Bisphenol A and Risk Assessment

In a recent article, vom Saal and Hughes (2005) proposed that a new risk assessment on bisphenol A (BPA) is needed because of the availability of extensive new literature, including "recent epidemiologic evidence that BPA is related to disease in women." Specifically, the only research that vom Saal and Hughes cited as evidence relating BPA to disease is a study by Takeuchi et al. (2004), which they describe as a case-control study that reports that ovarian disease in women is related to blood levels of BPA.

Vom Saal and Hughes (2005) have misrepresented the Takeuchi study (Takeuchi et al. 2004): It is not a case-control study, and it does not demonstrate that BPA is specifically associated with ovarian disease.

Takeuchi et al. (2004) conducted a small cross-sectional descriptive study that assessed 73 women with respect to serum BPA, hormone concentrations, and their clinical condition at a single point in time. Women were categorized clinically as normal (either obese or nonobese), or as having hyperprolactinemia, hypothalamic amenorrhea, or polycystic ovary syndrome (PCOS) (again, either obese or nonobese). The six groups in the study each contained as many as 19 subjects (nonobese normal group) and as few as 6 subjects (PCOS obese group). The authors reported that serum BPA was higher in women with PCOS (both obese and not obese) and obese normal women than normal women who were not obese. There were also significant positive correlations between serum BPA and various androgens. Takeuchi et al. (2004) concluded that there is a strong relationship between serum BPA and androgen, and they noted that there are a number of possible explanations for this relationship.

Takeuchi et al. (2004) appropriately acknowledged that their study was a hypothesis-generating study and they did not attempt to draw conclusions about causal relationships.

Vom Saal and Hughes (2005) overstated the importance of this low-level epidemiologic evidence by referring to it as a case-control study. A case-control study is a more rigorous epidemiologic study in which a group of cases (i.e., with the disease of interest) is compared to a group of controls (i.e., without the disease of interest) with respect to exposures that occurred before the development of disease. Rather, Takeuchi et al. (2004) conducted a cross-sectional study in which both exposure and disease were assessed at a single point in time. When both exposure and outcome are assessed at a single point in time, it is not possible to determine whether the exposure preceded the clinical condition or whether the clinical condition affected the individual's level of exposure. A cross-sectional study cannot test hypotheses; at most, it can merely examine correlations. Furthermore, cross-sectional studies cannot control for confounding factors that may obscure the true relationship between exposure and disease (Hennekens and Buring 1987).

Vom Saal and Hughes (2005) overlooked the intended primary focus of the paper by Takeuchi et al. (2004), which is that there is a relationship between serum BPA and androgen levels. The exact nature of this relationship is not known at this time and Takeuchi et al. (2004) speculate that BPA may stimulate androgen production, or, more likely, androgen may suppress the metabolism of BPA. Consequently, women who have clinical conditions that are associated with elevated androgen (e.g., PCOS or obesity) may have elevated levels of BPA as a result of their elevated androgen. The cross-sectional study by Takeuchi et al. cannot shed light on the time course of events and, therefore, cannot address causal relationships among any of the variables studied in these women.

In addition, a number of recent studies have reported that several of the ELISA kits available for measurement of serum BPA [the analytic method used by Takeuchi et al. (2004)] overestimate BPA concentrations and exhibit considerable cross-reactivity, calling into question the validity of results generated by such methods (Fukata and Mori 2004; Fukata et al. 2003; Kawaguchi et al. 2003). Furthermore, it is well known that BPA is metabolized and eliminated rapidly (Volkel et al. 2002), so serum levels provide only a snapshot of BPA exposure within the last day. It is not meaningful to correlate an acute exposure (serum BPA at one time-point) with a chronic disease that took years to develop. Chronic exposure to BPA would have to be demonstrated and not assumed.

The Takeuchi et al. (2004) study suggests a hypothesis that could be further examined in an appropriately controlled analytic study. It should not be portrayed as recent epidemiologic evidence that demonstrates an association between blood levels of BPA and clinical disease in women.

The author is a consultant for the Weinberg Group in Washington, DC.

