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CUMMULATIVE EFFECTS OF ADMINISTRATION MIXTURES OF “ANTIANDROGENS” IN RATS: A NEW FRAMEWORK BASED UPON COMMON SYSTEMS RATHER THAN COMMON MECHANISMS
Citation:
GRAY, L. E., C. V. RIDER, K. HOWDESHELL, A. K. HOTCHKISS, V. S. WILSON, P. M. Foster, AND J. R. FURR. CUMMULATIVE EFFECTS OF ADMINISTRATION MIXTURES OF “ANTIANDROGENS” IN RATS: A NEW FRAMEWORK BASED UPON COMMON SYSTEMS RATHER THAN COMMON MECHANISMS. Presented at Society for the Study of Reproduction Annual Meeting, Pittsburgh, PA, July 18 - 22, 2009.
Impact/Purpose:
To be presented at the Society for the Study of Reproduction Annual Meeting 2009, Pittsburgh, PA
Description:
Since humans and wildlife are exposed to more than one chemical at a time, concern has arisen about the effects of complex mixtures on reproduction and development. To date, different regulatory groups have not yet developed consistent approaches to conducting assessments of the risks of mixtures to human health. One commonly used approach is based upon the assumption that chemicals that act via common mechanisms of toxicity will act jointly (Dose addition) whereas chemicals that act via disparate mechanisms will act independently (Response addition). The consequence of the assumption that Response addition rather than Dose addition modeling accurately predicts the effects of mixtures of chemicals with different mechanisms of toxicity is that response addition models predict that there is no effect of the mixture if the level of each chemical is low (0+0+0+…….= 0% affected) whereas Dose addition models may predict that serious effects will occur even though the level of each chemical is too low to produce any effects individually (0+0+0+….= 100% affected). Over the last ten years our laboratory as been conducting studies to determine how mixtures of endocrine disrupting chemicals behave when administered during sexual differentiation of rats. The approach has been to use chemicals with 1) well characterized mechanisms of toxicity and 2) known dose-related reproductive effects. The effects of the mixtures are then compared to the effects predicted by Response- and Dose addition modeling to determine which model more accurately predicts the effects of mixture of chemicals with similar and disparate mechanisms of toxicity. The chemicals used in these studies include pesticides that are androgen receptor antagonist (procymidone, vinclozolin, prochloraz, linuron), and/or inhibitors of steroid hormone synthesis (linuron and prochloraz), plasticizers like the phthalates (inhibit fetal Leydig cell hormone synthesis) and the potent Ah receptor agonist 2,3,7,8 tetrachloro-dibenzo-dioxin (TCDD). In the mixture studies we combined pairs of AR antagonists, pairs of phthalates, phthalates with AR antagonists and seven chemicals (four pesticides and four phthalates). In the new, unpublished studies, presented herein, we examined the effects of in utero exposure to a mixture of TCDD plus a phthalate on epididymal differentiation and a complex mixture of ten chemicals (four pesticides and six phthalates) on several androgen-dependent endpoints in the male rat. Results of these studies clearly demonstrate that Dose addition models more accurately predict the effects of these mixtures on male rat sexual differentiation. For example, when the mixture of ten chemicals was administered in utero, 100% of the males displayed reproductive tract malformations. The Dose addition model predicted this (0+0+…0 = 100% affected) whereas the Response addition predicted that none of the males would be malformed (0+0+…0 = 0% affected). Based upon these results and similar results from other laboratories we propose that the regulatory framework for cumulative risk assessments should not be based upon common mechanisms of toxicity, as this under-predicts the effects of mixtures of chemicals with dissimilar mechanisms of toxicity. Rather, the framework should be based upon the disruption of common fetal targets or systems during development regardless of the mechanism of toxicity. Furthermore, a recently National Academy of Science Panel, formed at the request of the USEPA to advise the Agency on how to conduct a cumulative risk assessment on the phthalates came to the same conclusion, stating that the framework for cumulative risk assessments should be based upon common targets and not narrowly on common mechanisms of toxicity. This abstract does not necessarily reflect EPA policy. Supported in part by NTP, NIEHS Interagency Cooperative Research Agreement HHS Y1-ES- 8014-01; EPA RW75922855-01-0.
