Predicting health effects of exposures to compounds with estrogenic activity: methodological issues.

Abstract

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 1 05(Suppl 3): 655-663 (1997)

Evidence for the Bioactivation of 4-Nonylphenol to Quinone Methide andortho-Benzoquinone Metabolites in Human Liver Microsomes

“…The MS spectrum of M7 showed a deprotonated molecular ion at m / z 524.2427, 305.0680 Da higher than that of 4-NP, indicating the incorporation of a GS moiety to molecule 4-NP (Table ). In negative ESI analysis, the characteristic fragment ions of this GSH conjugate were mainly derived from the GSH moiety (Figure ), which are the same as those reported for other GSH conjugates with different instruments , . The high energy mass spectrum of M7 revealed a diagnostic fragment ion of a GSH conjugate at m / z 306.0733 (deprotonated GSH moiety).…”

“…The mean daily oral intake of nonylphenol by humans is estimated to be 0.16 mg/day . The potential risk of 4-NP to human populations is still unclear and is a topic of considerable debate − .…”

Critical windows of exposure for children's health: cancer in human epidemiological studies and neoplasms in experimental animal models.

“…As noted previously, the multigenerational effect of DES could be mediated both directly by exposed blastocysts and by the maternal gestational environment (147). A number of plant-derived and anthropogenic compounds have endocrine-disrupting activity and may mimic many developmental effects of DES (208). Persistent endocrino-logical and immunological toxic effects of various perinatal exposures are well known; these should be studied systematically with regard to effects on postnatal carcinogenesis.…”

Identification of Alkylphenols and Other Estrogenic Phenolic Compounds in Wastewater, Septage, and Groundwater on Cape Cod, Massachusetts

“…The potential health effects of exposure to the alkylphenols and other weakly estrogenic chemicals is the subject of considerable debate (15)(16)(17)(18)(19). Pharmaceutical and endogenous estrogens are considerably more potent than alkylphenols in screening tests (11), and so they may be more important sources of exposure to estrogenic chemicals.…”

“…Pharmaceutical and endogenous estrogens are considerably more potent than alkylphenols in screening tests (11), and so they may be more important sources of exposure to estrogenic chemicals. However, it has been argued that in vitro and short-term in vivo screening tests for estrogenic activity may not provide an adequate basis for predicting safe levels of exposure to the weakly estrogenic synthetic chemicals (15,17). The toxicology of EDCs is an area of intensive research.…”