Risk assessment initiatives for noncancer endpoints: implications for risk characterization of chemical mixtures

Current methods employed in risk assessment for noncarcinogens are associated with the estimation of reference doses (RfDs). These strategies reflect (appropriately) a protective philosophy in both theory and practice. The approaches are limited, however, in terms of the ability to project the likelihood of specific hazard above the reference dose and to integrate the health hazards of exposure to chemical mixtures (including both cancer and noncancer endpoints). Ongoing efforts that address guidelines for risk assessment of non-carcinogens, both singly and as components of mixtures, are presented. Included is a description of the range of potential biological response categories and associated parallel issues of adversity and severity. For example, the progression of histopathological change, organ system dysfunction and organismal disability is examined as it may affect risk characterization of mixtures. Mechanistic principles are suggested as an appropriate focus to systematically evaluate this progression. Once established, these principles may provide a reasonable framework in which to more accurately characterize risks associated with chemical mixtures.