  DOI: 10.1177/096032718800700216
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    Survival after acute benzalkonium chloride poisoning
    van Berkel M; de Wolff F A
    Human toxicology (1988), 7 (2), 191-3 ISSN:0144-5952.
    There is no expanded citation for this reference.
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    Chataigner, D.; Garnier, R.; Sans, S.; Efthymiou, M. L. [Acute accidental poisoning with hospital disinfectant. 45 cases of which 13 with fatal outcome]. Presse Med. 1991, 20 (16), 741– 743
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    Acute accidental poisoning with hospital disinfectant. 45 cases of which 13 with fatal outcome
    Chataigner D; Garnier R; Sans S; Efthymiou M L
    Presse medicale (Paris, France : 1983) (1991), 20 (16), 741-3 ISSN:0755-4982.
    Airsane HP 800 is a disinfectant widely used in hospitals as a powder to be diluted in water. It mainly contains a mixture of quaternary ammonium compounds. Forty five cases of acute accidental poisoning with this product have been reported to the Paris Poison Centre. All the victims were mentally disturbed patients: 2 were young adults hospitalized in psychiatric units and the other 43 were old people hospitalized for senile dementia. All ingested the solid preparation which was left in their room by hospital workers who did not know it was dangerous. Corrosive burns of the mouth, pharynx, oesophagus and sometimes of the respiratory tract were produced in most patients. Thirteen of them died. All were old persons. Ten had inhalation pneumonitis and died of acute respiratory distress one hour to twelve days after taking the powder. Progressive deterioration was responsible for the death of the other three between the 19th and 40th days. These severe accidental poisonings could easily be prevented by a better information of hospital workers, and by storing the disinfectant and preparing the solution beyond the reach of patients.
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    Hitosugi, M.; Maruyama, K.; Takatsu, A. A Case of Fatal Benzalkonium Chloride Poisoning. Int. J. Legal Med. 1998, 111 (5), 265– 266,  DOI: 10.1007/s004140050166
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    A case of fatal benzalkonium chloride poisoning
    Hitosugi M; Maruyama K; Takatsu A
    International journal of legal medicine (1998), 111 (5), 265-6 ISSN:0937-9827.
    Five elderly persons with senile dementia accidentally ingested Hoesmin, a 10% aqueous solution of benzalkonium chloride (BAC). The condition of one patient, an 84-year-old woman whose lips and oral cavity became erythematous, gradually deteriorated. Although gastric lavage was performed, the patient died 3 h after ingestion of Hoesmin. Autopsy revealed corrosive changes of the mucosal surfaces of the tongue, pharynx, larynx, esophagus and stomach which may have come in contact with BAC. In addition, BAC was detected in the serum. We conclude that the patient died of BAC poisoning. Fatal BAC poisoning is rare and autopsy findings in only a few cases of BAC poisoning have been reported. Our findings emphasize the risk of oral ingestion of BAC.
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    Xue, Y.; Hieda, Y.; Kimura, K.; Nishiyama, T.; Adachi, T. Sensitive Determination of Benzalkonium Chloride in Blood and Tissues Using High-Performance Liquid Chromatography with Solid-Phase Extraction. Leg. Med. 2002, 4 (4), 232– 238,  DOI: 10.1016/S1344-6223(02)00036-6
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    Sensitive determination of benzalkonium chloride in blood and tissues using high-performance liquid chromatography with solid-phase extraction
    Xue, Yuying; Hieda, Yoko; Kimura, Kojiro; Nishiyama, Takashi; Adachi, Toshinori
    Legal Medicine (2002), 4 (4), 232-238CODEN: LEGMFI; ISSN:1344-6223. (Elsevier Science Ireland Ltd.)
    A sensitive and simple high-performance liq. chromatog. assay for benzalkonium chloride (BZK) in biol. samples was developed. The biol. samples, spiked with domiphen used as an internal std., were purified by solid-phase extn. The major homologues of BZK in pharmaceutical products (C12 and C14) were eluted at 24 and 36 min using a YMC-Pack CN column (4.6×250 mm, 5 μm) with a mobile phase, mixt. of acetonitrile and sodium acetate buffer (48:52), and monitored at 254 nm. The most dominant component C12 was selected as an indicator to quantify BZK, and adjustment was then done based on the proportion of C12 in the BZK product. Good linearity was obtained in the range of 0.1-3 μg, and the limit of detection was 20 ng as a loaded amt. on column. The recoveries of BZK in serum and tissues ranged from 54 to 90%. In a practical case, 0.16 μg/mL of BZK was quantified in serum collected several hours after accidental ingestion. The method is simple, sensitive and reliable for detg. BZK levels in practical biol. samples.
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    Mishima-Kimura, S.; Yonemitsu, K.; Ohtsu, Y.; Sasao, A.; Tsutsumi, H.; Furukawa, S.; Nishitani, Y. Liquid Chromatography-Tandem Mass Spectrometry Detection of Benzalkonium Chloride (BZK) in a Forensic Autopsy Case with Survival for 18 Days Post BZK Ingestion. Leg. Med. 2018, 32, 48– 51,  DOI: 10.1016/j.legalmed.2018.02.006
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    102
    Liquid chromatography-tandem mass spectrometry detection of benzalkonium chloride (BZK) in a forensic autopsy case with survival for 18 days post BZK ingestion
    Mishima-Kimura, Satoko; Yonemitsu, Kosei; Ohtsu, Yuki; Sasao, Ako; Tsutsumi, Hiroshi; Furukawa, Shota; Nishitani, Yoko
    Legal Medicine (2018), 32 (), 48-51CODEN: LEGMFI; ISSN:1344-6223. (Elsevier Ireland Ltd.)
    We report a forensic autopsy case of an elderly man who ingested unknown amt. of germicidal disinfectant contg. 50% benzalkonium chloride (BZK). He survived for 18 days after BZK ingestion and then died because of pneumonia. A liq. chromatog.-tandem mass spectrometry (LC-MS/MS) method was used to detect three BZK compds. (C12-BZK, C14-BZK and C16-BZK) in the blood. Extn. of BZK was carried out according to a modified QuEChERS method. Chromatog. sepn. was achieved on an ODS column and detection was performed in selected reaction monitoring mode. The accuracy and the precision were acceptable for quant. anal. in the concn. range of 10-200 ng/mL for the three BZK compds. BZK was detected in heart and femoral vein blood samples even 18 days after BZK ingestion. Taking into consideration clin. information during 18 days hospitalization and the autopsy findings, the cause of death was attributed to BZK poisoning. Several toxicokinetic factors regarding absorption and excretion of BZK in the body were also discussed to elucidate the detection of BZK such a long time after ingestion.
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    DeLeo, P. C.; Tu, V.; Fuls, J. Systemic Absorption of Benzalkonium Chloride after Maximal Use of a Consumer Antiseptic Wash Product. Regul. Toxicol. Pharmacol. 2021, 124, 104978,  DOI: 10.1016/j.yrtph.2021.104978
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    Systemic absorption of benzalkonium chloride after maximal use of consumer antiseptic wash product
    DeLeo, Paul C.; Tu, Victoria; Fuls, Janice
    Regulatory Toxicology and Pharmacology (2021), 124 (), 104978CODEN: RTOPDW; ISSN:0273-2300. (Elsevier Inc.)
    An in vivo pharmacokinetic study was conducted using consumer antiseptic wash contg. 0.13% benzalkonium chloride (BAC) to assess the effect of dermal absorption on long-term systemic exposure to BAC. The objective of the study was to det. blood levels of BAC under maximal use conditions. Subjects were enlisted to wash their hands 60 s with soap contg. 0.13% BAC 30 times per day over an 8-9 h time period for 5 consecutive days. The test product with the highest absorption potential was selected based on market share and results from in vitro permeation testing. Blood plasma was collected from subjects on 32 occasions over the 6-day study period. Plasma samples were analyzed for the C12 and C14 homologs of BAC using LC-MS/MS with a lower limit of quantitation (LLOQ) of 106.9 and 32.6 ng/L, resp. For the 32 subjects, C12 homolog was detected above the LLOQ in only four of 1,024 plasma samples at 117.8-191.7 ng/L, and C14 homolog was detected in only one sample at 59.5 ng/L. Consequently, systemic exposure to BAC in antimicrobial soap is very low and below the level of concern identified by the U.S. Food and Drug Administration (500 ng/L) even under maximal use conditions.
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    Kim, M. K.; Han, L.; Choi, M. K.; Han, Y. H.; Kim, D. D.; Chung, S. J.; Shim, C. K. Dose Dependency in the Oral Bioavailability of an Organic Cation Model, Tributylmethyl Ammonium (TBuMA), in Rats: Association with the Saturation of Efflux by the P-Gp System on the Apical Membrane of the Intestinal Epithelium. J. Pharm. Sci. 2005, 94 (12), 2644– 2655,  DOI: 10.1002/jps.20456
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    104
    Dose dependency in the oral bioavailability of an organic cation model, tributylmethyl ammonium (TBuMA), in rats: Association with the saturation of efflux by the P-gp system on the apical membrane of the intestinal epithelium
    Kim, Moon Kyoung; Han, Liwei; Choi, Min Koo; Han, Yong-Hae; Kim, Dae-Duk; Chung, Suk-Jae; Shim, Chang-Koo
    Journal of Pharmaceutical Sciences (2005), 94 (12), 2644-2655CODEN: JPMSAE; ISSN:0022-3549. (Wiley-Liss, Inc.)
    The oral bioavailability of tributylmethyl ammonium (TBuMA), an org. cation (OC), exhibited a dose-dependency (i.e., 17, 27, and 35% at doses of 0.4, 4, or 12 μmol/kg, resp.) in the rat. Relevant mechanisms were investigated in the present study by estg. the mucosal to serosal (m-s) and serosal to mucosal (s-m) transport of TBuMA across the rat ileum in an Ussing chamber expt. The m-s permeability rapidly increased with TBuMA concn. in the mucosal side, and then becoming const. at high TBuMA concns. Various studies, including temp.- and potential-dependency and inhibition expts., revealed that carrier-mediated transport mechanisms (most likely OCT1, OCT3, and P-gp) are involved in the s-m transport of TBuMA, and the satn. of the transport at higher concns. is responsible for the concn.-dependency in the m-s permeability or dose-dependency of the bioavailability of TBuMA. A nonlinear regression of the m-s transport, based on the assumption of a mixed process of linear diffusion and saturable efflux, exhibited a clearance (CLlinear) of 0.343 μL/min/cm2 for the passive diffusion, and an apparent Km of 241 μM for the saturable process. The Km value is consistent with the concn. range in the intestine which is expected to be achieved after the oral dosing of TBuMA at a dose of 0.4 μmol/kg (i.e., 68∼185 μM). Interestingly, the m-s transport of TBuMA was increased by the presence of P-gp substrates or inhibitors in the mucosal side, but not by the mucosal presence of OCT substrates or inhibitors, suggesting that only efflux transport systems on the apical membrane (e.g., P-gp), but not those on the serosal membrane (e.g., OCT1 and OCT3), of the intestinal epithelial cells, are involved in the dose-dependency or concn. dependency. A similar relation seems likely for drugs that are substrates of efflux transporters on the apical membrane of the intestinal epithelium.
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  105. 105
    Hong, S. S.; Moon, S. C.; Shim, C. K. Mechanism of Intestinal Transport of an Organic Cation, Tributylmethylammonium in Caco-2 Cell Monolayers. Arch. Pharm. Res. 2006, 29 (4), 318– 322,  DOI: 10.1007/BF02968577
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    105
    Mechanism of intestinal transport of an organic cation, tributylmethylammonium in Caco-2 cell monolayers
    Hong, Soon-Sun; Moon, Sang-Cherl; Shim, Chang-Koo
    Archives of Pharmacal Research (2006), 29 (4), 318-322CODEN: APHRDQ; ISSN:0253-6269. (Pharmaceutical Society of Korea)
    Many quaternary ammonium salts are incompletely absorbed after their oral administration and may also be actively secreted into the intestine. However, the underlying mechanism(s) that control the transport of these cations across the intestinal epithelium is not well understood. In this study, the mechanism of absorption of quaternary ammonium salts was investigated using Caco-2 cell monolayers, a human colon carcinoma cell line. Tributylmethylammonium (TBuMA) was used as a model quaternary ammonium salts. When TBuMA was administrated at a dose of 13.3 imole/kg via iv and oral routes, the AUC values were 783.7 ± 43.6 and 249.1 ± 28.0 μmole·min/L for iv and oral administration, indicating a lower oral bioavailability of TBuMA (35.6%). The apparent permeability across Caco-2 monolayers from the basal to the apical side was 1.3 times (p<0.05) greater than that from the apical to the basal side, indicating a net secretion of TBuMA in the intestine. This secretion appeared to be responsible for the low oral bioavailability of the compd., probably mediated by p-gp (p-glycoprotein) located in the apical membrane. In addn., the uptake of TBuMA by the apical membrane showed a Na+ dependency. Thus, TBuMA appears to absorbed via a Na+ dependent carrier and is then secreted via p-gp related carriers.
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  106. 106
    Smit, J. W.; Schinkel, A. H.; Weert, B.; Meijer, D. K. Hepatobiliary and Intestinal Clearance of Amphiphilic Cationic Drugs in Mice in Which Both mdr1a and mdr1b Genes Have Been Disrupted. Br. J. Pharmacol. 1998, 124 (2), 416– 424,  DOI: 10.1038/sj.bjp.0701845
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    106
    Hepatobiliary and intestinal clearance of amphiphilic cationic drugs in mice in which both mdr1a and mdr1b genes have been disrupted
    Smit, Johan W.; Schinkel, Alfred H.; Weert, Betty; Meijer, Dirk K. F.
    British Journal of Pharmacology (1998), 124 (2), 416-424CODEN: BJPCBM; ISSN:0007-1188. (Stockton Press)
    We have used mice with homozygously disrupted mdr1a and mdr1b genes (mdr1a/1b (-/-) mice) to study the role of the mdr1-type P-glycoprotein (P-gp) in the elimination of cationic amphiphilic compds. from the body. These mice lack drug-transporting P-gps, but show no physiol. abnormalities under lab. conditions and have normal bile flow. 3H-labeled cationic drugs were administered i.v. to mice as a single bolus dose and the disposition of the studied cationic drugs was investigated by focusing on drug secretion into bile, intestinal lumen and urine. Hepatobiliary secretion of the investigated cationic drugs was profoundly reduced in mice devoid of the mdr1-type P-gps. In fact, the cumulative biliary output, measured during 1 h, of the small type 1 compds. tri-butylmethyl ammonium (TBuMA) and azidoprocainamide methiodide (APM), as well as of the more bulky type 2 cationic drug vecuronium, was reduced by at least 70% in the mdr1a/1b (-/-) mice compared to wild-type. The intestinal secretion of TBuMA, APM and vecuronium was also profoundly reduced in mdr1a/1b (-/-) mice compared to wild-type mice. The absence of the mdr1-type P-gp resulted in virtual elimination of intestinal secretion of TBuMA and APM (>90% reduced as compared to wild-type (P = 0.0001 and 0.0022, resp.)). The intestinal secretion of the type 2 cation drug vecuronium was reduced by 58% (P = 0.0004) compared to the wild-type mice. Increased renal clearances of both the type 1 compds. TBuMA and APM and also of the type 2 cationic compd. vecuronium in the mdr1a/1b (-/-) mice were obsd. Furthermore, the balance between hepatic, intestinal and renal clearances of small type 1 org. cations clearly shifted towards a predominant role for renal clearance. Increased renal clearance may be explained by (over)expression of addnl. mechanisms for renal org. cation secretion, alternatively they may also point to an as yet undefined role of P-glycoprotein in kidney physiol. and renal secretory function. We conclude that the elimination from the body of a broad spectrum of cationic amphiphilic drugs via liver and intestine, is largely dictated by the activity of mdr1-type P-glycoproteins.
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  107. 107
    Isomaa, B. Absorption, Distribution and Excretion of [14-C]CTAB, a Quarternary Ammonium Surfactant, in the Rat. Food Cosmet. Toxicol. 1975, 13 (2), 231– 237,  DOI: 10.1016/S0015-6264(75)80008-3
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    107
    Absorption, distribution, and excretion of carbon-14-labeled cetyltrimethylammonium bromide (14C-CTAB), a quaternary ammonium surfactant, in the rat
    Isomaa, B.
    Food and Cosmetics Toxicology (1975), 13 (2), 231-7CODEN: FCTXAV; ISSN:0015-6264.
    The absorption, distribution and excretion of orally administered 14C-labeled cetyltrimethylammonium bromide (CTAB) [57-09-0], a quaternary ammonium surfactant, was studied in female rats. About 80% of radioactivity was found in the gastro-intestinal tract 8 hr after administration. Only small amts. were found in the blood plasma and about 2% of the administered radioactivity was excreted in the bile during the 1st 12 hr after treatment. The low levels of radioactivity in the serum and bile, together with the large amts. of radioactivity found in the gastro-intestinal tract, indicated poor intestinal absorption of CTAB. Only small amts. of radioactivity were found in the liver, kidneys, spleen, heart, lungs and skeletal muscle, and the tissue radioactivity declined rapidly, only traces being found in the examd. tissues 4 days after CTAB administration. Within 3 days of ingestion, 92% of the administered radioactivity had been excreted in the feces and 1% in the urine. No radioactivity was found in the expired CO2 collected during day 1 after administration of CTAB. Thin-layer chromatog. of bile and urine samples indicated that CTAB was metabolized to some extent in the rat.
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  108. 108
    Xue, Y.; Hieda, Y.; Saito, Y.; Nomura, T.; Fujihara, J.; Takayama, K.; Kimura, K.; Takeshita, H. Distribution and Disposition of Benzalkonium Chloride Following Various Routes of Administration in Rats. Toxicol. Lett. 2004, 148 (1–2), 113– 123,  DOI: 10.1016/j.toxlet.2003.12.068
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    108
    Distribution and disposition of benzalkonium chloride following various routes of administration in rats
    Xue, Yuying; Hieda, Yoko; Saito, Yoji; Nomura, Takeshi; Fujihara, Junko; Takayama, Koji; Kimura, Kojiro; Takeshita, Haruo
    Toxicology Letters (2004), 148 (1-2), 113-123CODEN: TOLED5; ISSN:0378-4274. (Elsevier Science Ireland Ltd.)
    Benzalkonium chloride (BZK) is a cationic surfactant used widely as a disinfectant, preservative and sanitizer in hospitals, at home and many public places. The toxicity of BZK is not well established although several human fatalities have been reported over the years. In this study, distribution and disposition of BZK following oral administration (PO) and intravascular (jugular vein (JV), femoral artery (FA), femoral vein (FV) and jugular artery (JA)) administration in rats were investigated along with pathol. examns. Toxic doses of 250 and 15 mg/kg of BZK were used for PO and intravascular administration, resp. The fatal effects of BZK appeared soon in JV-, FV- or JA-rats, but took hours in PO or FA-rats. No rat receiving BZK via FA survived longer than 1 day. The PO-rats that aspirated BZK into their lungs had some systemic symptoms and higher blood and tissue concns. of BZK. The blood BZK levels and kinetics were similar among the different routes of intravascular administration, but the lung and kidney levels were higher in JV-rats. Pathol. examns. confirmed severe congestion and edema in the lungs and kidneys. These results suggest that (1) the toxic effects of BZK varied depending on the route of administration, (2) the degree of toxicity correlated with peak blood and tissue concns. in orally dosed rats, (3) different toxicol. progressions and manifestations were obsd. in FA- and JV-dosed rats even though these groups had similar blood concn. profiles, and (4) lung and kidney are reservoirs for BZK and considered to be the target organs of BZK.
