Extrapolation of Reproductive Risks From Animal and Human Data

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


Assessment of human reproductive risk from developmental toxicity data involves three steps: (1) conducting animal and, if possible, human studies; (2) evaluating these data; and (3) using these data in the extrapolation of reproductive risk to humans. The last step is derived from toxicology data and is based on a system of concepts and conservative suppositions. Some of these concepts, such as maternal health and its possible influence on fetal and postnatal development as well as the relative significance of fetal aberrations and malformations, have recently received considerable attention regarding their importance in human risk estimation. Based on these revised concepts and other newer ones that are logically admissible, a framework of risk extrapolation is proposed in this chapter.


Safety Factor Cleft Palate Developmental Toxicity Fetal Malformation Human Risk 
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  1. Aliverti, V., Bonanomi, L., Giavini, E., Leone, V.G., and Mariani, L. (1980) Effects of glycerol formal on embryonic development in the rat. Toxicol. Appl. Pharmacol. 56: 93–100.PubMedCrossRefGoogle Scholar
  2. Andrew, F.D., and Staples, R.E. (1977) Prenatal toxicity of medroxyprogesterone acetate in rabbits, rats and mice. Teratology 15: 25–32.PubMedCrossRefGoogle Scholar
  3. Andrew, F.D., and Staples, R.E. (1977) Prenatal toxicity of medroxyprogesterone acetate in rabbits, rats and mice. Teratology 15: 25–32.PubMedCrossRefGoogle Scholar
  4. Biddle, F.G. (1978) Use of dose-response relationships to discriminate between the mechanisms of cleft palate induction by different teratogens: An argument for discussion. Teratology 18: 247–252.PubMedCrossRefGoogle Scholar
  5. Coate, W.B., Hoberman, A.M., and Durloo, R.S. (1982) Inhalation teratology study of benzene in rats. In The Toxicology of Petroleum Hydrocarbons, pp. 239–248, American Petroleum Institute, Washington, D.C.Google Scholar
  6. Coate, W.B., Hoberman, A.M., and Durloo, R.S. (1984) Inhalation teratology study of benzene in rats. In Applied Toxicology of Petroleum Hydrocarbons (H.N. MacFarland, C.E. Holdsworth, J.A. MacGregor, R.W. Call, and M.L. Kane, Eds.), pp. 187–198, Advances in Modern Environmental Toxicology, Vol. 6, Princeton Scientific Publishers, Princeton, New Jersey.Google Scholar
  7. DiCarlo, F.J., Jr. (1980) Syndromes of cardivascular malformations induced by copper citrate in hamsters. Teratology 21: 89–101.PubMedCrossRefGoogle Scholar
  8. Donaldson, H.H. (1924) The Rat—Data and Reference Tables for the Albino Rat (Mus norvegicus albinus) and the Norway Rat (Mus norvegicus), Ed. 2, Revised, Memoirs No. 6, Wistar Institute Anatomy and Biology, Philadelphia.Google Scholar
  9. 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.PubMedCrossRefGoogle Scholar
  10. Frankos, V.H. (1985) FDA perspectives on the use of teratology data for human risk assessment. Fundam. Appl. Toxicol. 5: 615–625.PubMedCrossRefGoogle Scholar
  11. Frederick, G.L. (1985) Assessment of teratogenic potential of therapeutic agents: Preclinical toxicology. Clin. Invest. Med. 8: 323–327.PubMedGoogle Scholar
  12. Friend, D.W., Trenholm, H.L., Fiser, P.S., Thompson, B.K., and Harlin, K.E. (1983) Effect on dam performance and fetal development of deoxynivalenol (vomitoxin) contaminated wheat in the diet of pregnant gilts. Can. J. Anim. Sci. 63: 689–698.CrossRefGoogle Scholar
  13. Goodman, L.S., and Gilman, A. (1970) The Pharmacological Basis of Therapeutics. A Textbook of Pharmacology, Toxicology, and Therapeutics for Physicians and Medical Students, Ed. 4, MacMillian, New York.Google Scholar
  14. Grabowski, C., and Payne, D.B. (1980) An electrocardiographic study of cardiovascular problems in Mirex-fed rat fetuses. Teratology 22: 167–177.PubMedCrossRefGoogle Scholar
  15. Green, J.D., Leong, B.K.J., and Laskin, S. (1978) Inhaled benzene fetotoxicity in rats. Toxicol. Appl. Pharmacol. 46: 9–18.CrossRefGoogle Scholar
  16. Hayes, W.C., Cobel-Geard, S.R., Hanley, 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
