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CUMULATIVE DEVELOPMENTAL EFFECTS OF ENDOCRINE DISRUPTERS: SYNERGY OR ADDITIVITY?
Citation:
Gray Jr., L E., J S. Ostby, J. R. Furr, C J. Wolf, A. K. Hotchkiss, L G. Parks, M. G. Price, C R. Lambright, AND V S. Wilson. CUMULATIVE DEVELOPMENTAL EFFECTS OF ENDOCRINE DISRUPTERS: SYNERGY OR ADDITIVITY? Presented at Society for the Study of Reproduction, Cincinnati, OH, July 19-22, 2003.
Description:
Exposure to chemicals with hormonal activity during critical developmental periods can disrupt reproductive function and development. Within the last decade, several classes of pesticides and toxic substances have been shown to disrupt differentiation of the male rat reproductive tract by interfering with the synthesis or action of fetal Leydig cell steroid and peptide hormones. Vinclozolin (V) and procymidone (P) are pesticides that induce malformations by acting as androgen receptor (AR) antagonists. In contrast, some phthalate esters induce malformations by inhibiting fetal Leydig cell hormone production. The pesticides linuron (L) and prochloraz act both as AR antagonists and by inhibiting steroid hormone production. Typically, the potential risk of these chemicals to humans and wildlife is assessed on a chemical-by-chemical basis without consideration of concurrent exposures to other endocrine disrupting chemicals (EDCs) However, in 1996 the Food Quality Protection Act mandated that the US Environmental Protection Agency (EPA) consider the cumulative risk from multiple chemical exposures that acted via a common mechanism. EPA is now in the process of evaluating how it is going to assess the cumulative effects of exposure to antiandrogenic pesticides. The studies described herein begin to provide a framework for the Agency in this endeavor. We are executing relatively simple mixture studies to demonstrate what types of EDCs produce cumulative reproductive toxicity when administered during sexual differentiation of the male rat reproductive tract. In these studies, pairs of "antiandrogenic" chemicals were coadministered on days 14-18 of gestation with one another or individually using sub- or near threshold dosage levels equivalent to about 1/2 the ED50 for causing hypospadias. Studies included: 1) two AR antagonists (V plus P; each at 50 mg/kg/d), 2) two phthalate esters (dibutyl (DBP) and benzylbutyl phthalate (BBP), each at 500 mg/kg/d), 3) a phthalate ester plus and an AR antagonist (DBP (500) plus P(50)) and 4) L (75 mg/kg/d) plus BBP (500). Dose response studies have shown that the relative potency of DBP and BBP is about ten-fold less than than of V or P (relative potency factors (RPF) for hypospadias). We expected that by themselves V, P, L, DBP and BBP would not induce hypospadias or any other malformations at these dose levels, but, if the toxicity was cumulative, mixing two together would be equivalent to doubling the dose of one toxicant and this "dose" would induce hypospadias in about 50% of the males. Reproductive organ weights and malformations of other tissues should also display cumulative responses to the mixtures. All of the results to date indicate that the effects are dose-additive, and not synergistic. This would indicate that the "antiandrogens" included in the "common mechanism group" to be evaluated in a cumulative risk assessment should be broadly rather than narrowly defined to include both AR antagonists and inhibitors of fetal hormone production. We also found that the RPF of each chemical varied predictably from endpoint to endpoint, based upon the specific mechanism of action. Thus, in contrast to the RPFs for hypospadias, where V=P=1 and DBP=BBP=0.1, the RPFs for gubernacular genesis are DBP=BBP=1 and L, V and P=0. The RPFs vary from tissue to tissue because all the above toxicants disrupt the androgen pathway but only the phthalate esters inhibit insulin-like 3 peptide synthesis. Gubernacular agenesis was present in the BBP+DBP group, but not in the L+BBP or DBP+P groups. Our results indicate that chemicals that alter differentiation of the reproductive system during the same period of development will produce cumulative, dose-additive effects. Our ability to predict these effects is enhanced by specific knowledge about the mechanism of toxicity of each chemical. We anticipate that as we expand the study design to include AhR agonists and potent estrogens, we also observe cumulative effects on specific reproductive target organs.