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  109. 109
    Song, I. S.; Choi, M. K.; Jin, Q. R.; Shim, W. S.; Shim, C. K. Increased Affinity to Canalicular P-Gp via Formation of Lipophilic Ion-Pair Complexes with Endogenous Bile Salts Is Associated with Mw Threshold in Hepatobiliary Excretion of Quaternary Ammonium Compounds. Pharm. Res. 2010, 27 (5), 823– 831,  DOI: 10.1007/s11095-010-0075-0
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    109
    Increased Affinity to Canalicular P-gp via Formation of Lipophilic Ion-Pair Complexes with Endogenous Bile Salts is Associated with Mw Threshold in Hepatobiliary Excretion of Quaternary Ammonium Compounds
    Song, Im-Sook; Choi, Min-Koo; Jin, Qing-Ri; Shim, Won-Sik; Shim, Chang-Koo
    Pharmaceutical Research (2010), 27 (5), 823-831CODEN: PHREEB; ISSN:0724-8741. (Springer)
    We intended to elucidate the mechanism of the mol. wt. (Mw) threshold (i.e., 200 ± 50) for appreciable hepatobiliary excretion of quaternary ammonium compds. (QACs) in rats. We measured the effect of ion-pair complexation of QACs with taurodeoxycholate (TDC), an endogenous anionic bile salt, on the apparent partition coeffs. (APC) of QACs between n-octanol and phosphate buffer, and the inhibition of org. cation transporter1 (OCT1)- and P-glycoprotein (P-gp)-mediated transport of representative substrates. By measuring the APC, we demonstrated that there is a Mw threshold of 200 ± 50 in the ion-pair complexation of QACs with an endogenous bile salt, TDC. We also demonstrated, by measuring the inhibition of relevant transports, that a Mw threshold of 200 ± 50 exists for the binding of QACs to canalicular P-gp, but not for sinusoidal OCT1. The Mw threshold values for ion-pair formation and P-gp binding were identical and consistent with the reported Mw threshold value for appreciable biliary excretion of QACs in rats. Mw-dependent binding of QACs to canalicular P-gp contributes in part to the mechanism of the Mw threshold of 200 ± 50. The formation of lipophilic ion-pair complexes with bile salts, followed by stronger binding to canalicular P-gp, appears to accelerate biliary excretion of QACs with a high Mw.
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  110. 110
    Song, I. S.; Choi, M. K.; Shim, W. S.; Shim, C. K. Transport of Organic Cationic Drugs: Effect of Ion-Pair Formation with Bile Salts on the Biliary Excretion and Pharmacokinetics. Pharmacol. Ther. 2013, 138 (1), 142– 154,  DOI: 10.1016/j.pharmthera.2013.01.006
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    110
    Transport of organic cationic drugs: Effect of ion-pair formation with bile salts on the biliary excretion and pharmacokinetics
    Song, I. S.; Choi, M. K.; Shim, W. S.; Shim, C. K.
    Pharmacology & Therapeutics (2013), 138 (1), 142-154CODEN: PHTHDT; ISSN:0163-7258. (Elsevier)
    A review. More than 40% of clin. used drugs are org. cations (OCs), which are pos. charged at a physiol. pH, and recent reports have established that these drugs are substrates of membrane transporters. The transport of OCs via membrane transporters may play important roles in gastrointestinal absorption, distribution to target sites, and biliary and/or renal elimination of various OC drugs. Almost 40 years ago, a mol. wt. (Mw) threshold of 200 was reported to exist in rats for monoquaternary ammonium (mono QA) compds. to be substantially (e.g., >10% of iv dose) excreted to bile. It is well known that some OCs interact with appropriate endogenous org. anions in the body (e.g., bile salts) to form lipophilic ion-pair complexes. The ion-pair formation may influence the affinity or binding of OCs to membrane transporters that are relevant to biliary excretion. In that sense, the assocn. of the ion-pair formation with the existence of the Mw threshold appears to be worthy of examn. It assumes the ion-pair formation of high Mw mono QA compds. (i.e., >200) in the presence of bile salts in the liver, followed by accelerated transport of the ion-pair complexes via relevant bile canalicular transporter(s). In this article, therefore, the transport of OC drugs will be reviewed with a special focus on the ion-pair formation hypothesis. Such information will deepen the understanding of the pharmacokinetics of OC drugs as well as the physiol. roles of endogenous bile salts in the detoxification or phase II metab. of high Mw QA drugs.
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  111. 111
    Dresser, M. J.; Xiao, G.; Leabman, M. K.; Gray, A. T.; Giacomini, K. M. Interactions of N-Tetraalkylammonium Compounds and Biguanides with a Human Renal Organic Cation Transporter (hOCT2). Pharm. Res. 2002, 19 (8), 1244– 1247,  DOI: 10.1023/A:1019870831174
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    111
    Interactions of n-tetraalkylammonium compounds and biguanides with a human renal organic cation transporter (hOCT2)
    Dresser, Mark J.; Xiao, Guangqing; Leabman, Maya K.; Gray, Andrew T.; Giacomini, Kathleen M.
    Pharmaceutical Research (2002), 19 (8), 1244-1247CODEN: PHREEB; ISSN:0724-8741. (Kluwer Academic/Plenum Publishers)
    The interactions of n-tetraalkylammonium (nTAA) compds. and biguanides with human org. cation transporters (hOCT1 and hOCT2) were evaluated to det. whether these transporters are functionally distinct. The biguanides have similar affinities for hOCT1 and hOCT2, while considerable differences were noted between hOCT1 and hOCT2 in their interaction with nTAA compds. This indicated that there are significant differences in the binding sites of these paralogous transporters.
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  112. 112
    Chen, Y.; Zhang, S.; Sorani, M.; Giacomini, K. M. Transport of Paraquat by Human Organic Cation Transporters and Multidrug and Toxic Compound Extrusion Family. J. Pharmacol. Exp. Ther. 2007, 322 (2), 695– 700,  DOI: 10.1124/jpet.107.123554
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    112
    Transport of paraquat by human organic cation transporters and multidrug and toxic compound extrusion family
    Chen, Ying; Zhang, Shuzhong; Sorani, Marco; Giacomini, Kathleen M.
    Journal of Pharmacology and Experimental Therapeutics (2007), 322 (2), 695-700CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)
    Paraquat (N,N-dimethyl-4-4'-bipiridinium; PQ), a widely used herbicide, when ingested accidentally or intentionally can cause major organ toxicities in lung, liver, and kidney. Because PQ is primarily eliminated in the kidney, renal elimination, including tubular transport, plays a crit. role in controlling systemic exposure to the herbicide. The goal of this study was to det. the mol. identities of the transporters involved in the renal elimination of PQ. Using stably transfected human embryonic kidney (HEK)-293 cells, we examd. the role of human org. cation transporters (hOCTs, SLC22A1-3) and human multidrug and toxic compd. extrusion (hMATE)1 in the cellular accumulation and cytotoxicity of PQ. We found that overexpression of hOCT2 but not hOCT1 and hOCT3 in HEK-293 cells significantly enhanced the accumulation and cytotoxicity of PQ (-fold increase for uptake was 12 ± 0.5, p < 0.01; -fold increase of cytotoxicity was 18 ± 1.5, p < 0.001). The kinetics of PQ transport was altered in cells expressing a genetic polymorphism of hOCT2 (A270S) in comparison with those expressing the ref. hOCT2. In addn., the cellular accumulation and cytotoxicity of PQ were also enhanced in cells expressing hMATE1 (-fold increase for uptake was 18 ± 3.7, p < 0.0001; -fold increase of cytotoxicity was 5.7 ± 0.5, p < 0.0001). These results suggest that hOCT2 and hMATE1 mediate PQ transport. These transporters may play an important role in the accumulation and renal excretion of PQ, and they may serve as mol. targets for the prevention and treatment of PQ-induced nephrotoxicity.
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  113. 113
    Vora, B.; Green, E. A. E.; Khuri, N.; Ballgren, F.; Sirota, M.; Giacomini, K. M. Drug-Nutrient Interactions: Discovering Prescription Drug Inhibitors of the Thiamine Transporter ThTR-2 (SLC19A3). Am. J. Clin. Nutr. 2020, 111 (1), 110– 121,  DOI: 10.1093/ajcn/nqz255
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    113
    Drug-nutrient interactions: discovering prescription drug inhibitors of the thiamine transporter ThTR-2 (SLC19A3)
    Vora Bianca; Green Elizabeth A E; Giacomini Kathleen M; Khuri Natalia; Ballgren Frida; Sirota Marina
    The American journal of clinical nutrition (2020), 111 (1), 110-121 ISSN:.
    BACKGROUND: Transporter-mediated drug-nutrient interactions have the potential to cause serious adverse events. However, unlike drug-drug interactions, these drug-nutrient interactions receive little attention during drug development. The clinical importance of drug-nutrient interactions was highlighted when a phase III clinical trial was terminated due to severe adverse events resulting from potent inhibition of thiamine transporter 2 (ThTR-2; SLC19A3). OBJECTIVE: In this study, we tested the hypothesis that therapeutic drugs inhibit the intestinal thiamine transporter ThTR-2, which may lead to thiamine deficiency. METHODS: For this exploration, we took a multifaceted approach, starting with a high-throughput in vitro primary screen to identify inhibitors, building in silico models to characterize inhibitors, and leveraging real-world data from electronic health records to begin to understand the clinical relevance of these inhibitors. RESULTS: Our high-throughput screen of 1360 compounds, including many clinically used drugs, identified 146 potential inhibitors at 200 μM. Inhibition kinetics were determined for 28 drugs with half-maximal inhibitory concentration (IC50) values ranging from 1.03 μM to >1 mM. Several oral drugs, including metformin, were predicted to have intestinal concentrations that may result in ThTR-2-mediated drug-nutrient interactions. Complementary analysis using electronic health records suggested that thiamine laboratory values are reduced in individuals receiving prescription drugs found to significantly inhibit ThTR-2, particularly in vulnerable populations (e.g., individuals with alcoholism). CONCLUSIONS: Our comprehensive analysis of prescription drugs suggests that several marketed drugs inhibit ThTR-2, which may contribute to thiamine deficiency, especially in at-risk populations.
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  114. 114
    Groothuis, F. A.; Timmer, N.; Opsahl, E.; Nicol, B.; Droge, S. T. J.; Blaauboer, B. J.; Kramer, N. I. Influence of in Vitro Assay Setup on the Apparent Cytotoxic Potency of Benzalkonium Chlorides. Chem. Res. Toxicol. 2019, 32 (6), 1103– 1114,  DOI: 10.1021/acs.chemrestox.8b00412
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    114
    Influence of in Vitro Assay Setup on the Apparent Cytotoxic Potency of Benzalkonium Chlorides
    Groothuis, Floris A.; Timmer, Niels; Opsahl, Eystein; Nicol, Beate; Droge, Steven T. J.; Blaauboer, Bas J.; Kramer, Nynke I.
    Chemical Research in Toxicology (2019), 32 (6), 1103-1114CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)
    The nominal concn. is generally used to express concn.-effect relationships in in vitro toxicity assays. However, the nominal concn. does not necessarily represent the exposure concn. responsible for the obsd. effect. Surfactants accumulate at interphases and likely sorb to in vitro system components such as serum protein and well plate plastic. The extent of sorption and the consequences of this sorption on in vitro readouts is largely unknown for these chems. The aim of this study was to demonstrate the effect of sorption to in vitro components on the obsd. cytotoxic potency of benzalkonium chlorides (BAC) varying in alkyl chain length (6-18 carbon atoms, C6-18) in a basal cytotoxicity assay with the rainbow trout gill cell line (RTgill-W1). Cells were exposed for 48h in 96-well plates to increasing concn. of BACs in exposure medium contg. 0, 60 μM Bovine Serum Albumin (BSA) or 10% fetal bovine serum (FBS). Before and after exposure, BAC concns. in exposure medium were anal. detd. Based on freely dissolved concns. at the end of the exposure, median effect concns. (EC50) decreased with increasing alkyl chain length up to 14 carbons. For BAC with alkyl chains of twelve or more carbons, EC50s based on measured concns. after exposure in supplement-free medium were up to 25-times lower than EC50 calcd. using nominal concns. When BSA or FBS was added to the medium, a decrease in cytotoxic potency of up to 22 times was obsd. for BAC with alkyl chains of eight or more carbons. The results of this study emphasize the importance of expressing the in vitro readouts as a function of a dose metric that is least influenced by assay setup to compare assay sensitivities and chem. potencies.
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  115. 115
    van der Sluijs, P.; Meijer, D. K. Binding of Drugs with a Quaternary Ammonium Group to Alpha-1 Acid Glycoprotein and Asialo Alpha-1 Acid Glycoprotein. J. Pharmacol. Exp. Ther. 1985, 234 (3), 703– 707
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    115
    Binding of drugs with a quaternary ammonium group to alpha-1 acid glycoprotein and asialo alpha-1 acid glycoprotein
    Van der Sluijs, Peter; Meijer, Dirk K. F.
    Journal of Pharmacology and Experimental Therapeutics (1985), 234 (3), 703-7CODEN: JPETAB; ISSN:0022-3565.
    The interaction of 8 mono- and 4 bisquaternary ammonium compds. with α-1 acid glycoprotein and its desialylated deriv. was investigated. Protein binding was performed in vitro by equil. dialysis at 37°. The simple monoquaternary ammonium compds. tributylmethylammonium iodide [3085-79-8] tripropylmethylammonium iodide [3531-14-4], triethylmethylammonium iodide [994-29-6] and procainethobromide [17010-70-7] were not appreciably bound (unbound fraction > 0.99). Excellent neg. correlations of unbound fraction and the log of the octanol-Krebs partition coeff. were obtained for thiazinamium iodide [26212-80-6], N-methylimipramine iodide [16870-81-8], N-methyldeptropine [99287-13-5], and d-tubocurarine [57-95-4] both for α-1 acid glycoprotein (r = -0.99) and asialo α-1 acid glycoprotein (r = -0.94). Bisquaternary ammonium compds., with the exception of hexafluorenium [4844-10-4], were only poorly bound. N-Methyl-deptropine, N-methylimipramine and thiazinamium were more avidly bound to α-1 acid glycoprotein than to albumin, in spite of their polar character. The interaction of N-methyldeptropine with α-1 acid glycoprotein was studied in more detail. Scatchard plots revealed the presence of 2 classes of binding sites. N-Methyldeptropine could effectively be displaced by imipramine from its high-affinity binding site. This points to the presence of a common high-affinity binding site for tertiary and quaternary ammonium compds. on α-1 acid glycoprotein.
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    Kera, H.; Fuke, C.; Usumoto, Y.; Nasu, A.; Maeda, K.; Mukai, M.; Sato, W.; Tanabe, M.; Kuninaka, H.; Ihama, Y. Kinetics and Distribution of Benzalkonium Compounds with Different Alkyl Chain Length Following Intravenous Administration in Rats. Leg. Med. 2021, 48, 101821,  DOI: 10.1016/j.legalmed.2020.101821
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    116
    Kinetics and distribution of benzalkonium compounds with different alkyl chain length following intravenous administration in rats
    Kera, Hitomi; Fuke, Chiaki; Usumoto, Yosuke; Nasu, Ayako; Maeda, Kazuho; Mukai, Moe; Sato, Wakana; Tanabe, Momoka; Kuninaka, Hikaru; Ihama, Yoko
    Legal Medicine (2021), 48 (), 101821CODEN: LEGMFI; ISSN:1344-6223. (Elsevier Ireland Ltd.)
    Benzalkonium chloride is widely used in disinfectants. Several toxicol. and fatal cases have been reported; however, little is known about its kinetics and distribution. We investigated the kinetic characteristics and distribution of benzalkonium cation (BZK) based on the length of the alkyl chains C12, C14, and C16. Rats were treated i.v. with BZK soln. (dose, 13.9 mg/kg) contg. equal amts. of the three homologues. Kinetic parameters in the blood were assessed, and BZK distribution in the blood and tissues was examd. both in rapid i.v. (IV) and drip i.v. (DIV) administrations. BZK concns. were analyzed by liq. chromatog.-tandem mass spectrometry (LC-MS/MS). BZK with longer alkyl chains showed lower elimination tendencies and remained in the blood for a longer duration. Concns. of BZK were higher in the heart, lung, spleen, and kidney than those in the blood, and lower in the brain and fat. In both the IV and DIV groups, the lung, liver, spleen, and fat samples showed higher concns. of the longer alkyl chains (BZK-C12 < -C14 < -C16), and the opposite trend was obsd. in the kidney (BZK-C16 < -C14 < -C12). Only the heart and muscle samples displayed the homologues in ratios comparable to the original administered solns. Differences between IV and DIV groups could be identified by comparing concns. of BZK homologues in the heart, lung, spleen, and kidney samples. We found that the kinetics and distribution of BZK were influenced by the alkyl chain length, and analyzing each BZK homologues in blood and tissue samples may provide useful information.
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  117. 117
    Hughes, R. D.; Millburn, P.; Williams, R. T. Molecular Weight as a Factor in the Excretion of Monoquaternary Ammonium Cations in the Bile of the Rat, Rabbit and Guinea Pig. Biochem. J. 1973, 136 (4), 967– 978,  DOI: 10.1042/bj1360967
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    117
    Molecular weight as a factor in the excretion of monoquaternary ammonium cations in the bile of the rat, rabbit, and guinea pig
    Hughes, Robin D.; Millburn, Peter; Williams, R. Tecwyn
    Biochemical Journal (1973), 136 (4), 967-78CODEN: BIJOAK; ISSN:0264-6021.
    On i.p. injection of 14C-labeled monoquaternary ammonium or pyridinium cations into rats, rabbits, or guinea pigs, <10% of the dose was excreted in bile for compds. with low mol. wts. and greater amts. for compds. with higher mol. wts. The mol. wt. needed for biliary excretion of such cations to 10% or more of the dose is probably 200 +- 50.
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  118. 118
    Neef, C.; Oosting, R.; Meijer, D. K. Structure-Pharmacokinetics Relationship of Quaternary Ammonium Compounds. Elimination and Distribution Characteristics. Naunyn. Schmiedebergs. Arch. Pharmacol. 1984, 328 (2), 103– 110,  DOI: 10.1007/BF00512058
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    118
    Structure-pharmacokinetics relationship of quaternary ammonium compounds. Elimination and distribution characteristics
    Neef C; Oosting R; Meijer D K
    Naunyn-Schmiedeberg's archives of pharmacology (1984), 328 (2), 103-10 ISSN:0028-1298.
    The pharmacokinetics of a series of fourteen monoquaternary ammonium ions, with gradually increasing molecular weight, were studied in anaesthetized rats after intravenous bolus injection and/or constant infusion. Distribution to the eliminating organs and elimination rate into bile, urine and intestinal lumen as well as the plasma disappearance were investigated. All compounds showed a double exponential plasma disappearance pattern. Initial half lives (alpha-phase) varied between 0.5 and 3 min, half lives of the beta-phase varied between 30 and 70 min. Total plasma clearance within the series of compounds ranges from 2.3-13.7 ml/min, in general increasing with molecular weight. The relative contribution of biliary, urinary, and intestinal elimination to the total plasma clearance varied widely within the series of organic cations. Renal clearance of all the compounds exceeded that of mannitol, indicating involvement of active renal transport processes. Excretion via the kidneys was the only important excretory pathway for compounds with molecular weights less than 156. The low biliary excretion of the compounds of M less than 156 was not due to a deficient hepatic penetration since uptake into the liver was very rapid. Only the high molecular weight compounds (greater than 156) showed a profound bile/plasma concentration ratio ranging from 13 to 830. For these compounds also an "uphill" excretion process into the gut lumen seems to be involved representing up to 15% of the administered dose. It is concluded that elimination patterns for organic cations of various structure differ much more than their overall distribution characteristics.
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  119. 119
    Luz, A.; DeLeo, P.; Pechacek, N.; Freemantle, M. Human Health Hazard Assessment of Quaternary Ammonium Compounds: Didecyl Dimethyl Ammonium Chloride and Alkyl (C12-C16) Dimethyl Benzyl Ammonium Chloride. Regul. Toxicol. Pharmacol. 2020, 116, 104717,  DOI: 10.1016/j.yrtph.2020.104717
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    119
    Human health hazard assessment of quaternary ammonium compounds: Didecyl dimethyl ammonium chloride and alkyl (C12-C16) dimethyl benzyl ammonium chloride
    Luz, Anthony; DeLeo, Paul; Pechacek, Nathan; Freemantle, Mike
    Regulatory Toxicology and Pharmacology (2020), 116 (), 104717CODEN: RTOPDW; ISSN:0273-2300. (Elsevier Inc.)
