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RELTIVE POTENCIES OF SELECTED DIHALOACETATES AND THEIR MAJOR METABOLITES IN RODENT WHOLE EMBRYO CULTURE
Citation:
Hunter III, E S., M R. Blanton, AND E H. Rogers. RELTIVE POTENCIES OF SELECTED DIHALOACETATES AND THEIR MAJOR METABOLITES IN RODENT WHOLE EMBRYO CULTURE. Presented at Society of Toxicology, New Orleans, LA, March 6-10, 2005.
Description:
Relative potencies of selected dihaloacetic acids and their major metabolites in rodent whole embryo culture.
S. Hunter, M. Blanton, E. Rogers
RTD, NHEERL, ORD, US EPA, RTP, NC, 27711
Haloacetic acids (HAA) are produced by disinfection and present in tap water. Several of the HAAs produce adverse developmental effects when administered to rodent models. To better understand the causes of HAA-induced effects in vivo we compared the time and concentration dependent effects of three developmentally toxic HAAs (bromochloro-(BCA), dibromo-(DBA) and dichloro-(DCA) acetates) and their major metabolites (glyoxylate(GO), glycolate(G), oxalate(O)) in whole embryo culture. CD-1 mouse conceptuses (3-6 somite stage, GD8) were exposed to parent or metabolite for 1, 3, 6 or 24H and morphological development evaluated at 24H. A 24H exposure to each of the compounds produced dysmorphogenesis. To compare the potencies of these compounds an ED05 benchmark concentration (BMC) was calculated for induction of dysmorphogenesis. The relative potencies and BMC of these compounds are BCA(52?M) = DBA(69?M) > GO(442?M) > G(645?M) > O(792?M) > DCA(1792?M). Conceptuses were then exposed to these compounds for 1, 3 or 6H at concentrations that produced high rates of dysmorphogenesis with a 24H exposure. A 3 or 6H exposure to 300?M BCA produced prosencephalic and pharyngeal arch defects. A 6H exposure to 11000?M DCA produced severely malformed embryos. A 6H exposure to 300?M DBA altered somitogenesis but not morphogenesis. A 6H exposure to 1500?M GO, 3500?M G or 3500?M O did not produce defects. Therefore, BCA could be the proximate toxicant because it disrupts development with short-term exposures and at concentrations lower than the metabolites. DBA requires exposures longer than 6H to disrupt morphogenesis but is more potent than the metabolites. Exposure to DCA disrupts development, but much lower concentrations of the metabolites are sufficient to produce those effects. Therefore when administered in vivo, BCA is likely the proximate toxicant, and the metabolites are the likely toxicants when DCA is administered. More information relating time and concentration will be needed to determine if the effects of DBA administration are the result of DBA and/or its metabolites. This abstract does not represent EPA policy.