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. 1999 Aug;107(Suppl 4):631–638. doi: 10.1289/ehp.99107s4631

Quantitative mechanistically based dose-response modeling with endocrine-active compounds.

M E Andersen 1, R B Conolly 1, E M Faustman 1, R J Kavlock 1, C J Portier 1, D M Sheehan 1, P J Wier 1, L Ziese 1
PMCID: PMC1567506  PMID: 10421774

Abstract

A wide range of toxicity test methods is used or is being developed for assessing the impact of endocrine-active compounds (EACs) on human health. Interpretation of these data and their quantitative use in human and ecologic risk assessment will be enhanced by the availability of mechanistically based dose-response (MBDR) models to assist low-dose, interspecies, and (italic)in vitro(/italic) to (italic)in vivo(/italic) extrapolations. A quantitative dose-response modeling work group examined the state of the art for developing MBDR models for EACs and the near-term needs to develop, validate, and apply these models for risk assessments. Major aspects of this report relate to current status of these models, the objectives/goals in MBDR model development for EACs, low-dose extrapolation issues, regulatory inertia impeding acceptance of these approaches, and resource/data needs to accelerate model development and model acceptance by the research and the regulatory community.

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Selected References

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  1. Allen B. C., Kavlock R. J., Kimmel C. A., Faustman E. M. Dose-response assessment for developmental toxicity. II. Comparison of generic benchmark dose estimates with no observed adverse effect levels. Fundam Appl Toxicol. 1994 Nov;23(4):487–495. doi: 10.1006/faat.1994.1133. [DOI] [PubMed] [Google Scholar]
  2. Allen B. C., Kavlock R. J., Kimmel C. A., Faustman E. M. Dose-response assessment for developmental toxicity. III. Statistical models. Fundam Appl Toxicol. 1994 Nov;23(4):496–509. doi: 10.1006/faat.1994.1134. [DOI] [PubMed] [Google Scholar]
  3. Andersen M. E., Barton H. A. Biological regulation of receptor-hormone complex concentrations in relation to dose-response assessments for endocrine-active compounds. Toxicol Sci. 1999 Mar;48(1):38–50. doi: 10.1093/toxsci/48.1.38. [DOI] [PubMed] [Google Scholar]
  4. Andersen M. E., Birnbaum L. S., Barton H. A., Eklund C. R. Regional hepatic CYP1A1 and CYP1A2 induction with 2,3,7,8-tetrachlorodibenzo-p-dioxin evaluated with a multicompartment geometric model of hepatic zonation. Toxicol Appl Pharmacol. 1997 May;144(1):145–155. doi: 10.1006/taap.1996.8067. [DOI] [PubMed] [Google Scholar]
  5. Andersen M. E., Clewell H. J., 3rd, Frederick C. B. Applying simulation modeling to problems in toxicology and risk assessment--a short perspective. Toxicol Appl Pharmacol. 1995 Aug;133(2):181–187. doi: 10.1006/taap.1995.1140. [DOI] [PubMed] [Google Scholar]
  6. Andersen M. E., Clewell H. J., 3rd, Gargas M. L., Smith F. A., Reitz R. H. Physiologically based pharmacokinetics and the risk assessment process for methylene chloride. Toxicol Appl Pharmacol. 1987 Feb;87(2):185–205. doi: 10.1016/0041-008x(87)90281-x. [DOI] [PubMed] [Google Scholar]
  7. Andersen M. E., Clewell H. J., 3rd, Gearhart J., Allen B. C., Barton H. A. Pharmacodynamic model of the rat estrus cycle in relation to endocrine disruptors. J Toxicol Environ Health. 1997 Oct 24;52(3):189–209. doi: 10.1080/00984109708984060. [DOI] [PubMed] [Google Scholar]
  8. Andersen M. E., Mills J. J., Gargas M. L., Kedderis L., Birnbaum L. S., Neubert D., Greenlee W. F. Modeling receptor-mediated processes with dioxin: implications for pharmacokinetics and risk assessment. Risk Anal. 1993 Feb;13(1):25–36. doi: 10.1111/j.1539-6924.1993.tb00726.x. [DOI] [PubMed] [Google Scholar]
