Ernest Hodgson - Society of Toxicology (SOT)



Ernest Hodgson – We Are Not Rodents: Environmental Toxicants and the Role of Human Studies Created by Mindy Reynolds and Wade Powell?Learning Objectives:To describe the use and limitations of animal models and the path to human in vitro studiesTo examine the mechanisms of inhibition and effects of induction by methylenedioxyphenyl chemicals in mammals.Describe how human in vitro studies can define variation, risk assessment, and potential human-specific interactions.To describe how isoforms of CYP450 alter metabolism of various pesticides.To explain how human variation can be used to understand risk assessment.??Recommended prerequisite topicsRoutes of exposureBiotransformationCytochrome P450 isoforms and mechanism?Study questionsWhat are some environments in which an individual can be exposed to toxicants?List some human toxicant metabolic interactions that can alter toxicity.Explain how carbaryl metabolism is effected by chlorpyrifos.Why is CYP2B6 more effective than CYP3A4 in the metabolism of chlorpyrifos and why is this important?What is the effect of fipronil of CYP3A4 levels?How does exposure to a mixture of DEET and fipronil alter transcript expression as compared to single exposure??Application of this Lecture to Vision and Change Core Concepts and Competencies. ?Core Concepts?EvolutionComparisons are made between animal models and humans, emphasizing both similarities and differences.?The Cytochromes P450, a multi-gene family, provide a starting point for discussions of gene duplication and molecular evolution.Structure and Function?Information flow, exchange, and storageInduction of CYP gene transcription by nuclear receptors.Pathways and transformations of energy and matterMetabolism of several compounds by CYPs.SystemsRNAseq data touches on pathway analysis.?Core Competencies?Ability to apply the process of science.The overall theme of transition from rodent to human models illustrates this core competency.Ability to use quantitative reasoningmRNA levels and enzyme activity measures are important and repeated applications of this competency. The relationship between Km and protein abundance for CYP3A4 vs. CYP2B6 is an especially intriguing example.Ability to use modeling and simulation?Ability to tap into the interdisciplinary nature of scienceThe relationship between metabolism and disposition/distribution of chemicals. Competencies ranged from reaction mechanisms to systems biology.Ability to communicate and collaborate with other disciplines?Ability to understand the relationship of science and society See especially slide 4, which illustrates the relationship between toxicant exposure and action to many societal issues, including agriculture, occupational environments, natural environments, domestic and urban environments, military installations and deployments, and superfund sites.????Vision and Change Core Concepts.Evolution. The diversity of life evolved over time by processes of mutation, selection, and genetic change. Structure and Function. Basic units of structure define the function of all living things. Information flow, exchange, and storage. The growth and behavior of organisms are activated through the expression of genetic information in context.Pathways and transformations of energy and matter. Biological systems grow and change by processes based upon chemical transformation pathways and are governed by the laws of thermodynamics.Systems. Living systems are interconnected and interacting. Core Competencies and Disciplinary Practice. Ability to apply the process of science. Biology is evidence based and grounded in the formal practices of observation, experimentation, and hypothesis testing.Ability to use quantitative reasoning. Biology relies on applications of quantitative analysis and mathematical reasoning.Ability to use modeling and simulation. Biology focuses on the study of complex systems.Ability to tap into the interdisciplinary nature of science. Biology is an interdisciplinary science.Ability to communicate and collaborate with other disciplines. Biology is a collaborative scientific discipline.Ability to understand the relationship of science and society. Biology is conducted in a societal context. ................
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