bromochloroacetic-acid and Abnormalities--Drug-Induced

The haloacetic acids (HAA) are a family of chemicals that are drinking water disinfection by-products. We previously reported that haloacetic acids, including several bromo- and chloro-HAAs, alter embryonic development when mouse conceptuses are directly exposed to these xenobiotics in whole embryo culture. Craniofacial dysmorphogenesis was observed in exposed embryos and a quantitative structure activity relationship (QSAR) for induction of cranial neural tube dysmorphogenesis was established for a series of 10 HAAs, which also included fluoro- and iodo-HAA representatives. In the current study, we evaluate the effects of exposing neurulation staged (3-6 somite pairs) CD-1 mouse conceptuses to bromochloro- (BCA), dibromochloro- (DBCA) and bromodichloro-acetic (BDCA) acids in whole embryo culture at concentrations ranging from 50 to 2500 microM. Morphological development was assessed after a 26 h exposure period. Exposure of conceptuses to these HAAs produced dysmorphogenesis, including prosencephalic and pharyngeal arch hypoplasia as well as eye and heart tube abnormalities. Benchmark concentrations for induction of neural tube dysmorphogenesis were 63, 500 and 536 microM for BCA, DBCA and BDCA, respectively. Our previously developed HAA QSAR accurately predicted placement of these three chemicals in the larger context of the previously tested di- and tri-HAAs, also correctly predicting that BCA would be more potent than DBCA and BDCA, and that the latter two HAAs would be near equi-potent. This study describes the concentration-dependent induction of dysmorphogenesis in whole embryo culture by three mixed chloro/bromo-HAAs and demonstrates the ability of the HAA QSAR to predict relative potencies within this family of xenobiotics.

Topics: Abnormalities, Drug-Induced; Acetates; Animals; Benchmarking; Dose-Response Relationship, Drug; Embryo Culture Techniques; Embryonic Development; Eye Abnormalities; Heart Defects, Congenital; Mice; Neural Tube Defects; Quantitative Structure-Activity Relationship

The haloacetic acids (HAAs) are a family of xenobiotics found in tap water as a result of drinking water disinfection. Administration of HAAs to rats produces a variety of adverse effects, including developmental toxicity. The dysmorphogenic potencies of all nine bromo/chloro-acetic acids have been determined in rodent whole embryo culture using standard 26-h exposure. Since the half-lives of the HAAs in vivo are typically <8 h, the developmental effects of short-term exposures to dihaloacetates were evaluated. Gestation day 8 (3-6 somite pairs) CD-1 mouse conceptuses were exposed to 11,000 microM dichloroacetic acid (DCA), 300 microM dibromoacetic acid (DBA) or 300 microM bromochloroacetic acid (BCA) for culture periods of 1, 3, 6 or 26 h. Following 1, 3 or 6 h of exposure to HAAs, conceptuses were transferred to control medium to complete a 26-h culture period. The amounts of HAAs present in embryos after 1, 3 and 6h of exposure were determined. Increased incidences of dysmorphic embryos were produced by 6 or 26-h exposures to DCA; a 26-h exposure to DBA; or 3, 6 or 26-h exposures to BCA. The dysmorphology produced was dependent upon the length of exposure and chemical. The embryonic concentration of each HAA (104.5, 2.5 and 2.6 pmol/microg protein for DCA, DBA and BCA, respectively) was reached by 1h of exposure and did not change at the subsequent time points examined. The current studies demonstrate that BCA is more potent than DBA or DCA at disrupting embryogenesis since shorter exposures alter morphogenesis. Since the embryonic HAA concentrations were the same at the three time points measured, the time-dependence in dysmorphogenesis does not appear to be a simple function of increasing embryonic concentration of these chemicals. These studies demonstrate that for these dihaloacetic acids relatively high concentrations and long exposures are needed to alter rodent development in vitro.

Topics: Abnormalities, Drug-Induced; Acetates; Animals; Dichloroacetic Acid; Embryo Culture Techniques; Embryo, Mammalian; Embryonic Development; Mice; Time Factors; Water Pollutants, Chemical

Adverse developmental effects of two haloacetic acids, bromochloroacetic acid (BCA) and dibromoacetic acid (DBA), were determined by using the Frog Embryo Teratogenesis Assay--Xenopus (FETAX). Xenopus embryos (150-400/concentration group) were exposed to 0, 8000, 10,000, 12,000, or 14,000 ppm BCA or 0, 10,000, 12,000, 14,000, or 16,000 ppm DBA for 96 h beginning from stage 8 (mid-blastula) to stage 46 (when primary organogenesis is complete). BCA produced 29, 83, and 100% mortality at 10,000, 12,000 and 14,000 ppm, respectively. Incidence of malformations among surviving embryos at 96 h for 10,000 and 12,000 ppm BCA were 8.4 and 68%. Thus LC50 and EC50 for BCA were between 10,000 and 12,000 ppm. DBA did not produce any significant mortality or malformation at any of the concentrations tested. In summary, BCA affected development of Xenopus embryos only at high concentrations, while DBA did not affect Xenopus development at the concentrations tested.

Topics: Abnormalities, Drug-Induced; Acetates; Animals; Dose-Response Relationship, Drug; Embryo, Nonmammalian; Embryonic and Fetal Development; Female; Random Allocation; Teratogens; Water Purification; Xenopus laevis

The chlorination of drinking water results in production of numerous disinfection by-products (DBPs). One of the important classes of DBPs is the haloacetic acids. We have previously shown that the haloacetic acids (HAs), dichloro (DCA), dibromo (DBA) and bromochloro (BCA) acetic acid are developmentally toxic in mouse whole embryo culture. Human exposure to these contaminants in drinking water would involve simultaneous exposure to all three HAs. This study explores the question of developmental toxicity interactions between these compounds. Gestational day (GD) 9.5 rat embryos were exposed to various concentrations of the three HAs (singly or in combination) for 48 h and then evaluated for dysmorphology. The embryonic effects from exposure to the single compounds and mixtures were evaluated using developmental score (DEVSC) as the parameter of comparison. Concentrations of individual compounds and mixtures were chosen (based on a dose-additivity model) which were predicted to produce scores 10 or 20% lower than control levels. Evaluations were performed on all possible combinations of the three HAs. The HAs were dysmorphogenic and resulted in primarily rotation and heart defects and to a lesser extent prosencephalic, visceral arch, and eye defects. The percent anomalies in the rat were comparable to those previously published for the mouse at comparable toxicant concentration. There was a low incidence of neural tube defects in the rat following exposure to the HAs. The rat neural tube appeared less sensitive to the HAs than did the mouse resulting in a higher rate of neural tube dysmorphology in the mouse. Following exposures to BCA and DBA, alone and in combination, there was a significant incidence of delayed embryonic caudal development with apparent normal development anterior to the second visceral arch. The developmental scores for embryos exposed to combinations of the three compounds, when compared to scores for embryos exposed to the single compounds, indicated that the dose-additivity model adequately predicted the observed toxicity and that the developmental toxicity of these water disinfection by-products appears to be additive in whole embryo culture (WEC).

Topics: Abnormalities, Drug-Induced; Abnormalities, Multiple; Acetates; Animals; Culture Techniques; Dichloroacetic Acid; Disinfectants; Dose-Response Relationship, Drug; Drug Combinations; Drug Interactions; Embryo, Mammalian; Female; Male; Pregnancy; Rats; Rats, Sprague-Dawley; Teratogens; Water Pollutants, Chemical