Ruthann Rudel
Silent Spring Institute, Newton, Massachusetts
Many substances are active in in vitro tests for estrogenic activity, but data from multigenerational and other toxicity studies are not available for many of those substances. Controversy has arisen, therefore, concerning the likelihood of adverse health effects. Based on a toxic equivalence factor risk assessment approach, some researchers have concluded that exposure to environmental estrogens is not associated with estrogen receptor (ER)-mediated health effects. Their rationale cites the low potency of these compounds in in vitro assays relative to estradiol, and the widespread exposure to pharmaceutical, endogenous, and dietary estrogens. This reasoning relies on two assumptions: that the relative estrogenic potency in in vitro assays is predictive of the relative potency for the most sensitive in vivo estrogenic effect; and that all estrogens act via the same mechanism to produce the most sensitive in vivo estrogenic effect. Experimental data reviewed here suggest that these assumptions may be inappropriate because diversity in both mechanism and effect exists for estrogenic compounds. Examples include variations in ER-ligand binding to estrogen response elements, time course of nuclear ER accumulation, patterns of gene activation, and other mechanistic characteristics that are not reflected in many in vitro assays, but may have significance for ER-mediated in vivo effects. In light of these data, this report identifies emerging methodological issues in risk assessment for estrogenic compounds: the need to address differences in in vivo end points of concern and the associated mechanisms; pharmacokinetics; the crucial role of timing and duration of exposure; interactions; and non-ER-mediated activities of estrogenic compounds. -- Environ Health Perspect 105(Suppl 3):655-663 (1997)
Key words: estrogen, environmental estrogen, phytoestrogen, dose response, risk assessment, mechanism, pharmacokinetics
This paper was presented in part at the Workshop on Hormones, Hormone Metabolism, Environment, and Breast Cancer held 28-29 September 1995 in New Orleans, Louisiana. Manuscript received at EHP 6 June 1996; manuscript accepted 22 August 1996.
I would like to acknowledge D. Davis and S. Swedis for their thoughtful suggestions on the work described here. Our research on this topic has been supported by the Massachusetts Department of Public Health as part of the Cape Cod Breast Cancer and Environment Study and by the Susan G. Komen Breast Cancer Foundation, Boston Race for the Cure.
Address correspondence to R. Rudel, Silent Spring Institute, 29 Crafts Street, Newton, MA 02158. Telephone: (617) 332-4288, ext. 14. Fax: (617) 332-4284. E-mail:rudel@silent.shore.net
Abbreviations used: DES, diethylstilbestrol; DMS, dimethylstilbestrol; ER, estrogen receptor; ERE, estrogen response element; GJIC, gap-junctional intercellular communication; GnRH, gonadotropin-releasing hormone; OP, 4-tert-octylphenol; PCBs, polychlorinated biphenyls; SDN-POA, sexually dimorphic nucleus in the preoptic area of the hypothalamus; SHBG, sex hormone-binding globulin; 2,3,7,8-TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TEF, toxic equivalence factor.
Last Update: April 10, 1997