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

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CHAPTER 2Experimental <strong>Approach</strong>es to Evaluate Mechanismsof Developmental ToxicityElaine M. Faustman, Julia M. Gohlke, Rafael A. Ponce, Thomas A. Lewandowski,Marguerite R. Seeley, Stephen G. Whittaker, and William C. GriffithCONTENTSI. Introduction ..........................................................................................................................16A. Definitions....................................................................................................................16B. General Mechanistic Considerations...........................................................................16C. Guidelines for Evaluating Critical Events ..................................................................18D. Levels of Mechanistic Inquiry.....................................................................................20E. Genomic Conservation ................................................................................................21F. Processes of Organogenesis and Implication of Three-DimensionalContext of Evaluation..................................................................................................231. Cell-Signaling Pathways........................................................................................232. Cell-Cell Communication......................................................................................27II. Examples of Mechanistic <strong>Approach</strong>es.................................................................................28A. Mitotic Interference .....................................................................................................291. 5-Fluorouracil ........................................................................................................292. Radiation................................................................................................................303. Antitubulin Agents.................................................................................................304. Methylmercury.......................................................................................................30B. Altered Energy Sources...............................................................................................321. Inhibitors of Mitochondrial Respiration................................................................322. Cocaine ..................................................................................................................333. Rhodamine Dyes....................................................................................................33C. Enzyme Inhibition .......................................................................................................331. Methotrexate ..........................................................................................................332. Chlorpyrifos ...........................................................................................................343. 5-Fluorouracil ........................................................................................................354. Mevinolin...............................................................................................................35D. Nucleic Acids...............................................................................................................351. Hydroxyurea ..........................................................................................................352. Cytosine Arabinoside.............................................................................................36E. Mutations .....................................................................................................................371. Alkylating Agents ..................................................................................................382. Aromatic Amines...................................................................................................393. Radiation................................................................................................................3915© 2006 by Taylor & Francis Group, LLC
16 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITIONF. Alterations in Gene Expression...................................................................................401. Retinoic Acid .........................................................................................................402. Dioxin ....................................................................................................................413. New Directions in “Omic” Research ....................................................................42G. Programmed Cell Death ..............................................................................................421. Retinoic Acid .........................................................................................................432. Dioxin ....................................................................................................................433. Ethanol...................................................................................................................44III. Conclusions ..........................................................................................................................46Acknowledgments............................................................................................................................46References ........................................................................................................................................47I. INTRODUCTIONDaedalus, an architect famous for his skill, constructed the maze, confusing the usual marks ofdirection, and leading the eye of the beholder astray by devious paths winding in different directions.Thanks to the help of the princess Ariadne, Theseus rewound the thread he had laid, retraced his steps,and found the elusive gateway…The purpose of this chapter is to review methodological approaches for elucidating the mechanismsby which chemical and physical agents cause or contribute to dysmorphogenesis and teratogenicity.Emphasis is given to the approaches rather than to agent-specific mechanisms, and the focus is onhow molecular and cellular information is combined to evaluate mechanistic hypotheses.A. DefinitionsIn order to develop this paper, a few common definitions must be discussed. Mechanisms of toxicaction is used to refer to the detailed molecular understanding of how chemicals can impair normalphysiological processes and hence, produce developmental toxicity. Mechanistic information caninclude biochemical, genetic, molecular, cellular, and/or organ systems information. 1 Mode of actionfor developmental toxicants is frequently used to refer to the identification of critical steps that canexplain how an agent can produce developmental toxicity and usually refers to a less detailed butmore comprehensive description of the overall process of developmental toxicity. This chapter willinclude a discussion of approaches used for understanding mechanisms for all four endpoints ofdevelopmental toxicity: lethality, growth retardation, morphological defects (teratogenicity), andfunctional impacts. Throughout this chapter, the general term developmental dynamics is used todescribe the genetic, biochemical, molecular, cellular, organ, and organism level processes thatchange throughout development and that define and characterize the developing organism at eachlife stage. 2 The term kinetics is used to refer to the absorption, distribution, and metabolism ofchemicals because many of our discussions of developmental dynamics directly relate to the amountand form of the environmental or pharmacological agent that reaches the developing organism.B. General Mechanistic ConsiderationsFigure 2.1 shows an overall framework for assessing the effects of a toxicant on development. 1,3This figure illustrates how both kinetic and dynamic considerations are needed to link exposurewith developmental outcome. It provides a context for collecting mechanistic data and for orderingsequence of events data that structures a mode of action hypothesis. This framework has beenOvid© 2006 by Taylor & Francis Group, LLC
