Mode of action and tissue dosimetry in current and future risk assessments

Two fundamental concepts have emerged to organize contemporary approaches to chemical risk assessment - mode of action and tissue dosimetry. Mode of action specifies the nature of the interactions between the chemical and the body that lead to toxic responses and should, under optimal circumstances, also specify the form of the tissue dose that leads to these effects. This paper highlights recent development of biologically based dose response (BBDR) models for specific toxic endpoints that use knowledge on mode of action to specify measures of dose. These dose measures then are used to support low dose and interspecies extrapolations. We first focus on a series of dose response models developed for several compounds that produce nasal toxicity. These examples demonstrate a range of model structures from simple dosimetry models (methylmethacrylate) to linkage of dosimetry with specific biological processes involved in carcinogenesis (formaldehyde). Two BBDR models with dioxin illustrate the organization of biological and dosimetry information into specific testable hypotheses that could distinguish these different models and lead to a more uniform approach to risk assessment for this compound. A final section discusses the impact of molecular biology and the genomic revolution in relation to development of BBDR models for specific toxic endpoints.