Advanced Search

Journal Navigation

Journal Home

Subscriptions

Archive

Contact Us

Table of Contents

Sign In to gain access to subscriptions and/or personal tools.
Toxicologic Pathology
This Article
Right arrow Abstract Freely available
Right arrow Free Full Text (Free PDF) Free
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Saved Citations
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Request Reprints
Right arrow Add to My Marked Citations
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Right arrow Citing Articles via Scopus
Google Scholar
Right arrow Articles by Ashby, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ashby, J.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

Validation of In Vitro and In Vivo Methods for Assessing Endocrine Disrupting Chemicals

John Ashby

Zeneca Central Toxicology Laboratory, Alderley Park, Cheshire, United Kingdom, John.Ashby{at}CTL.Zeneca.com

The concepts that require validation in terms of the subject of endocrine disruption are listed and discussed. The main mechanisms by which endocrine disruption can occur are identified, and the assays required for the detection of adverse endocrine disruption toxicities associated with these mechanisms are discussed. The process of assay validation is considered. The validation of structure-activity relationships, the need for reference chemicals, and the problems recently encountered when attempting to reproduce endocrine disruption data are also explored. The most important conclusions derived from this analysis are that given the immature state of research into endocrine disruption toxicity, testing strategies and the types of assay employed should be kept under constant review; inevitably researchers need to accept the fact that future revision of each assay will be required. Second, given the current absence of any chemical that is universally accepted to be devoid of endocrine toxicity, assay specificity will be difficult to assess, and that imposes the need for alternative objective criteria for assessing the value of individual assays.

Key Words: Endocrine disruptors • endocrine modulators • testing strategy • assays • validation

