Mode of action considerations in the quantitative assessment of tumour responses in the liver

Chemical carcinogenesis is a complex, multi-stage process and the relationship between dose and tumour formation is an important consideration in the risk assessment of chemicals. Extrapolation from empirical dose-response relationships obtained in experimental studies has been criticized, as it fails to take into account information on mode of action. Strategies for incorporating mode of action information into the risk assessment of chemical carcinogens are described, with a focus on hepatic cancer. Either toxicokinetic or toxicodynamic processes can be addressed. Whilst the former have been the focus of more attention to date, for example by using physiologically based modelling, there is increasing interest in the development of mode of action-based toxicodynamic models. These have the advantage that they do not require extreme assumptions, and may be amenable to paramaterization using human data. This is rarely if ever possible when using conventional dose-tumour response relationships. The approaches discussed are illustrated using chloroform as a case study. This compound is converted to a cytotoxic metabolite, phosgene, by CYP2E1 in liver and/or kidney. Cytotoxicity results in proliferative regeneration, with increased probability of tumour formation. Both physiologically based toxicokinetic and toxicodynamic models have been developed, and it is possible to use probabilistic approaches incorporating, for example, data on the distribution of hepatic CYP2E1 levels. Mode of action can provide an invaluable link between observable, experimental data, on both toxicokinetics and toxicodynamics, and chemical-specific risk assessment, based on physiological approaches.