  17. Hazleton Laboratories America, Inc. (1982) Inhalation teratology study of benzene in rats (sponsored by the American Petroleum Institute, published as Coate et al. 1982, 1984 ).Google Scholar
  18. Hill, A.B. (1971) Principles of Medical Statistics, Ed. 9, Oxford University Press, New York.Google Scholar
  19. Hogan, M.D., and Hoel, D.G. (1982) Extrapolation to man. In Principles and Methods of Toxicology ( A.W. Hayes, Ed.), pp. 711–731, Raven Press, New York.Google Scholar
  20. Hudak, A., and Ungvary, G. (1978) Embryotoxic effects of benzene and its methyl derivatives: Toluene, xylene. Toxicology 11: 55–63.PubMedCrossRefGoogle Scholar
  21. Hudak, A., Tatrai, E., Lorincz, M., Barcza, G., and Ungvary, G. (1980) Dependence on concentration of the embryotoxic action of benzene inhalation on CFY rats. Morphol. Igazsagugyi Orv. Sz. 20: 261–268.PubMedGoogle Scholar
  22. Hutchings, D.E. (1983) Behavioral teratology: A new frontier in neurobehavioral research. In Teratogenesis and Reproductive Toxicology ( E.M. Johnson and D.M. Kochhar, Eds.), pp. 207–235, Springer-Verlag, Berlin.CrossRefGoogle Scholar
  23. HWC (National Health and Welfare and Environment, Canada) (1986) Guidelines on the Use of Mutagenicity Tests in the Toxicology Evaluation of Chemicals, National Health and Welfare, National Health and Welfare, Department of Environmental Contaminants Advisory Committee on Mutagenesis, Ottawa.Google Scholar
  24. Johnson, E.M., and Christian, M.S. (1986) An overview of considerations basic to extrapolation, evaluation and interpretation of developmental toxicity safety evaluation data. Developmental Toxicology for the General Toxicologist (continuing education course), Society of Toxicology, Akron, Ohio.Google Scholar
  25. Khera, K.S. (1973) N,N-Ethylenethiourea: Teratogenic study in rats and rabbits. Teratology 7: 243–252.CrossRefGoogle Scholar
  26. Khera, K.S. (1984) Maternal toxicity—A possible factor in fetal malformations in mice. Teratology 29: 411–416.PubMedCrossRefGoogle Scholar
  27. 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
  28. Khera, K.S., Arnold, D.L., Whalen, C., Angers, G., and Scott, P.M. (1984) Vomitoxin (4-deoxynivalenol): Effects on reproduction of mice and rats. Toxicol. Appl. Pharmacol. 74: 345–356.PubMedCrossRefGoogle Scholar
  29. Khera, K.S., and Tryphonas, L. (1977) Ethylenethiourea-induced hydrocephalus: Pre-and postnatal pathogenesis in rats given a single oral dose during pregnancy. Toxicol. Appl. Pharmacol. 42: 85–97.PubMedCrossRefGoogle Scholar
  30. Khera, K.S., Villeneuve, D.C., Terry, G., Panopio, L., Nash, L., and Trivett, G. (1976) Mirex: A teratogenicity, dominant lethal and tissue distribution study in rats. Food Cosmet. Toxicol. 14: 25–29.PubMedCrossRefGoogle Scholar
  31. Khera, K.S., Whalen, C., and Angers, G. (1986) A teratology study on vomitoxin (4-deoxynivalenol) in rabbits. Food Chem. Toxicol. 24: 421–424.PubMedCrossRefGoogle Scholar
  32. Kimmel, C.A., Buelke-Sam, J., and Adams, J. (1985) Collaborative Behavioral Teratology Study: Implications, current applications and future directions. Neurobehay. Toxicol. Teratol. 7: 669–673.Google Scholar
  33. Kimmel, C.A., and Young, J.F. (1983) Correlating pharmacokinetics and teratogenic endpoints. Fundam. Appl. Toxicol. 3: 250–255.PubMedCrossRefGoogle Scholar
  34. Kimmel, G.L. (1981) Developmental aspects of chemical interaction with cellular receptors. In Developmental Toxicology ( C. Kimmel and J. Buelke-Sam, Eds.), pp. 115–130, Raven Press, New York.Google Scholar
  35. Kimmel, G.L. (1985) In vitro tests in screening teratogens: Considerations to aid the validation process. Prog. Clin. Biol. Res. 163C: 259–263.Google Scholar
  36. Kimmel, G.L., Smith, K., Kochhar, D.M., and Pratt, R.M. (1982) Overview of in vitro teratogenicity testing: Aspects of validation and application to screening. Teratogenesis Carcinog. Mutagen. 2: 221–229.PubMedCrossRefGoogle Scholar
  37. Kury, G., Chaube, S., and Murphy, M.L. (1968) Teratogenic effects of some purine analogues on fetal rats. Arch. Pathol. 86: 395–402.Google Scholar
  38. Larsson, K.S., Elwin, C.E., Gabrielsson, J., Paalzow, L., and Wachmeister, C.A. (1982) Do teratogenicity tests serve their objectives? Lancet ii:439.Google Scholar