References

  • Ankley G., et al (30 authors) (1998). Overview of a workshop on screening methods for detecting potential (anti-)estrogenic/androgenic chemicals in wildlife. Environ Toxicol Chem 17: 68-87.[CrossRef][Web of Science]
  • Anonymous (1997). Endocrine/Estrogen Letter, July 22. Washington, DC.
  • Ashby J. (1997). A hierarchical approach to the evaluation of chemicals for estrogenic and other endocrine-disrupting properties. Environ Toxicol Pharmacol 3: 87-90.[CrossRef]
  • Ashby J., Elliott BM (1997). Reproducibility of endocrine disruption data. Regul Toxicol Pharmacol 26: 94-95 (editorial).[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Ashby J., Houthoff E., Kennedy SJ, Stevens J., Bars R., Jekat FW, Campbell P., Van Miller J, Carpanini FM, Randall Glp (1997). The challenge posed by endocrine-disrupting chemicals. Environ Health Perspect 105: 164-169.[Web of Science][Medline] [Order article via Infotrieve]
  • Ashby J., Tinwell H. (1998). Uterotrophic activity of bisphenol A in the immature rat. Environ Health Perspect 106: 719-720.[Web of Science][Medline] [Order article via Infotrieve]
  • Ashby J., Tinwell H., Lefevre PA, Odum J., Paton D., Millward SW, Tittensor S., Brooks AN (1997). Normal sexual development of rats exposed to butyl benzyl phthalate from conception to weaning. Regul Toxicol Pharmacol 26: 102-118.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Ashby J., Waters MD, Preston A., Adler ID, Douglas GR, Fielder R., Shelby MD, Anderson D., Sofuni T., Gopalan Hnb, Becking G., Sonich-Mullin C. (1996). IPCS harmonization of methods for the prediction and quantification of human carcinogenic/mutagenic hazard, and for indicating the probable mechanism of action of carcinogens. Mutat Res 352: 153-157.[Web of Science][Medline] [Order article via Infotrieve]
  • Ball M., Karcher W. (1995). The validation of alternative test methods. ATLA 23: 884-886.
  • Black LJ, Sato M., Rowley ER, Magee DE, Bekele A., Williams DC, Cullinan GJ, Bendele R., Kaufman FG, Bensch WR, Frolic CA, Termine JD, Bryant HU (1994). Raloxifene (LY139481 HCl) prevents bone loss and reduces serum cholesterol without causing uterine hypertrophy in ovariectomized rats. J Clin Invest 93: 63-69.[Web of Science][Medline] [Order article via Infotrieve]
  • Brzozowski AM, Pike Acw, Dauter Z., Hubbard RE, Bonn T., Engstrom O., Ohman L., Greene GL, Gustaffson J-A., Carlquist M. (1997). Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 389: 753-757.[CrossRef][Medline] [Order article via Infotrieve]
  • Campbell PM, Hutchinson TH (1998). Wildlife and endocrine disrupters: Requirement for hazard identification. Environ Toxicol Chem 17: 127-135.[CrossRef][Web of Science]
  • Colborn T, Clement C, eds. (1992). Chemically-induced alterations in sexual and functional development: The wildlife-human connection. Princeton Scientific Publishing, Princeton, New Jersey.
  • Connor K., Ramamoorthy K., Moore M., Mustain M., Chen I., Safe S., Zacharewski T., Gillesby B., Joyeux A., Balaguer P. (1997). Hydroxylated polychlorinated biphenyls (PCB) as estrogens and antiestrogens: Structure activity relationships. Toxicol Appl Pharmacol 145: 111-113.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Cooke PS, Zhao Y., Hansen LG (1996). Neonatal polychlorinated biphenyl treatment increases adult testis size and sperm production in the rat. Toxicol Appl Pharmacol 136: 112-117.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Evans GL, Bryant HU, Magee DE, Turner RT (1996). Raloxifene inhibits bone turnover and prevents further cancellous bone loss in adult ovariectomized rats with established osteopenia. Endocrinology 137: 4139-4144.[Abstract]
  • Hess RA, Cooke PS (1996). Symposium overview—Endocrine modulation of reproduction. Fundam Appl Toxicol 29: 1-17.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Hill AB (1965). Environment and disease—Association or causation. Proc R Soc Med 58: 295-300.[Web of Science][Medline] [Order article via Infotrieve]
  • Horwitz KB (1995). When tamoxifen turns bad. Endocrinology 136: 821-823 (editorial).[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Jansen HT, Cooke PS, Porcelii J., Liu T-C., Hansen LG (1993). Estrogenic and antiestrogenic actions of PCBs in the female rat: In vitro and in vivo studies. Reprod Toxicol 7: 237-248.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Kelce WR, Lambright CR. Gray EL, Roberts KP (1997). Vinclozolin and p,p'DDE alter androgen-dependent gene expression: In vivo and in vitro confirmation of an androgen receptor-mediated mechanism. Toxicol Appl Pharmacol 142: 192-200.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Kelce WR, Stone CR, Laws SC, Gray EL, Kemppainen JA, Wilson EM (1995). Persistent DDT metabolite p,p'DDE is a potent androgen receptor antagonist. Nature 375: 581-585.[CrossRef][Medline] [Order article via Infotrieve]
