Teratogenicity (Embryotoxicity) Studies: Design, Conduct, and Evaluation

  • K. S. Khera
  • H. C. Grice
  • D. J. Clegg
Part of the Current Issues in Toxicology book series (CI TOXICOLOGY)


The principal source of evidence for adverse effects on fetal development that are recognized at term is teratogenicity studies in experimental animals. The design of these studies should be appropriate for the intended purpose, and their conduct should conform to high standards. This is necessary to provide assurance that the data used in risk estimation are sound. In this chapter only basic principles related to these elements are discussed. References cited in the text should be consulted for details regarding the design and conduct of such studies.


Fetal Death Fetal Weight Developmental Toxicity Good Laboratory Practice Fetal Malformation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Book, J.A. and Rayner, S.A. (1950) A clinical and genetical study of anencephaly. Hum. Genet. 2: 61–84.Google Scholar
  2. Butler, N.R. and Alberman, E.D. (1969) Perinatal Problems: The Second Report of the 1958 British Perinatal Mortality Survey, p. 287, Williams Wilkins, Baltimore.Google Scholar
  3. Buttar, H.S., Dupuis, I., and Khera, K.S. (1978) Dimethadione-induced fetotoxicity in rats. Toxicology 9: 155–164.PubMedCrossRefGoogle Scholar
  4. Chaube, S. and Murphy, M.L. (1968) The tertatogenic effects of the recent drugs active in cancer chemotherapy. Adv. Tertol. 3: 181–237.Google Scholar
  5. Clark, R.L., Robertson, R.T., Minsker, D.H., Cohen, S.M., Tocco, D.J., Allen, H.L., James, M.L., and Bokelman, D.L. (1984) Diflunisal-induced hemolytic anemia as a cause of teratogenicity in rabbits. Teratology 30: 319–332.PubMedCrossRefGoogle Scholar
  6. CMEA (1982) Methodological recommendations, protocols, experimental studies for establishment of threshold levels of the effect of industrial compounds on reproductive function, pp. 58–75. In Problemi promislenoi toksikologii, SEV, Postoiannaja komissija po sotrudnicestvu v oblasti zdravoohranenijs, Moskva.Google Scholar
  7. Coppenger, C.J. and Brown, S.O. (1965) Postnatal manifestations in albino rats continuously irridated during prenatal development. Tex. Rep. Biol. Med. 23: 45–55.PubMedGoogle Scholar
  8. Cowen, D. and Geller, M. (1960) Long-term pathological effects of prenatal X-irradiation on the central nervous system of the rat. J. Neuropath. Exp. Neurol. 19: 488–527.PubMedCrossRefGoogle Scholar
  9. Creasy, M.R. and Alberman, E.D. (1976) Congenital malformations of the central nervous system in spontaneous abortions. J. Med. Genet. 13: 9–16.PubMedCrossRefGoogle Scholar
  10. ECETOC (European Chemical Industry Ecology and Toxicology Centre) (1979) Good Laboratory Practice, Monograph No. 1, European Chemical Industry Ecology and Toxicology Centre, Brussels.Google Scholar
  11. Enslein, K., Lander, T.R., and Strange, J.R. (1983) Teratogenesis: A statistical structure-activity model. Teratogenesis Carcinog. Mutagen. 3: 289–309.Google Scholar
  12. EPA (Environmental Protection Agency) (1981) Assessment of Risks to Human Reproduction and Development of the Human Conceptus from Exposure to Environmental Substances, Contract No. W-7405-eng-26.Google Scholar
  13. EPA (Environmental Protection Agency) (1983a) Toxic substances control; good laboratory practice standards; final rule. Fed. Regist. 48: 53922–53944.Google Scholar
  14. EPA (Environmental Protection Agency) (1983b) Pesticide programs; good laboratory practice standards; final rule. Fed. Regist. 48: 53946–53969.Google Scholar
  15. EPA (Environmental Protection Agency) (1984a) Risk Assessment and Management: Framework for Decision Making, EPA 600/9–85–002.Google Scholar
  16. EPA (Environmental Protection Agency) (1984b) Proposed guidelines for the health assessment of suspect developmental toxicants. Fed. Regist. 49: 46324–46331.Google Scholar
  17. Fabro, S., Shull, G., and Brown, N.A. (1982) The relative teratogenic index and teratogenic potency: Proposed components of developmental toxicity risk assessment. Teratogenesis Carcinog. Mutagen. 2: 61–76.Google Scholar
  18. FDA (Food and Drug Administration) (1970) Food and Drug Administration Advisory Committee on Protocols for Safety Evaluation: Panel on reproduction report on reproduction studies in the safety evaluation of food additives and pesticide residues. Toxicol. Appl. Pharmacol. 16: 264–296.CrossRefGoogle Scholar
  19. FDA (Food and Drug Administration) (1978) Nonclinical laboratory studies. Good laboratory practice regulations. Fed. Regist. 43: 59986–60020.Google Scholar
  20. Fuyuta, M., Fujimoto, T., and Hirata, S. (1978) Embryotoxic effects of methylmercuric chloride administered to mice and rats during organogenesis. Teratology 18: 353–366.PubMedCrossRefGoogle Scholar
  21. Hayes, W.C., Cobel-Geard, S.R., Hanely, T.R., Jr., Murray, J.S., Freshour, N.L., Rao, K.S., and John, J.A. (1981) Teratogenic effects of vitamin A palmitate in Fischer 344 rats. Drug Chem. Toxicol. 4: 283–295.PubMedCrossRefGoogle Scholar
