title: Explanation of non-additive effects in mixtures of similar mode of action chemicals.
abstract: Many models have been developed to predict the combined effect of drugs and chemicals. Most models are classified into two additive models: independent action (IA) and concentration addition (CA). It is generally considered if the modes of action of chemicals are similar then the combined effect obeys CA; however, many empirical studies report nonlinear effects deviating from the predictions by CA. Such deviations are termed synergism and antagonism. Synergism, which leads to a stronger toxicity, requires more careful management, and hence it is important to understand how and which combinations of chemicals lead to synergism. In this paper, three types of chemical reactions are mathematically modeled and the cause of the nonlinear effects among chemicals with similar modes of action was investigated. Our results show that combined effects obey CA only when the modes of action are exactly the same. Contrary to existing knowledge, combined effects are generally nonlinear even if the modes of action of the chemicals are similar. Our results further show that the nonlinear effects vanish out when the chemical concentrations are low, suggesting that the current management procedure of assuming CA is rarely inappropriate because environmental concentrations of chemicals are generally low.
authors.affiliation: National Institute for Advanced Industrial Science and Technology, Research Institute of Science for Safety and Sustainability, 16-1 Onogawa, Tsukuba, Ibaraki 305-8569, Japan. Electronic address: masashi-kamo@aist.go.jp.
authors.forename: Masashi
authors.initials: M
authors.lastname: Kamo
authors.affiliation: Center for Environmental Risk Research, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibaraki 305-8506, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yokomizo
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D004357:Drug Synergism; D004784:Environmental Monitoring; D004785:Environmental Pollutants / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D004798:Enzymes / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D016014:Linear Models; D008962:Models, Theoretical; D017711:Nonlinear Dynamics; D018570:Risk Assessment; D013379:Substrate Specificity; D018675:Toxicity Tests / Q000379:methods*
chemical_list: D004785:Environmental Pollutants; D004791:Enzyme Inhibitors; D004798:Enzymes
keywords: Antagonism; Chemical mixture; Mode of action; Risk assessment; Synergism