Toxic Action Data for the Mixture of Concern and Component Mixtures

This chapter provides a review and evaluation of the literature pertinent to joint toxic action of the mixture and its components. 2.1 Mixture of Concern Toxicological data or PBPK models were not available for the complete mixture of concern. Toxicological and mechanistic data, but no PBPK models, were available for all of the binary mixtures, but were limited. For some binary mixtures, few or no pertinent mammalian studies were available. For others, the data were conflicting, and durations and routes of chemical administration (e.g., intravenous) were of questionable relevance. Because of the relative paucity of information for chlorpyrifos and lead or mercury/methylmercury, the literature searches were broadened to include other organophosphorus insecticides. Data on joint action with lead or mercury/methylmercury were identified for methyl chlorpyrifos, parathion, methyl parathion, diazinon, fenitrothion, and fenthion, which, like chlorpyrifos, are phosphorothioates (organophosphorus compounds that contain the P=S functional group, which requires metabolism to P=O for anticholinester­ ase activity). Additional similarities to chlorpyrifos are that these triester compounds have one aryl and two alkyl substituents. See Appendix D for the structure of chlorpyrifos and its active metabolite, chlorpyrifos oxon, as well as the structure of methylmercury. Data on joint action with lead or mercury/methylmercury also were identified for two phosphorodithioate insecticides: malathion and dimethoate. These compounds are less similar to chlorpyrifos; in addition to the double bonded sulfur atom, they contains a sulfur rather than an oxygen in one of the ester linkages, and do not have an aryl substituent. In addition, unlike chlorpyrifos, malathion contains two carboxylic acid ester groups, which are susceptible to metabolism by carboxylesterases, and dimethoate contains an amide group.