  22. Johnson, E.M. (1981) Screening for teratogenic hazards: Nature of the problems. Annu. Rev. Pharmacol. Toxicol. 21: 417–429.PubMedCrossRefGoogle Scholar
  23. Johnson, E.M. (1984) A prioritization and biological decision tree for developmental toxicity safety evaluations. J. Am. Coll. Toxicol. 3: 141–147.CrossRefGoogle Scholar
  24. Johnson, E.M. (1987) A tier system for developmental toxicity evaluation based on considerations of exposure and effect relationships. Teratology 35: 405–427.PubMedCrossRefGoogle Scholar
  25. Kavlock, R.J., Chernoff, N., and Rogers, E.H. (1985) The effect of acute maternal toxicity on fetal development in the mouse. Teratogenesis Carcinog. Mutagen. 5: 3–13.PubMedCrossRefGoogle Scholar
  26. Khera, K.S. (1981) Common fetal aberrations and their teratologic significance: A review. Fun-dam. Appl.Toxicol. 1: 13–18.Google Scholar
  27. Khera, K.S. (1984) Maternal toxicity—A possible factor in fetal malformations in mice. Teratology 29: 411–416.PubMedCrossRefGoogle Scholar
  28. Khera, K.S. (1985) Maternal toxicity: A possible etiological factor in embryo-fetal deaths and fetal malformations of rabbit-rodent species. Teratology 31: 129–153.PubMedCrossRefGoogle Scholar
  29. McLaren, A. and Michie, D. (1960) Congenital runts. In Ciba Foundation Symposium on Congenital Malformations ( G.E.W. Wolstenholme and C.M. O’Connor, Eds.), pp. 178–198, J. A. Churchill, London.Google Scholar
  30. Mitchell, S.C., Korones, S.B., and Berendes, H.W. (1971) Congenital heart disease in 56,109 births. Incidence and natural history. Circulation 43: 323–332.PubMedGoogle Scholar
  31. Mosier, H.D., Jr., Dearden, L.C., Jansons, R.A., Roberts, R.C., and Biggs, C.S. (1982) Disproportionate growth of organs and body weight following glucocorticoid treatment of the rat fetus. Dey. Pharmacol. Ther. 4: 89–105.Google Scholar
  32. Naeye, R.L. (1980) Effects of maternal nutrition on the outcome of pregnancy. In Human Embryonic and Fetal Death ( I.H. Porter and E.B. Hook, Eds.), pp. 197–206, Academic Press, Toronto.Google Scholar
  33. NAS (National Academy of Sciences) (1977) Reproduction and Teratogenicity Tests, Principles and Procedures for Evaluating the Toxicology of Household Substances, 7, pp. 99–110, National Academy of Sciences, Washington, D.C.Google Scholar
  34. NHW (National Health and Welfare) (1973) The Testing of Chemicals for Carcinogenicity, Mutagenicity, Teratogenicity, National Health and Welfare, Canada.Google Scholar
  35. Nishimura, H. (1969) Incidence of malformations in abortions. In Congenital Malformations ( F.C. Fraser, V.A. McKusick, and R. Robinson, Eds.), pp. 275–283, National Foundation—March of Dimes, Excerpta Medica, New York.Google Scholar
  36. OECD (Organization for Economic Cooperation and Development) (1981) Teratogenicity, OECD guidelines for testing of chemicals No. 414, Organization for Economic Cooperation and Development, Paris.Google Scholar
  37. Page, N., Sawbney, D., and Ryon, M.G. (1980) Proceedings of the Workshop on Subchronic Toxicity Testing, Oakridge National Laboratory, Interagency Agreement No. 80-D-X0453, U.S. Environmental Protection Agency, Washington, D.C.Google Scholar
  38. Pinto-Machado, J. (1985) External examination of limb positions in near-term mouse fetuses: An experimental study and review of the literature published in teratology. Teratology 31: 413–423.PubMedCrossRefGoogle Scholar
  39. Richards, I.D. (1973) Fetal and infant mortality associated with congenital malformations. Br. J. Prey. Soc. Med. 27: 85–90.Google Scholar
  40. Schardein, J.L. (1983) Teratogenic risk assessment. Past, present and future. Issues Rev. Teratol. 1: 181–214.Google Scholar
  41. Sterz, H., Sponer, G., Neubert, P., and Hebold, G. (1985) A postulated mechanism of ßsympathomimetic induction of rib and limb anomalies in rat fetuses. Teratology 31: 401–412.PubMedCrossRefGoogle Scholar
  42. Task Force of Past Presidents (1982) Animal data in hazard evaluations: Paths and pitfalls. Fundam. Appl. Toxicol. 2: 101–107.CrossRefGoogle Scholar
  43. WHO (World Health Organization) (1984) Principles for Evaluating Health Risks to Progeny Associated with Exposure to Chemicals during Pregnancy, Environmental Health Criteria 30, World Health Organization, Geneva.Google Scholar
  44. Wickramaratne, G.A., Killick, M.E., and Appleby, H. (1987) Supernumerary ribs: A transient developmental defect in the rat. In Pesticide Science and Biotechnology ( R. Greenhalgh and T.R. Roberts, Eds.), pp. 557–559, Blackwell Science Publication, Boston.Google Scholar

Copyright information

© Springer-Verlag New York Inc. 1989

Authors and Affiliations

  • K. S. Khera
    • 1
  • H. C. Grice
    • 2
  • D. J. Clegg
    • 1
  1. 1.Health Protection BranchHealth and Welfare CanadaOttawaCanada
  2. 2.NepeanCanada

Personalised recommendations