Advances in understanding mechanisms of toxicity and implications for risk assessment

Knowledge of mechanism of action of a toxicant can greatly improve the accuracy of risk estimation by replacing with data the many default assumptions of risk assessment. Results from studies on comparative pharmacokinetics, metabolism, cell biology, and molecular biology have been successfully applied to problems of interspecies extrapolation, interindividual differences in susceptibility, and the relevance of high-dose findings for low-dose risk estimation. Examples are provided. Extremely rapid progress in understanding the molecular control of embryonic pattern formation and organogenesis has the potential to significantly improve the accuracy of risk assessment, especially by providing a sounder basis for characterizing interspecies differences, individual susceptibility, and multifactorial (gene-environment) etiologies of abnormal development. However, it will be necessary to quantitate toxicant-induced changes at the molecular level and to determine the level of change needed to perturb higher levels of biological organization at which adverse effects are manifested. It will also be important for risk assessment methodology to evolve so that it can better and more routinely accommodate mechanistic information. There is great potential for the recent and coming advances in knowledge of the molecular and cellular basis of abnormal development to be applied to risk assessment. Consideration should be given to shifting some of the resources now allocated to hazard screening to investigating the mechanisms of chemically induced abnormal development.