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A retrospective cohort study was carried out in a cardboard factory in Germany to investigate the association between exposure to trichloroethene (TRI) and renal cell cancer. The study group consisted of 169 men who had been exposed to TRI for at least 1 year between 1956 and 1975. The average observation period was 34 years. By the closing day of the study (December 31, 1992) 50 members of the cohort had died, 16 from malignant neoplasms. In 2 out of these 16 cases, kidney cancer was the cause of death, which leads to a standard mortality ratio of 3.28 compared with the local population. Five workers had been diagnosed with kidney cancer: four with renal cell cancers and one with a urothelial cancer of the renal pelvis. The standardized incidence ratio compared with the data of the Danish cancer registry was 7.97 (95% CI: 2.59-18.59). After the end of the observation period, two additional kidney tumors (one renal cell and one urothelial cancer) were diagnosed in the study group. The control group consisted of 190 unexposed workers in the same plant. By the closing day of the study 52 members of this cohort had died, 16 from malignant neoplasms, but none from kidney cancer. No case of kidney cancer was diagnosed in the control group. The direct comparison of the incidence on renal cell cancer shows a statistically significant increased risk in the cohort of exposed workers. Hence, in all types of analysis the incidence of kidney cancer is statistically elevated among workers exposed to TRI.(ABSTRACT TRUNCATED AT 250 WORDS)

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The bioactivation mechanism of S-(1,2-dichlorovinyl)-L-cysteine (DCVC) and S-(1,2,2-trichlorovinyl)-L-cysteine (TCVC) was studied with cysteine conjugate beta-lyase (beta-lyase) from Salmonella typhimurium and with the pyridoxal phosphate model N-dodecylpyridoxal bromide (PL-Br) as catalysts and with GC/MS to identify the metabolites formed. PL-Br converted S-2-benzothiazolyl-L-cysteine to 2-mercaptobenzothiazole and S-benzyl-L-cysteine to benzyl mercaptan, demonstrating the ability of PL-Br to serve as a model for beta-lyase. PL-Br and bacterial beta-lyase converted DCVC to chloroacetic acid and chlorothionoacetic acid and TCVC to dichloroacetic acid. Incubations of PL-Br with the S-conjugates in the presence of diethylamine resulted in the formation of N,N-diethylchlorothioacetamide from DCVC and of N,N-diethyldichlorothioacetamide from TCVC. Attempts to trap the enethiols, which are the expected initial products formed by beta-elimination, by reaction with methyl iodide in incubations with the beta-lyase model were not successful. The formation of thioacylating agents from the enethiols may contribute to the cytotoxic and mutagenic effects of DCVC and TCVC.

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S-(3-Oxopropyl)glutathione, the glutathione conjugate of acrolein, has been reported to be nephrotoxic. The objective of the present studies was to investigate the bioactivation mechanism of the analogues S-(3-oxopropyl)-N-acetyl-L-cysteine (1) and S-(3-oxopropyl)-N-acetyl-L-cysteine S-oxide (2) and to test the hypothesis that the cytotoxicity of 1 is associated with its latent potential to release acrolein in kidney cells. Mechanistic considerations indicated that sulfoxidation of sulfide 1 to form S-oxide 2 and a subsequent general-base-catalyzed beta-elimination reaction would release the cytotoxin acrolein. Hence the release of acrolein from 1 and 2 was studied in chemical systems, and their cytotoxicity was investigated in cultured LLC-PK1 cells and in isolated rat renal proximal tubular cells. Acrolein formation from S-oxide 2, but not from sulfide 1, was observed under basic conditions and with phosphate as the base. Kinetic analysis indicated that a general-base-catalyzed reaction was involved. Both S-conjugates 1 and 2 were cytotoxic in LLC-PK1 cells and in isolated rat renal proximal tubular cells, and the cytotoxicity of sulfide 1, but not of S-oxide 2, in isolated renal proximal tubular cells was reduced in presence of methimazole, an inhibitor of the flavin-containing monooxygenase. These findings indicate that the cytotoxicity of S-conjugate 1 is associated with a novel bioactivation mechanism that involves sulfoxidation followed by a general-base-catalyzed elimination of acrolein from S-oxide 2.

Glutathione conjugation has been identified as an important detoxication reaction. However, in recent years several glutathione-dependent bioactivation reactions have been identified. Current knowledge on the mechanisms and the possible biological importance of these reactions are discussed. 1. Dichloromethane is metabolized by glutathione conjugation to formaldehyde via S-(chloromethyl)glutathione. Both compounds are reactive intermediates and may be responsible for the dichloromethane-induced tumorigenesis in sensitive species. 2. Vicinal dihaloalkanes are transformed by glutathione S-transferase-catalyzed reactions to mutagenic and nephrotoxic S-(2-haloethyl)glutathione S-conjugates. Electrophilic episulphonium ions are the ultimate reactive intermediates formed. 3. Several polychlorinated alkenes are bioactivated in a complex, glutathione-dependent pathway. The first step is hepatic glutathione S-conjugate formation followed by cleavage to the corresponding cysteine S-conjugates, and, after translocation to the kidney, metabolism by renal cysteine conjugate beta-lyase. Beta-Lyase-dependent metabolism of halovinyl cysteine S-conjugates yields electrophilic thioketenes, whose covalent binding to cellular macromolecules is responsible for the observed toxicity of the parent compounds. 4. Finally, hepatic glutathione conjugate formation with hydroquinones and aminophenols yields conjugates that are directed to gamma-glutamyltransferase-rich tissues, such as the kidney, where they undergo alkylation or redox cycling reactions, or both, that cause organ-selective damage.