Among the fundamental principles of chemical mixture toxicity that remain to be clarified are the relationships between the type of combined effect obtained and each of the following: time-dependent toxicity, the molecular site or sites of action of the agents, and chemical reactivity mechanisms. The work proposed in this application is designed to help determine these relationships, thereby providing a sounder fundamental basis from which to perform risk assessments for chemicals in combination. The approach involves mixture toxicity testing of various soft electrophiles using a previously developed Microtox(r).-based mixture toxicity assay. This assay utilizes the bioluminescent marine bacterium Vibrio fischeri. The chemicals evaluated in combination, soft electrophiles, are agents that preferentially react with specific molecules within proteins. The toxicity of soft electrophiles, both singly and in combination, is of current concern due to their use as fragrance additives in common household products and various industrial processes that can lead to skin sensitization and environmental contamination. By testing chemicals in binary combinations: a) from within the same reaction mechanism, or b) across different reaction mechanisms, and c) across varying reactivity rates (from very fast to very slow and non-reactive), it will be possible to more completely develop/expand the theoretical framework for understanding chemical mixture toxicity from a mechanistic perspective. Preliminary data suggests that mixture toxicity often resembles the dose- addition combined effect, generally, but with results for many combinations that significantly deviate from dose-addition -the combined effect expected for agents working at the same, single molecular site of action. Upon completion, the project will have generated a wealth of toxicity data that will be used to define the relationships between the combined toxic effects obtained, the time-dependent toxicity of the individual agents, the molecular site(s) of toxic action of the agents and their chemical reactivity mechanisms. PUBLIC HEALTH RELEVEANCE: The relevance of this research to public health in that it will evaluate the toxicity, both alone and in mixtures, of specific chemicals that cause skin sensitization - an allergic reaction occurring in sensitive people due to physical contact (e.g., skin, mucous membranes) with these agents. Additionally, many of these chemicals are used in industrial processes and, therefore, have the potential to be harmful to people who produce, transport, or handle them. Environmental releases of these chemicals are possible, which could also affect public health. ? ? ? ? ?
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