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EFFECTS OF MIXTURES OF PHTHALATES AND OTHER TOXICANTS ON SEXUAL DIFFERENTIATON IN RATS: A RISK FRAMEWORK BASED UPON DISRUPTION OF COMMON DEVELOPING SYSTEMS
Citation:
GRAY, L. E., C. Rider, K. Howdeshell, J. Furr, C. Lambright, P. Foster, AND V. Wilson. EFFECTS OF MIXTURES OF PHTHALATES AND OTHER TOXICANTS ON SEXUAL DIFFERENTIATON IN RATS: A RISK FRAMEWORK BASED UPON DISRUPTION OF COMMON DEVELOPING SYSTEMS. Presented at Society of Toxicology 49th Annual meeting, Salt Lake City, UT, March 07 - 11, 2010.
Impact/Purpose:
This is an short article that will be combined by the editors with the articles from the 2 other symposia speakers and then published by the Endocrinology Society in the June edition of Endocrine News(3/12/2009)
Description:
Since humans are exposed to more than one chemical at a time, concern has arisen about the effects ofmixtures ofphthalates and other chemicals on human reproduction and development. We are conducting studies to determine 1) what effects associated with in utero phthalate exposure, 2) which phthalates disrupt sexual differentiation, and 3) how mixtures ofphthalates behave when combined with other phthalates or with other toxicants. In the mixture studies we have examined the postnatal development ofmale rat offspring after in utero exposure to 1) pairs of AR antagonists, 2) pairs ofphthalates, 3) phthalates with AR antagonists, 4) five phthalates, 5) seven chemicals (four pesticides and three phthalates), 6) ten chemicals (four pesticides and six phthalates) and 7) the potent Ah receptor agonist 2,3,7,8-tetrachlorodibenzodioxin plus a phthalate. We also have examined the effects of these chemicals on fetal male rat hormone levels and testicular gene expression levels. Results of these studies demonstrate that only Dose Addition models accurately predict the effects of these mixtures on male rat sexual differentiation. For example, when ten chemicals were administered in utero, 100% of the males displayed reproductive tract malformations as predicted by Dose Addition models whereas Response Addition models predicted that none of the males would be malformed. We propose that the regulatory framework for cumulative risk assessments should not be based upon common mechanisms of toxicity, as this underpredicts 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. This abstract does not necessarily reflect EPA policy. NTP, NIEHS/EP A Interagency Cooperative Research AgreementHHS Y1-ES-8014-01;EPARW75922