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Second EditionDEVELOPMENTALandREPRO
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Published in 2006 byCRC PressTaylor
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Chapter 12Chapter 13Chapter 14Chapt
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The EditorRonald D. Hood, Ph.D., is
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Alan M. HobermanArgus ResearchHorsh
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APPENDIX ATerminology of Anatomical
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TERMINOLOGY OF ANATOMICAL DEFECTS 9
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Organ/StructureCodeNumberObservatio
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Organ/Structure10145 Ocular colobom
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Organ/StructurePulmonaryarteryPulmo
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Terminology of developmental abnorm
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Organ/StructureCervicalcentrumCodeN
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Organ/Structure10689 Misshapen thor
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Organ/StructureSacralcentrumSacralv
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968 DEVELOPMENTAL REPRODUCTIVE TOXI
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1000 DEVELOPMENTAL REPRODUCTIVE TOX
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Table 1Human Non-human Primate Rat
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Table 1 (continued)Sertoli CellsHum
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Table 2 (continued) Landmarks in th
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Table 2 (continued) Landmarks in th
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Page 231 and 232: PART IPrinciples and Mechanisms© 2
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CHAPTER 6Comparative Features of Ve
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COMPARATIVE FEATURES OF VERTEBRATE
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Table 6.2Comparative reproductive a
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Maturation andRelease ofGametesSper
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Amniotic cavity 9.5 1.5 1-4 1-4,6,9
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Posteriorcardinal veinsestablishedT
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PosteriorcardinaldegenerationRight
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StomachappearsThirdpharyngealpouch;
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Table 6.6DescriptionComparative ges
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ParathyroidParathyroids 12.5 6.2 41
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Table 6.8DescriptionComparative ges
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Formation ofchoroid plexusof latera
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Optic nervefibers presentDifferenti
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Table 6.10DescriptionMuscular Syste
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Distalphalanges offingersseparatedF
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Table 6.11DescriptionIntermediateme
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Table 6.12DescriptionComparative ge
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CHAPTER 7Developmental Toxicity Tes
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DEVELOPMENTAL TOXICITY TESTING —
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Female 0.00-0.69 0.004-0.39 0.00-0.
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Figure 8.11775Pott DescribesScrotal
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The underlying physiology of juveni
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Table 8.5Total body composition by
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Table 8.6Serum chemistry values for
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Table 8.7Parameter bHematology valu
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CHAPTER 9Significance, Reliability,
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DEVELOPMENTAL AND REPRODUCTIVE TOXI
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Prior to the early 1980s, numerous
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Figure 9.51906Food andDrugs Act2000
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Table 9.18Selected comparison point
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Table 9.33Selected comparison point
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Table 9.48What do regulatorswant to
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CHAPTER 10Testing for Reproductive
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TESTING FOR REPRODUCTIVE TOXICITY 4
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We would like to acknowledge the ef
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CHAPTER 12Role of Xenobiotic Metabo
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ROLE OF XENOBIOTIC METABOLISM IN DE
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y ESR spectrometry. 122 Further ESR
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CHAPTER 13Use of Toxicokinetics in
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USE OF TOXICOKINETICS IN DEVELOPMEN
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CHAPTER 17Statistical Analysis for
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STATISTICAL ANALYSIS FOR DEVELOPMEN
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CHAPTER 19Perspectives on the Devel
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PERSPECTIVES ON THE DEVELOPMENTAL A
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Guideline OECD 415 (One Generation)
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The Office of Prevention, Pesticide
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CHAPTER 20Human Studies — Epidemi
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HUMAN STUDIES 801I. INTRODUCTIONEpi
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HUMAN STUDIES 803is actively trying
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HUMAN STUDIES 805100908070Induced a
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HUMAN STUDIES 8071009590>37 w33-36
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HUMAN STUDIES 80940003500Mean birth
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HUMAN STUDIES 811from monstrous, us
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HUMAN STUDIES 815G. Childhood Cance
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HUMAN STUDIES 823are used, but the
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HUMAN STUDIES 829B. The Formation o
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HUMAN STUDIES 837with spina bifida
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HUMAN STUDIES 83926. Haglund, B. an
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CHAPTER 21Developmental and Reprodu
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