Accurate chemical mixture toxicity assessment has been hindered by improper use of chemical mixture toxicity models and inadequate or inappropriate testing and evaluation methods. The work proposed herein will evaluate an improved mixture testing method coupled with a new, modern approach for evaluating such toxicity. The new methodology combines the advantages of the 'fixed-dose' and the 'fixed-ratio' approaches using Xenopus laevis embryos as the model organism. The method uses concentration-response data to determine mixture toxicity via comparison with the 'dose-addition' and the 'independence' models of mixture toxicity. Testing will include 15 chemical combinations, each incorporating 36 treatments. The 15 combinations selected for testing will bring forth a rigorous evaluation of the relationship of toxicity models to common or different mechanisms of toxicity. The model chemicals to be tested in combinations are osteolathyrogens, chemicals which induce improper connective tissue cross-linking in developing embryos. This misdevelopment can be brought about by at least four distinct mechanisms. By combining the new testing and evaluation scheme with these select combinations the following can be determined: (1) the effectiveness of the new approach in determining mixture toxicity (combined effects); (2) the relationship of the combined effects to mixture toxicity models; (3) the relationship of osteolathyrogenic mechanisms to the combined effect obtained; and (4) the relationship between the sites of lesions in the embryo, the mechanisms of osteolathyrism, chemical structure, and the number of lesions per site for each combined effect observed. Upon successful completion of the study, the methodology will be useful in further studies of mixture toxicity hazards related to human and environmental health.
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