Teratological evaluation of chemical mixtures have shown four basic joint action types, but the nature of these joint actions is not understood. Similar work in acute toxicity indicates that the type of joint action may be related to the mode(s) of action of the toxicants. Therefore, work proposed herein will focus on determining if a consistent relationship exists between teratogenic joint actions and the mechanism(s) of chemical teratogens. Since 65 to 70% of human malformations cannot be attributed to any one cause, the possibility of multiple causative agents may become increasingly important in hazard assessment. To examine these ideas, FETAX (Frog Embryo Teratogenesis Assay: Xenopus) will be used to evaluate the teratogenic joint action of chemical combinations, both among and between each of two groups of chemical teratogens. Each group of chemicals: 1) osteolathyrogens, 2) short-chain carboxylic acids (SCCAs), is thought to represent a different, distinct mode of teratogenesis. In accordance with the present hypothesis, any combination of osteolathyrogens or any combination of SCCAs should show a strictly additive teratogen joint action. In contrast, any combination of an osteolathyrogen and an SCCA should have less than additive rates of malformation. Preliminary data indicates this is the case, but determination of the consistency of the relationship is needed. If a consistent teratogenic joint action is observed when only one teratogenic mechanism is represented while a different joint action is seen when two mechanisms are represented, the testing strategy could be valuable in hazard assessment of chemical mixtures; especially when used in conjunction with quantitative structure- activity relationships (QSARs) for teratogenesis. This is so, because a simple QSAR represents a single biological endpoint (e.g., teratogenesis) for a single mechanism of action (e.g., osteolathyrism). In this study, 6 binary combinations of osteolathyrogens, 6 binary combinations of SCCAs, and 8 combinations of an osteolathyrogen and an SCCA will be evaluated with FETAX to determine if consistent teratogenic joint actions are observed in each of the three cases. FETAX is ideal to examine the joint actions since confounding factors, such as metabolism and protein-toxicant binding, can be controlled. This work should lead to a better understanding of the nature of teratogenic joint actions and provide a basis for developing a more efficient safety testing strategy for developmental toxicity of chemical mixtures.
| Dawson, D A (1994) Joint actions of carboxylic acid binary mixtures on Xenopus embryo development: comparison of joint actions for malformation types. Arch Environ Contam Toxicol 27:243-9 |
| Dawson, D A (1993) Comparative joint actions of semicarbazide and thiosemicarbazide on induction of malformations and osteolathyrism in mixtures with benzoic hydrazide. Teratog Carcinog Mutagen 13:23-33 |
| Dawson, D A (1993) Joint action of benzoic hydrazide and beta-aminopropionitrile on Xenopus embryo development. Toxicology 81:123-30 |