    A review. Quaternary ammonium compds. (Quats) are a large class of permanently charged cationic chems. that are used in a variety of consumer and industrial products for their antimicrobial properties. Didecyl di-Me ammonium chloride (DDAC) and alkyl (C12, C14, C16) di-Me benzyl ammonium chloride (C12-C16 ADBAC) are frequently used as active ingredients in antimicrobials and are the focus of the current hazard assessment. Robust toxicol. databases exist for both DDAC and C12-C16 ADBAC; however, the majority of available studies for DDAC and C12-C16 ADBAC are unpublished, but have been submitted to and reviewed by regulatory agencies (i.e., EPA and European Chems. Agency) to support antimicrobial product registration. With the objective of contributing to public understanding of the robust and complete toxicol. database available for DDAC and C12-C16 ADBAC, a comprehensive review was conducted using available peer-reviewed literature and unpublished data submitted to and summarized by regulatory agencies. A review of available literature indicates that DDAC and C12-C16 ADBAC have similar hazard profiles. Both DDAC and C12-C16 ADBAC are poorly absorbed via the oral and dermal exposure routes (≤10%), are not systemically distributed, and are primarily excreted in feces. DDAC and C12-C16 ADBAC are not dermal sensitizers, are not specific developmental or reproductive toxicants, are not carcinogenic or genotoxic, and do not cause systemic toxicity. DDAC and C12-C16 ADBAC are irritating/corrosive to skin at high concns., and are acutely toxic via the oral, dermal (C12-C16 ADBAC only), and inhalation exposure routes; however, both DDAC and C12-C16 ADBAC are considered non-volatile and are not readily aerosolized. Both DDAC and C12-C16 ADBAC can cause toxicity in repeated dose oral toxicity studies with no-obsd.-adverse-effect levels ranging from 10 to 93.1 mg/kg-day for DDAC and 3.7-188 mg/kg-day for C12-C16 ADBAC in subchronic and chronic studies conducted with beagles, mice, and rats. The toxicol. effects assocd. with reported lowest-obsd.-adverse-effect levels for both DDAC and C12-C16 ADBAC are consistently characterized by reduced food consumption, reduced mean body wt., reduced body wt. gain, and local irritation. These effects are consistent with the mode of action of an irritating/corrosive chem. Based upon currently available data, the main concern assocd. with exposure to DDAC and C12-C16 ADBAC is local effects through irritation.
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  120. 120
    Burruss, B. L.; Fisher, L. C.; Hostetler, K. A. Absorption, Distribution, Metabolism, and Excretion of Didecyl Dimethyl Ammonium Chloride (DDAC) in Rats. The Toxicologist, No 3109; 59th Annual Meeting & ToxExpo, March 10–14, 2019; Oxford University Press, 2019. https://www.toxicology.org/pubs/docs/Tox/2019Tox.pdf (accessed 2022-07-17).
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    Burruss, B. L.; Fisher, L. C.; Hostetler, K. A.. Absorption, Distribution, Metabolism, and Excretion of Alkyl Dimethyl Benzyl Ammonium Chloride (ADBAC) in Rats. The Toxicologist, No 3110; 59th Annual Meeting & ToxExpo, March 10–14, 2019; Oxford University Press, 2019. https://www.toxicology.org/pubs/docs/Tox/2019Tox.pdf (accessed 2022-07-17).
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    Koppel, N.; Maini Rekdal, V.; Balskus, E. P. Chemical Transformation of Xenobiotics by the Human Gut Microbiota. Science 2017, 356 (6344), eaag2770,  DOI: 10.1126/science.aag2770
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    Herron, J. M.; Hines, K. M.; Tomita, H.; Seguin, R. P.; Cui, J. Y.; Xu, L. Multi-Omics Investigation Reveals Benzalkonium Chloride Disinfectants Alter Sterol and Lipid Homeostasis in the Mouse Neonatal Brain. Toxicol. Sci. 2019, 171 (1), 32– 45,  DOI: 10.1093/toxsci/kfz139
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    123
    Multiomics investigation reveals benzalkonium chloride disinfectants alter sterol and lipid homeostasis in the mouse neonatal brain
    Herron, Josi M.; Hines, Kelly M.; Tomita, Hideaki; Seguin, Ryan P.; Cui, Julia Yue; Xu, Libin
    Toxicological Sciences (2019), 171 (1), 32-45CODEN: TOSCF2; ISSN:1096-0929. (Oxford University Press)
    Lipids are crit. for neurodevelopment; therefore, disruption of lipid homeostasis by environmental chems. is expected to have detrimental effects on this process. Previously, we demonstrated that the benzalkonium chlorides (BACs), a class of commonly used disinfectants, alter cholesterol biosynthesis and lipid homeostasis in neuronal cell cultures in a manner dependent on their alkyl chain length. However, the ability of BACs to reach the neonatal brain and alter sterol and lipid homeostasis during neurodevelopment in vivo has not been characterized. Therefore, the goal of this study was to use targeted and untargeted mass spectrometry and transcriptomics to investigate the effect of BACs on sterol and lipid homeostasis and to predict the mechanism of toxicity of BACs on neurodevelopmental processes. After maternal dietary exposure to 120 mg BAC/kg body wt./day, we quantified BAC levels in the mouse neonatal brain, demonstrating for the first time that BACs can cross the blood-placental barrier and enter the developing brain. Transcriptomic anal. of neonatal brains using RNA sequencing revealed alterations in canonical pathways related to cholesterol biosynthesis, liver X receptor-retinoid X receptor (LXR/RXR) signaling, and glutamate receptor signaling. Mass spectrometry anal. revealed decreases in total sterol levels and downregulation of triglycerides and diglycerides, which were consistent with the upregulation of genes involved in sterol biosynthesis and uptake as well as inhibition of LXR signaling. In conclusion, these findings demonstrate that BACs target sterol and lipid homeostasis and provide new insights for the possible mechanisms of action of BACs as developmental neurotoxicants.
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  124. 124
    de Groot, A. C.; White, I. R.; Flyvholm, M. A.; Lensen, G.; Coenraads, P. J. Formaldehyde-Releasers in Cosmetics: Relationship to Formaldehyde Contact Allergy. Part 1. Characterization, Frequency and Relevance of Sensitization, and Frequency of Use in Cosmetics. Contact Dermatitis 2010, 62 (1), 2– 17,  DOI: 10.1111/j.1600-0536.2009.01615.x
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    124
    Formaldehyde-releasers in cosmetics: relationship to formaldehyde contact allergy. Part 1. Characterization, frequency and relevance of sensitization, and frequency of use in cosmetics
    de Groot, Anton C.; White, Ian R.; Flyvholm, Mari-Ann; Lensen, Gerda; Coenraads, Pieter-Jan
    Contact Dermatitis (2010), 62 (1), 2-17CODEN: CODEDG; ISSN:0105-1873. (Wiley-Blackwell)
    A review. In this part of a series of review articles on formaldehyde-releasers and their relationship to formaldehyde contact allergy, formaldehyde-releasers in cosmetics are discussed. In this first part of the article, key data are presented including frequency of sensitization and of their use in cosmetics. In Europe, low frequencies of sensitization have been obsd. to all releasers: 2-bromo-2-nitropropane-1,3-diol 0.4-1.2%, diazolidinyl urea 0.5-1.4%, imidazolidinyl urea 0.3-1.4%, quaternium-15 0.6-1.9% (for DMDM hydantoin no recent data are available). All releasers score (far) higher prevalences in the USA; the possible explanations for this are discussed. The relevance of pos. patch test reactions has been insufficiently investigated. In the USA, approx. 20% of cosmetics and personal care products (stay-on products: 17%, rinse-off products 27%) contain a formaldehyde-releaser. The use of quaternium-15 is decreasing. For Europe, there are no comparable recent data available. In the second part of the article, the patch test relationship of the releasers in cosmetics to formaldehyde contact allergy will be reviewed and it will be assessed whether products preserved with formaldehyde-releasers may contain enough free formaldehyde to pose a threat to individuals who have contact allergy to formaldehyde.
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  125. 125
    Fasth, I. M.; Ulrich, N. H.; Johansen, J. D. Ten-Year Trends in Contact Allergy to Formaldehyde and Formaldehyde-Releasers. Contact Dermatitis 2018, 79 (5), 263– 269,  DOI: 10.1111/cod.13052
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    125
    Ten-year trends in contact allergy to formaldehyde and formaldehyde-releasers
    Fasth, Ida M.; Ulrich, Nina H.; Johansen, Jeanne D.
    Contact Dermatitis (2018), 79 (5), 263-269CODEN: CODEDG; ISSN:0105-1873. (Wiley-Blackwell)
    Preservatives such as formaldehyde and formaldehyde-releasers are common causes of contact allergy. To examine trends in contact allergy to formaldehyde and formaldehyde-releasers in patch tested patients in Denmark over a 10-yr period (2007-2016), and to investigate relevant sources of formaldehyde among the patients. A cross-sectional registry study on patch test data from patients tested with formaldehyde and formaldehyde-releasers (N = 8463) was performed. The presence of released formaldehyde in products from formaldehyde-allergic patients was identified with chem. analyses (chromotropic acid or acetylacetone test). The prevalence of contact allergy to formaldehyde 1% was 1.5%, and ranged between 0.97% and 2.3%, with a decreasing trend in this 10-yr period. Contact allergy to formaldehyde 2% was found in 2.4%, and no significant trend was obsd. Quaternium-15 was the formaldehyde-releaser most often pos. (0.86%). Patients allergic to formaldehyde often had simultaneous pos. patch test reactions to formaldehyde-releasers (36%). Almost 63% of the patients with formaldehyde allergy used products that released formaldehyde; cosmetics were the most common sources. Although contact allergy to formaldehyde 1% decreased in this 10-yr time period, contact allergies to formaldehyde and formaldehyde-releasers overall remain frequent in patients. In most cases, formaldehyde-allergic patients are exposed to ≥1 products contg. formaldehyde. Improved regulation on permitted amts. of free formaldehyde in cosmetics is still warranted, including direct labeling of formaldehyde when it is present in small but relevant amts.
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  126. 126
    Warshaw, E. M.; Ahmed, R. L.; Belsito, D. V.; DeLeo, V. A.; Fowler, J. F., Jr.; Maibach, H. I.; Marks, J. G., Jr; Toby Mathias, C. G.; Pratt, M. D.; Rietschel, R. L.; Sasseville, D.; Storrs, F. J.; Taylor, J. S.; Zug, K. A. Contact Dermatitis of the Hands: Cross-Sectional Analyses of North American Contact Dermatitis Group Data, 1994–2004. J. Am. Acad. Dermatol. 2007, 57 (2), 301– 314,  DOI: 10.1016/j.jaad.2007.04.016
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    126
    Contact dermatitis of the hands: cross-sectional analyses of North American Contact Dermatitis Group Data, 1994-2004
    Warshaw Erin M; Ahmed Rehana L; Belsito Donald V; DeLeo Vincent A; Fowler Joseph F Jr; Maibach Howard I; Marks James G Jr; Toby Mathias C G; Pratt Melanie D; Rietschel Robert L; Sasseville Denis; Storrs Frances J; Taylor James S; Zug Kathryn A
    Journal of the American Academy of Dermatology (2007), 57 (2), 301-14 ISSN:.
    BACKGROUND: Hand dermatitis, including irritant and allergic contact dermatitis (ACD), is common. OBJECTIVE: To evaluate allergens, relevant irritants, sources and occupations associated with hand contact dermatitis using North American Contact Dermatitis Group (NACDG) data. METHODS: A cross-sectional analysis of 22,025 patients patch tested between 1994 and 2004. RESULTS: Hand involvement was found in 6953 patients; 959 had ACD as the only diagnosis. In these 959 patients, the 12 most frequent relevant allergens were quaternium-15 (16.5%), formaldehyde (13.0%), nickel sulfate (12.2%), fragrance mix (11.3%), thiuram mix (10.2%), balsam of Peru (9.6%), carba mix (7.8%), neomycin sulfate (7.7%), bacitracin (7.4%), methyldibromoglutaronitrile/phenoxyethanol 2.0% (7.4%), cobalt chloride (6.5%), and methyldibromoglutaronitrile/phenoxyethanol 2.5% (6.3%). Rubber allergens were most commonly associated with occupation. One third of patients with hand ACD had identifiable relevant irritants. LIMITATIONS: Cross-sectional analyses prevent evaluation of causal associations. CONCLUSION: In NACDG patients with hand ACD, the most common allergens included preservatives, metals, fragrances, topical antibiotics, and rubber additives.
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  127. 127
    Perrenoud, D.; Bircher, A.; Hunziker, T.; Sutter, H.; Bruckner-Tuderman, L.; Stäger, J.; Thürlimann, W.; Schmid, P.; Suard, A.; Hunziker, N. Frequency of Sensitization to 13 Common Preservatives in Switzerland. Swiss Contact Dermatitis Research Group. Contact Dermatitis 1994, 30 (5), 276– 279,  DOI: 10.1111/j.1600-0536.1994.tb00597.x
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    127
    Frequency of sensitization to 13 common preservatives in Switzerland. Swiss Contact Dermatitis Research Group
    Perrenoud D; Bircher A; Hunziker T; Suter H; Bruckner-Tuderman L; Stager J; Thurlimann W; Schmid P; Suard A; Hunziker N
    Contact dermatitis (1994), 30 (5), 276-9 ISSN:0105-1873.
    From February 1989 to January 1990, the Swiss Contact Dermatitis Research Group conducted a 1-year study to examine the frequency of sensitization to a series of 13 common preservatives. A group of 2295 consecutive outpatients with suspected allergic contact dermatitis (age range 7-90 years, with a mean age of 42; 911 males, 1384 females) was tested. The %s of positive reactions to the preservatives studied are as follows, in descending order: formaldehyde 5.7%, benzalkonium chloride 5.5%, Kathon CG 5.5%, thimerosal 4.2%, chlorhexidine digluconate 2.0%, DMDM hydantoin 1.7%, paraben mix 1.7%, chloroacetamide 1.5%, Bronopol 1.2%, imidazolidinyl urea 1.0%, quaternium 15 1.0%, triclosan 0.8%, 2,4-dichlorobenzyl alcohol 0.4%. These relatively high values suggest a heavy exposure of the Swiss population to topical preservatives. Compared to previous studies, the sensitization rate to Kathon CG has stabilized in Switzerland over the last 2 years. Sensitization to formaldehyde portrayed impressive geographical variation, with sensitization rates up to 9% in western and only 3% in eastern Switzerland. The low sensitization rate to parabens argues for their inclusion in a medicament or preservative series, rather than in the standard series.
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  128. 128
    Isaac, J.; Scheinman, P. L. Benzalkonium Chloride: An Irritant and Sensitizer. Dermatitis 2017, 28 (6), 346– 352,  DOI: 10.1097/DER.0000000000000316
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    128
    Benzalkonium Chloride: An Irritant and Sensitizer
    Isaac, Jahdonna; Scheinman, Pamela L.
    Dermatitis (2017), 28 (6), 346-352CODEN: DERMCG; ISSN:1710-3568. (Lippincott Williams & Wilkins)
    Background: Benzalkonium chloride (BAK) is a known irritant, and potentially cross-reacting quaternary ammonium compds. are commonly used as preservatives in personal care products. Objective: The aim of the study was to review pos. reactions to BAK in 615 patients patch tested for suspected allergic contact dermatitis. Methods: A retrospective chart review was performed in 615 patients patch tested from June 2015 to Oct. 2016. All patients were tested to a Modified American Contact Dermatitis Society core series of 70 allergens including BAK (0.1% aq.). Initial readings were performed at 48 h with final readings performed between 72 and 168 h. Results were graded as + (weak: papules and erythema), ++ (strong: papules and edema or vesicles), or +++ (extreme: coalescing vesicles, spreading or bullous reactions). Results: A total of 141 men (23%) and 475 women (77%) were tested (mean age, 49 years). Four hundred thirty-two (70%) were atopic. Of 615 patients, 198 (32%) tested pos. to BAK, and 64 (10%) had ++ or +++ reactions at their final reading. On av., BAK-pos. patients were using at least 1 product contg. BAK or possible cross-reactors. Conclusions: Widespread exposure to irritants in dermatitis patients can predispose to sensitization. Products contg. BAK or potential cross-reactors should be used carefully in patients with compromised skin barriers.
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  129. 129
    Kreipe, K.; Forkel, S.; Heinemann, K. E.; Amschler, K.; Fuchs, T.; Geier, J.; Buhl, T. Contact Sensitizations to Disinfectants Containing Alcohols or Quaternary Ammonium Compounds Are Rarely of Clinical Relevance. Contact Dermatitis 2021, 85, 211,  DOI: 10.1111/cod.13844
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    129
    Contact sensitizations to disinfectants containing alcohols or quaternary ammonium compounds are rarely of clinical relevance
    Kreipe, Katharina; Forkel, Susann; Heinemann, Kim-Elisabeth; Amschler, Katharina; Fuchs, Thomas; Geier, Johannes; Buhl, Timo
    Contact Dermatitis (2021), 85 (2), 211-214CODEN: CODEDG; ISSN:0105-1873. (Wiley-Blackwell)
    The use of disinfectants is part of the everyday life of people, esp. in the medical profession. During the coronavirus disease 2019 (COVID-19) pandemic, the use of disinfectants continues to increase and is of fundamental importance in infection control. To det. the frequency of sensitization and the value of patch testing to didecyldimethylammonium chloride (DDAC) and the alcs. ethanol, 1-propanol, and isopropanol. Clin. patch test data of 145 patients with suspected contact allergy to disinfectants were retrospective analyzed. Among the 145 patients patch tested with the different alcs., only one nurse was detected with a possible allergy to 1-propanol. Addnl. patch testing in 84 patients with DDAC 0.05% resulted in five patients with weakly pos. reactions only, without clin. relevance. Patch testing with DDAC 0.03% showed no pos. reactions at all on day 3 readings. DDAC and alcs. are rarely responsible for allergic contact dermatitis. The accused products of the patients should be checked for other allergens and further additives with skin-irritating properties. Individual susceptibility and mishandling of the disinfectants should be considered.
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  130. 130
    Steinkjer, B. Contact Dermatitis from Cetyl Pyridinium Chloride in Latex Surgical Gloves. Contact Dermatitis 1998, 39 (1), 29– 30,  DOI: 10.1111/j.1600-0536.1998.tb05808.x
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    130
    Contact dermatitis from cetyl pyridinium chloride in latex surgical gloves
    Steinkjer, Bjarte
    Contact Dermatitis (1998), 39 (1), 29-30CODEN: CODEDG; ISSN:0105-1873. (Munksgaard International Publishers Ltd.)
    Cetyl pyridinium chloride, found in Biogel latex gloves, caused allergic contact dermatitis in humans.
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    Cahill, J.; Nixon, R. Allergic Contact Dermatitis to Quaternium 15 in a Moisturizing Lotion. Australas. J. Dermatol. 2005, 46 (4), 284– 285,  DOI: 10.1111/j.1440-0960.2005.00210.x
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    131
    Allergic contact dermatitis to quaternium 15 in a moisturizing lotion
    Cahill Jennifer; Nixon Rosemary
    The Australasian journal of dermatology (2005), 46 (4), 284-5 ISSN:0004-8380.
    A 56-year-old nurse from a rural area presented with a 12-month history of hand dermatitis. She had previously been patch tested by a local medical practitioner with the thin-layer rapid-use epicutaneous test, which had shown allergies to quaternium 15 and formaldehyde. After testing, she was prescribed methylprednisolone aceponate 1 mg/g cream by the medical practitioner, but was not informed that quaternium 15 is contained in the Microshield moisturizing lotion she was using at work. When her dermatitis persisted, she saw a dermatologist, who advised her to avoid the Microshield moisturizing lotion, and use a waterless hand cleanser on return to work. The diagnoses were firstly allergic contact dermatitis from quaternium 15 in the moisturizing lotion, and secondly irritant contact dermatitis from nursing work. This case highlights both the presence of quaternium 15 in a product commonly used in health-care settings in Australia, and the importance of offering informed, appropriate advice to patients following patch testing.
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    Tosti, A.; Piraccini, B. M.; Bardazzi, F. Occupational Contact Dermatitis due to Quaternium 15. Contact Dermatitis 1990, 23 (1), 41– 42,  DOI: 10.1111/j.1600-0536.1990.tb00082.x
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    Occupational contact dermatitis due to quaternium 15
    Tosti A; Piraccini B M; Bardazzi F
    Contact dermatitis (1990), 23 (1), 41-2 ISSN:0105-1873.
