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416 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITIONDespite confirmation of the aforementioned assumptions and the presence of a rich and accuratehistorical control database, the investigator may not be able to draw definitive conclusions becauseof equivocal findings. In this scenario, the only recourse is to perform additional studies, perhapswith increased sample size and/or increased dosage levels.Important decisions must be made based on these data sets. In the case of drugs, many of theendpoints assessed in nonclinical reproductive safety studies may not be principal endpoints inclinical trials (e.g., functional assessments, hormone analyses, and intrauterine growth and development).For environmental chemicals, human exposure is often unknown and unmonitored, andcould involve multiple compounds. As a result, determination of a proximate human reproductivetoxicant is often impossible. Therefore, reproductive hazard identification in animal studies isparamount in protecting human health.Human tragedies have led to the refinement and enhancement of regulatory guideline requirements.As a result, there exists a general confidence in the ability to detect reproductive hazards.This is especially true when effects are manifested across multiple well-validated animal modelsand/or studies with overlapping treatment regimes or endpoints. As our knowledge of the basicbiology of animal models and humans advances, study designs and the strength of assumptionsused for animal-to-human extrapolation will continue to improve. The challenge facing investigatorsis application of emerging scientific principles to hazard identification and ultimately risk assessment.Faulty study design and interpretation can keep a needed treatment from an affected humanpopulation or conversely expose those populations to unnecessary risk.ACKNOWLEDGEMENTSThe authors would like to acknowledge with deep appreciation the efforts of various individualswho contributed in tangible ways to the completion of this project. Special thanks to KerinClevidence, Michelle Edwards, and Jeanette Howell, who labored diligently to compile and verifymuch of the WIL historical control data referenced in this chapter. The authors would also like torecognize the numerous staff members at WIL, too many to mention individually, who throughtheir dedication, hard work, and meticulous data collection over the past 10 to 20 years have laidthe foundation for this chapter.REFERENCES1. DeSesso, J.M., Harris, S.B., and Swain, S.M., The design, evaluation, and interpretation of developmentaltoxicity tests, in Toxicology and Risk Assessment: Principles, Methods, and Applications, Fan,A.M. and Chang, L.W., Eds., Marcel Dekker, New York, 1996, p. 227.2. Palmer, A.K. and Ulbrich, B., Data presentation in developmental toxicity studies: an aid to evaluation?in Handbook of Developmental Toxicology, Hood. R.D., Ed., CRC Press, Boca Raton, FL, 1997, chap. 8.3. Daston, G. and Kimmel, C.A., Eds., An Evaluation and Interpretation of Reproductive Endpoints forHuman Health Risk Assessment, International Life Sciences Institute, Washington, DC,1998.4. European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC), Guidance on Evaluationof Reproductive Toxicity Data, Monograph No. 31, 2002.5. U.S. Food and Drug Administration, Reviewer Guidance: Integration of Study Results to AssessConcerns about Human Reproductive and Developmental Toxicities (Draft), Center for Drug Evaluationand Research, 2001.6. Wilson, J.G., Environment and Birth Defects, Academic Press, New York, 1973.7. Brent, R.L., Drug testing for teratogenicity: its implications, limitations and application to man, inDrugs and Fetal Development, Klingberg, M.A., Abramovici, A., and Cheneke, J., Eds., Plenum Press,New York, 1972, p. 31.© 2006 by Taylor & Francis Group, LLC
DEVELOPMENTAL AND REPRODUCTIVE TOXICITY STUDY FINDINGS 4178. Nishimura, H. and Tanimura, T, Chemical Aspects of the Teratogenicity of Drugs, Elsevier, New York,1976.9. Fraser, F.C., Relation of animal studies to the problem in man, in Handbook of Teratology, Vol. 1,Wilson, J.G. and Fraser, F.C., Eds., Plenum Press, New York, 1979, p. 75.10. Snow, M.H.L. and Tam, P.P.L., Is compensatory growth a complicating factor in mouse teratology?,Nature, 279, 555, 1979.11. U.S. Food and Drug Administration, National Center for Toxicological Research, Reliability of ExperimentalStudies for Predicting Hazards to Human Development (Kimmel, C.A., Holson, J.F., Hogue,C.I., and Carlo, G.L., Eds.), NCTR Technical Report for Experiment No. 6015, Jefferson, AR, 1984.12. National Research Council, Scientific Frontiers in Developmental Toxicology and Risk Assessment,National Academy Press, Washington, DC, 2000.13. Ulbrich, B. and Palmer, A.K., Detection of effects on male reproduction — a literature survey, J. Am.Coll. Toxicol., 14, 293, 1995.14. Clegg, J.A., Adverse drug reactions, Toxicol. Rev., 13, 235, 