The Measurement of 2-Thiothiazolidine-4-carboxylic Acid as an Index of the in Vivo Release of CS2 by Dithiocarbamates
Received January 10, 1996 Abstract: Dithiocarbamates and their disulfides are used extensively as
agricultural fungicides, as
accelerators of the vulcanization process of rubber in industry, and as
therapeutic agents in
medicine. The widespread uses of these compounds in agriculture,
industry, and medicine
provide many avenues of exposure to the human population.
Subchronic to chronic exposures
to some dithiocarbamates have resulted in the development of neuropathy
in humans and
experimental animals. Decomposition to CS2 presents a
potential mechanism through which
the toxicity of dithiocarbamates may be mediated. The purpose of
this study was to determine
the potential of dithiocarbamates to release CS2 in
vivo. The ability to release CS2 was
assessed
by measuring urinary 2-thiothiazolidine-4-carboxylic acid (TTCA), which
is used in industry
to measure the exposure of workers to CS2. In this
study, rats were housed individually in
metabolic cages and given daily equimolar ip or po doses (1.5 mmol/kg)
of N,N-diethyldithiocarbamate (DEDC), disulfiram (DS), N-methyldithiocarbamate
(NMDC), or CS2 for 5 days,
and TTCA was measured in urine collected at 24 h intervals. For
each compound administered,
TTCA was produced in all of the treated animals and the amount of TTCA
eliminated in urine
from po administration was significantly greater than that from ip
administration. The relative
rates of TTCA elimination in urine were DS > DEDC 
CS2
> NMDC for both routes of
administration. Following administration of
N,N-diethyl[13C=S]dithiocarbamate,
carbon-13
enrichment at the thiocarbonyl carbon of TTCA was demonstrated using
13C NMR. Analysis
of urinary TTCA proved to be useful both for establishing the in
vivo release of CS2 by
dithiocarbamate containing compounds and for evaluating the
bioavailability of CS2. The
results appear especially relevant to disulfiram, which is given orally
for sustained periods in
the treatment of alcoholism and has resulted in the development of
neuropathy in susceptible
individuals.
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