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DOSE ADDITIVITY OF ATRAZINE AND BROMODICHLOROMETHANE IN CAUSING PREGNANCY LOSS IN F344 RATS
Narotsky, M G., D S. Best, S. R. Bielmeier, AND R L. Cooper. DOSE ADDITIVITY OF ATRAZINE AND BROMODICHLOROMETHANE IN CAUSING PREGNANCY LOSS IN F344 RATS. Presented at Society of Toxicology, Salt Lake City, UT, March 09 - 13, 2003.
DOSE ADDITIVITY OF ATRAZINE AND BROMODICHLOROMETHANE IN CAUSING
PREGNANCY LOSS IN F344 RATS.
AUTHORS (ALL): Narotsky, Michael G1; Best, Deborah S1; Bielmeier, Susan R2; Cooper, Ralph L1
SPONSOR NAME: James E Andrews
1. Reproductive Toxicology Division, USEPA, ORD, NHEERL, Research Triangle Park, NC, USA;
2. Curriculum in Toxicology, University of North Carolina, Chapel Hill, NC, USA;
Atrazine (ATRZ), a widely used herbicide, and bromodichloromethane (BDCM), a disinfection by-product found in drinking water, have both been shown to cause pregnancy loss, i.e., full-litter resorption (FLR), in F344 rats. Although chemically quite different, both ATRZ and BDCM have similar modes of action; ATRZ- and BDCM-induced pregnancy loss are associated with reduced levels of luteinizing hormone (LH) and progesterone during the LH-dependent period of gestation. ATRZ and BDCM co-exist in drinking water; thus, we sought to evaluate their cumulative effect on pregnancy maintenance using a dose-additivity model. Each agent was administered alone at near-threshold doses and in combination at one-half of the near-threshold doses. If synergistic, the two sub-threshold doses would combine to cause a greater-than-threshold response. Both agents were administered by gavage (BDCM in 10% alkamuls EL-620, then ATRZ in 1% methylcellulose) on gestation days 6-10. Each agent was administered alone at 40 mg/kg/d (LOEL=50 mg/kg); whereas the two were administered together at 20 mg/kg/d each. Dams were allowed to deliver and litters were examined on postnatal days 1 and 6. Uteri of nonparous females were stained with 10% ammonium sulfide to detect FLR. Alone or in combination, the agents were maternally toxic, causing weight loss after the first dose. As expected, 40 mg/kg of each chemical was a near-threshold dose for causing FLR; low rates (5-6%; 1 affected of 18-19 dams) were seen for each chemical alone. In combination, no FLR was seen (n=19). Thus, in this study, ATRZ and BDCM clearly lacked synergy in their ability to cause pregnancy loss in F344 rats. Although we did not assess the possibility of antagonism, these results are consistent with the default risk-assessment assumption of dose additivity for agents with the same mechanism.
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Record Details:Record Type: DOCUMENT (PRESENTATION/ABSTRACT)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB
REPRODUCTIVE TOXICOLOGY DIVISION