1994.15. Buiatti, E, Barchielli, A., Geddes, M., Nastasi, L., Kriebel, D., Franchini, M., and Scarselli, G., Riskfactors in male infertility, Arch. Environ. Health, 39, 266, 1984.16. Paul, M. and Himmelstein J., Reproductive hazards in the workplace: what the practitioner needs toknow about chemical exposures, Obstet. Gynecol., 71, 921, 1988.17. Thomas, M.J. and Thomas, J.A., Toxic responses of the reproductive system, in Casarett & Doull’sToxicology, the Basic Science of Poisons, Klassen, C.D., Ed., McGraw-Hill, New York, 2001, p. 673.18. Waller, D.P., Killinger, J.M., Zaneveld, L.J.D., Physiology and toxicology of the male reproductivetract, in Endocrine Toxicology, Thomas, J.A., Korach, K.S., and McLachlan, J.A., Eds., Raven, NewYork, 1985, p. 269.19. Scialli, A.R. and Lemasters, G.K., Epidemiologic aspects of reproductive toxicology, in ReproductiveToxicology, 2nd ed., Witorsch, R.J., Ed., Raven Press, 1995, p. 241.20. Potashnik, G. and Porath, A., Dibromochloropropane (DBCP): a 17-year reassessment of testicularfunction and reproductive performance, J. Occup. Environ. Med., 37, 1287, 1995.21. Goldsmith, J.R., Dibromochloropropane: epidemiological findings and current questions, Ann. N. Y.Acad. Sci., 26, 837, 1997.22. Meistrich, M.L., Wilson, G., Shuttlesworth, G.A., and Porter, K.L., Dibromochloropropane inhibitsspermatogonial development in rats, Reprod. Toxicol., 17, 263, 2003.23. Cooper, R.L., Neuroendocrine control of female reproduction, in Reproductive and Endocrine Toxicology(Comprehensive Toxicology, Vol. 10), Boekelheide, K., Chapin, R.E., Hoyer, P.B., and Harris,C., Eds., Elsevier, New York, 1997, p. 273.24. Eldridge, J.C., Wetzel, L.T., Stevens, J.T., and Simpkins, J.W., The mammary tumor response intriazine-treated female rats: a threshold-mediated interaction with strain and species-specific reproductivesenescence, Steroids, 64, 672, 1999.25. Cooper, R.L., Goldman, J.M., and Rehnberg, G.L., Neuroendocrine control of reproductive functionin the aging female rodent, J. Am. Geriatric Sci., 34, 735, 1986.26. Cooper, R.L., Stoker, T.E., Goldman, J.M., Parrish, M.B., and Tyrey, L., Effect of atrazine on ovarianfunction in the rat, Reprod. Toxicol., 10(4), 257, 1996.27. U.S. Food and Drug Administration, Guidelines for Reproduction Studies for Safety Evaluation ofDrugs for Human Use, 1966.28. U.S. Federal Food and Drugs Act of 1906, Public Law No. 59-384, 34 Stat. 768, 1906.29. U.S. Federal Food, Drug and Cosmetic Act, 21 U.S.C. 301, 1938.30. Green, R., Burrill, M., and Ivy, A., Experimental intersexuality: the paradoxical effects of estrogenson the sexual development of the female rat, Anat. Rec., 74, 429, 1939.31. Green, R., Burrill, M., and Ivy, A., Experimental intersexuality: modification of sexual developmentof the white rat with synthetic estrogen, Proc. Soc. Exp. Biol. Med., 41, 169, 1939.32. Herbst, A.L., Ulfelder, H., and Poskanzer, D.C., Adenocarcinoma of the vagina: association of maternalstilbestrol therapy with tumor appearance in young women, N. Eng. J. Med., 284, 878, 1971.33. Herbst, A.L., Cole, P., Colton, T., Robboy, S.J., and Scully, R.E., Age-incidence and risk of diethylstilbestrol-relatedclear cell adenocarcinoma of the vagina and cervix, Am. J. Obstet. Gynecol., 128,43, 1977.© 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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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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POSTNATAL DEVELOPMENTAL MILESTONES
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PART IPrinciples and Mechanisms© 2
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4 DEVELOPMENTAL REPRODUCTIVE TOXICO
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10 DEVELOPMENTAL REPRODUCTIVE TOXIC
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Table 2.6Receptor(Official Name a )
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Clearly, more research needs to be
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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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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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Formation ofchoroid plexusof latera
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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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CHAPTER 9Significance, Reliability,
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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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We would like to acknowledge the ef
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CHAPTER 12Role of Xenobiotic Metabo
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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 829B. The Formation o
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CHAPTER 21Developmental and Reprodu
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