    There is no expanded citation for this reference.
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  133. 133
    Finch, T. M.; Prais, L.; Foulds, I. S. Occupational Allergic Contact Dermatitis from Quaternium-15 in an Electroencephalography Skin Preparation Gel. Contact Dermatitis 2001, 44 (1), 36– 37,  DOI: 10.1034/j.1600-0536.2001.440107-11.x
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    De Quintana Sancho, A.; Ratón, J. A.; Eizaguirre, X. Occupational Allergic Contact Dermatitis Caused by N,N-Didecyl-N-Methyl-Poly(oxyethyl) Ammonium Propionate in a Dental Assistant. Contact Dermatitis 2014, 70 (6), 379– 380,  DOI: 10.1111/cod.12174
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    134
    Occupational allergic contact dermatitis caused by N,N-didecyl-N-methyl-poly(oxyethyl) ammonium propionate in a dental assistant
    De Quintana Sancho Adrian; Raton Juan Antonio; Eizaguirre Xabier
    Contact dermatitis (2014), 70 (6), 379-80 ISSN:.
    There is no expanded citation for this reference.
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  135. 135
    Robinson, A. J.; Foster, R. S.; Halbert, A. R.; King, E.; Orchard, D. Granular Parakeratosis Induced by Benzalkonium Chloride Exposure from Laundry Rinse Aids. Australas. J. Dermatol. 2017, 58 (3), e138– e140,  DOI: 10.1111/ajd.12551
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    Anderson, S. E.; Shane, H.; Long, C.; Lukomska, E.; Meade, B. J.; Marshall, N. B. Evaluation of the Irritancy and Hypersensitivity Potential Following Topical Application of Didecyldimethylammonium Chloride. J. Immunotoxicol. 2016, 13 (4), 557– 566,  DOI: 10.3109/1547691X.2016.1140854
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    136
    Evaluation of the irritancy and hypersensitivity potential following topical application of didecyldimethylammonium chloride
    Anderson, Stacey E.; Shane, Hillary; Long, Carrie; Lukomska, Ewa; Meade, B. Jean; Marshall, Nikki B.
    Journal of Immunotoxicology (2016), 13 (4), 557-566CODEN: JIOMAP; ISSN:1547-691X. (Taylor & Francis Ltd.)
    Didecyldimethylammonium chloride (DDAC) is a dialkyl-quaternary ammonium compd. that is used in numerous products for its bactericidal, virucidal and fungicidal properties. There have been clin. reports of immediate and delayed hypersensitivity reactions in exposed individuals; however, the sensitization potential of DDAC has not been thoroughly investigated. The purpose of these studies was to evaluate the irritancy and sensitization potential of DDAC following dermal exposure in a murine model. DDAC induced significant irritancy (0.5 and 1%), evaluated by ear swelling in female Balb/c mice. Initial evaluation of the sensitization potential was conducted using the local lymph node assay (LLNA) at concns. ranging from 0.0625-1%. A concn.-dependent increase in lymphocyte proliferation was obsd. with a calcd. EC3 value of 0.17%. Dermal exposure to DDAC did not induce increased prodn. of IgE as evaluated by phenotypic anal. of draining lymph node B-cells (IgE + B220+) and measurement of total serum IgE levels. Addnl. phenotypic analyses revealed significant and dose-responsive increases in the abs. no. of B-cells, CD4 + T-cells, CD8 + T-cells and dendritic cells in the draining lymph nodes, along with significant increases in the percentage of B-cells (0.25% and 1% DDAC) at Day 10 following 4 days of dermal exposure. There was also a significant and dose-responsive increase in the no. of activated CD44 + CD4 + and CD8 + T-cells and CD86 + B-cells and dendritic cells following exposure to all concns. of DDAC. These results demonstrate the potential for development of irritation and hypersensitivity responses to DDAC following dermal exposure and raise concerns about the use of this chem. and other quaternary ammonium compds. that may elicit similar effects.
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  137. 137
    Shane, H. L.; Lukomska, E.; Stefaniak, A. B.; Anderson, S. E. Divergent Hypersensitivity Responses Following Topical Application of the Quaternary Ammonium Compound, Didecyldimethylammonium Bromide. J. Immunotoxicol. 2017, 14 (1), 204– 214,  DOI: 10.1080/1547691X.2017.1397826
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    137
    Divergent hypersensitivity responses following topical application of the quaternary ammonium compound, didecyldimethylammonium bromide
    Shane, Hillary L.; Lukomska, Ewa; Stefaniak, Aleksandr B.; Anderson, Stacey E.
    Journal of Immunotoxicology (2017), 14 (1), 204-214CODEN: JIOMAP; ISSN:1547-691X. (Taylor & Francis Ltd.)
    Didecyldimethylammonium bromide (DDAB) is a fourth generation dialkyl-quaternary ammonium compd. (QAC) that is used in numerous products for its antimicrobial properties. While many QACs have been assocd. with allergic disease, the toxicity and sensitization of DDAB have not been thoroughly investigated. The purpose of these studies was to evaluate the irritancy and sensitization potential of DDAB following dermal application in a murine model. DDAB induced significant irritancy (0.0625-2%), evaluated by ear swelling in female BALB/c mice. Initial evaluation of the sensitization potential was conducted using the local lymph node assay (LLNA) at concns. ranging from 0.0625% to 2%. A concn.-dependent increase in lymphocyte proliferation was obsd. with a calcd. EC3 value of 0.057%. Immune cell phenotyping along with local and systemic IgE levels were evaluated following 4 and 14 days of dermal application. Phenotypic analyses revealed significant and dose-responsive increases in the abs. no. of B-cells, CD4+ T-cells, CD8+ T-cells, and dendritic cells in the draining lymph nodes (DLNs) following 4 and 14 days of dermal exposure with significant increases in the no. of activated B-cells and dendritic cells. However, increased activation of CD4+ T-cell and CD8+ T-cells was only obsd. following four days of DDAB exposure. Exposure to DDAB also induced increased prodn. of IgE as evaluated by phenotypic anal. of DLN B-cells (IgE+ B-cells) and measurement of total serum IgE levels following 14 days but not four days of dermal application. Significant increases in gene expression were obsd. in the DLN (Il-4, Il-10, and ox40l) and ear (tslp) following 4 and 14 days of DDAB exposure. These results demonstrate the potential for development of irritation and hypersensitivity responses to DDAB following dermal exposure and raise concerns about the effects of exposure duration on hypersensitivity responses.
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  138. 138
    Shane, H. L.; Lukomska, E.; Kashon, M. L.; Anderson, S. E. Topical Application of the Quaternary Ammonium Compound Didecyldimethylammonium Chloride Activates Type 2 Innate Lymphoid Cells and Initiates a Mixed-Type Allergic Response. Toxicol. Sci. 2019, 168 (2), 508– 518,  DOI: 10.1093/toxsci/kfz002
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    138
    Topical application of the quaternary ammonium compound didecyldimethylammonium chloride activates type 2 innate lymphoid cells and initiates a mixed-type allergic response
    Shane, Hillary L.; Lukomska, Ewa; Kashon, Michael L.; Anderson, Stacey E.
    Toxicological Sciences (2019), 168 (2), 508-518CODEN: TOSCF2; ISSN:1096-0929. (Oxford University Press)
    Didecyldimethylammonium chloride (DDAC) is an antimicrobial dialkyl-quaternary ammonium compd. used in industrial and com. products. Clin. data suggest that DDAC exposure elicits multiple types of hypersensitivity reactions; here, we confirm this observation in a BALB/c murine model. To examine the immunol. mechanism behind this mixed-type response and the potential involvement of type 2 innate lymphoid cells (ILC2s), we assessed early immune responses in the skin following topical DDAC exposure (0.125% and 0.5%). DDAC exposure resulted in a rapid and dramatic increase in the Th2-skewing and ILC2-activating cytokine thymic stromal lymphopoietin. Correspondingly, dermal ILC2s were activated 24h after DDAC exposure, resulting in increased expression of CD25, ICOS and KLRG1, and decreased CD127 throughout 7 days of exposure. Following ILC2 activation, the Th2 cytokine IL-4 was elevated compared with control mice in total ear protein lysate (0.5% DDAC). Rag2-/- mice were used to det. a functional role for ILC2s in DDAC-induced sensitization. ILC2s from Rag2-/- mice were similarly activated by DDAC and, importantly, produced significant levels of IL-4 and IL-5 in the skin (0.5% DDAC). These data indicate that ILC2s contribute to early Th2 immune responses following DDAC exposure. ILC2s have been previously implicated in allergic responses, but to our knowledge have not been thoroughly investigated in chem. sensitization. These results indicate that following DDAC exposure, skin ILC2s become activated and produce Th2 cytokines, providing a possible mechanism for the development of the mixed-type allergic responses commonly obsd. with chem. sensitizers.
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  139. 139
    Anderson, S. E.; Baur, R.; Kashon, M.; Lukomska, E.; Weatherly, L.; Shane, H. L. Potential Classification of Chemical Immunologic Response Based on Gene Expression Profiles. J. Immunotoxicol. 2020, 17 (1), 122– 134,  DOI: 10.1080/1547691X.2020.1758855
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    139
    Potential classification of chemical immunologic response based on gene expression profiles
    Anderson, Stacey E.; Baur, Rachel; Kashon, Michael; Lukomska, Ewa; Weatherly, Lisa; Shane, Hillary L.
    Journal of Immunotoxicology (2020), 17 (1), 122-134CODEN: JIOMAP; ISSN:1547-691X. (Taylor & Francis Ltd.)
    In these studies, mice were dermally exposed to representative antimicrobial chems. (sensitizers: didecyldimethylammonium chloride (DDAC), ortho-phthalaldehyde (OPA), irritants: benzal-konium chloride (BAC), and adjuvant: triclosan (TCS)) and the mRNA expression of cytokines and cellular mediators was evaluated using real-time qPCR in various tissues over a 7-days period. All antimicrobials caused increases in the mRNA expression of the danger signals Tslp (skin), and S100a8 (skin, blood, lung). Expression of the TH2 cytokine Il4 peaked at different timepoints for the chems. based on exposure duration. Unique expression profiles were identified for OPA (Il10 in lymph node, Il4 and Il13 in lung) and TCS (Tlr4 in skin). Addnl., all chems. except OPA induced decreased expression of the cellular adhesion mol. Ecad. Overall, the results from these studies suggest that unique gene expression profiles are implicated following dermal exposure to various antimicrobial agents, warranting the need for addnl. studies. In order to advance the development of preventative and therapeutic strategies to combat immunol. disease, underlying mechanisms of antimicrobial-induced immunomodulation must be fully understood. This understanding will aid in the development of more effective methods to screen for chem. toxicity, and may potentially lead to more effective treatment strategies for those suffering from immune diseases.
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    Association of Occupational and Environmental Clinics. AOEC Exposure Code List. http://www.aoecdata.org/Default.aspx (accessed 2021-06-01).
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    Gonzalez, M.; Jégu, J.; Kopferschmitt, M. C.; Donnay, C.; Hedelin, G.; Matzinger, F.; Velten, M.; Guilloux, L.; Cantineau, A.; de Blay, F. Asthma among Workers in Healthcare Settings: Role of Disinfection with Quaternary Ammonium Compounds. Clin. Exp. Allergy 2014, 44 (3), 393– 406,  DOI: 10.1111/cea.12215
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    141
    Asthma among workers in healthcare settings: role of disinfection with quaternary ammonium compounds
    Gonzalez, M.; Jegu, J.; Kopferschmitt, M.-C.; Donnay, C.; Hedelin, G.; Matzinger, F.; Velten, M.; Guilloux, L.; Cantineau, A.; de Blay, F.
    Clinical & Experimental Allergy (2014), 44 (3), 393-406CODEN: CLEAEN; ISSN:0954-7894. (Wiley-Blackwell)
    Summary : Introduction : An increased incidence of asthma has been reported among healthcare workers. The role of quaternary ammonium compds. (QACs), commonly used in cleaning/disinfection products, has not been clearly defined. The aim of this study was to analyze assocns. between asthma and occupational exposure to disinfectants, esp. QACs. Methods : The study was performed on a stratified random sample of the various healthcare departments of 7 healthcare settings. The study included: questionnaire, phys. examn. and specific IgE assays. Occupational exposure assessment was performed by means of a work questionnaire, workplace studies and a review of products ingredients. Data were analyzed by logistic regression. Results : Response rate was 77%; 543 workers (89% female) participated; 37.1% were registered nurses (RNs), 16.4% auxiliary nurses (ANs), 17.3% cleaners; 32.8% were atopic. 335 participants were exposed to QACs. Nursing professionals reported a significantly higher risk of reported physician-diagnosed asthma and, for RNs, of nasal symptoms at work than administrative staff working in healthcare sector. This risk was particularly marked during disinfection tasks and when exposure to QACs. Exposure to QACs increased significantly the risk of reported physician-diagnosed asthma and nasal symptoms at work (adjusted OR = 7.5 and 3.2, resp.). No significant assocn. was found with other exposures such as latex glove use, chlorinated products/bleach or glutaraldehyde. Conclusion : RNs and ANs presented a higher risk of reported asthma than administrative staff. The highest risk was assocd. with tasks involving diln. of disinfection products by manual mixing, suggesting possible exposure to repeated peaks of concd. products known to be strong respiratory irritants. Workplace interventions should be conducted to more clearly det. QAC exposure and improve disinfection procedures.
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  142. 142
    Paris, C.; Ngatchou-Wandji, J.; Luc, A.; McNamee, R.; Bensefa-Colas, L.; Larabi, L.; Telle-Lamberton, M.; Herin, F.; Bergeret, A.; Bonneterre, V.; Brochard, P.; Choudat, D.; Dupas, D.; Garnier, R.; Pairon, J. C.; Agius, R. M.; Ameille, J. Work-Related Asthma in France: Recent Trends for the Period 2001–2009. Occup. Environ. Med. 2012, 69 (6), 391– 397,  DOI: 10.1136/oemed-2011-100487
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    142
    Work-related asthma in France: recent trends for the period 2001-2009
    Paris Christophe; Ngatchou-Wandji Joseph; Luc Amandine; McNamee Roseanne; Bensefa-Colas Lynda; Larabi Lynda; Telle-Lamberton Maylis; Herin Fabrice; Bergeret Alain; Bonneterre Vincent; Brochard Patrick; Choudat Dominique; Dupas Dominique; Garnier Robert; Pairon Jean-Claude; Agius Raymond M; Ameille Jacques
    Occupational and environmental medicine (2012), 69 (6), 391-7 ISSN:.
    OBJECTIVE: Knowledge on the time-course (trends) of work-related asthma (WRA) remains sparse. The aim of this study was to describe WRA trends in terms of industrial activities and the main causal agents in France over the period 2001-2009. METHOD: Data were collected from the French national network of occupational health surveillance and prevention (Reseau National de Vigilance et de Prevention des Pathologies Professionnelles (RNV3P)). Several statistical models (non-parametric test, zero-inflated negative binomial, logistic regression and time-series models) were used and compared with assess trends. RESULTS: Over the study period, 2914 WRA cases were included in the network. A significant decrease was observed overall and for some agents such as isocyanates (p = 0.007), aldehydes (p = 0.01) and latex (p = 0.01). Conversely, a significant increase was observed for cases related to exposure to quaternary ammonium compounds (p = 0.003). The health and social sector demonstrated both a growing number of cases related to the use of quaternary ammonium compounds and a decrease of cases related to aldehyde and latex exposure. CONCLUSIONS: WRA declined in France over the study period. The only significant increase concerned WRA related to exposure to quaternary ammonium compounds. Zero-inflated negative binomial and logistic regression models appear to describe adequately these data.
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    Bernstein, J. A.; Stauder, T.; Bernstein, D. I.; Bernstein, I. L. A Combined Respiratory and Cutaneous Hypersensitivity Syndrome Induced by Work Exposure to Quaternary Amines. J. Allergy Clin. Immunol. 1994, 94 (2), 257– 259,  DOI: 10.1016/0091-6749(94)90048-5
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    143
    A combined respiratory and cutaneous hypersensitivity syndrome induced by work exposure to quaternary amines
    Bernstein J A; Stauder T; Bernstein D I; Bernstein I L
    The Journal of allergy and clinical immunology (1994), 94 (2 Pt 1), 257-9 ISSN:0091-6749.
    The quaternary amine, benzalkonium chloride, has been associated with cutaneous and mucosal delayed hypersensitivity reactions and with paradoxical bronchoconstriction after use of aerosolized asthma medications. Until now, quaternary amines have not been reported to cause occupational asthma. We describe a case of occupational asthma caused by prolonged exposure to a cleaning solution containing benzalkonium chloride in the workplace. Single-blind, placebo-controlled, open-room challenges were performed to determine the specific agent responsible for the patient's symptoms. Pulmonary function and epicutaneous challenge tests were also performed. The patient had positive responses to challenges with a liquid toilet bowl cleaner containing benzalkonium chloride but was unreactive to other agents tested. Removal from the workplace resulted in complete resolution of symptoms. The exact mechanisms responsible for occupational asthma induced by quaternary amines remain unknown; however, this case emphasizes the importance of recognizing reactive chemicals as possible causes.
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    Burge, P. S.; Richardson, M. N. Occupational Asthma due to Indirect Exposure to Lauryl Dimethyl Benzyl Ammonium Chloride Used in a Floor Cleaner. Thorax 1994, 49 (8), 842– 843,  DOI: 10.1136/thx.49.8.842
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    144
    Occupational asthma due to indirect exposure to lauryl dimethyl benzyl ammonium chloride used in a floor cleaner
    Burge P S; Richardson M N
    Thorax (1994), 49 (8), 842-3 ISSN:0040-6376.
    The case is described of a 44 year old pharmacist who developed severe occupational asthma threatening his continued employment, confirmed by serial measurement of peak expiratory flow at home and work. The cause was found to be the cleaning agent used in his office when it was unoccupied. Bronchial challenge testing identified the specific agent to which he was sensitised as lauryl dimethyl benzyl ammonium chloride, a constituent of the floor cleaner. Substitution of this floor cleaner by a simple detergent cleaner led to a substantial improvement in his asthma, confirmed by repeated serial peak flow measurements.
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    Purohit, A.; Kopferschmitt-Kubler, M. C.; Moreau, C.; Popin, E.; Blaumeiser, M.; Pauli, G. Quaternary Ammonium Compounds and Occupational Asthma. Int. Arch. Occup. Environ. Health 2000, 73 (6), 423– 427,  DOI: 10.1007/s004200000162
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    145
    Quaternary ammonium compounds and occupational asthma
    Purohit, A.; Kopferschmitt-Kubler, M.-C.; Moreau, C.; Popin, E.; Blaumeiser, M.; Pauli, G.
    International Archives of Occupational and Environmental Health (2000), 73 (6), 423-427CODEN: IAEHDW; ISSN:0340-0131. (Springer-Verlag)
    Objective: Quaternary ammonium compds., among which benzalkonium chloride is one of the best-known, are commonly used as antiseptics, disinfectants, detergents and preservatives. They can cause occupational asthma, which however, has been rarely reported so far, despite wide use of these products. We report three such cases. Possible mechanisms causing asthma are discussed, taking into account their characteristics. Methods and results: Our patients, all female nurses, manifested asthma symptoms upon handling disinfectant solns. contg. benzalkonium chloride. Work-related fall in PEFR was obsd. in all of them. The diagnosis was confirmed by challenge tests where the patients were exposed, in a closed chamber, to suspected disinfectant contained in a tray. All of the women developed early or delayed symptoms upon exposure. Similar challenge tests to placebo or other disinfectants devoid of quaternary ammonium compd. were neg. Conclusion: These three cases, in addn. to others reported in the literature, point out an as yet poorly known etiol. of occupational asthma to quaternary ammonium compds. in hospital employees. The exact mechanism of the action remains unexplained.
