Accurately assessing the risks of chemicals in combination to human and environmental health has been hindered by inadequate or inappropriate mixture toxicity testing and data analysis methods. The work proposed in this application will allow for determination of the relationship of combined toxicant effects to common/different specific mechanisms by which the toxicants act. Determination of such a relationship would provide a valuable base from which to perform risk assessment. The testing and analysis approach taken combines the advantages of the 'fixed-dose' and 'fixed-ratio' testing strategies to accurately determine the combined toxic effect (e.g. dose addition, amplification, independence, antagonism) of two chemicals given together. Along with single chemical concentration-response curves, seven mixture-response curves are generated per combination with this data being statistically evaluated for conformity to the dose-addition and independence models of combined effect. Additional tests will help determine if data resembling dose-addition is actually indicative of a two-receptor-one transducer effect. The model chemicals are osteolathyrogens from six chemical groups, selected because of the four specific mechanisms of action by which the chemicals may disrupt cross-linking of developing connective tissue fibers. By testing chemicals working by the same and by different specific mechanisms, any consistent relationship between combined effect and mechanism of action should be discerned. Toxicity testing involves early embryos of the African clawed frog (Xenopus laevis) exposed to the osteolathyrogens for 96-hours. Disruption of connective tissue fiber cross-linking is easily detected by pathological examination of the notochord in presented tadpoles. Results to date have led to the development of four general combined effect/mechanism of action toxicity models, which will be more rigorously evaluated by the tests to be conducted. Upon completion, the project should provide a definitive answer as to whether there is a relationship between the combined toxic effect produced and the mechanism(s) by which the toxicants act.
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