THE MEASUREMENT OF 2-THIOTHIAZOLIDINE-4-CARBOXYLIC ACID AS AN INDEX OF THE IN-VIVO RELEASE OF CS2 BY DITHIOCARBAMATES

Dithiocarbamates and their disulfides are used extensively as agricult ural fungicides, as accelerators of the vulcanization process of rubbe r in industry, and as therapeutic agents in medicine. The widespread u ses of these compounds in agriculture, industry, and medicine provide many avenues of exposure to the human population. Subchronic to chroni c 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 dithioca rbamates may be mediated. The purpose of this study was to determine t he 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 expos ure 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-methyldithi ocarbamate (NMDC), or CS2 for 5 days, and TTCA was measured in urine c ollected at 24 h intervals. For each compound administered, TTCA was p roduced in all of the treated animals and the amount of TTCA eliminate d in urine from po administration was significantly greater than that from ip administration. The relative rates of TTCA elimination in urin e were DS > DEDC congruent to CS2 > NMDC for both routes of administra tion. Following administration of N,N-diethyl[C-13=S]dithiocarbamate, carbon-13 enrichment at the thiocarbonyl carbon of TTCA was demonstrat ed using C-13 NMR. Analysis of urinary TTCA proved to be useful both f or establishing the in vivo release of CS2 by dithiocarbamate containi ng compounds and for evaluating the bioavailability of CS2. The result s appear especially relevant to disulfiram, which is given orally for sustained periods in the treatment of alcoholism and has resulted in t he development of neuropathy in susceptible individuals.