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    Vandenplas, O.; D’Alpaos, V.; Evrard, G.; Jamart, J.; Thimpont, J.; Huaux, F.; Renauld, J.-C. Asthma Related to Cleaning Agents: A Clinical Insight. BMJ. Open 2013, 3 (9), e003568  DOI: 10.1136/bmjopen-2013-003568
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    Bellier, M.; Barnig, C.; Renaudin, J. M.; Sbinne, B.; Lefebvre, F.; Qi, S.; de Blay, F. Importance of Specific Inhalation Challenge in the Diagnosis of Occupational Asthma Induced by Quaternary Ammonium Compounds. J. Allergy Clin. Immunol. Pract. 2015, 3 (5), 819– 820,  DOI: 10.1016/j.jaip.2015.05.026
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    Importance of specific inhalation challenge in the diagnosis of occupational asthma induced by quaternary ammonium compounds
    Bellier Mael; Renaudin Jean Marie; Sbinne Brigitte; Barnig Cindy; Lefebvre Francois; Qi Shanshan; de Blay Frederic
    The journal of allergy and clinical immunology. In practice (2015), 3 (5), 819-20 ISSN:.
    There is no expanded citation for this reference.
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    LaKind, J. S.; Goodman, M. Methodological Evaluation of Human Research on Asthmagenicity and Occupational Cleaning: A Case Study of Quaternary Ammonium Compounds (“quats”). Allergy Asthma Clin. Immunol. 2019, 15 (1), 69,  DOI: 10.1186/s13223-019-0384-8
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    148
    Methodological evaluation of human research on asthmagenicity and occupational cleaning: a case study of quaternary ammonium compounds ("quats")
    LaKind Judy S; LaKind Judy S; Goodman Michael
    Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology (2019), 15 (), 69 ISSN:1710-1484.
    In this paper, we review methodological approaches used in studies that evaluated the association between occupational exposure to quaternary ammonium compounds (quats) and occupational asthma. This association is of interest because quats are a common active ingredient of disinfectants and have been linked to work-related asthma in some circumstances. However, any evidence-based assessment of an exposure-outcome association needs to consider both strengths and limitations of the literature. We focus on publications cited by various US and international organizations. Eighteen investigations included in the review fall into two broad categories: case reports and challenge studies of individual patients and population studies that examined the association between quats and asthma occurrence in groups of subjects. We evaluated these studies guided by questions that address whether: exposure data on specific quat(s) and other agents that may cause asthma were included, new asthma cases were differentiated from asthma exacerbation, and information on respiratory sensitivity versus irritation was given. We also assessed consistency across studies. Studies of individual patients, particularly those that provided detailed information on challenge test results, document cases of asthma induced by exposure to quats. By contrast, studies of occupational groups with the highest potential for quats exposure (e.g., cleaners and farmers) do not consistently report increased incidence of asthma due specifically to quats. The unresolved methodological issues include: poor understanding of exposure pathways considering that quats are non-volatile, lack of quantitative data allowing for identification of an asthmagenicity threshold, insufficient information on whether quats are sensitizers or act via dose-dependent irritation or some other mechanism, and inability to quantify risk of new-onset asthma attributable to quats. Another important area of uncertainty is the lack of information on the specific quats being used. There is also a lack of data capable of distinguishing the effects of quats from those of other chemical and biological workplace exposures. The current state-of-the-science does not allow a proper assessment of the potential link between quats and occupational asthma.
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  149. 149
    Clausen, P. A.; Frederiksen, M.; Sejbæk, C. S.; Sørli, J. B.; Hougaard, K. S.; Frydendall, K. B.; Carøe, T. K.; Flachs, E. M.; Meyer, H. W.; Schlünssen, V.; Wolkoff, P. Chemicals Inhaled from Spray Cleaning and Disinfection Products and Their Respiratory Effects. A Comprehensive Review. Int. J. Hyg. Environ. Health 2020, 229, 113592,  DOI: 10.1016/j.ijheh.2020.113592
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    149
    Chemicals inhaled from spray cleaning and disinfection products and their respiratory effects. A comprehensive review
    Clausen, Per A.; Frederiksen, Marie; Sejbaek, Camilla S.; Soerli, Jorid B.; Hougaard, Karin S.; Frydendall, Karen B.; Caroee, Tanja K.; Flachs, Esben M.; Meyer, Harald W.; Schlunssen, Vivi; Wolkoff, Peder
    International Journal of Hygiene and Environmental Health (2020), 229 (), 113592CODEN: IJEHFT; ISSN:1438-4639. (Elsevier GmbH)
    A review. Spray cleaning and disinfection products have been assocd. with adverse respiratory effects in professional cleaners and among residents doing domestic cleaning. This review combines information about use of spray products from epidemiol. and clin. studies, in vivo and in vitro toxicol. studies of cleaning chems., as well as human and field exposure studies. The most frequent chems. in spray cleaning and disinfection products were compiled, based on registrations in the Danish Product Registry. The chems. were divided into acids, bases, disinfectants, fragrances, org. solvents, propellants, and tensides. In addn., an assessment of selected cleaning and disinfectant chems. in spray products was carried out. Chems. of concern regarding respiratory effects (e.g. asthma) are corrosive chems. such as strong acids and bases (including ammonia and hypochlorite) and quaternary ammonium compds. (QACs). However, the evidence for respiratory effects after inhalation of QACs is ambiguous. Common fragrances are generally not considered to be of concern following inhalation. Solvents including glycols and glycol ethers as well as propellants are generally weak airway irritants and not expected to induce sensitization in the airways. Mixing of certain cleaning products can produce corrosive airborne chems. We discuss different hypotheses for the mechanisms behind the development of respiratory effects of inhalation of chems. in cleaning agents. An integrative assessment is needed to understand how these chems. can cause the various respiratory effects.
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    Larsen, S. T.; Verder, H.; Nielsen, G. D. Airway Effects of Inhaled Quaternary Ammonium Compounds in Mice. Basic Clin. Pharmacol. Toxicol. 2012, 110 (6), 537– 543,  DOI: 10.1111/j.1742-7843.2011.00851.x
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    Airway effects of inhaled quaternary ammonium compounds in mice
    Larsen, Soeren T.; Verder, Henrik; Nielsen, Gunnar D.
    Basic & Clinical Pharmacology & Toxicology (2012), 110 (6), 537-543CODEN: BCPTBO; ISSN:1742-7835. (Wiley-Blackwell)
    Quaternary ammonium compds. (QAC) constitute a family of widely used chem. substances. The QAC benzalkonium chloride (BAC) has caused bronchoconstriction in human beings by poorly understood mechanisms and lung damage at high concn. as shown in a single rat study. This study evaluates acute airway effects in mice after inhalation of aerosols of the QACs, BAC, hexadecyl tri-Me ammonium bromide (HTA), cetyl pyridinium chloride (CPC) and di-Me dioctadecyl ammonium bromide (DDA). The QACs gave rise to concn.-dependent decreases in the tidal vol. (VT) and a concomitant increase in respiratory rate indicating pulmonary irritation. The potencies of the QAC to induce these effects were in the order: BAC > HTA = CPC > DDA. Furthermore, inhalation of BAC and CPC aerosols gave rise to pulmonary inflammation as apparent from bronchoalveolar lavage. Stimulation of nasal trigeminal nerve endings by QAC, which may serve as a warning signal, was absent.
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  151. 151
    Kwon, D.; Lim, Y. M.; Kwon, J. T.; Shim, I.; Kim, E.; Lee, D. H.; Yoon, B. I.; Kim, P.; Kim, H. M. Evaluation of Pulmonary Toxicity of Benzalkonium Chloride and Triethylene Glycol Mixtures Using in Vitro and in Vivo Systems. Environ. Toxicol. 2019, 34 (5), 561– 572,  DOI: 10.1002/tox.22722
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    151
    Evaluation of pulmonary toxicity of benzalkonium chloride and triethylene glycol mixtures using in vitro and in vivo systems
    Kwon, Doyoung; Lim, Yeon-Mi; Kwon, Jung-Taek; Shim, Ilseob; Kim, Eunji; Lee, Doo-Hee; Yoon, Byung-Il; Kim, Pilje; Kim, Hyun-Mi
    Environmental Toxicology (2019), 34 (5), 561-572CODEN: ETOXFH; ISSN:1520-4081. (John Wiley & Sons, Inc.)
    Benzalkonium chloride (BAC) is a widely used disinfectant/preservative, and respiratory exposure to this compd. has been reported to be highly toxic. The purpose of this study was to est. the toxicity of BAC and TEG mixts. to pulmonary organs using in vitro and in vivo expts. Human alveolar epithelial (A549) cells incubated with BAC (1-10 μg/mL) for 24 h showed significant cytotoxicity, while TEG (up to 1000 μg/mL) did not affect cell viability. However, TEG in combination with BAC aggravated cell damage and inhibited colony formation as compared to BAC alone. TEG also exacerbated BAC-promoted prodn. of reactive oxygen species (ROS) and redn. of glutathione (GSH) level in A549 cells. However, pretreatment of the cells with N-acetylcysteine (NAC) alleviated the cytotoxicity, indicating oxidative stress could be a mechanism of the toxicity. Quantification of intracellular BAC by LC/MS/MS showed that cellular distribution/absorption of BAC was enhanced in A549 cells when it was exposed together with TEG. Intratracheal instillation of BAC (400 μg/kg) in rats was toxic to the pulmonary tissues while that of TEG (up to 1000 μg/kg) did not show any harmful effect. A combination of nontoxic doses of BAC (200 μg/kg) and TEG (1000 μg/kg) promoted significant lung injury in rats, as shown by increased protein content and lactate dehydrogenase (LDH) activity in bronchoalveolar lavage fluids (BALF).
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  152. 152
    Choi, H. Y.; Lee, Y. H.; Lim, C. H.; Kim, Y. S.; Lee, I. S.; Jo, J. M.; Lee, H. Y.; Cha, H. G.; Woo, H. J.; Seo, D. S. Assessment of Respiratory and Systemic Toxicity of Benzalkonium Chloride Following a 14-Day Inhalation Study in Rats. Part. Fibre Toxicol. 2020, 17 (1), 5,  DOI: 10.1186/s12989-020-0339-8
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    152
    Assessment of respiratory and systemic toxicity of Benzalkonium chloride following a 14-day inhalation study in rats
    Choi, Hye-Yeon; Lee, Yong-Hoon; Lim, Cheol-Hong; Kim, Yong-Soon; Lee, In-Seop; Jo, Ji-Min; Lee, Ha-Young; Cha, Hyo-Geun; Woo, Hee Jong; Seo, Dong-Seok
    Particle and Fibre Toxicology (2020), 17 (1), 5CODEN: PFTABQ; ISSN:1743-8977. (BioMed Central Ltd.)
    In the present study, we aimed to evaluate the respiratory toxicity of BAC due to its inhalation at exposure concns. of 0.8 (T1 group), 4 (T2 group) and 20 (T3 group) mg/m3. In our previous study on the acute inhalational toxicity of BAC, bleeding from the nasal cavity was obsd. in all the rats after exposure to 50 mg/m3 BAC. Therefore, in this study, 20 mg/m3 was set as the highest exposure concn., followed by 4 and 0.8 mg/m3 as the medium and low concns. for 6 h/day and 14 days, resp. After exposure, recovery periods of 2 and 4 wk were provided. Addnl., alveolar lavage fluid was analyzed in males of the BAC-exposed groups at the end of exposure and 2 wk after exposure to evaluate oxidative damage. In the T3 group exposed to BAC, deep breathing, hoarseness, and nasal discharge were obsd. along with a decline in feed intake and body wt., and nasal discharge was also obsd. in the T1 and T2 groups. ROS/RNS, IL-1β, IL-6, and MIP-2 levels decreased in a concn.-dependent manner in the bronchoalveolar lavage fluid. Histopathol. examn. showed cellular changes in the nasal cavity and the lungs of the TI, T2, and T3 groups. As a result, it was confirmed that the target organs in the respiratory system were the nasal cavity and the lungs. The adverse effects were evaluated as reversible responses to oxidative damage.
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  153. 153
    Ohnuma, A.; Yoshida, T.; Horiuchi, H.; Fukumori, J.; Tomita, M.; Kojima, S.; Takahashi, N.; Fukuyama, T.; Hayashi, K.; Yamaguchi, S.; Ohtsuka, R.; Kashimoto, Y.; Kuwahara, M.; Takeda, M.; Kosaka, T.; Nakashima, N.; Harada, T. Altered Pulmonary Defense System in Lung Injury Induced by Didecyldimethylammonium Chloride in Mice. Inhal. Toxicol. 2011, 23 (8), 476– 485,  DOI: 10.3109/08958378.2011.584080
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    153
    Altered pulmonary defense system in lung injury induced by didecyldimethylammonium chloride in mice
    Ohnuma, Aya; Yoshida, Toshinori; Horiuchi, Haruka; Fukumori, Junko; Tomita, Mariko; Kojima, Sayuri; Takahashi, Naofumi; Fukuyama, Tomoki; Hayashi, Koichi; Yamaguchi, Satoru; Ohtsuka, Ryoichi; Kashimoto, Yukiko; Kuwahara, Maki; Takeda, Makio; Kosaka, Tadashi; Nakashima, Nobuaki; Harada, Takanori
    Inhalation Toxicology (2011), 23 (8), 476-485CODEN: INHTE5; ISSN:0895-8378. (Informa Healthcare)
    Didecyldimethylammonium chloride (DDAC), a representative dialkyl-quaternary ammonium compd. (QAC), could contaminate working atmospheres when used in disinfectant operation and adversely affect human health. Furthermore, the development of bacteria resistant to DDAC might become public health concern. We postulated that DDAC instillation in the lungs alters pulmonary antioxidant and antimicrobial responses and increases susceptibility to systemic administration of a bacterial component lipopolysaccharide (LPS). Mice were intratracheally instilled with DDAC and sacrificed 1, 3, or 7 days after treatment. Pulmonary cytotoxicity in recovered bronchoalveolar lavage was evident on Days 1 and 7, and inflammatory cell influx and interleukin-6 expression peaked on Day 7, in assocn. with altered antioxidant and antimicrobial responses, as demonstrated by measuring heme oxygenase-1, glutathione peroxidase 2, lactoferrin, and mouse β-defensin-2 and -3 mRNA in the lung samples. The impaired defense system tended to enhance the inflammatory reaction caused by a systemic administration of LPS; the effect was in assocn. with increased expression of toll-like receptor-4 mRNA. The results suggest that DDAC alters pulmonary defense system, which may contribute to susceptibility to an exogenous infectious agent.
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  154. 154
    Abdelhamid, L.; Cabana-Puig, X.; Mu, Q.; Moarefian, M.; Swartwout, B.; Eden, K.; Das, P.; Seguin, R. P.; Xu, L.; Lowen, S.; Lavani, M.; Hrubec, T. C.; Jones, C. N.; Luo, X. M. Quaternary Ammonium Compound Disinfectants Reduce Lupus-Associated Splenomegaly by Targeting Neutrophil Migration and T-Cell Fate. Front. Immunol. 2020, 11, 575179,  DOI: 10.3389/fimmu.2020.575179
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    154
    Quaternary ammonium compound disinfectants reduce lupus-associated splenomegaly by targeting neutrophil migration and T-cell fate
    Abdelhamid, Leila; Cabana-Puig, Xavier; Mu, Qinghui; Moarefian, Maryam; Swartwout, Brianna; Eden, Kristin; Das, Prerna; Seguin, Ryan P.; Xu, Libin; Lowen, Sarah; Lavani, Mital; Hrubec, Terry C.; Jones, Caroline N.; Luo, Xin M.
    Frontiers in Immunology (2020), 11 (), 575179CODEN: FIRMCW; ISSN:1664-3224. (Frontiers Media S.A.)
    Hypersensitivity reactions and immune dysregulation have been reported with the use of quaternary ammonium compd. disinfectants (QACs). We hypothesized that QAC exposure would exacerbate autoimmunity assocd. with systemic lupus erythematosus (lupus). Surprisingly, however, we found that compared to QAC-free mice, ambient exposure of lupus-prone mice to QACs led to smaller spleens with no change in circulating autoantibodies or the severity of glomerulonephritis. This suggests that QACs may have immunosuppressive effects on lupus. Using a microfluidic device, we showed that ambient exposure to QACs reduced directional migration of bone marrow-derived neutrophils toward an inflammatory chemoattractant ex vivo. Consistent with this, we found decreased infiltration of neutrophils into the spleen. While bone marrow-derived neutrophils appeared to exhibit a pro-inflammatory profile, upregulated expression of PD-L1 was obsd. on neutrophils that infiltrated the spleen, which in turn interacted with PD-1 on T cells and modulated their fate. Specifically, QAC exposure hindered activation of splenic T cells and increased apoptosis of effector T-cell populations. Collectively, these results suggest that ambient QAC exposure decreases lupus-assocd. splenomegaly likely through neutrophil-mediated toning of T-cell activation and/or apoptosis. However, our findings also indicate that even ambient exposure could alter immune cell phenotypes, functions, and their fate. Further investigations on how QACs affect immunity under steady-state conditions are warranted.
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  155. 155
    Melin, V. E.; Potineni, H.; Hunt, P.; Griswold, J.; Siems, B.; Werre, S. R.; Hrubec, T. C. Exposure to Common Quaternary Ammonium Disinfectants Decreases Fertility in Mice. Reprod. Toxicol. 2014, 50, 163– 170,  DOI: 10.1016/j.reprotox.2014.07.071
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    155
    Exposure to common quaternary ammonium disinfectants decreases fertility in mice
    Melin, Vanessa E.; Potineni, Haritha; Hunt, Patricia; Griswold, Jodi; Siems, Bill; Werre, Stephen R.; Hrubec, Terry C.
    Reproductive Toxicology (2014), 50 (), 163-170CODEN: REPTED; ISSN:0890-6238. (Elsevier Inc.)
    Quaternary ammonium compds. (QACs) are antimicrobial disinfectants commonly used in com. and household settings. Extensive use of QACs results in ubiquitous human exposure, yet reproductive toxicity has not been evaluated. Decreased reproductive performance in lab. mice coincided with the introduction of a disinfectant contg. both alkyl di-Me benzyl ammonium chloride (ADBAC) and didecyl di-Me ammonium chloride (DDAC). QACs were detected in caging material over a period of several months following cessation of disinfectant use. Breeding pairs exposed for six months to a QAC disinfectant exhibited decreases in fertility and fecundity: increased time to first litter, longer pregnancy intervals, fewer pups per litter and fewer pregnancies. Significant morbidity in near term dams was also obsd. In summary, exposure to a common QAC disinfectant mixt. significantly impaired reproductive health in mice. This study illustrates the importance of assessing mixt. toxicity of commonly used products whose components have only been evaluated individually.
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  156. 156
    Melin, V. E.; Melin, T. E.; Dessify, B. J.; Nguyen, C. T.; Shea, C. S.; Hrubec, T. C. Quaternary Ammonium Disinfectants Cause Subfertility in Mice by Targeting Both Male and Female Reproductive Processes. Reprod. Toxicol. 2016, 59, 159– 166,  DOI: 10.1016/j.reprotox.2015.10.006
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    156
    Quaternary ammonium disinfectants cause subfertility in mice by targeting both male and female reproductive processes
    Melin, Vanessa E.; Melin, Travis E.; Dessify, Brian J.; Nguyen, Christina T.; Shea, Caroline S.; Hrubec, Terry C.
    Reproductive Toxicology (2016), 59 (), 159-166CODEN: REPTED; ISSN:0890-6238. (Elsevier Inc.)
    Alkyl di-Me benzyl ammonium chloride (ADBAC) and didecyl di-Me ammonium chloride (DDAC) are common ingredients in household bathroom and kitchen cleaning sprays. ADBAC + DDAC cause reproductive toxicity in mice. The aim of the present study was to investigate gender-specific reproductive effects from ADBAC + DDAC. Female reprodn. was assessed through ovulation, oocyte implantation, and estrus cycling. Male reproductive function was assessed by sperm concn., motility, and viability. Nos. of corpora lutea were not different after 2 wk, but decreased after 8 wk of ADBAC + DDAC exposure. Dams exposed for 5 wk to ADBAC + DDAC spent significantly less time in estrus. ADBAC + DDAC exposed males exhibited declines in both sperm concn. and motility, but not sperm viability. Subfertility in mice from ADBAC + DDAC exposure is, therefore, mediated through reproductive disturbances in both females and males. While the effect of ADBAC + DDAC exposure on human health is unclear, widespread exposure necessitates further consideration of their potential reproductive toxicity.
