Use of mechanistic information in risk assessment for toxic chemicals.

Risk assessment (RA) for toxic chemicals is assumed to be a scientific activity providing a framework of principles for the complication and evaluation of all available scientific information and the rational extrapolation to human health effects in as quantitative terms as possible and with a high degree of certainty. Sensible public health decisions are made more certain through the use of mechanistic information throughout the 4 steps in RA: hazard identification, dose-response assessment, exposure (dose) assessment and risk characterisation. Examples of the use of mechanistic information to assess risks of systemic, developmental/reproductive and neurotoxic effects show how to move away from the presently used threshold/no observable adverse effect/uncertainty factor default methodology towards an evaluation based on all available scientific data. The experience gained in cancer RA in the use of metabolic and tissue binding (receptor) models as well as physiologically based pharmacokinetic (PBPK) and pharmacodynamic (PBPD) models can be transferred to non-cancer RA. A good example is the use of a PBPK model for the hepatoxicity of chloroform. As in cancer RA, as default positions are replaced by biological data the risk assessments become less uncertain when extrapolating between species. Combining information on tissue dosimetry and response data can also provide an estimate of variability within populations, which is impossible with present default type methodology but essential for adequate risk characterisation. Unlike the cancer field there is no single hypothesis for the mechanism of action for the multitude of non-cancer end-points studied.