Mechanistic approaches for mixture risk assessments-present capabilities with simple mixtures and future directions

Mechanistic studies with simple mixtures have provided insights into the nature of interactions among chemicals that lead to non-additive effects and have elucidated the exposure conditions under which interactions are likely to occur. This paper discusses studies on four mixtures: (1) 1,1-dichloroethylene and trichloroethylene, (2) carbon tetrachloride and Kepone, (3) hexane and methyl-n-butylketone, and (4) coplanar and non-coplanar polychlorinated biphenyls. These mechanistic studies show that interactions should be described at the level of target tissue dose and are best categorized as either pharmacokinetic (PK) or pharmacodynamic (PD) interactions. In PK interactions the presence of a second chemical alters the kinetics such that a unit of administered dose no longer produces a unit of dose at the target tissue. In PD interactions, the presence of other compounds alters the PDs such that a unit tissue dose no longer produces a unit of response. Physiologically based pharmacokinetic (PBPK) models for mixtures have become important tools for predicting conditions under which interactions are likely to alter the assumption of additivity and have permitted calculation of interaction thresholds with more confidence. New cumulative risk assessment approaches have provided opportunities to classify compounds on the basis of similar chemistry-based modes of action (cholinesterase inhibitors) or similar physiological modes of action (diverse chemicals that alter a common biological outcome, such as defeminization of the developing nervous system). The latter examples present challenges for expanding our risk assessment paradigm to focus on the biology of responses more than on the kinetics of the xenobiotics. Some of the future advances in mixture research will depend on progress in systems biology, a discipline that integrates information across multiple level of biological organization producing PD models of normal function and assessing conditions under which exposures to chemicals lead to the perturbations sufficiently great to produce toxicity and disease. We describe briefly the elements of a systems biology approach for assessing the interactions between various PCB congeners.