The application of physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling to understanding the mechanism of action of hazardous substances. 1995

M A Medinsky
Chemical Industry Institute of Toxicology, Research Triangle Park, NC 27709, USA.

Much of toxicology research is focused on elucidating the nature of the mechanisms through which various xenobiotics exert their toxic effects. The central issue in extrapolating laboratory experiments to the human situation is whether mechanisms which are operative in laboratory animals are similar to mechanisms operating in humans. The underlying assumption is that understanding mechanisms permits rational extrapolation between species, across routes of exposure, or from high to low doses. There are two general classes of mechanisms of action. First, there are the mechanisms that result in the translation of an exposure concentration to the effective dose at the target site. The mechanisms that are operative at a pharmacokinetic level include those that are physiologically driven and those that are metabolically based. Second are mechanisms through which the dose at the target site elicits the ultimate adverse response. These are pharmacodynamic in nature and refer to the action of the effective dose at the target site. Altered gene regulation, cytotoxicity, and cell proliferation are examples of processes involving potential adverse effects at the target site. A quantitative understanding of the mechanisms involved in going from exposure to dose and dose to response can aid in answering the question of whether or not these mechanisms in animals and humans are similar or different.

UI MeSH Term Description Entries
D008954 Models, Biological Theoretical representations that simulate the behavior or activity of biological processes or diseases. For disease models in living animals, DISEASE MODELS, ANIMAL is available. Biological models include the use of mathematical equations, computers, and other electronic equipment. Biological Model,Biological Models,Model, Biological,Models, Biologic,Biologic Model,Biologic Models,Model, Biologic
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D015386 Hazardous Substances Elements, compounds, mixtures, or solutions that are considered severely harmful to human health and the environment. They include substances that are toxic, corrosive, flammable, or explosive. Biohazard,Hazardous Chemical,Hazardous Chemicals,Hazardous Material,Hazardous Materials,Hazardous Substance,Toxic Environmental Substance,Toxic Substances, Environmental,Biohazards,Chemicals, Hazardous,Environmental Substances, Toxic,Toxic Environmental Substances,Chemical, Hazardous,Environmental Substance, Toxic,Environmental Toxic Substances,Material, Hazardous,Materials, Hazardous,Substance, Hazardous,Substance, Toxic Environmental,Substances, Environmental Toxic,Substances, Hazardous,Substances, Toxic Environmental
D018570 Risk Assessment The qualitative or quantitative estimation of the likelihood of adverse effects that may result from exposure to specified health hazards or from the absence of beneficial influences. (Last, Dictionary of Epidemiology, 1988) Assessment, Risk,Benefit-Risk Assessment,Risk Analysis,Risk-Benefit Assessment,Health Risk Assessment,Risks and Benefits,Analysis, Risk,Assessment, Benefit-Risk,Assessment, Health Risk,Assessment, Risk-Benefit,Benefit Risk Assessment,Benefit-Risk Assessments,Benefits and Risks,Health Risk Assessments,Risk Analyses,Risk Assessment, Health,Risk Assessments,Risk Benefit Assessment,Risk-Benefit Assessments

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