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  157. 157
    Hostetler, K. A.; Fisher, L. C.; Burruss, B. L. Reproductive Toxicity Assessment of Alkyl Dimethyl Benzyl Ammonium Chloride and Didecyl Dimethyl Ammonium Chloride in CD® Rats. Birth Defects Res. 2021, 113 (19), 1368– 1389,  DOI: 10.1002/bdr2.1955
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    157
    Reproductive toxicity assessment of alkyl dimethyl benzyl ammonium chloride and didecyl dimethyl ammonium chloride in CD rats
    Hostetler, Keith A.; Fisher, Louan C.; Burruss, Benjamin L.
    Birth Defects Research (2021), 113 (19), 1368-1389CODEN: BDRIDA; ISSN:2472-1727. (John Wiley & Sons, Inc.)
    To det. the potential of alkyl di-Me benzyl ammonium chloride (ADBAC) and didecyl di-Me ammonium chloride (DDAC) to induce reproductive toxicity in CD rats in two independent 2-generation reprodn. studies conducted according to Good Lab. Practices and standardized testing guidelines. Male and female rats (parents and offspring) were allowed continual free access to diets contg. concns. of ADBAC (0, 300, 1,000, or 2,000 ppm) or DDAC (0, 300, 750, or 1,500 ppm), beginning with F0 generation adults at 10 wk prior to breeding. No clin. signs of toxicity were obsd. in parental rats or their offspring in either study. Dietary exposure of parental rats to ADBAC or DDAC at the highest concns. produced transient decreases in body wt. and/or body wt. changes with no or minimal corresponding redn. in food consumption. Offspring (F1 and F2) in the highest concn. group in each study also exhibited reduced body wts., often with a corresponding redn. in wt. change, beginning on postnatal day (PND) 14 through weaning on PND 28. This redn. in pup body wt. corresponded to initiation of self-feeding. Based on reduced body wts., the no obsd. adverse effect level (NOAEL) for adult and offspring systemic toxicity was 1,000 ppm for ADBAC and 750 ppm for DDAC (equiv. to approx. daily oral doses of 59 and 45 mg/kg/day, resp.). The reproductive and developmental NOAEL for F0, F1, and F2 generation male and female rats was 2,000 ppm for ADBAC and 1,500 ppm for DDAC (equiv. to approx. daily oral doses of 118 and 91 mg/kg/day, resp.).
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    Dalgard, D. W.; Coval, D. E. Method for the Control of Fertility. U. S. Pat. US3869550A, March 4, 1975 (accessed 2022-07-17).
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    Biomonitoring California Scientific Guidance Panel. Potential Designated Chemicals: Quaternary Ammonium Compounds: Materials for March 4, 2020 Meeting of the Scientific Guidance Panel for Biomonitoring California , March 4, 2020 (accessed 2022-07-17).
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    Datta, S.; He, G.; Tomilov, A.; Sahdeo, S.; Denison, M. S.; Cortopassi, G. In Vitro Evaluation of Mitochondrial Function and Estrogen Signaling in Cell Lines Exposed to the Antiseptic Cetylpyridinium Chloride. Environ. Health Perspect. 2017, 125 (8), 087015,  DOI: 10.1289/EHP1404
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    160
    In vitro evaluation of mitochondrial function and estrogen signaling in cell lines exposed to the antiseptic cetylpyridinium chloride
    Datta, Sandipan; He, Guochun; Tomilov, Alexey; Sahdeo, Sunil; Denison, Michael S.; Cortopassi, Gino
    Environmental Health Perspectives (2017), 125 (8), 087015/1-087015/7CODEN: EVHPAZ; ISSN:1552-9924. (U. S. Department of Health and Human Services, National Institutes of Health)
    Background: Quaternary ammonium salts (QUATS), such as cetylpyridinium chloride (CPC) and benzalkonium chloride (BAK), are frequently used in antiseptic formulations, including toothpastes, mouthwashes, lozenges, throat and nasal sprays, and as biocides. Although in a recent ruling, the U.S. Food and Drug Administration (FDA) banned CPC from certain products and requested more data on BAK's efficacy and safety profile, QUATS, in general, and CPC and BAK, in particular, continue to be used in personal health care, food, and pharmaceutical and cleaning industries. Objectives: We aimed to assess CPC's effects on mitochondrial toxicity and endocrine disruption in vitro. Method: Mitochondrial O2 consumption and ATP (ATP) synthesis rates of osteosarcoma cybrid cells were measured before and after CPC and BAK treatment. Antiestrogenic effects of the compds. were measured by a luciferase-based assay using recombinant human breast carcinoma cells (VM7Luc4E2, ERalpha-pos.). Results: CPC inhibited both mitochondrial O2 consumption [half maximal inhibitory concn. IC50): 3.8 μM] and ATP synthesis (IC50: 0.9 μM), and addnl. findings supported inhibition of mitochondrial complex 1 as the underlying mechanism for these effects. In addn., CPC showed concn.-dependent antiestrogenic activity half maximal effective concn. [(EC50): 4.5 μM)]. BAK, another antimicrobial QUATS that is structurally similar to CPC, and the pesticide rotenone, a known complex 1 inhibitor, also showed mitochondrial inhibitory and antiestrogenic effects. In all three cases, there was overlap of the antiestrogenic activity with the mitochondrial inhibitory activity. Conclusions: Mitochondrial inhibition in vitro occurred at a CPC concn. that may be relevant to human exposures. The antiestrogenic activity of CPC, BAK, rotenone, and triclosan may be related to their mitochondrial inhibitory activity. Our findings support the need for addnl. research on the mitochondrial inhibitory and antiestrogenic effects of QUATS, including CPC and BAK.
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    Hrubec, T. C.; Melin, V. E.; Shea, C. S.; Ferguson, E. E.; Garofola, C.; Repine, C. M.; Chapman, T. W.; Patel, H. R.; Razvi, R. M.; Sugrue, J. E.; Potineni, H.; Magnin-Bissel, G.; Hunt, P. A. Ambient and Dosed Exposure to Quaternary Ammonium Disinfectants Causes Neural Tube Defects in Rodents. Birth Defects Res. 2017, 109 (14), 1166– 1178,  DOI: 10.1002/bdr2.1064
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    161
    Ambient and dosed exposure to quaternary ammonium disinfectants causes neural tube defects in rodents
    Hrubec, Terry C.; Melin, Vanessa E.; Shea, Caroline S.; Ferguson, Elizabeth E.; Garofola, Craig; Repine, Claire M.; Chapman, Tyler W.; Patel, Hiral R.; Razvi, Reza M.; Sugrue, Jesse E.; Potineni, Haritha; Magnin-Bissel, Geraldine; Hunt, Patricia A.
    Birth Defects Research (2017), 109 (14), 1166-1178CODEN: BDRIDA; ISSN:2472-1727. (John Wiley & Sons, Inc.)
    Background : Quaternary ammonium compds. are a large class of chems. used for their antimicrobial and antistatic properties. Two common quaternary ammonium compds., alkyldimethylbenzyl ammonium chloride (ADBAC) and didecyldimethyl ammonium chloride (DDAC), are combined in common cleaners and disinfectants. Introduction of a cleaner contg. ADBAC+DDAC in the vivarium caused neural tube defects (NTDs) in mice and rats. Methods : To further evaluate this finding, male and female mice were dosed in the feed at 60 or 120 mg/kg/day, or by oral gavage at 7.5, 15, or 30 mg/kg ADBAC+DDAC. Mice also received ambient exposure to ADBAC+DDAC from the disinfectant used in the mouse room. Embryos were evaluated on gestational day 10 for NTDs, and fetuses were evaluated on gestational day 18 for gross and skeletal malformations. Results : We found increased NTDs with exposure to ADBAC+DDAC in both rats and mice. The NTDs persisted for two generations after cessation of exposure. Notably, male exposure alone was sufficient to cause NTDs. Equally significant, ambient exposure from disinfectant use in the vivarium, influenced the levels of NTDs to a greater extent than oral dosing. No gross or significant axial skeletal malformations were obsd. in late gestation fetuses. Placental abnormalities and late gestation fetal deaths were increased at 120 mg/kg/day, which might explain the lack of malformations obsd. in late gestation fetuses. Conclusion : These results demonstrate that ADBAC+DDAC in combination are teratogenic to rodents. Given the increased use of these disinfectants, further evaluation of their safety in humans and their contribution to health and disease is essential.
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    Cholesterol modification of hedgehog signaling proteins in animal development
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    Science (Washington, D. C.) (1996), 274 (5285), 255-259CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
    Hedgehog (Hh) proteins comprise a family of secreted signaling mols. essential for patterning a variety of structures in animal embryogenesis. During biosynthesis, Hh undergoes an autocleavage reaction, mediated by its carboxyl-terminal domain, that produces a lipid-modified amino-terminal fragment responsible for all known Hh signaling activity. Here it is reported that cholesterol is the lipophilic moiety covalently attached to the amino-terminal signaling domain during autoprocessing and that the carboxyl-terminal domain acts as an intramol. cholesterol transferase. This use of cholesterol to modify embryonic signaling proteins may account for some of the effects of perturbed cholesterol biosynthesis on animal development.
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    Mauch, D. H.; Nägler, K.; Schumacher, S.; Göritz, C.; Müller, E.-C.; Otto, A.; Pfrieger, F. W. CNS Synaptogenesis Promoted by Glia-Derived Cholesterol. Science 2001, 294, 1354– 1357,  DOI: 10.1126/science.294.5545.1354
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    CNS synaptogenesis promoted by glia-derived cholesterol
    Mauch, Daniela H.; Naegler, Karl; Schumacher, Stefan; Goertzz, Christian; Mueller, Eva-Christina; Otto, Albrecht; Pfrieger, Frank W.
    Science (Washington, DC, United States) (2001), 294 (5545), 1354-1357CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
    The mol. mechanisms controlling synaptogenesis in the central nervous system (CNS) are poorly understood. Previous reports showed that a glia-derived factor strongly promotes synapse development in cultures of purified CNS neurons. Here, we identify this factor as cholesterol complexed to apolipoprotein E-contg. lipoproteins. CNS neurons produce enough cholesterol to survive and grow, but the formation of numerous mature synapses demands addnl. amts. that must be provided by glia. Thus, the availability of cholesterol appears to limit synapse development. This may explain the delayed onset of CNS synaptogenesis after glia differentiation and neurobehavioral manifestations of defects in cholesterol or lipoprotein homeostasis.
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    Francis, K. R.; Ton, A. N.; Xin, Y.; O’Halloran, P. E.; Wassif, C. A.; Malik, N.; Williams, I. M.; Cluzeau, C. V.; Trivedi, N. S.; Pavan, W. J.; Cho, W.; Westphal, H.; Porter, F. D. Modeling Smith-Lemli-Opitz Syndrome with Induced Pluripotent Stem Cells Reveals a Causal Role for Wnt/β-Catenin Defects in Neuronal Cholesterol Synthesis Phenotypes. Nat. Med. 2016, 22 (4), 388– 396,  DOI: 10.1038/nm.4067
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    Modeling Smith-Lemli-Opitz syndrome with induced pluripotent stem cells reveals a causal role for Wnt/β-catenin defects in neuronal cholesterol synthesis phenotypes
    Francis, Kevin R.; Ton, Amy N.; Xin, Yao; O'Halloran, Peter E.; Wassif, Christopher A.; Malik, Nasir; Williams, Ian M.; Cluzeau, Celine V.; Trivedi, Niraj S.; Pavan, William J.; Cho, Wonhwa; Westphal, Heiner; Porter, Forbes D.
    Nature Medicine (New York, NY, United States) (2016), 22 (4), 388-396CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)
    Smith-Lemli-Opitz syndrome (SLOS) is a malformation disorder caused by mutations in DHCR7, which impair the redn. of 7-dehydrocholesterol (7DHC) to cholesterol. SLOS results in cognitive impairment, behavioral abnormalities and nervous system defects, though neither affected cell types nor impaired signaling pathways are fully understood. Whether 7DHC accumulation or cholesterol loss is primarily responsible for disease pathogenesis is also unclear. Using induced pluripotent stem cells (iPSCs) from subjects with SLOS, we identified cellular defects that lead to precocious neuronal specification within SLOS derived neural progenitors. We also demonstrated that 7DHC accumulation, not cholesterol deficiency, is crit. for SLOS-assocd. defects. We further identified downregulation of Wnt/β-catenin signaling as a key initiator of aberrant SLOS iPSC differentiation through the direct inhibitory effects of 7DHC on the formation of an active Wnt receptor complex. Activation of canonical Wnt signaling prevented the neural phenotypes obsd. in SLOS iPSCs, suggesting that Wnt signaling may be a promising therapeutic target for SLOS.
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    Porter, F. D.; Herman, G. E. Malformation Syndromes Caused by Disorders of Cholesterol Synthesis. J. Lipid Res. 2011, 52 (1), 6– 34,  DOI: 10.1194/jlr.R009548
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    165
    Malformation syndromes caused by disorders of cholesterol synthesis
    Porter Forbes D; Herman Gail E
    Journal of lipid research (2011), 52 (1), 6-34 ISSN:.
    Cholesterol homeostasis is critical for normal growth and development. In addition to being a major membrane lipid, cholesterol has multiple biological functions. These roles include being a precursor molecule for the synthesis of steroid hormones, neuroactive steroids, oxysterols, and bile acids. Cholesterol is also essential for the proper maturation and signaling of hedgehog proteins, and thus cholesterol is critical for embryonic development. After birth, most tissues can obtain cholesterol from either endogenous synthesis or exogenous dietary sources, but prior to birth, the human fetal tissues are dependent on endogenous synthesis. Due to the blood-brain barrier, brain tissue cannot utilize dietary or peripherally produced cholesterol. Generally, inborn errors of cholesterol synthesis lead to both a deficiency of cholesterol and increased levels of potentially bioactive or toxic precursor sterols. Over the past couple of decades, a number of human malformation syndromes have been shown to be due to inborn errors of cholesterol synthesis. Herein, we will review clinical and basic science aspects of Smith-Lemli-Opitz syndrome, desmosterolosis, lathosterolosis, HEM dysplasia, X-linked dominant chondrodysplasia punctata, Congenital Hemidysplasia with Ichthyosiform erythroderma and Limb Defects Syndrome, sterol-C-4 methyloxidase-like deficiency, and Antley-Bixler syndrome.
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    Herron, J.; Reese, R. C.; Tallman, K. A.; Narayanaswamy, R.; Porter, N. A.; Xu, L. Identification of Environmental Quaternary Ammonium Compounds as Direct Inhibitors of Cholesterol Biosynthesis. Toxicol. Sci. 2016, 151 (2), 261– 270,  DOI: 10.1093/toxsci/kfw041
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    Identification of environmental quaternary ammonium compounds as direct inhibitors of cholesterol biosynthesis
    Herron, Josi; Reese, Rosalyn C.; Tallman, Keri A.; Narayanaswamy, Rohini; Porter, Ned A.; Xu, Libin
    Toxicological Sciences (2016), 151 (2), 261-270CODEN: TOSCF2; ISSN:1096-0929. (Oxford University Press)
    In this study, we aim to identify environmental mols. that can inhibit cholesterol biosynthesis, potentially leading to the same biochem. defects as obsd. in cholesterol biosynthesis disorders, which are often characterized by congenital malformations and developmental delay. Using the Distributed Structure-Searchable Toxicity (DSSTox) Database Network developed by EPA, we first carried out in silico screening of environmental mols. that display structures similar to AY9944, a known potent inhibitor of 3β-hydroxysterol-Δ7-reductase (DHCR7)-the last step of cholesterol biosynthesis. Mols. that display high similarity to AY9944 were subjected to test in mouse and human neuroblastoma cells for their effectiveness in inhibiting cholesterol biosynthesis by analyzing cholesterol and its precursor using gas chromatog.-mass spectrometry. We found that a common disinfectant mixt., benzalkonium chlorides (BACs), exhibits high potency in inhibiting DHCR7, as suggested by greatly elevated levels of the cholesterol precursor, 7-dehydrocholesterol (7-DHC). Subsequent structure-activity studies suggested that the potency of BACs as Dhcr7 inhibitors decrease with the length of their hydrocarbon chain: C10>C12»C14>C16. Real-time qPCR anal. revealed upregulation of the genes related to cholesterol biosynthesis and downregulation of the genes related to cholesterol efflux, suggesting a feedback response to the inhibition. Furthermore, an oxidative metabolite of 7-DHC that was previously identified as a biomarker in vivo was also found in cells exposed to BACs by liq. chromatog.-mass spectrometry. Our findings suggest that certain environmental mols. could potently inhibit cholesterol biosynthesis, which could be a new link between environment and developmental disorders.
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  167. 167
    Herron, J. M.; Tomita, H.; White, C. C.; Kavanagh, T. J.; Xu, L. Benzalkonium Chloride Disinfectants Induce Apoptosis, Inhibit Proliferation, and Activate the Integrated Stress Response in a 3-D in Vitro Model of Neurodevelopment. Chem. Res. Toxicol. 2021, 34 (5), 1265– 1274,  DOI: 10.1021/acs.chemrestox.0c00386
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    167
    Benzalkonium Chloride Disinfectants Induce Apoptosis, Inhibit Proliferation, and Activate the Integrated Stress Response in a 3-D in Vitro Model of Neurodevelopment
    Herron, Josi M.; Tomita, Hideaki; White, Collin C.; Kavanagh, Terrance J.; Xu, Libin
    Chemical Research in Toxicology (2021), 34 (5), 1265-1274CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)
    We previously found that the widely used disinfectants, benzalkonium chlorides (BACs), alter cholesterol and lipid homeostasis in neuronal cell lines and in neonatal mouse brains. Here, we investigate the effects of BACs on neurospheres, an in vitro three-dimensional model of neurodevelopment. Neurospheres cultured from mouse embryonic neural progenitor cells (NPCs) were exposed to increasing concns. (from 1 to 100 nM) of a short-chain BAC (BAC C12), a long-chain BAC (BAC C16), and AY9944 (a known DHCR7 inhibitor). We found that the sizes of neurospheres were decreased by both BACs but not by AY9944. Furthermore, we obsd. potent inhibition of cholesterol biosynthesis at the step of DHCR7 by BAC C12 but not by BAC C16, suggesting that cholesterol biosynthesis inhibition is not responsible for the obsd. redn. in neurosphere growth. By using immunostaining and cell cycle anal., we found that both BACs induced apoptosis and decreased proliferation of NPCs. To explore the mechanisms underlying their effect on neurosphere growth, we carried out RNA sequencing on neurospheres exposed to each BAC at 50 nM for 24 h, which revealed the activation of the integrated stress response by both BACs. Overall, these results suggest that BACs affect neurodevelopment by inducing the integrated stress response in a manner independent of their effects on cholesterol biosynthesis.
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    Javadov, S.; Kozlov, A. V.; Camara, A. K. S. Mitochondria in Health and Diseases. Cells 2020, 9 (5), 1177,  DOI: 10.3390/cells9051177
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    Dykens, J. A.; Marroquin, L. D.; Will, Y. Strategies to Reduce Late-Stage Drug Attrition due to Mitochondrial Toxicity. Expert Rev. Mol. Diagn. 2007, 7 (2), 161– 175,  DOI: 10.1586/14737159.7.2.161
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    Strategies to reduce late-stage drug attrition due to mitochondrial toxicity
    Dykens, James A.; Marroquin, Lisa D.; Will, Yvonne
    Expert Review of Molecular Diagnostics (2007), 7 (2), 161-175CODEN: ERMDCW; ISSN:1473-7159. (Future Drugs Ltd.)
    A review. Mitochondrial dysfunction is increasingly implicated in the etiol. of drug-induced toxicities and neg. side-effect profiles. Early identification of mitochondrial liabilities for new chem. entities is therefore crucial for avoiding late-stage attrition during drug development. Limitations of traditional methods for assessing mitochondrial dysfunction have discouraged routine evaluation of mitochondrial liabilities. To circumvent this bottleneck, a high-throughput screen has been developed that measures oxygen consumption; one of the most informative parameters for the assessment of mitochondrial status. This technique has revealed that some, but not all, members of many major drug classes have mitochondrial liabilities. This dichotomy encourages optimism that efficacy can be disassocd. from mitochondrial toxicity, resulting in safer drugs in the future.