  • Ketzenellenbogen BS, Korach KS (1997). A new actor in the estrogen receptor drama. Endocrinology 138: 861-862 (editorial).[Free Full Text]
  • Kuiper Ggjm, Carlsson B., Grandien K., Enmark E., Haggblad J. Nilsson S., Gustafsson JA (1997). Comparison of the ligand binding specificity and transcript tissue distribution of oestrogen receptors alpha and beta. Endocrinology 138: 863-870.[Abstract/Free Full Text]
  • McLachlan JA (1993). Functional toxicology: A new approach to detect biologically active xenobiotics. Environ Health Perspect 101: 386-387.[Web of Science][Medline] [Order article via Infotrieve]
  • Nagel SC, Vom Saal FS, Thayer KA, Dhar MG, Boechler M., Welshons WV (1997). Relative binding affinity-serum modified access (RBA-SMA) assay predicts the relative in vivo bioactivity of the xenoestrogens bisphenol A and octylphenol. Environ Health Perspect 105: 70-76.[Web of Science][Medline] [Order article via Infotrieve]
  • Reel JR, Lamb JC, Neal BH ( 1996). Survey and assessment of mammalian estrogen biological assays for hazard characterization. Fundam Appl Toxicol 34: 288-305.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Scialli AR (1997). Identifying teratogens: The tyranny of lists. Reprod Toxicol 11: 555-559.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Sharpe RM, Fisher JS, Millar MM, Jobling S., Sumpter JP (1995). Gestational and lactational exposure of rats to xenoestrogens results in reduced testicular size and sperm production. Environ Health Perspect 103: 1136-1143.[Web of Science][Medline] [Order article via Infotrieve]
  • Shelby MD, Newbod RR, Tully DB, Chae K., Davis L. (1996). Assessing environmental chemicals for estrogenicity using a combination of in vitro and in vivo assays. Environ Health Perspect 104: 1296-1300.[Web of Science][Medline] [Order article via Infotrieve]
  • Shull JD, Spady TJ, Snyder MC, Johansson SL, Pennington KL (1997). Ovary- intact, but not ovariectomized female ACI rats treated with 17beta-estradiol rapidly develop mammary carcinoma. Carcinogenesis 18: 1595-1601.[Abstract/Free Full Text]
  • Singletary K., MacDonald C., Wallig M. (1997). The plasticizer benzyl butyl phthalate (BBP) inhibits 7,12-dimethylbenz[a]anthracene (DMBA)—Induced rat mammary DNA adduct formation and tumorigenesis. Carcinogenesis 18: 1669-1673.[Abstract/Free Full Text]
  • Sohoni P., Sumpter JP (1998). Several environmental oestrogens are also anti-androgens. J Endocrinol 158: 327-339.[Abstract]
  • Steinmetz R., Brown NG, Allen DL, Bigsby RM, Ben-Jonathan N. (1997). The environmental estrogen bisphenol A stimulates prolactin release in vitro and in vivo. Endocrinology 138: 1780-1786.[Abstract/Free Full Text]
  • Willson TM, Noris JD, Wagner BL, Asplin I., Baer P., Brown RH, Jones SA, Henke B., Sauls H., Wolfe S., Morris DC, McDonnell DP (1997). Dissection of the molecular mechanism of action of GW5638, a novel estrogen receptor ligand, provides insights into the role of estrogen receptor in bone. Endocrinology 138: 3901-3911.[Abstract/Free Full Text]
  • Yang NN, Venugopalan M., Hardikar S., Glasebrook A. (1996). Identification of an estrogen response element activated by metabolites of 17beta-estradiol and raloxifene. Science 273: 1222-1225.[Abstract]

Toxicologic Pathology, Vol. 28, No. 3, 432-437 (2000)
DOI: 10.1177/019262330002800312
Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?


This article has been cited by other articles:


Home page
 Proc. Natl. Acad. Sci. USAHome page
T. B. Hayes, A. Collins, M. Lee, M. Mendoza, N. Noriega, A. A. Stuart, and A. Vonk
Hermaphroditic, demasculinized frogs after exposure to the herbicide atrazine at low ecologically relevant doses
PNAS, April 16, 2002; 99(8): 5476 - 5480.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol PatholHome page
L. Tryphonas and C. Gopinath
A Synopsis of the Third International Federation of Societies of Toxicologic Pathologists Conference
Toxicol Pathol, May 1, 2000; 28(3): 370 - 374.
[PDF]

This Article
Right arrow Abstract Freely available
Right arrow Free Full Text (Free PDF) Free
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Saved Citations
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Request Reprints
Right arrow Add to My Marked Citations
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Right arrow Citing Articles via Scopus
Google Scholar
Right arrow Articles by Ashby, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ashby, J.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?