  39. McEvoy, G.K., and McQuarrie, G W. (1984) American Hospital Formulatory Service. American Society of Hospital Pharmacists, Bethesda, Maryland.Google Scholar
  40. Murphy, M.L., Dagg, C.P., and Karnofsky, D.A. (1957) Comparison of teratogenic chemicals in the rat and chick embryos. Pediatrics 19: 701–714.PubMedGoogle Scholar
  41. Murphy, M.L., and Karnofsky, D.A. (1956) Effect of azaserine and other growth inhibiting agents on fetal development of the rat. Cancer 9: 955–962.PubMedCrossRefGoogle Scholar
  42. Nau, H., Zierer, R., Spielmann, H., Neubert, D., and Gansau, C. (1981) A new model for embryotoxicity testing: Teratogenicity and pharmacokinetics of valproic acid following constant-rate administration in the mouse using human therapeutic drug and metabolite concentrations. Life Sci. 29: 2803–2814.PubMedCrossRefGoogle Scholar
  43. Nawrot, P.S., and Staples, R.E. (1979) Embryo-fetal toxicity and teratogenicity of benzene and toluene in the mouse. Teratology 19: 41A.Google Scholar
  44. Oser, B.L. (1981) Man is not a big rat. Toxicology Forum Proceedings, Washington, D.C.Google Scholar
  45. Rodics, K., Hudak, A., Tatrai, E., Lorincz, M., Barcza, G., and Ungvary, G. (1980) Embryo-toxic effects of benzene inhalation. Acta Morphol. Acad. Sci. Hung. 28: 220–221.Google Scholar
  46. Schardein, J.L. (1976). Drugs as Teratogens, pp. 55–254, CRC Press, Cleveland, Ohio.Google Scholar
  47. Schardein, J.L. (1987) Approaches to defining the relationship of maternal and developmental toxicity. Teratogenesis Carcinog. Mutagen. 7: 255–271.PubMedCrossRefGoogle Scholar
  48. Shah, R.M., and Chaudhry, A.P. (1973) Hydrocortisone-induced cleft palate in hamsters. Teratology 7: 191–194.PubMedCrossRefGoogle Scholar
  49. Shepard, T.H. (1980) Catalog of Teratogenic Agents, Ed. 3, Johns Hopkins University Press, Baltimore.Google Scholar
  50. Staples, R.E. (1976) Predictiveness and limitations of test methods in teratology: Overview. Environ. Health Perspect. 18: 95–96.PubMedCrossRefGoogle Scholar
  51. Strobino, B.R., Kline, J., and Stein, Z. (1978) Chemical and physical exposures of parents: Effects on human reproduction and offspring. Early Hum. Dey. 1: 371–399.CrossRefGoogle Scholar
  52. Sunderman, F.W., Jr., Allpass, P.R., Mitchell, J.M., Baslet, R.C., and Albert, D.M. (1979) Eye malformations in rats: Induction by prenatal exposure to nickel carbonyl. Science 203: 550–553.PubMedCrossRefGoogle Scholar
  53. Tatrai, E., Rodics, K., and Ungvary, G. (1980a) Embryotoxic effects of simultaneously applied exposure of benzene and toluene. Folia Morphol. (Praha) 28: 286–289.Google Scholar
  54. Tatrai, E., Ungvary, G., Hudak, A., Rodics, K., Lorincz, M., and Barcza, G. (1980b) Concentration dependence of the embryotoxic effects of benzene inhalation in CFY rats. J. Hyg. Epidemiol. Microbiol. Immunol. 24: 363–371.PubMedGoogle Scholar
  55. Thompson, D.J., Molello, J.A., and Strebing, R.J. (1978) Teratogenicity of adriamycin and daunomycin in the rat and rabbit. Teratology 17: 151–157.PubMedCrossRefGoogle Scholar
  56. Vorhees, C.V., Brunner, R.L., and Butcher, R.E. (1979) Psychotropic drugs as behavioral teratogens. Science 205: 1220–1225.PubMedCrossRefGoogle Scholar
  57. Walker, B.E. (1971) Induction of cleft palate in rats with antiinflammatory drugs. Teratology 4: 39–42.PubMedCrossRefGoogle Scholar
  58. 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
  59. WHO (World Health Organization) (1985) Guidelines for the Study of Genetic Effects in Human Populations, International Programme on Chemical Safety, Environmental Health Criteria 46, World Health Organization, Geneva.Google Scholar
  60. Wilson, J. (1978) Handbook of Teratology, Vol. 4, Research Procedures and Data Analysis, Plenum Press, New York.Google Scholar
  61. Wilson, J.G. (1973) Environment and Birth Defects, pp. 1–350, Academic Press, New York.Google Scholar
  62. Young, B.B. (1986) Birth-defects testing should not ignore the mind. Washington Post, Health, p. 6, February 5, 1986.Google Scholar
  63. Young, J.F., and Holson, J.F. (1978) Utility of pharmacokinetics in designing toxicological protocols and improving interspecies extrapolation. J. Environ. Pathol. Toxicol. 2: 169–186.PubMedGoogle 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

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