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    Datta, S.; Baudouin, C.; Brignole-Baudouin, F.; Denoyer, A.; Cortopassi, G. A. The Eye Drop Preservative Benzalkonium Chloride Potently Induces Mitochondrial Dysfunction and Preferentially Affects LHON Mutant Cells. Invest. Ophthalmol. Vis. Sci. 2017, 58 (4), 2406– 2412,  DOI: 10.1167/iovs.16-20903
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    The eye drop preservative Benzalkonium chloride potently induces mitochondrial dysfunction and preferentially affects LHON mutant cells
    Datta, Sandipan; Baudouin, Christophe; Brignole-Baudouin, Francoise; Denoyer, Alexandre; Cortopassi, Gino A.
    Investigative Ophthalmology & Visual Science (2017), 58 (4), 2406-2412CODEN: IOVSDA; ISSN:1552-5783. (Association for Research in Vision and Ophthalmology)
    Benzalkonium chloride (BAK) is the most commonly used eye drop preservative. Benzalkonium chloride has been assocd. with toxic effects such as ''dry eye'' and trabecular meshwork degeneration, but the underlying biochem. mechanism of ocular toxicity by BAK is unclear. In this study, we propose a mechanistic basis for BAK's adverse effects. Mitochondrial O2 consumption rates of human corneal epithelial primary cells (HCEP), osteosarcoma cybrid cells carrying healthy (control) or Leber hereditary optic neuropathy (LHON) mutant mtDNA [11778(G>A)], were measured before and after acute treatment with BAK. Mitochondrial ATP (ATP) synthesis and cell viability were also measured in the BAK-treated control: LHON mutant and human-derived trabecular meshwork cells (HTM3). Benzalkonium chloride inhibited mitochondrial ATP (IC50, 5.3μM) and O2 consumption (IC50, 10.9μM) in a concn.-dependent manner, by directly targeting μmitochondrial complex I. At its pharmaceutical concns. (107-667 M), BAK inhibited mitochondrial function >90%. In addn., BAK elicited concn.-dependent cytotoxicity to cybrid cells (IC50, 22.8μM) and induced apoptosis in HTM3 cells at similar concns. Furthermore, we show that BAK directly inhibits mitochondrial O2 consumption in HCEP cells (IC50, 3.8μM) at 50-fold lower concns. than used in eye drops, and that cells bearing mitochondrial blindness (LHON) mutations are further sensitized to BAK's mitotoxic effect. Benzalkonium chloride inhibits mitochondria of human corneal epithelial cells and cells bearing LHON mutations at pharmacol. relevant concns., and we suggest this is the basis of BAK's ocular toxicity. Prescribing BAK-contg. eye drops should be avoided in patients with mitochondrial deficiency, including LHON patients, LHON carriers, and possibly primary open-angle glaucoma patients.
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    Rogov, A. G.; Goleva, T. N.; Sukhanova, E. I.; Epremyan, K. K.; Trendeleva, T. A.; Ovchenkova, A. P.; Aliverdieva, D. A.; Zvyagilskaya, R. A. Mitochondrial Dysfunctions May Be One of the Major Causative Factors Underlying Detrimental Effects of Benzalkonium Chloride. Oxid. Med. Cell. Longev. 2020, 2020, 8956504,  DOI: 10.1155/2020/8956504
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    Mitochondrial Dysfunctions May Be One of the Major Causative Factors Underlying Detrimental Effects of Benzalkonium Chloride
    Rogov Anton G; Goleva Tatyana N; Sukhanova Evgeniya I; Epremyan Khoren K; Trendeleva Tatiana A; Ovchenkova Alexandra P; Zvyagilskaya Renata A; Aliverdieva Dinara A
    Oxidative medicine and cellular longevity (2020), 2020 (), 8956504 ISSN:.
    Benzalkonium chloride (BAC) is currently the most commonly used antimicrobial preservative in ophthalmic solutions, nasal sprays, and cosmetics. However, a large number of clinical and experimental investigations showed that the topical administration of BAC-containing eye drops could cause a variety of ocular surface changes, from ocular discomfort to potential risk for future glaucoma surgery. BAC-containing albuterol may increase the risk of albuterol-related systemic adverse effects. BAC, commonly present in personal care products, in cosmetic products can induce irritation and dose-dependent changes in the cell morphology. The cationic nature of BAC (it is a quaternary ammonium) suggests that one of the major targets of BAC in the cell may be mitochondria, the only intracellular compartment charged negatively. However, the influence of BAC on mitochondria has not been clearly understood. Here, the effects of BAC on energy parameters of rat liver mitochondria as well as on yeast cells were examined. BAC, being a "weaker" uncoupler, potently inhibited respiration in state 3, diminished the mitochondrial membrane potential, caused opening of the Ca2+/Pi-dependent pore, blocked ATP synthesis, and promoted H2O2 production by mitochondria. BAC triggered oxidative stress and mitochondrial fragmentation in yeast cells. BAC-induced oxidative stress in mitochondria and yeast cells was almost totally prevented by the mitochondria-targeted antioxidant SkQ1; the protective effect of SkQ1 on mitochondrial fragmentation was only partial. Collectively, these data showed that BAC acts adversely on cell bioenergetics (especially on ATP synthesis) and mitochondrial dynamics and that its prooxidant effect can be partially prevented by the mitochondria-targeted antioxidant SkQ1.
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    Klaren, W. D.; Rusyn, I. High-Content Assay Multiplexing for Muscle Toxicity Screening in Human-Induced Pluripotent Stem Cell-Derived Skeletal Myoblasts. Assay Drug Dev. Technol. 2018, 16 (6), 333– 342,  DOI: 10.1089/adt.2018.860
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    High-Content Assay Multiplexing for Muscle Toxicity Screening in Human-Induced Pluripotent Stem Cell-Derived Skeletal Myoblasts
    Klaren, William D.; Rusyn, Ivan
    Assay and Drug Development Technologies (2018), 16 (6), 333-342CODEN: ADDTAR; ISSN:1540-658X. (Mary Ann Liebert, Inc.)
    Skeletal muscle-assocd. toxicity is an underresearched area in the field of high-throughput toxicity screening; hence, the potential adverse effects of drugs and chems. on skeletal muscle are largely unknown. Novel organotypic microphysiol. in vitro models are being developed to replicate the contractile function of skeletal muscle; however, the throughput and a need for specialized equipment may limit the utility of these tissue chip models for screening. In addn., recent developments in stem cell biol. have resulted in the generation of induced pluripotent stem cell (iPSC)-derived skeletal myoblasts that enable high-throughput in vitro screening. This study set out to develop a high-throughput multiplexed assay using iPSC-derived skeletal myoblasts that can be used as a first-pass screen to assess the potential for chems. to affect skeletal muscle. We found that cytotoxicity and cytoskeletal integrity are most useful and reproducible assays for the skeletal myoblasts when evaluating overall cellular health or gauging disruptions in actin polymn. following 24 h of exposure. Both assays are based on high-content imaging and quant. image processing to derive quant. phenotypes. Both assays showed good to excellent assay robustness and reproducibility measured by interplate and interday replicability, coeffs. of variation of neg. controls, and Z'-factors for pos. control chems. Concn. response assessment of muscle-related toxicants showed specificity of the obsd. effects compared to the general cytotoxicity. Overall, this study establishes a high-throughput multiplexed assay using skeletal myoblasts that may be used for screening and prioritization of chems. for more complex tissue chip-based and in vivo evaluation.
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    Inácio, Â. S.; Costa, G. N.; Domingues, N. S.; Santos, M. S.; Moreno, A. J.; Vaz, W. L.; Vieira, O. V. Mitochondrial Dysfunction Is the Focus of Quaternary Ammonium Surfactant Toxicity to Mammalian Epithelial Cells. Antimicrob. Agents Chemother. 2013, 57 (6), 2631– 2639,  DOI: 10.1128/AAC.02437-12
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    Mitochondrial dysfunction is the focus of quaternary ammonium surfactant toxicity to mammalian epithelial cells
    Inacio, Angela S.; Costa, Gabriel N.; Domingues, Neuza S.; Santos, Maria S.; Moreno, Antonio J. M.; Vaz, Winchil L. C.; Vieira, Otilia V.
    Antimicrobial Agents and Chemotherapy (2013), 57 (6), 2631-2639CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)
    Surfactants have long been known to have microbicidal action and have been extensively used as antiseptics and disinfectants for a variety of general hygiene and clin. purposes. Among surfactants, quaternary ammonium compds. (QAC) are known to be the most useful antiseptics and disinfectants. However, our previous toxicol. studies showed that QAC are also the most toxic surfactants for mammalian cells. An understanding of the mechanisms that underlie QAC toxicity is a crucial first step in their rational use and in the design and development of more effective and safer mols. We show that QAC-induced toxicity is mediated primarily through mitochondrial dysfunction in mammalian columnar epithelial cell cultures in vitro. Toxic effects begin at sublethal concns. and are characterized by mitochondrial fragmentation accompanied by decreased cellular energy charge. At very low concns., several QAC act on mitochondrial bioenergetics through a common mechanism of action, primarily by inhibiting mitochondrial respiration initiated at complex I and, to a lesser extent, by slowing down coupled ADP phosphorylation. The result is a redn. of cellular energy charge which, when reduced below 50% of its original value, induces apoptosis. The lethal effects are shown to be primarily a result of this process. At higher doses (closer to the crit. micellar concn.), QAC induce the complete breakdown of cellular energy charge and necrotic cell death.
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    Shirai, A.; Sumitomo, T.; Kurimoto, M.; Maseda, H.; Kourai, H. The Mode of the Antifungal Activity of Gemini-Pyridinium Salt against Yeast. Biocontrol Sci. 2009, 14 (1), 13– 20,  DOI: 10.4265/bio.14.13
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    The mode of the antifungal activity of gemini-pyridinium salt against yeast
    Shirai, Akihiro; Sumitomo, Tomoko; Kurimoto, Mayuko; Maseda, Hideaki; Kourai, Hiroki
    Biocontrol Science (2009), 14 (1), 13-20CODEN: BISCFY; ISSN:1342-4815. (Society for Antibacterial and Antifungal Agents, Japan)
    The gemini quaternary salt (gemini-QUAT) contg. two pyridinium residues per mol., 3,3'-(2,7-dioxaoctane)bis(1-decylpyridinium bromide) (3DOBP-4,10), exerted fungicidal activity against Saccharomyces cerevisiae accompanied by respiration inhibition and the cytoplasmic material leakage of ATP, magnesium, and potassium ions. We previously found that gemini-QUAT exerted bacterioclastic action against Escherichia coli by causing the rapid and abundant leakage of turbid materials from the cells. In addn., the first stage of the bacterioclastic action was the leakage of magnesium ions, outer membrane protein E, ATP, and lipopolysaccharides. Here, we investigated how the gemini-QUAT 3DOBP-4,10 exerts fungicidal action against S. cerevisiae. The results showed that that ≥ 0.4 μM 3DOBP-4,10 stopped respiration and that ≥ 3.0, 1.0 and 1.0 μM caused the leakage of cytoplasmic components ATP, magnesium and potassium ions, resp. Scanning and transmission electron micrographs showed a preserved cell wall structure, whereas intracellular organelles were destroyed in cells incubated with 3DOBP-4,10. We postulated that 3DOBP-4,10 exerts Its fungicidal action against S. cerevisiae not through cell wall destruction and protein leakage, but rather by penetrating the cell wall and disrupting the membranes of organelles.
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    Shirai, R.; Hirano, F.; Ohkura, N.; Ikeda, K.; Inoue, S. Up-Regulation of the Expression of Leucine-Rich alpha(2)-Glycoprotein in Hepatocytes by the Mediators of Acute-Phase Response. Biochem. Biophys. Res. Commun. 2009, 382 (4), 776– 779,  DOI: 10.1016/j.bbrc.2009.03.104
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    Up-regulation of the expression of leucine-rich α2-glycoprotein in hepatocytes by the mediators of acute-phase response
    Shirai, Ryoichi; Hirano, Fumiyasu; Ohkura, Naoki; Ikeda, Kiyoshi; Inoue, Seiji
    Biochemical and Biophysical Research Communications (2009), 382 (4), 776-779CODEN: BBRCA9; ISSN:0006-291X. (Elsevier B.V.)
    Leucine-rich α2-glycoprotein (LRG) is a plasma protein in which leucine-rich repeats (LRRs) were first discovered. Although the physiol. function of LRG is not known, increases in the serum level of LRG have been reported in various diseases. Here, the authors found that LRG was induced by recombinant human IL-6 in human hepatoma HepG2 cells. The induction of LRG by IL-6 was up-regulated synergistically with either IL-1β or TNFα in a pattern similar to those for type 1 acute-phase proteins. The authors also found that lipopolysaccharide (LPS) administered i.p. to mice enhanced dose-dependently the expression of LRG mRNA in the liver as well as those for mouse major acute-phase proteins. These results strongly suggest that LRG was a secretory type 1 acute-phase protein whose expression was up-regulated by the mediator of acute-phase response.
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    Inácio, Â. S.; Domingues, N. S.; Nunes, A.; Martins, P. T.; Moreno, M. J.; Estronca, L. M.; Fernandes, R.; Moreno, A. J. M.; Borrego, M. J.; Gomes, J. P.; Vaz, W. L. C.; Vieira, O. V. Quaternary Ammonium Surfactant Structure Determines Selective Toxicity towards Bacteria: Mechanisms of Action and Clinical Implications in Antibacterial Prophylaxis. J. Antimicrob. Chemother. 2016, 71 (3), 641– 654,  DOI: 10.1093/jac/dkv405
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    Quaternary ammonium surfactant structure determines selective toxicity towards bacteria: mechanisms of action and clinical implications in antibacterial prophylaxis
    Inacio, Angela S.; Domingues, Neuza S.; Nunes, Alexandra; Martins, Patricia T.; Moreno, Maria J.; Estronca, Luis M.; Fernandes, Rui; Moreno, Antonio J. M.; Borrego, Maria J.; Gomes, Joao P.; Vaz, Winchil L. C.; Vieira, Otilia V.
    Journal of Antimicrobial Chemotherapy (2016), 71 (3), 641-654CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)
    Broad-spectrum antimicrobial activity of quaternary ammonium surfactants (QAS) makes them attractive and cheap topical prophylactic options for sexually transmitted infections and perinatal vertically transmitted urogenital infections. Although attributed to their high affinity for biol. membranes, the mechanisms behind QAS microbicidal activity are not fully understood. The authors evaluated how QAS structure affects antimicrobial activity and whether this can be exploited for use in prophylaxis of bacterial infections. Acute toxicity of QAS to in vitro models of human epithelial cells and bacteria were compared to identify selective and potent bactericidal agents. Bacterial cell viability, membrane integrity, cell cycle and metab. were evaluated to establish the mechanisms involved in selective toxicity of QAS. QAS toxicity normalized relative to surfactant crit. micelle concn. showed n-dodecylpyridinium bromide (C12PB) to be the most effective, with a therapeutic index of ∼10 for an MDR strain of Escherichia coli and >20 for Neisseria gonorrhoeae after 1 h of exposure. Three modes of QAS antibacterial action were identified: impairment of bacterial energetics and cell division at low concns.; membrane permeabilization and electron transport inhibition at intermediate doses; and disruption of bacterial membranes and cell lysis at concns. close to the crit. micelle concn. In contrast, toxicity to mammalian cells occurs at higher concns. and, as the authors previously reported, results primarily from mitochondrial dysfunction and apoptotic cell death. Thus, short chain (C12) n-alkyl pyridinium bromides have a sufficiently large therapeutic window to be good microbicide candidates.
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    United States Environmental Protection Agency. Alternative Test Methods and Strategies to Reduce Vertebrate Animal Testing. https://www.epa.gov/assessing-and-managing-chemicals-under-tsca/alternative-test-methods-and-strategies-reduce (accessed 2021-06-03).
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    Murray, C. J L; Ikuta, K. S.; Sharara, F.; Swetschinski, L.; Robles Aguilar, G.; Gray, A.; Han, C.; Bisignano, C.; Rao, P.; Wool, E. Global Burden of Bacterial Antimicrobial Resistance in 2019: A Systematic Analysis. Lancet 2022, 399 (10325), 629– 655,  DOI: 10.1016/S0140-6736(21)02724-0
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    Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis
    Murray, Christopher J. L.; Ikuta, Kevin Shunji; Sharara, Fablina; Swetschinski, Lucien; Aguilar, Gisela Robles; Gray, Authia; Han, Chieh; Bisignano, Catherine; Rao, Puja; Wool, Eve; et al.
    Lancet (2022), 399 (10325), 629-655CODEN: LANCAO; ISSN:0140-6736. (Elsevier Ltd.)
    Antimicrobial resistance (AMR) poses a major threat to human health around the world. Previous publications have estd. the effect of AMR on incidence, deaths, hospital length of stay, and health-care costs for specific pathogen-drug combinations in select locations. To our knowledge, this study presents the most comprehensive ests. of AMR burden to date. We estd. deaths and disability-adjusted life-years (DALYs) attributable to and assocd. with bacterial AMR for 23 pathogens and 88 pathogen-drug combinations in 204 countries and territories in 2019. We obtained data from systematic literature reviews, hospital systems, surveillance systems, and other sources, covering 471 million individual records or isolates and 7585 study-location-years. We used predictive statistical modeling to produce ests. of AMR burden for all locations, including for locations with no data. Our approach can be divided into five broad components: no. of deaths where infection played a role, proportion of infectious deaths attributable to a given infectious syndrome, proportion of infectious syndrome deaths attributable to a given pathogen, the percentage of a given pathogen resistant to an antibiotic of interest, and the excess risk of death or duration of an infection assocd. with this resistance. Using these components, we estd. disease burden based on two counterfactuals: deaths attributable to AMR (based on an alternative scenario in which all drug-resistant infections were replaced by drug-susceptible infections), and deaths assocd. with AMR (based on an alternative scenario in which all drug-resistant infections were replaced by no infection). We generated 95% uncertainty intervals (UIs) for final ests. as the 25th and 975th ordered values across 1000 posterior draws, and models were cross-validated for out-of-sample predictive validity. We present final ests. aggregated to the global and regional level. On the basis of our predictive statistical models, there were an estd. 4.95 million (3.62-6.57) deaths assocd. with bacterial AMR in 2019, including 1.27 million (95% UI 0.911-1.71) deaths attributable to bacterial AMR. At the regional level, we estd. the all-age death rate attributable to resistance to be highest in western sub-Saharan Africa, at 27.3 deaths per 100 000 (20.9-35.3), and lowest in Australasia, at 6.5 deaths (4.3-9.4) per 100 000. Lower respiratory infections accounted for more than 1.5 million deaths assocd. with resistance in 2019, making it the most burdensome infectious syndrome. The six leading pathogens for deaths assocd. with resistance (Escherichia coli, followed by Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa) were responsible for 929 000 (660 000-1 270 000) deaths attributable to AMR and 3.57 million (2.62-4.78) deaths assocd. with AMR in 2019. One pathogen-drug combination, meticillin-resistant S aureus, caused more than 100 000 deaths attributable to AMR in 2019, while six more each caused 50 000-100 000 deaths: multidrug-resistant excluding extensively drug-resistant tuberculosis, third-generation cephalosporin-resistant E coli, carbapenem-resistant A baumannii, fluoroquinolone-resistantE coli, carbapenem-resistant K pneumoniae, and third-generation cephalosporin-resistant K pneumoniae. To our knowledge, this study provides the first comprehensive assessment of the global burden of AMR, as well as an evaluation of the availability of data. AMR is a leading cause of death around the world, with the highest burdens in low-resource settings. Understanding the burden of AMR and the leading pathogen-drug combinations contributing to it is crucial to making informed and location-specific policy decisions, particularly about infection prevention and control programs, access to essential antibiotics, and research and development of new vaccines and antibiotics. There are serious data gaps in many low-income settings, emphasizing the need to expand microbiol. lab. capacity and data collection systems to improve our understanding of this important human health threat.
