Chloroform renal toxicity

Many laboratory animal models have been used to describe the toxicity and pharmacology of chloroform. By far, the most commonly used laboratory animal species are the rat and mouse models. Generally, the pharmacokinetic and toxicokinetic data gathered from rats and mice compare favorably with the limited information available from human studies. PBPK models have been developed using pharmacokinetic and toxicokinetic data for use in risk assessment work for the human. The models are discussed in depth in Section 2.3.5. As mentioned previously, male mice have a sex-related tendency to develop severe renal disease when exposed to chloroform, particularly by the inhalation and oral exposure routes. This effect appears to be species-related as well, since experiments in rabbits and guinea pigs found no sex-related differences in renal toxicity. 

The renal toxicity of chloroform in rats after intraperitoneal dosing has also been reported (Kroll et al. 1994a, 1994b). 

Probably the best example of a sex difference in toxicity is that of the renal toxicity of chloroform in mice. The males are markedly more sensitive than the females, and this difference can be removed by castration of the male animals and subsequently restored by administration of androgens. 

Metabolic activation. Although the kidney does not contain as much cytochromes P-450 as the liver, there is sufficient activity to be responsible for metabolic activation, and other oxidative enzymes such as those of the prostaglandin synthetase system are also present. Such metabolic activation may underlie the renal toxicity of chloroform and paracetamol (see chap. 7). Other enzymes such as C-S lyase and GSH transferase may also be involved in the activation of compounds such as hexachlorobutadiene (see chap. 7). In some cases, hepatic metabolism may be involved followed by transport to the kidney and subsequent toxicity. 

The hepatic and renal toxicities of chloroform are selectively modified by induction of the drug-metabolizing enzyme systems in those organs (ref. 39) and the production of phosgene is strongly indicated (ref. 40). 

Male and female animals of the same strain and species usually react to toxicants similarly. It must be borne in mind, however, that there are marked differences in the hormonal makeup between sexes, and this can result in notable differences in responses. Chloroform produces damage to liver and kidney in humans and mice. In mice, however, chloroform produces nephrotoxicity only in males. Furthermore, administration of testosterone (male hormone) to the female mouse followed by chloroform results in kidney damage. Clearly, there are androgen (male) receptors in the kidney that sensitize males to chloroform-induced nephrotoxicity. In rats, exposure to the hydrocarbon decalin results in a renal nephropathy and tumor formation in the male but not female, and this is associated with an ot2-globulin protein accumulation. Treatment of females with testosterone followed by decalin also produces renal toxicity and protein accumulation. These examples demonstrate that kidney function differs between the sexes and, consequently, toxic manifestations will vary between males and females. 

Chloroform, dichloroacetic acid, and trichloroacetic acid are disinfection byproducts of water chlorination. In a study of laboratory rats it was shown that both dichloroacetic acid and trichloroacetic acid increase the renal toxicity of chloroform in test animals J10l... 

I. Mechanism of toxicity. Carbon tetrachloride and chloroform are CNS depressants and potent hepatic and renal toxins. They may also increase the sensitivity of the myocardium to arrhythmogenic effects of catecholamines. The mechanism of hepatic and renal toxicity is thought to be a result of a toxic free-radical intermediate of cytochrome P-450 metabolism. (Bioactivation of CCI4 has become a model for chemical toxicity induced by free radicals.) Chronic use of metabolic enzyme inducers such as phenobarbital and ethanol increases the toxicity of carbon tetrachloride. Carbon tetrachloride is a known animal and suspected human carcinogen. Chloroform is embryotoxic and an animal carcincogen. 

Renal Effects. The kidney is also a major target of ehloroform-induced toxicity in humans. Oliguria was observed 1 day after the ingestion of 3,755 or 2,410 mg/kg chloroform (Piersol et al. 1933 ... 

Administration of chloroform to laboratory animals resulted in the depletion of renal GSH, indicating that GSH reacts with reactive intermediates, thus reducing the kidney damage otherwise caused by the reaction of these intermediates with tissue MMBs (Hook and Smith 1985 Smith and Hook 1983, 1984 Smith et al. 1984). Similarly, chloroform treatment resulted in the depletion of hepatic GSH and alkylation of MMBs (Docks and Krishna 1976). Other studies demonstrated that sulfhydryl compounds such as L-cysteine (Bailie et al. 1984) and reduced GSH (Kluwe and Hook 1981) may provide protection against nephrotoxicity induced by chloroform. The sulfhydryl compound N-acetylcysteine is an effective antidote for poisoning by acetaminophen, which, like chloroform, depletes GSH and produces toxicity by reactive intermediates. 

Ilett KF, Reid WD, Sipes IG, et al. 1973. Chloroform toxicity in mice Correlation of renal and hepatic necrosis with covalent binding of metabolites to tissue macromolecules. Exp Mol Pathol 19 215-229. 

Chloroform is an anesthetic and solvent, which may be nephrotoxic and hepato toxic. It requires metabolic activation by cytochrome P-450, and male mice are more susceptible to the nephrotoxicity than females, which are more likely to suffer hepatic damage. The renal damage, proximal tubular necrosis, is accompanied by fatty infiltration. The metabolic activation, which may take place in the kidney, produces phosgene, which is reactive and can bind to critical proteins. 

Kluwe, W.M., K.M. McCormack and J.B. Hook, "Selective Modification of Renal and Hepatic Toxicities of Chloroform by Induction of Drug-Metabolizing Enzyme Systems in Kidney... 

The mechanism of chloroform nephrotoxicity involves the oxidation of chloroform to trichloro-methanol by renal cytochrome P-450 isozymes (Figure 6). The trichloromethanol readily eliminates HCl to form the highly reactive toxicant phosgene (COCI2). The phosgene can (1) be detoxified by conjugation with two molecules of glutathione, (2) react with water to form two molecules of HCl and one molecule of CO2, or (3) covalently bind to renal macromolecules to disrupt cellular function and induce nephrotoxicity. 

Lilly PD, Ross Tm, Pegram RA. Trihalomethane comparative toxicity Acute renal and hepatic toxicity of chloroform and bromodichloromethane following aqueous gavage. FundAppl Toxicol 1997 40(1) 101—10. 

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