The toxicological evaluation of large numbers of chemicals is hampered by time and resources. Approaches to this problem have been the development of rapid and cost effective non- mammalian toxicity test systems, or mathematical models relating biological activity to molecular structure and physiochemical parameters. In this proposal these two techniques are combined in an effort to: 1) generate a data matrix on relative biological activities and molecular descriptors for a series of 41 chemicals, which, based on preliminary experiments and molecular structure, have the potential to be reactive and teratogenic by the mechanism of osteolathyrism; 2) generate regression equations which relate toxicity and teratogenicity to a single or group of molecular regression properties. It is hypothesized that the completion of this data matrix and subsequent statistical testing will identify the chemical mode of action, how changes in chemical structure alter relative toxicities, and what molecular descriptor are significant in predicting these toxicities. The Frog Embryo Teratogenesis Assay: Xenopus (FETAX) is a toxicity test system that is quick and inexpensive. This developmently relevant assay allows for the quantitation of a number of biological end-points including lethality (LC50), abnormality (EC50), relative teratogenic index (RTI =LC50/EC), growth (length) and stage of development. Osteolathyrism is the inability of collagen and elastin fibers to cross-link properly due to interference with the enzyme lysyl oxidase. In FETAX such connective tissue lesions are characterized by a kinked tail, herniated nototchord and disorganization of the fibers of the notochordal sheath. Preliminary data reveal the acid hydrazine structure is required for the induction of osteolyathyrism. These data also show that the alteration of this structure, either by deletion or addition results in quantitative changes in dose-response end-points. A review of the literature suggests that chemicals having a like mode of toxic action (e.g. osteolathyrism) can be mathemetically modeled by regression equations using a molar-based quantitation of activity (i.e. LC50, EC50, RTI) as the dependent variable and the use of hydrophobic, electronic, reactive and steric parameters as independent variables. The objectives of this proposal will be pursued by: 1) determining embryo toxic end-points in the FETAX system; molecular descriptors; and 5) developing structure- activity relationships. These investigations will be useful in establishing this non-mamalian species for toxicological testing. Also, they will provide the quality and type of data now obtained through the use of more traditional whole surrogate as FETAX can serve a sentinel of ecological damage.
| Dawson, D A; Schultz, T W; Baker, L L et al. (1990) Structure-activity relationships for osteolathyrism. III. Substituted thiosemicarbazides. J Appl Toxicol 10:59-64 |
| Schultz, T W; Ranney, T S (1988) Structure-activity relationships for osteolathyrism: II. Effects of alkyl-substituted acid hydrazides. Toxicology 53:147-59 |