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  180. 180
    Kampf, G. Biocidal Agents Used for Disinfection Can Enhance Antibiotic Resistance in Gram-Negative Species. Antibiotics (Basel) 2018, 7 (4), 110,  DOI: 10.3390/antibiotics7040110
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    180
    Biocidal agents used for disinfection can enhance antibiotic resistance in gram-negative species
    Kampf, Guenter
    Antibiotics (Basel, Switzerland) (2018), 7 (4), 110CODEN: ABSNC4; ISSN:2079-6382. (MDPI AG)
    Biocidal agents used for disinfection are usually not suspected to enhance cross-resistance to antibiotics. The aim of this review was therefore to evaluate the effect of 13 biocidal agents at sublethal concns. on antibiotic resistance in Gram-neg. species. A medline search was performed for each biocidal agent on antibiotic tolerance, antibiotic resistance, horizontal gene transfer, and efflux pump. In cells adapted to benzalkonium chloride a new resistance was most frequently found to ampicillin (eight species), cefotaxime (six species), and sulfamethoxazole (three species), some of them with relevance for healthcare-assocd. infections such as Enterobacter cloacae or Escherichia coli. With chlorhexidine a new resistance was often found to ceftazidime, sulfamethoxazole and imipenem (eight species each) as well as cefotaxime and tetracycline (seven species each). Cross-resistance to antibiotics was also found with triclosan, octenidine, sodium hypochlorite, and didecyldimethylammonium chloride. No cross-resistance to antibiotics has been described after low level exposure to ethanol, propanol, peracetic acid, polyhexanide, povidone iodine, glutaraldehyde, and hydrogen peroxide. Taking into account that some biocidal agents used in disinfectants have no health benefit (e.g., in alc.-based hand rubs) but may cause antibiotic resistance it is obvious to prefer products without them.
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  181. 181
    Buffet-Bataillon, S.; Tattevin, P.; Bonnaure-Mallet, M.; Jolivet-Gougeon, A. Emergence of Resistance to Antibacterial Agents: The Role of Quaternary Ammonium Compounds-a Critical Review. Int. J. Antimicrob. Agents 2012, 39 (5), 381– 389,  DOI: 10.1016/j.ijantimicag.2012.01.011
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    181
    Emergence of resistance to antibacterial agents: the role of quaternary ammonium compounds - A critical review
    Buffet-Bataillon, Sylvie; Tattevin, Pierre; Bonnaure-Mallet, Martine; Jolivet-Gougeon, Anne
    International Journal of Antimicrobial Agents (2012), 39 (5), 381-389CODEN: IAAGEA; ISSN:0924-8579. (Elsevier B.V.)
    A review. Quaternary ammonium compds. (QACs) are widely distributed in hospitals, industry, and cosmetics. Little attention was focused on the potential impact of QACs on the emergence of antibiotic resistance in patients and the environment. To assess this issue, we conducted a literature review on QAC chem. structure, fields of application, mechanism of action, susceptibility testing, prevalence, and co- or cross-resistance to antibiotics. Special attention was paid to the effects of QACs on microflora; in particular, the issue of the potential of QACs for applying selective pressure on multiple-antibiotic-resistant organisms was raised. It was found that there is a lack of standardized procedures for interpreting susceptibility test results. QACs have different impacts on the min. inhibitory concns. of antibacterials depending on the antibacterial compd. investigated, the resistance genes involved, the measuring methodol. and the interpretative criteria. The unmet needs for adequate detection of reduced susceptibility to QACs and antibiotics include (i) a consensus definition for resistance, (ii) epidemiol. cut-off values and (iii) clin. resistance breakpoints. This review advocates the design of international guidelines for QAC use.
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  182. 182
    Chaplin, C. E. Bacterial Resistance to Quaternary Ammonium Disinfectants. J. Bacteriol. 1952, 63 (4), 453– 458,  DOI: 10.1128/jb.63.4.453-458.1952
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    182
    Bacterial resistance to quaternary ammonium compounds
    Chaplin, C. E.
    Journal of Bacteriology (1952), 63 (), 453-8CODEN: JOBAAY; ISSN:0021-9193.
    Serratia marcescens, normally suppressed by less than 100 p.p.m., was adapted to grow in 100,000 p.p.m. of alkyldimethylbenzylammonium chloride. Intense staining by Sudan black B, an increase in ether-sol. fraction, a decrease in electrophoretic mobility, and the removal of resistance by the action of lipase all support the belief that the acquired resistance is dependent upon an increased lipide content of the cell.
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  183. 183
    Adair, F. W.; Geftic, S. G.; Gelzer, J. Resistance of Pseudomonas to Quaternary Ammonium Compounds. II. Cross-Resistance Characteristics of a Mutant of Pseudomonas Aeruginosa. Appl. Microbiol. 1971, 21 (6), 1058– 1063,  DOI: 10.1128/am.21.6.1058-1063.1971
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    183
    Resistance of Pseudomonas to quaternary ammonium compounds. II. Cross-resistance characteristics of a mutant of Pseudomonas aeruginosa
    Adair, Frank W.; Geftic, Sam G.; Gelzer, Justus
    Applied Microbiology (1971), 21 (6), 1058-63CODEN: APMBAY; ISSN:0003-6919.
    Benzalkonium chloride (I)-resistant mutants of P. aeruginosa grown in the presence of I (1000 μg/ml) were at least 20-fold more sensitive to polymyxin B and colistin sulfate than the I-sensitive parent strain. I-sensitive cells selected for resistance to polymyxin B (500 μg/ml) remained sensitive to I. The amt. of carbenicillin, gentamicin sulfate, or rifampin needed to prevent the growth of either I-sensitive or -resistant strains did not differ significantly. EDTA (400 μg/ml) inhibited the growth of I-resistant cells, whereas the I-sensitive strain grew at a concn. of 100,000 μg EDTA/ml. I-resistant cells were cross-resistant to >1,000 μg/ml concns. of 5 quaternary ammonium compds. including 3 with C16-alkyls and 2 with shorter length alkyl groups. The I-sensitive strain was also resistant to >1,000 μg/ml concns. of 3 quaternary ammonium compds. with C16-alkyl groups, but in addn. to I was inhibited by ≤200 μg/ml of 2 quaternary ammonium compds. contg. groups of <16 carbon atoms.
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  184. 184
    Yim, J. H.; Song, K. Y.; Kim, H.; Bae, D.; Chon, J. W.; Seo, K. H. Effectiveness of Calcium Hypochlorite, Quaternary Ammonium Compounds, and Sodium Hypochlorite in Eliminating Vegetative Cells and Spores of Bacillus Anthracis Surrogate. J. Vet. Sci. 2021, 22 (1), e11-e11  DOI: 10.4142/jvs.2021.22.e11
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    Kwaśniewska, D.; Chen, Y.-L.; Wieczorek, D. Biological Activity of Quaternary Ammonium Salts and Their Derivatives. Pathogens 2020, 9 (6), 459,  DOI: 10.3390/pathogens9060459
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    185
    Biological activity of quaternary ammonium salts and their derivatives
    Kwasniewska, Dobrawa; Chen, Ying-Lien; Wieczorek, Daria
    Pathogens (2020), 9 (6), 459CODEN: PATHCD; ISSN:2076-0817. (MDPI AG)
    Besides their pos. role, microorganisms are related to a no. of undesirable effects, including many diseases, biodeterioration and food spoilage, so when their presence is undesired, they must be controlled. Numerous biocides limiting the development of microorganisms have been proposed, however, in this paper the biocidal and inhibitory activity of quaternary ammonium salts (QASs) and their zwitterionic derivs. is addressed. This paper presents the current state of knowledge about the biocidal activity of QAS and their derivs. Moreover, the known mechanisms of antimicrobial activity and the problem of emerging resistance to QAS are discussed. The latest trends in the study of surfactants and their potential use are also presented.
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  186. 186
    Hu, J.; Ben Maamar, S.; Glawe, A. J.; Gottel, N.; Gilbert, J. A.; Hartmann, E. M. Impacts of Indoor Surface Finishes on Bacterial Viability. Indoor Air 2019, 29 (4), 551– 562,  DOI: 10.1111/ina.12558
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    186
    Impacts of indoor surface finishes on bacterial viability
    Hu Jinglin; Ben Maamar Sarah; Glawe Adam J; Hartmann Erica M; Gottel Neil; Gilbert Jack A
    Indoor air (2019), 29 (4), 551-562 ISSN:.
    Microbes in indoor environments are constantly being exposed to antimicrobial surface finishes. Many are rendered non-viable after spending extended periods of time under low-moisture, low-nutrient surface conditions, regardless of whether those surfaces have been amended with antimicrobial chemicals. However, some microorganisms remain viable even after prolonged exposure to these hostile conditions. Work with specific model pathogens makes it difficult to draw general conclusions about how chemical and physical properties of surfaces affect microbes. Here, we explore the survival of a synthetic community of non-model microorganisms isolated from built environments following exposure to three chemically and physically distinct surface finishes. Our findings demonstrated the differences in bacterial survival associated with three chemically and physically distinct materials. Alkaline clay surfaces select for an alkaliphilic bacterium, Kocuria rosea, whereas acidic mold-resistant paint favors Bacillus timonensis, a Gram-negative spore-forming bacterium that also survives on antimicrobial surfaces after 24 hours of exposure. Additionally, antibiotic-resistant Pantoea allii did not exhibit prolonged retention on antimicrobial surfaces. Our controlled microcosm experiment integrates measurement of indoor chemistry and microbiology to elucidate the complex biochemical interactions that influence the indoor microbiome.
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  187. 187
    Perry-Dow, K. A.; de Man, T. J. B.; Halpin, A. L.; Shams, A. M.; Rose, L. J.; Noble-Wang, J. A. The Effect of Disinfectants on the Microbial Community on Environmental Healthcare Surfaces Using next Generation Sequencing. Am. J. Infect. Control 2022, 50 (1), 54– 60,  DOI: 10.1016/j.ajic.2021.08.027
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    187
    The effect of disinfectants on the microbial community on environmental healthcare surfaces using next generation sequencing
    Perry-Dow, Kristen Allison; de Man, Tom J. B.; Halpin, Alison Laufer; Shams, Alicia M.; Rose, Laura J.; Noble-Wang, Judith A.
    American Journal of Infection Control (2022), 50 (1), 54-60CODEN: AJICDC; ISSN:0196-6553. (Elsevier Inc.)
    Healthcare-assocd. infections are a significant economic burden and cause of avoidable morbidity and mortality within healthcare systems. The contribution of environmental contamination to healthcare-assocd. infection transmission has been recognized, but the mechanisms by which transmission occurs are still being investigated. The objective of this study was to characterize the microbial communities of disinfected, non-crit. healthcare surfaces using next generation sequencing technol. Composite environmental surface samples were from high-touch surfaces in rooms of patients isolated for infections with multidrug-resistant organisms during their hospitalization. Information on the disinfectant product used and cleaning type (routine or terminal) was collected. 16S rRNA gene amplicon sequencing and anal. were performed. Community anal. was conducted to det. the bacterial compn. and compare the detection of target pathogens by culture from 94 Contact Precaution rooms. Overall percent agreement between culture and sequence methods ranged from 52%-88%. A significant difference was obsd. in bacterial compn. between rooms cleaned with bleach and those cleaned with a quaternary ammonium compd. for composite 2 (overbed table, i.v. pole, and inner room door handle) (ANOSIM R = 0.66, P = .005) but not composite 1 (bed rails, television remote control unit, call buttons, and telephone). Surfaces in bleach-cleaned rooms contained a higher proportion of gram-pos. microbiota, whereas rooms cleaned with quaternary ammonium compd. contained a higher proportion of gram-neg. microbiota, suggesting disinfectant products may impact the healthcare environment microbiome.
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  188. 188
    Han, Y.; Zhou, Z.-C.; Zhu, L.; Wei, Y.-Y.; Feng, W.-Q.; Xu, L.; Liu, Y.; Lin, Z.-J.; Shuai, X.-Y.; Zhang, Z.-J.; Chen, H. The Impact and Mechanism of Quaternary Ammonium Compounds on the Transmission of Antibiotic Resistance Genes. Environ. Sci. Pollut. Res. Int. 2019, 26 (27), 28352– 28360,  DOI: 10.1007/s11356-019-05673-2
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    188
    The impact and mechanism of quaternary ammonium compounds on the transmission of antibiotic resistance genes
    Han Yue; Zhou Zhen-Chao; Zhu Lin; Wei Yuan-Yuan; Feng Wan-Qiu; Xu Lan; Liu Yang; Lin Ze-Jun; Shuai Xin-Yi; Zhang Zhi-Jian; Chen Hong
    Environmental science and pollution research international (2019), 26 (27), 28352-28360 ISSN:.
    The emergence of antibiotic resistance genes (ARGs) in microbes can be largely attributed to the abuse and misuse of antibiotics and biocides. Quaternary ammonium compounds (QACs) have been used worldwide as common disinfectants and detergents; however, their potential impact on the spread and diffusion of ARGs is still unknown. In this study, we detected the QAC resistance gene (qacEΔ1), the 1 integron gene (intI1), and 12 ARGs (sul1, sul2, cfr, cml, fexA, tetA, tetG, tetQ, tetX, ermB, blaTEM, and dfrA1) in 48 water samples from three watersheds by quantitative PCR (qPCR). We investigated the evolution of bacterial antibiotic resistance under QAC and antibiotic environmental pressures by long-term continuous culture. In addition, five QACs were selected to investigate the effect of QAC on the efficiency of conjugation transfer. The changes in bacterial cell membrane and production of reactive oxygen species (ROS) were detected by flow cytometry, revealing the mechanism by which QAC affects the spread of antibiotic resistance. Our results showed that the QAC resistance gene was ubiquitous in watersheds and it had significant correlation with intI1 and seven ARGs (r = 0.999, p < 0.01). QACs could increase the resistance of bacteria to multiple antibiotics. Furthermore, all five QACs promoted the conjugation transfer of the RP4 plasmid; the optimal concentration of QACs was about 10(-1)-10(-2) mg/L and their transfer efficiencies were between 1.33 × 10(-6) and 8.87 × 10(-5). QACs enhanced membrane permeability of bacterial cells and stimulated bacteria to produce ROS, which potentially promoted the transfer of plasmids between bacteria. In conclusion, this study demonstrated that QACs may facilitate the evolution and gene transfer of antibiotic resistance gene among microbiome.
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    Levy, S. B. Active Efflux, a Common Mechanism for Biocide and Antibiotic Resistance. Symp. Ser. Soc. Appl. Microbiol. 2002, 92 (31), 65S– 71S,  DOI: 10.1046/j.1365-2672.92.5s1.4.x
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    Adair, F. W.; Geftic, S. G.; Gelzer, J. Resistance of Pseudomonas to Quaternary Ammonium Compounds. I. Growth in Benzalkonium Chloride Solution. Appl. Microbiol. 1969, 18 (3), 299– 302,  DOI: 10.1128/am.18.3.299-302.1969
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    190
    Resistance of Pseudomonas to quaternary ammonium compounds. I. Growth in benzalkonium chloride solution
    Adair, Frank W.; Geftic, Sam G.; Gelzer, Justus
    Applied Microbiology (1969), 18 (3), 299-302CODEN: APMBAY; ISSN:0003-6919.
    Resistant cells of Pseudomonas aeruginosa and a waterborne Pseudomonas species strain Z-R were able to multiply in N-free minimal salts soln. contg. various concns. of com. prepared, NH4OAc-buffered, benzalkonium chloride (CBC), a potent antimicrobial agent. As the CBC concn. increased, growth increased until it leveled off or was completely depressed. Minimal salts solns. of pure benzalkonium chloride (PBC) contg. no NH4OAc did not support bacterial growth. When NH4OAc was added to PBC solns. in the same concns. found in com. CBC solns., growth patterns developed that were comparable to those found with CBC. Likewise, (NH4)2SO4 added to PBC solns. supported growth of both organisms. P. aeruginosa was initially resistant to CBC levels of 0.02% but it was adapted to tolerate levels as high as 0.36%. Strain Z-R was naturally resistant to 0.4% CBC. Since NH4OAc carried over by the CBC used in drug formulations and disinfectant solns. has the potential to support the growth of resistant bacteria and thus make possible the risk of serious infection, it is suggested that regulations allowing the presence of NH4OAc in CBC soln. be reconsidered.
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    Loughlin, M. F.; Jones, M. V.; Lambert, P. A. Pseudomonas Aeruginosa Cells Adapted to Benzalkonium Chloride Show Resistance to Other Membrane-Active Agents but Not to Clinically Relevant Antibiotics. J. Antimicrob. Chemother. 2002, 49 (4), 631– 639,  DOI: 10.1093/jac/49.4.631
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    191
    Pseudomonas aeruginosa cells adapted to benzalkonium chloride show resistance to other membrane-active agents but not to clinically relevant antibiotics
    Loughlin, M. F.; Jones, M. V.; Lambert, P. A.
    Journal of Antimicrobial Chemotherapy (2002), 49 (4), 631-639CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)
    Our objective was to det. whether strains of Pseudomonas aeruginosa can adapt to growth in increasing concns. of the disinfectant benzalkonium chloride (BKC), and whether co-resistance to clin. relevant antimicrobial agents occurs. Attempts were made to det. what phenotypic alterations accompanied resistance and whether these explained the mechanism of resistance. Strains were serially passaged in increasing concns. of BKC in static nutrient broth cultures. Serotyping and genotyping were used to det. purity of the cultures. Two strains were examd. for cross-resistance to other disinfectants and antibiotics by broth diln. MIC detn. Alterations in outer membrane proteins and lipopolysaccharide (LPS) expressed were examd. by SDS-PAGE. Cell surface hydrophobicity and charge, uptake of disinfectant and proportion of specific fatty acid content of outer and cytoplasmic membranes were detd. Two P. aeruginosa strains showed a stable increase in resistance to BKC. Co-resistance to other quaternary ammonium compds. was obsd. in both strains; chloramphenicol and polymyxin B resistance were obsd. in one and a redn. in resistance to tobramycin obsd. in the other. However, no increased resistance to other biocides (chlorhexidine, triclosan, thymol) or antibiotics (ceftazidime, imipenem, ciprofloxacin, tobramycin) was detected. Characteristics accompanying resistance included alterations in outer membrane proteins, uptake of BKC, cell surface charge and hydrophobicity, and fatty acid content of the cytoplasmic membrane, although no evidence was found for alterations in LPS. Each of the two strains had different alterations in phenotype, indicating that such adaptation is unique to each strain of P. aeruginosa and does not result from a single mechanism shared by the whole species.
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    Sakagami, Y.; Yokoyama, H.; Nishimura, H.; Ose, Y.; Tashima, T. Mechanism of Resistance to Benzalkonium Chloride by Pseudomonas Aeruginosa. Appl. Environ. Microbiol. 1989, 55 (8), 2036– 2040,  DOI: 10.1128/aem.55.8.2036-2040.1989
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    Mechanism of resistance to benzalkonium chloride by Pseudomonas aeruginosa
    Sakagami, Yoshikazu; Yokoyama, Hiroshi; Nishimura, Hiroshi; Ose, Youki; Tashima, Toshio
    Applied and Environmental Microbiology (1989), 55 (8), 2036-40CODEN: AEMIDF; ISSN:0099-2240.
    The mechanisms of resistance of P. aeruginosa to benzalkonium chloride (BC) were studied. The effluence of cell components was obsd. in susceptible P. aeruginosa by electron microscopy, but resistant P. aeruginosa seemed to be undamaged. No marked changes in cell surface potential between Escherichia coli NIJHC-2 and a spheroplast strain were found. The contents of phospholipids (PL) and fatty and neutral lipids (FNL) in the cell walls of resistant P. aeruginosa were higher than those in the cell walls of susceptible P. aeruginosa. The amts. of BC adsorbed to PL and FNL of cell walls of BC-resistant P. aeruginosa were lower than those for BC-susceptible P. aeruginosa. Fifteen species of cellular fatty acids were identified by capillary gas chromatog. and gas chromatog.-mass spectrometry. The ability of BC to permeate the cell wall was reduced because of the increase in cellular fatty acids. These results suggested that the resistance of P. aeruginosa to BC is mainly a result of increases in the contents of PL and FNL. In resistant P. aeruginosa, the decrease in the amt. of BC adsorbed is likely to be the result of increases in the contents of PL and FNL.
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  193. 193
    Nagai, K.; Murata, T.; Ohta, S.; Zenda, H.; Ohnishi, M.; Hayashi, T. Two Different Mechanisms Are Involved in the Extremely High-Level Benzalkonium Chloride Resistance of a Pseudomonas Fluorescens Strain. Microbiol. Immunol. 2003, 47 (10), 709– 715,  DOI: 10.1111/j.1348-0421.2003.tb03440.x