Joseph A. Politch
Department of Obstetrics and Gynecology
Boston University School of Medicine
Boston, Massachusetts
E-mail: politch@bu.edu

References

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Bisphenol A: vom Saal and Hughes Respond

Our commentary describing the extensive new literature reporting low-dose effects of bisphenol A (BPA) in experimental animals (vom Saal and Hughes 2005) was written in response to a report from the Harvard Center for Risk Analysis (HCRA) by Gray et al. (2004), who concluded that "the weight of the evidence for low-dose effects [of BPA] is very weak." The HCRA report was funded by the American Plastics Council and involved a selective review of only 19 of a much larger number of studies that could have been reviewed. In our commentary we showed that a comprehensive review of the now extensive literature concerning studies in experimental animals that used doses of BPA within the range of human exposure led to exactly the opposite conclusion from that reached in the HCRA report (Gray et al. 2004), which was released 2.5 years after it was written.

At this time there are only two published epidemiologic studies showing a relationship between blood levels of BPA and diseases in humans. In his letter, Politch focuses his attention on a single study by Takeuchi et al. (2004) that describes a relationship between BPA in blood and polycystic ovary disease (PCOS) in Japanese women. In a second recently published article, Sugiura-Ogasawara et al. (2005) reported a relationship between blood levels of BPA and recurrent miscarriage in Japanese women. Politch seeks to deflect attention from the central issue of our review by focusing only on the study by Takeuchi et al. (2004) and stating that such studies "cannot address causal relationships" and suggesting that "appropriately controlled" human studies are required. We are certain that readers of Environmental Health Perspectives (EHP) realize that these are criticisms that can be directed at all epidemiologic studies, which can never achieve the control required in laboratory experiments. Additionally, there is always some risk in arguing the methodologic details of a peer-reviewed publication in one field of scientific research (epidemiology) when the commentator's core expertise (biopsychology) lies elsewhere. Most importantly, based on his criticism of the levels of BPA reported in the blood of women by Takeuchi et al. (2004), Politch appears to be unaware of the large literature concerning the levels of BPA in human blood, urine, and tissues from studies conducted in different regions of the world reporting virtually identical mean and/or median values. For example, in a recent study at the Centers for Disease Control and Prevention, Calafat et al. (2005) found BPA in 95% of the human urine samples they assayed--in the same range reported in human blood in other studies (e.g., Schonfelder et al. 2002; Tan and Mohd 2003). All of this published literature is listed in a document available on the University of Missouri Endocrine Disruptor web site (Endocrine Disruptors Group 2005).

One point-of-view expressed by Politch that we strongly support is the proposition that human studies linking developmental exposure with adult disease are also required, based on the extensive evidence that the developing fetus and neonate are the most vulnerable to endocrine disruption. We hope that the planned National Children's Study will address this issue and begin to characterize which exposures are and are not consequential for human health. In the absence of such a study, which will take decades to complete, we rely on experimental studies in animals to make decisions regarding the potential hazards posed by chemicals.

Our comment that the epidemiologic evidence "adds to our concern" about the potential hazards posed to humans by BPA hardly qualifies as justification for the criticism that we "overstated the importance" of this or any other single study. Our concern about the potential hazards of BPA to humans is justified by the fact that the limited epidemiologic studies do follow and generally support findings from over 125 experiments with laboratory animals showing that low doses of BPA cause adverse effects on a wide range of outcomes. We also pointed out in our article (vom Saal and Hughes 2005) that 100% of the studies showing significant effects of BPA in laboratory animals were funded by government agencies, and 100% of the studies funded by chemical corporations conclude that the same low doses of BPA do not cause significant effects. What is crucial in relation to the critique by Politch is that the two epidemiologic studies relating BPA in blood to diseases in women are consistent with the findings from studies of the hazards of BPA in animals at doses that lead to blood levels in animals within and below those detected in human blood.

The authors declare they have no competing financial interests.

Frederick S. vom Saal
Division of Biological Sciences
University of Missouri
Columbia, Missouri
E-mail: vomsaalf@missouri.edu

Claude Hughes
Department of Biology
East Carolina University
Greenville, North Carolina

References