  9. Barton H. A., Andersen M. E. A model for pharmacokinetics and physiological feedback among hormones of the testicular-pituitary axis in adult male rats: a framework for evaluating effects of endocrine active compounds. Toxicol Sci. 1998 Oct;45(2):174–187. doi: 10.1006/toxs.1998.2538. [DOI] [PubMed] [Google Scholar]
  10. Blumenthal G. M., Kohn M. C., Portier C. J. A mathematical model of production, distribution, and metabolism of melatonin in mammalian systems. Toxicol Appl Pharmacol. 1997 Nov;147(1):83–92. doi: 10.1006/taap.1997.8247. [DOI] [PubMed] [Google Scholar]
  11. Clewell H. J., 3rd, Andersen M. E. Use of physiologically based pharmacokinetic modeling to investigate individual versus population risk. Toxicology. 1996 Jul 17;111(1-3):315–329. doi: 10.1016/0300-483x(96)03385-9. [DOI] [PubMed] [Google Scholar]
  12. Conolly R. B., Andersen M. E. An approach to mechanism-based cancer risk assessment for formaldehyde. Environ Health Perspect. 1993 Dec;101 (Suppl 6):169–176. doi: 10.1289/ehp.93101s6169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Conolly R. B., Andersen M. E. Hepatic foci in rats after diethylnitrosamine initiation and 2,3,7,8-tetrachlorodibenzo-p-dioxin promotion: evaluation of a quantitative two-cell model and of CYP 1A1/1A2 as a dosimeter. Toxicol Appl Pharmacol. 1997 Oct;146(2):281–293. doi: 10.1006/taap.1997.8248. [DOI] [PubMed] [Google Scholar]
  14. Constan A. A., Yang R. S., Baker D. C., Benjamin S. A. A unique pattern of hepatocyte proliferation in F344 rats following long-term exposures to low levels of a chemical mixture of groundwater contaminants. Carcinogenesis. 1995 Feb;16(2):303–310. doi: 10.1093/carcin/16.2.303. [DOI] [PubMed] [Google Scholar]
  15. Cook J. C., Klinefelter G. R., Hardisty J. F., Sharpe R. M., Foster P. M. Rodent Leydig cell tumorigenesis: a review of the physiology, pathology, mechanisms, and relevance to humans. Crit Rev Toxicol. 1999 Mar;29(2):169–261. doi: 10.1080/10408449991349203. [DOI] [PubMed] [Google Scholar]
  16. Crews D., Bergeron J. M., Bull J. J., Flores D., Tousignant A., Skipper J. K., Wibbels T. Temperature-dependent sex determination in reptiles: proximate mechanisms, ultimate outcomes, and practical applications. Dev Genet. 1994;15(3):297–312. doi: 10.1002/dvg.1020150310. [DOI] [PubMed] [Google Scholar]
  17. Crews D., Cantú A. R., Bergeron J. M. Temperature and non-aromatizable androgens: a common pathway in male sex determination in a turtle with temperature-dependent sex determination? J Endocrinol. 1996 Jun;149(3):457–463. doi: 10.1677/joe.0.1490457. [DOI] [PubMed] [Google Scholar]
  18. Daston G. P., Gooch J. W., Breslin W. J., Shuey D. L., Nikiforov A. I., Fico T. A., Gorsuch J. W. Environmental estrogens and reproductive health: a discussion of the human and environmental data. Reprod Toxicol. 1997 Jul-Aug;11(4):465–481. doi: 10.1016/s0890-6238(97)00014-2. [DOI] [PubMed] [Google Scholar]
  19. Ferrell J. E., Jr, Machleder E. M. The biochemical basis of an all-or-none cell fate switch in Xenopus oocytes. Science. 1998 May 8;280(5365):895–898. doi: 10.1126/science.280.5365.895. [DOI] [PubMed] [Google Scholar]
  20. Frederick C. B., Bush M. L., Lomax L. G., Black K. A., Finch L., Kimbell J. S., Morgan K. T., Subramaniam R. P., Morris J. B., Ultman J. S. Application of a hybrid computational fluid dynamics and physiologically based inhalation model for interspecies dosimetry extrapolation of acidic vapors in the upper airways. Toxicol Appl Pharmacol. 1998 Sep;152(1):211–231. doi: 10.1006/taap.1998.8492. [DOI] [PubMed] [Google Scholar]
  21. Gaido K. W., Leonard L. S., Lovell S., Gould J. C., Babaï D., Portier C. J., McDonnell D. P. Evaluation of chemicals with endocrine modulating activity in a yeast-based steroid hormone receptor gene transcription assay. Toxicol Appl Pharmacol. 1997 Mar;143(1):205–212. doi: 10.1006/taap.1996.8069. [DOI] [PubMed] [Google Scholar]
