Risk assessment and biological mechanisms: lessons learned, future opportunities

During the past decade, toxicological research has been dominated by two themes; investigations to elucidate the mechanisms of action of toxicants and studies to provide information to support improved assessments of human health risks. The conduct of mechanistic investigations was given an early impetus by advances in biochemistry and cell biology and, more recently, by related advances in molecular biology. Research to provide information for improved human health risk assessments was stimulated by the 1983 NAS/NRC report that provided a codified structure for conducting risk assessments. At first glance, it would appear that the two themes are closely related and, indeed, should represent parts of a joined theme. However, examination of the toxicology/risk assessment literature of the past decade indicates that this has not been the case. Reports of mechanistic studies infrequently indicate how the information can be used to provide improved estimates of human risk from exposure to toxicants. If reference is made, it is usually qualitative in nature. Neither is examination of the risk assessment literature reassuring. Mechanistic studies may be cited; however, the final step of the process, risk characterization, is usually dominated by the use of default options grounded in conservative interpretations of generic scientific knowledge. Two examples are reviewed that stand out as illustrations of how mechanistic information can be used to make a difference in risk assessments: (1) consideration of the alpha 2u-globulin-mediated mechanism for evaluating male rat data for relevance in assessing human risks of renal cancer and (2) the use of DNA-protein cross-links as an internal dose metric in cross-species extrapolation of nasal cancer risks from inhaled formaldehyde. This paper reviews past experience on these topics and suggests a strategy for increasing the use of mechanistic information in risk assessments. A key component of the strategy is to use the risk assessment process to identify research needs/opportunities that, if addressed, will reduce the use of default options, thereby reducing the uncertainties in risk assessments. Another component of the strategy is to identify a few chemicals anticipated to exert their effect via different mechanisms and whose mechanisms of dosimetry and disease pathogenesis can be investigated in-depth within a risk assessment framework; this identification will create prototype approaches as alternatives to the use of default options that have major impact on the outcome of the risk assessment process.