Mechanistic Considerations for Carcinogenic Risk Estimation: Chloroform

Abstract

Chloroform has been reported to induce cancer in rodents after chronic administration of high doses by gavage. However, the interpretation of these findings is hampered by a lack of knowledge concerning the relative roles of genetic and nongenetic mechanisms in these bioassays. The present studies were carried out in male B6C3F1 mice in order to investigate the potential of chloroform to induce genetic damage and/or organ toxicity at the sites where tumors have been observed in the various bioassays. These studies revealed that carcinogenic doses of chloroform produced severe necrosis at the sites where tumors later developed. This was demonstrated by light microscopy as well as by determination of the cellular regeneration index following administration of 3H-thymidine. Noncarcinogenic doses of chloroform failed to induce these responses. In contrast, studies of DNA alkylation and DNA repair in vivo failed to give any indication that chloroform had produced the type of genetic alterations associated with known genotoxic chemicals. These data suggest that the-primary mechanism of chloroform-induced carcinogenesis is nongenetic in nature. If the same mechanism predominates in man, there should be little to no carcinogenic risk associated with exposure to noncytotoxic levels of chloroform.

The role of different cytochrome P450 isoforms in in vitro chloroform metabolism

“…Its acute toxicity and carcinogenicity occur in the liver and/or kidney, depending on the species, strain, and gender (1). Lack of evidence of mutagenic properties, together with the occurrence of hepatic tumors at chloroform doses causing also some degree of hepatic necrosis, led to the hypothesis that chloroform-induced tumors are secondary to tissue damage and compensatory cell proliferation (2)(3)(4)(5). However, the significance of short-term genotoxicity tests applied to chloroform has been questioned (6), and, more recently, other studies (7,8) have casted doubt on a purely epigenetic mechanism for chloroform-induced hepatic tumors.…”

Carcinogenicity of by-products of disinfection in mouse and rat liver.

“…Chloroform administered in corn oil has been shown to induce hepatocellular carcinomas in mice and epithelial tumors in the kidney of male rats (35). The inability of chloroform to bind significantly to liver and kidney DNA (44)(45)(46) and its lack or very low level of genotoxicity (31,(36)(37)(38)(39)(40)(41)(42)(43) has led to the proposal that the carcinogenicity of chloroform results from a nongenotoxic mechanism such as tumor promotion (45,46). Because the mechanism of carcinogenicity (i.e., genotoxic or nongenotoxic) of a substance has major implications in interspecies and low-dose extrapolation, we attempted to demonstrate the nongenotoxic and tumor-promoting mechanism for the carcinogenic activity of chloroform.…”

“…Chloroform has been shown to lack or at most possess minimum genotoxic activity (31,(36)(37)(38)(39)(40)(41)(42) and has also been shown to not bind significantly to liver or kidney DNA in rats (43)(44)(45). These findings have led to the proposal that the hepatocarcinogenicity of chloroform in mice results from a nongenotoxic mechanism such as tumor promotion (45,46). We therefore attempted to demonstrate the hepatic tumor-promoting activity of chloroform in mice.…”

Chloroform (Trichlormethan) [MAK Value Documentation in German language, 2003]

“…In einer zweiten Untersuchung wurde bei der Maus nach intraperitonealer Gabe von 15 mg Chloroform/kg KG keine kovalente Bindung in der Leber nachgewiesen (DiazGomez und Castro 1980). Weiterhin wird in einer dritten Veröffentlichung davon berichtet, dass keine DNA-Bindung in Leber und Niere von Mäusen nachgewiesen wurde (Reitz et al 1982). Bei allen Untersuchungen zur kovalenten Bindung wurde die Radioaktivität bestimmt, DNA-Addukte wurden nicht identifiziert.…”