  22. Gray L. E., Wolf C., Mann P., Ostby J. S. In utero exposure to low doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin alters reproductive development of female Long Evans hooded rat offspring. Toxicol Appl Pharmacol. 1997 Oct;146(2):237–244. doi: 10.1006/taap.1997.8222. [DOI] [PubMed] [Google Scholar]
  23. Kavlock R. J., Allen B. C., Faustman E. M., Kimmel C. A. Dose-response assessments for developmental toxicity. IV. Benchmark doses for fetal weight changes. Fundam Appl Toxicol. 1995 Jul;26(2):211–222. doi: 10.1006/faat.1995.1092. [DOI] [PubMed] [Google Scholar]
  24. Kavlock R. J., Setzer R. W. The road to embryologically based dose-response models. Environ Health Perspect. 1996 Mar;104 (Suppl 1):107–121. doi: 10.1289/ehp.96104s1107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kohn M. C., Lucier G. W., Clark G. C., Sewall C., Tritscher A. M., Portier C. J. A mechanistic model of effects of dioxin on gene expression in the rat liver. Toxicol Appl Pharmacol. 1993 May;120(1):138–154. doi: 10.1006/taap.1993.1096. [DOI] [PubMed] [Google Scholar]
  26. Kohn M. C., Portier C. J. Effects of the mechanism of receptor-mediated gene expression on the shape of the dose-response curve. Risk Anal. 1993 Oct;13(5):565–572. doi: 10.1111/j.1539-6924.1993.tb00016.x. [DOI] [PubMed] [Google Scholar]
  27. Kohn M. C., Sewall C. H., Lucier G. W., Portier C. J. A mechanistic model of effects of dioxin on thyroid hormones in the rat. Toxicol Appl Pharmacol. 1996 Jan;136(1):29–48. doi: 10.1006/taap.1996.0004. [DOI] [PubMed] [Google Scholar]
  28. Leroux B. G., Leisenring W. M., Moolgavkar S. H., Faustman E. M. A biologically-based dose-response model for developmental toxicology. Risk Anal. 1996 Aug;16(4):449–458. doi: 10.1111/j.1539-6924.1996.tb01092.x. [DOI] [PubMed] [Google Scholar]
  29. Limbird L. E., Taylor P. Endocrine disruptors signal the need for receptor models and mechanisms to inform policy. Cell. 1998 Apr 17;93(2):157–163. doi: 10.1016/s0092-8674(00)81568-8. [DOI] [PubMed] [Google Scholar]
  30. Lucier G. W., Portier C. J., Gallo M. A. Receptor mechanisms and dose-response models for the effects of dioxins. Environ Health Perspect. 1993 Apr 22;101(1):36–44. doi: 10.1289/ehp.9310136. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. McGrath L. F., Georgopoulos P., Gallo M. A. Application of a biologically-based RFD estimation method to tetrachlorodibenzo-p-dioxin (TCDD) mediated immune suppression and enzyme induction. Risk Anal. 1996 Aug;16(4):539–548. doi: 10.1111/j.1539-6924.1996.tb01099.x. [DOI] [PubMed] [Google Scholar]
  32. McLachlan J. A., Newbold R. R., Shah H. C., Hogan M. D., Dixon R. L. Reduced fertility in female mice exposed transplacentally to diethylstilbestrol (DES). Fertil Steril. 1982 Sep;38(3):364–371. doi: 10.1016/s0015-0282(16)46520-9. [DOI] [PubMed] [Google Scholar]
  33. Parham F. M., Kohn M. C., Matthews H. B., DeRosa C., Portier C. J. Using structural information to create physiologically based pharmacokinetic models for all polychlorinated biphenyls. Toxicol Appl Pharmacol. 1997 Jun;144(2):340–347. doi: 10.1006/taap.1997.8139. [DOI] [PubMed] [Google Scholar]
  34. Parham F. M., Portier C. J. Using structural information to create physiologically based pharmacokinetic models for all polychlorinated biphenyls. II. Rates of metabolism. Toxicol Appl Pharmacol. 1998 Jul;151(1):110–116. doi: 10.1006/taap.1998.8441. [DOI] [PubMed] [Google Scholar]
  35. Portier C. J., Kaplan N. L. Variability of safe dose estimates when using complicated models of the carcinogenic process. A case study: methylene chloride. Fundam Appl Toxicol. 1989 Oct;13(3):533–544. doi: 10.1016/0272-0590(89)90290-x. [DOI] [PubMed] [Google Scholar]
