Academic journal article Environmental Health Perspectives

Sensitivity of the Immature Rat Uterotrophic Assay to Mixtures of Estrogens

Academic journal article Environmental Health Perspectives

Sensitivity of the Immature Rat Uterotrophic Assay to Mixtures of Estrogens

Article excerpt

We have evaluated whether mixtures of estrogens, present in the mix at doses that are individually inactive in the immature rat uterotrophic assay, can give a uterotrophic response. Seven chemicals were evaluated: nonylphenol, bisphenol A (BPA), methoxychlor, genistein (GEN), estradiol, diethylstilbestrol, and ethinyl estradiol. Dose responses in the uterotrophic assay were constructed for each chemical. The first series of experiments involved evaluating binary mixtures of BPA and GEN at dose levels that gave moderate uterotrophic responses when tested individually. The mixtures generally showed an intermediate or reduced uterotrophic effect compared with when the components of the mixture were tested alone at the dose used in the mixture. The next series of experiments used a multicomponent (complex) mixture of all seven chemicals evaluated at doses that gave either weakly positive or inactive uterotrophic responses when tested individually in the assay. Doses that were nominally equi-uterotrophic ranged over approximately six orders of magnitude for the seven chemicals. Doses of agents that gave a weak uterotrophic response when tested individually gave a marginally enhanced positive response in the assay when tested combined as a mixture. Doses of agents that gave a negative uterotrophic response when tested individually gave a positive response when tested as a mixture. These data indicate that a variety of different estrogen receptor (ER) agonists, present individually at subeffective doses, can act simultaneously to evoke an ER-regulated response. However, translating these findings into the process of environmental hazard assessment will be difficult. The simple addition of the observed, or predicted, activities for the components of a mixture is confirmed here to be inappropriate and to overestimate the actual effect induced by the mixture. Equally, isobole analysis is only suitable for two- or three-component mixtures, and concentration addition requires access to dose-response data and E[C.sub.50] values (concentration giving 50% of the maximum response) for the individual components of the mixture--requirements that will rarely be fulfilled for complex environmental samples. Given these uncertainties, we conclude that it may be most expedient to select and bioassay whole environmental mixtures of potential concern. Key words: anthropogenic estrogens, binary mixtures, complex mixtures, estrogenicity, immature rat uterotrophic assay, phytoestrogens, synthetic estrogens. Environ Health Perspect 112:575-582 (2004). doi:10.1289/ehp.6831 available via http://dx.doi.org/[Online 8 January 2004]

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Recognition that exposure to environmental estrogens may cause adverse reproductive effects led to the development of assays capable of detecting such compounds. These include in vitro assays, such as binding to the estrogen or androgen receptor (ER and AR, respectively), and/or gene in vitro expression assays. For more refined hazard assessments, a variety of in vivo rodent assays have been described, such as the rodent uterotrophic and Hershberger assays [Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC) 1998; Gray et al. 2002; Organisation for Economic Co-operation (OECD) 1998). However, humans and wildlife are exposed to mixtures of chemicals, and the best way to determine the sum of the activities of the individual components of the mixture, leading to a holistic assessment of hazard, remains open to discussion.

There are several approaches to the assessment of mixtures, ranging from the bioassay of whole mixtures (e.g., Heindel et al. 1994; Jobling et al. 2002; Rodgers-Gray et al. 2001) to the more analytical component-based approaches (e.g., Payne et al. 2001; Silva et al. 2002). In whole-mixture approaches, the mixture is treated as if it were one single chemical entity, whereas in the component-based approach the mixture effects are derived from consideration of the activities of the individual constituents of the mixture. …

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