Douglas A. Dawson

Initial evaluation of developmental malformation as an end point in mixture toxicity hazard assessment for aquatic vertebrates

The joint toxic action of three binary mixtures was determined for the embryo malformation endpoint of the aquatic FETAX (frog embryo teratogenesis assay: Xenopus) test system. Osteolathyrogenic compounds and short-chain carboxylic acids, representing separate, distinct modes of action for induction of malformation, were selected for testing in 96-hr, static-renewal tests. Three mixtures were tested for each combination, with each combination being tested on three separate occasions. Using toxic unit analysis, the combination of osteolathyrogens and the combination of carboxylic acids produced strictly additive (concentration addition) rates of malformation, while the combination of an osteolathyrogen and a carboxylic acid was less-than-additive (response addition) for induction of malformation. Therefore, developmental malformation may have value as an endpoint in mixture toxicity hazard assessment.

Developmental malformation of frog embryos an analysis of teratogenicity of chemical mixtures

Chemical compounds known to be teratogenic to frog embryos were tested singly and in binary mixtures and Weibull functions were used to model their concentration-response relationships. A separate Weibull function with an additive concentration variable modeled the mixtures using only single chemical test data. Seven chemicals in five binary mixtures at 3/1, 1/1, and 1/3 mixture proportions each were tested. The ratios of measured and calculated model parameters and median concentrations were estimated for comparing the results. The ratios ranged from 0.72 and 1.44 with an average at 0.99, an agreement that was qualitatively similar to modeling mixtures of narcotic chemicals which are known to produce additive concentration effects. The model reliability in determining mixture response classes and prediction of effects based on single chemical data was quantified. The model is useful for environmental risk assessment of chemical mixtures in hazardous waste sites and for the design of mixture experiments.

Joint action of benzoic hydrazide and β-aminopropionitrile on Xenopus embryo development

Binary mixtures of the osteolathyrogens benzoic hydrazide and beta-aminopropionitrile were tested to determine the joint action for these chemicals, by evaluating induction of malformation and osteolathyrism in developing frog embryos. Exposures, starting with late-blastula stage embryos, were for 96-h with solution renewal every 24-h. Five treatments were examined, each chemical alone (i.e., 1:0 and 0:1 solutions) and three mixtures (i.e., 3:1, 1:1, and 1:3). Following exposure, embryos were evaluated grossly and the incidences of all types of malformations and osteolathyrogenic lesions were determined. Toxic unit analysis and isobole diagrams indicated these chemicals were concentration additive in inducing malformations and osteolathyrism. Therefore, benzoic hydrazide and beta-aminopropionitrile induce osteolathyrism, in Xenopus embryos, in a similar manner.