  36. Reiter L. W., DeRosa C., Kavlock R. J., Lucier G., Mac M. J., Melillo J., Melnick R. L., Sinks T., Walton B. T. The U.S. federal framework for research on endocrine disruptors and an analysis of research programs supported during fiscal year 1996. Environ Health Perspect. 1998 Mar;106(3):105–113. doi: 10.1289/ehp.98106105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Russo I. H., Russo J. Mammary gland neoplasia in long-term rodent studies. Environ Health Perspect. 1996 Sep;104(9):938–967. doi: 10.1289/ehp.96104938. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Shapiro D. J., Barton M. C., McKearin D. M., Chang T. C., Lew D., Blume J., Nielsen D. A., Gould L. Estrogen regulation of gene transcription and mRNA stability. Recent Prog Horm Res. 1989;45:29–64. doi: 10.1016/b978-0-12-571145-6.50006-6. [DOI] [PubMed] [Google Scholar]
  39. Sheehan D. M., Branham W. S. Dissociation of estrogen-induced uterine growth and ornithine decarboxylase activity in the postnatal rat. Teratog Carcinog Mutagen. 1987;7(4):411–422. doi: 10.1002/tcm.1770070408. [DOI] [PubMed] [Google Scholar]
  40. Shuey D. L., Buckalew A. R., Wilke T. S., Rogers J. M., Abbott B. D. Early events following maternal exposure to 5-fluorouracil lead to dysmorphology in cultured embryonic tissues. Teratology. 1994 Dec;50(6):379–386. doi: 10.1002/tera.1420500603. [DOI] [PubMed] [Google Scholar]
  41. Shuey D. L., Lau C., Logsdon T. R., Zucker R. M., Elstein K. H., Narotsky M. G., Setzer R. W., Kavlock R. J., Rogers J. M. Biologically based dose-response modeling in developmental toxicology: biochemical and cellular sequelae of 5-fluorouracil exposure in the developing rat. Toxicol Appl Pharmacol. 1994 May;126(1):129–144. doi: 10.1006/taap.1994.1099. [DOI] [PubMed] [Google Scholar]
  42. Tata J. R., Baker B. S., Machuca I., Rabelo E. M., Yamauchi K. Autoinduction of nuclear receptor genes and its significance. J Steroid Biochem Mol Biol. 1993 Aug;46(2):105–119. doi: 10.1016/0960-0760(93)90286-6. [DOI] [PubMed] [Google Scholar]
  43. Tong W., Perkins R., Strelitz R., Collantes E. R., Keenan S., Welsh W. J., Branham W. S., Sheehan D. M. Quantitative structure-activity relationships (QSARs) for estrogen binding to the estrogen receptor: predictions across species. Environ Health Perspect. 1997 Oct;105(10):1116–1124. doi: 10.1289/ehp.971051116. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Tong W., Perkins R., Xing L., Welsh W. J., Sheehan D. M. QSAR models for binding of estrogenic compounds to estrogen receptor alpha and beta subtypes. Endocrinology. 1997 Sep;138(9):4022–4025. doi: 10.1210/endo.138.9.5487. [DOI] [PubMed] [Google Scholar]
  45. Tsai T. L., Katzenellenbogen B. S. Antagonism of development and growth of 7,12-dimethylbenz(a)anthracene-induced rat mammary tumors by the antiestrogen U 23,469 and effects on estrogen and progesterone receptors. Cancer Res. 1977 May;37(5):1537–1543. [PubMed] [Google Scholar]
  46. Vanden Heuvel J. P., Clark G. C., Kohn M. C., Tritscher A. M., Greenlee W. F., Lucier G. W., Bell D. A. Dioxin-responsive genes: examination of dose-response relationships using quantitative reverse transcriptase-polymerase chain reaction. Cancer Res. 1994 Jan 1;54(1):62–68. [PubMed] [Google Scholar]
  47. Yates F. E. Good manners in good modeling: mathematical models and computer simulations of physiological systems. Am J Physiol. 1978 May;234(5):R159–R160. doi: 10.1152/ajpregu.1978.234.5.R159. [DOI] [PubMed] [Google Scholar]
  48. vom Saal F. S., Timms B. G., Montano M. M., Palanza P., Thayer K. A., Nagel S. C., Dhar M. D., Ganjam V. K., Parmigiani S., Welshons W. V. Prostate enlargement in mice due to fetal exposure to low doses of estradiol or diethylstilbestrol and opposite effects at high doses. Proc Natl Acad Sci U S A. 1997 Mar 4;94(5):2056–2061. doi: 10.1073/pnas.94.5.2056. [DOI] [PMC free article] [PubMed] [Google Scholar]

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