The importance of appropriate controls, animal feed, and animal models in interpreting results from low-dose studies of bisphenol A

Abstract

Interpreting results of studies that report only negative effects is problematic. A number of published studies to determine whether chemicals with estrogenic activity can cause effects at low doses have not taken into account the possibility that the commercial animal feed being used can mask effects of even potent estrogenic drugs such as diethylstilbestrol (DES). In addition, the sensitivity of the strain of animal being used for the specific category of chemical being tested has not always been described. For environmental chemicals, such as the estrogenic polycarbonate plastic monomer bisphenol A, DES is an appropriate positive control for estrogenic effects, and using an appropriate low dose of DES can eliminate the possibility of false-negative conclusions of safety when the above or other variables contribute to the negative outcome. Only when simultaneous positive effects of low doses of a positive control chemical such as DES and negative effects of environmentally relevant low doses of the test chemical are demonstrated within the same experiment are conclusions of no effect of the test chemical warranted, and this has not been reported for bisphenol A in any study. Instead, more than 90 refereed journal publications have reported effects due to exposure to low doses of bisphenol A in a wide variety of animals (for references see: http://rcp.missouri.edu/endocrinedisruptors/ vomsaal/vomsaal.html). However, due to lack of attention to the importance of appropriate positive controls, a small number of studies reporting negative effects of bisphenol A have created a false sense of controversy regarding low-dose effects of bisphenol A.

An evaluation of evidence for the carcinogenic activity of bisphenol A

“…In addition to the route of administration, it is imperative that consistent environmental conditions be used to assess BPA impact on carcinogenesis in laboratory animals [98]. Specifically, care should be taken to minimize exposure to polycarbonate caging and plastic water bottles, an established source of BPA [25].…”

Usefulness of immature golden hamster (Mesocricetus auratus) as a model for uterotrophic assay

“…The animal species and diets are of great importance (26,30). Several studies demonstrated that some commonly used outbred rats and mice are less responsive to oestrogenic substances than certain inbred mouse and rat strains, at various oestrogensensitive endpoints.…”

“…Conversely, the uterotrophic assay performed on the immature model was shown to be more sensitive to an increase in uterine weight evoked by oestrogenic compounds than the model of ovariectomised animals (17). In both versions the baselines for negative and positive controls are necessary for a rational interpretation of the results (19,30).…”

“…However, it is expected that the risk to humans takes into account the results obtained in the most sensitive species (26,30).…”

Influence of dietary soy isoflavones on immature hamster uterotrophic and Hershberger assays

“…Therefore, besides the appropriate animal model and control groups (negative and positive), feed is of significant importance in interpreting results of the studies on endocrine disruptors (EDs) (1,2,31). Selection of the most appropriate diet for ED research conducted on rodent experimental models, is not only a current subject providing the current proposals to mass screen a wide range of endocrine-disrupting compounds (EDCs), but it is also a decision that should be put under a serious consideration before standardising or initiating such studies (29).…”