Estimation of toxicity of chemical mixtures through modeling of chemical interactions

The Agency for Toxic Substances and Disease Registry (ATSDR), in collaborat ion with the Dutch Organization for Applied Scientific Research (TNO) Nutri tion and Food Research Institute, is conducting studies to evaluate the rol e of chemical interactions in the expression of toxicity from low-level exp osure to combinations of chemicals. The goal of this collaborative effort i s to use a weight-of-evidence (WOE) approach to estimate joint toxicity of some simple chemical mixtures and to compare the estimations with test resu lts from animal toxicity studies. The WOE approach uses individual chemical dose-response assessments and algorithms that incorporate various assumpti ons regarding potential chemical interactions, Qualitative evaluations were prepared for binary combinations of chemicals for the effect of butyl hydr oxyanisole on di(2-ethylhexyl) phthalate, the effect of stannous chloride o n Cd chloride (CdCl2), and the effect of CdCl2 on loperamide, Analyses of t hese evaluations and their comparison with the conclusions of laboratory an imal experiments indicate that the WOE approach can be used to estimate qua litatively the joint toxicity of such simple mixtures. To further test the utility of the WOE approach, qualitative and semiquantitative evaluations w ere prepared for two chemical mixtures-one with similarly acting halogenate d aliphatics (trichloroethylene, tetrachlorcethylene, hexachloro-1,3-butadi ene [HCBD], and 1,1, 2-trichloro-3,3,3-trifluoropropene [TCTFP]) and the ot her with dissimilarly acting nephrotoxic components (mercuric chloride, lys inolalanine, D-limonene, and HCBD). These two sets of data were used to est imate the overall toxicities oi the mixtures using the WOE algorithm for th e mixture. The comparison of the results of the estimated toxicity with exp erimentally determined toxicity of the mixture of similarly acting nephroto xicants demonstrated that the WOE approach correctly adjusted for the obser ved interactions in experimental animal studies. However, this was not true for the mixture of dissimilarly acting nephrotoxicants. This could be attr ibuted to the fact that WOE evaluations are based on dose additivity that p ostulates 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 a pproach evaluations, based on consideration of common mechanisms for simple chemical mixtures, can lead to better estimates of joint toxicity of chemi cal mixtures than the default assumption of dose additivity. The results al so show that the WOE evaluations should be target-organ specific because no ne of the models tested could approximate the observed responses in organs other than the target organs in the laboratory animal studies.