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REPRODUCTIVE AND DEVELOPMENTAL EFFECTS SCREENING STUDIES
Impact/Purpose:
Reproductive and developmental screening studies are needed to identify drinking water chemicals (DBPs, CCLs) that pose the greatest risk to reproductive function and fetal development. Chemicals shown to be effective in screening evaluations are triggered for more sophisticated dose-response/ target organ evaluations within the Reproductive Toxicology Division (i.e. 14-day spermatotoxicity tests, pregnancy maintenance tests, Segment II tests), as well as outside the Division via Cooperative Agreements (e.g. multigeneration tests conducted by GLP). Collectively these studies provide critical data for Stage 2 and Stage 3 rule decisions.
Description:
Several DBPs, particularly the disubstituted haloacetic acids (e.g. dibromoacetic acid, bromochloroacetic acid), have been shown to produce reproductive and developmental toxicity in laboratory animals. In 1993, an expert panel convened by the EPA and the International Life Sciences Institute (ILSI) decided that: 1) screening studies should be implemented to fill critical data gaps; 2) fertility assessments should be enhanced; and 3) biomarkers of effect should be developed. More recently at a workshop convened by OW and NCEA it was decided that additional issues such as route of exposure, relevant animal models, mixtures of drinking water chemicals, and critical periods of reproductive development be addressed in future reproductive studies. Colorado State University has completed a study (funded via a Cooperative Agreement) to identify the most sensitive period of exposure to the relatively potent DBP, dibromoacetic acid (DBA), using a developmental reproductive study in the rabbit, a species which has a period of reproductive development more similar to that of humans. In this study, DBA was administered via drinking water from gestation day 15 through sexual maturity. More recently, the Research Triangle Institute conducted a multigenerational study (funded via a Cooperative Agreement) of another priority DBP, bormodichloroacetic acid (BCA). Our intramural studies have shown that bromodichloromethane induces pregnancy loss in the Fisher 334 rat, but not the Sprague Dawley rat. Moreover, this effect is observed only when exposures occur during the period of pregnancy that is maintained by luteinizing hormone; studies are underway to understnad the molecular basis for susceptibility to pregnancy loss.