A Practical Approach, Second Edition=Ronald D. Ho.pdf

EXPERIMENTAL APPROACHES TO EVALUATE MECHANISMS OF DEVELOPMENTAL TOXICITY 17Risk assessmentExposure assessment Toxicity assessment Risk characterizationExposure Toxico kinetics Toxico dynamics OutcomeInhalation Absorption Adolescent Normal parametersOralDevelopmental disorderDistributionChildDermal• LethalityMetabolismNewborn• Growth retardationEliminationConceptusOrgan, tissuesCellularOrganelleMolecular• Malformation• Altered functionCell signallingFigure 2.1Overall framework for assessing the effects of a toxicant on development. (Adapted from NationalResearch Council, Scientific Frontiers in Developmental Toxicity Risk Assessment, National AcademyPress, Washington, 2000, p. 354 and from Faustman, E. et al., IRARC Technical Report onDevelopmental Toxicity, Institute for Risk Analysis and Risk Communication, University of Washington,Seattle, WA, 2003. With permission.)Table 2.1 Example mechanisms for developmental toxicityMitotic interferenceAltered membrane function or signal transductionAltered energy sourcesEnzyme inhibitionAltered nucleic acid synthesisMutationsGene and protein expression changesAlterations in programmed cell deathmodified from the original National Academy of Sciences (NAS) framework to illustrate that theaffects of exposure during development can occur in utero, in newborns, in childhood, and in earlyadulthood. Manifestations of early exposures sometimes cannot be observed until adulthood. 4The study of mechanisms of toxicity is of vital importance not only for the insights providedinto the events underlying adverse developmental outcomes, but also for the information gainedconcerning the processes involved in normal development. Recently, there has been an increasedinterest in mechanistic information as a result of legislative actions. For example, in the FoodQuality Protection Act, exposure to agents that have common mechanisms of action should beconsidered in a cumulative manner. This has led to the joint evaluation of organophosphates inregard to their developmental neurotoxicity.Table 2.1 includes a list of potential mechanisms first proposed by Wilson 5 that included thefollowing general categories: mitotic interference, altered membrane function or signal transduction,altered energy sources, enzyme inhibition, altered nucleic acid synthesis, and mutations. Becausethese processes play essential roles in embryogenesis and normal development, it is logical toexpect that alterations may result in developmental toxicity, and the research literature is repletewith proof of this assumption. With our increased understanding of the molecular mechanisms© 2006 by Taylor & Francis Group, LLC