Estimation of toxicity of chemical mixtures through modeling of chemical interactions

The Agency for Toxic Substances and Disease Registry (ATSDR), in collaboration with the Dutch Organization for Applied Scientific Research (TNO) Nutrition and Food Research Institute, is conducting studies to evaluate the role of chemical interactions in the expression of toxicity from low-level exposure to combinations of chemicals. The goal of this collaborative effort is to use a weight-of-evidence (WOE) approach to estimate joint toxicity of some simple chemical mixtures and to compare the estimations with test results from animal toxicity studies. The WOE approach uses individual chemical dose-response assessments and algorithms that incorporate various assumptions regarding potential chemical interactions. Qualitative evaluations were prepared for binary combinations of chemicals for the effect of butyl hydroxyanisole on di(2-ethylhexyl)phthalate, the effect of stannous chloride on Cd chloride (CdCl2), and the effect of CdCl2 on loperamide. Analyses of these evaluations and their comparison with the conclusions of laboratory animal experiments indicate that the WOE approach can be used to estimate qualitatively the joint toxicity of such simple mixtures. To further test the utility of the WOE approach, qualitative and semiquantitative evaluations were prepared for two chemical mixtures--one with similarly acting halogenated aliphatics (trichloroethylene, tetrachloroethylene, hexachloro-1,3-butadiene[HCBD], and 1,1,2-trichloro-3,3,3-trifluoropropene [TCTFP]) and the other with dissimilarly acting nephrotoxic components (mercuric chloride, lysinolalanine, D-limonene, and HCBD). These two sets of data were used to estimate the overall toxicities of the mixtures using the WOE algorithm for the mixture. The comparison of the results of the estimated toxicity with experimentally determined toxicity of the mixture of similarly acting nephrotoxicants demonstrated that the WOE approach correctly adjusted for the observed interactions in experimental animal studies. However, this was not true for the mixture of dissimilarly acting nephrotoxicants. This could be attributed to the fact that WOE evaluations are based on dose additivity that postulates that all chemicals in a given mixture act in the same way--by the same mechanism--and differ only in their potencies. In these cases the WOE approach evaluations, based on consideration of common mechanisms for simple chemical mixtures, can lead to better estimates of joint toxicity of chemical mixtures than the default assumption of dose additivity. The results also show that the WOE evaluations should be target-organ specific because none of the models tested could approximate the observed responses in organs other than the target organs in the laboratory animal studies.