DNA-Reactive Carcinogens: Mode of Action and Human Cancer Hazard

Abstract

It has been known for decades that mutagenicity plays an important role in the activity of most carcinogens. This mutagenicity can result from direct damage to DNA through a chemical being DNA reactive or from indirect effects, such as through the production of oxygen radicals that then react with DNA. This article presents a set of key events whereby DNA reactivity initiates the process of carcinogenicity that leads to the subsequent mutation induction and enhanced cell proliferation that ultimately results in tumor development. This set of key events for DNA-reactive chemicals was applied to two case studies (aflatoxin B₁ and dichloromethane) with the aim of assessing the utility of the Human Relevance Framework (HRF) for this class of chemicals. The conclusions were that the HRF was a viable approach for the use of mechanistic data for DNA-reactive chemicals obtained from both laboratory animals and human cells in vivo and in vitro for predicting human carcinogenicity. In the case of aflatoxin B₁, the HRF could be used to predict that carcinogenicity in humans was a likely outcome. In contrast, the HRF predicted that the human carcinogenic potential of dichloromethane was at best less likely than in rodents; this conclusion was supported by the available epidemiological data.