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XENOENDOCRINE DISRUPTERS-TIERED SCREENING AND TESTING: FILLING KEY DATA GAPS
Citation:
Gray Jr., L E., J S. Ostby, V S. Wilson, C R. Lambright, K L. Bobseine, P C. Hartig, A. K. Hotchkiss, C J. Wolf, J. R. Furr, M. G. Price, L G. Parks, R L. Cooper, T E. Stoker, S C. Laws, S J. Degitz, K M. Jensen, M D. Kahl, J J. Korte, E A. Makynen, J E. Tietge, AND G T. Ankley. XENOENDOCRINE DISRUPTERS-TIERED SCREENING AND TESTING: FILLING KEY DATA GAPS. International Congress of Toxicology, Brisbane, AUSTRALIA, July 13, 2001.
Description:
ABSTRACT
The US Environmental Protection Agency (EPA) is developing a screening and testing program for endocrine disrupting chemicals (EDCs). High priority chemicals would be evaluated in the Tier 1 Screening (T1S) battery. Chemicals positive in T1S would then be tested (Tier 2). T1S includes in vitro estrogen (ER) and androgen (AR) receptor binding and/or gene expression, an assessment of steroidogenesis and mammalian and nonmammalian in vivo assays (Table 1). Using the rat, the uterotropic assay detects estrogens and antiestrogens, while steroidogenesis, estrogenicity and hypothalamic-pituitary-gonadal (HPG) function are assessed in a "Pubertal Female Assay". (Anti-) androgens are detected in the Hershberger Assay (androgen-dependent tissues in castrate-immature-male rats). Fish and amphibian assays also are being developed. The fathead minnow assay can identify EDCs displaying several mechanisms of concern, including androgen and estrogen receptor, androgen receptor antagonists and aromatase inhibitors, while the amphibian assay is designed to detect thyroid-active substances. Several alternative mammalian in vivo assays have been proposed. Of these, a short-term pubertal male rat assay appears most promising. An in utero -lactational screening protocol also is being evaluated. For Tier 2, the numbers of endocrine sensitive endpoints and offspring (F1) examined need to be expanded. Consideration also should be given to tailoring T2, based on the results of T1. For example, endpoints like anogenital distance at birth and nipple/areola retention in infant rats should be required in testing for androgens and antiandrogens because they are sensitive, permanent effects that are highly correlated with malformations and reproductive organ weight changes later in life. On the other hand, EDCs that display antithyroid, estrogenic or antiestrogenic activity display a different profile of developmental effects and these aforementioned endpoints are not sensitive to disruption by these mechanisms. Tier 1 and 2 also should examine relevant mixtures of EDCs. For example, toxicants that induce malformations in androgen-dependent tissues produce cumulative effects even when two chemicals act via different mechanisms of action.