Evaluating genotoxicity data to identify a mode of action and its application in estimating cancer risk at low doses: A case study involving carbon tetrachloride

Abstract

In the new USEPA cancer risk assessment guidelines, mode of action (MoA) information, combined with a determination of whether or not a chemical is mutagenic, plays an important role in determining whether a linear or nonlinear approach should be used to estimate cancer risks at low doses. In this article, carbon tetrachloride (CT) is used as an example to illustrate how mixed genotoxicity data can be evaluated and used to identify a likely MoA. CT is essentially negative in inducing gene mutations in Salmonella, but is consistently positive in inducing recombination and aneuploidy in fungi. Negative or equivocal results were seen in most in vitro and in vivo studies in mammals, including mutation studies in transgenic mice. However, DNA adducts, primarily those derived from oxidation- and lipid-peroxidation-derived products as well as DNA double-strand breaks and micronucleated cells, have been seen repeatedly in the liver of CT-treated animals. On the basis of the weight of evidence, CT should not be considered a directly mutagenic agent. Mutagenic as well as other genotoxic effects, as they occur, will most likely be generated through indirect mechanisms resulting from oxidative and lipid peroxidative damage and/or damage occurring during necrosis or apoptosis. As key events in this process are expected to occur in a nonlinear fashion, the expected relationship between CT dose and carcinogenic response in the liver is likely to be nonlinear with a steep dose response. This conclusion is consistent with rodent cancer bioassay results in which steep nonlinear dose responses have been seen.

Dose‐response analysis of bromate‐induced DNA damage and mutagenicity is consistent with low‐dose linear, nonthreshold processes

“…It may not be justified to assume that widely differing biological processes would lead to the same dose‐response patterns. Similar linear responses may not occur for agents which, for example, result in generation of ROS due to processes involving overt cellular toxicity and death [Takahashi et al,1998; Siesky et al,2002; Eastmond,2008]. It is also fair to note that other scenarios, for example, effective scavenging of a reactive intermediate at low doses, could create an apparent threshold for the 8‐OH‐dG generation but would not result in a downstream event's linear dependence on the dose.…”

An exploratory study of ambient air toxics exposure in pregnancy and the risk of neuroblastoma in offspring

“…Nonetheless it is well documented that carbon tetrachloride affects the sympathetic nervous system (Calvert and Brody, 1960). Its mechanism of causing carcinogenicity is not fully established, but it induces DNA adducts, double-strand breaks and micronucleated cells, perhaps as a result of oxidative stress and lipid peroxidation (Eastmond, 2008). Carbon tetrachloride has been linked to liver tumors in experimental studies, and in humans, some studies have linked it to NHL among exposed workers.…”

The relationship between multiple myeloma and occupational exposure to six chlorinated solvents

“…TCE and carbon tetrachloride have been shown to form DNA adducts and mutations in brain, testis, pancreas, kidney, liver, lung and spleen cells in rodents 43 44. DNA hypomethylation of protooncogenes, which is hypothesised to precede several types of cancer,45 has also been associated with exposure to TCE45 and chloroform 46…”