Mechanistic and toxicokinetic data reducing uncertainty in risk assessment

Risk characterization comprises hazard identification describing the intrinsic toxic potential of a chemical, knowledge of dose-response-relationships, as well as of toxicokinetics describing quantitatively the relation between external and internal dose and exposure assessment. Compounds that induce reversible effects, which are repaired during and after exposure, are considered thresholded and allow definition of a NOEL. Biological reactive intermediates of chemicals have the potential to bind covalently to cellular macromolecules like proteins and DNA. Such interaction may not be repaired completely. If damage is not repaired, the effect persists and accumulates upon repeated exposure. In such cases a NOEL cannot be determined. Thus, in the risk assessment process, data on covalent binding (CB) are of qualitative and together with toxicokinetics of quantitative significance. Qualitatively, CB, especially with DNA and in correlation with this to proteins, is indicative for an irreversible and non-thresholded mutagenic and carcinogenic effect. Absence or presence of CB assists to differentiate between primarily genotoxic and thresholded non-genotoxic carcinogens. Quantitatively, toxicokinetics together with CB are used to quantify internal exposure and target dose, which is a prerequisite for species-species extrapolation, and for extrapolation from high dose to low dose. For example, the toxicokinetics of the reactive intermediates of styrene and ethylene have been determined in rodents and humans and modeled to predict dose-responses of internal exposure. It is described in this communication that such information, together with other parameters like cell proliferation as a result of cytotoxicity, is the basis for quantitative risk assessment of human exposure to these compounds. Also for chlorobenzene, the relevance of toxicokinetics for estimating the human health risk is demonstrated.