|
Critique of JAMA Article on BPA
By Michael Kamrin
In their Journal of the American Medical Association article (1), Lang et al. conclude that their findings of an association between urinary bisphenol A (BPA) and medical disorders are consistent with studies in laboratory animals -- and that their results support the contention that exposures to low doses of BPA have adverse effects in humans. Although the study deploys sophisticated statistical analyses in exploring this association, a careful examination of the research methodology raises questions about the validity of their conclusions.
•First, and this is acknowledged by the authors of the article, the study is cross-sectional (assessing both urinary BPA concentration and health impact at only one instant in time) and is thus unable to establish cause and effect. What they do not emphasize is that the effects in question, i.e., diabetes and cardiovascular disease, can develop over a long period of time, so exposure levels of BPA during the period of disease development are the most pertinent to discerning any BPA impact, not those measured after the disease becomes evident. Since the authors provide no evidence that can be used to link concentrations they used in the study with _past_ levels, this research cannot be used to link exposure and adverse effect.
•Second, it is not clear that all of the most important variables were investigated in this study. As the authors note and reference (2,3), one important effect, diabetes, may be associated with exposures to xenobiotics other than BPA, e.g., PCBs. Although the urinary levels of a few other xenobiotics, namely phenolic compounds, were measured, concentrations of PCBs and other potentially confounding xenobiotics were not evaluated in the study. In addition, naturally occurring xenobiotics that exhibit endocrine activity, e.g., phtyoestrogens, were not considered at all in the research. Further, it does not appear that exposures to some agents that can affect liver enzyme levels, e.g., drugs, supplements, and alcohol, have been taken into account. The lack of consideration of such important possible confounders, e.g., xenobiotics and naturally occurring estrogenic compounds in the diet, seriously reduces confidence in the conclusions presented in the article.
•At least as important as these two study deficiencies, is the question of whether or not the fundamental burden of toxicological proof, dose-response, has been met. The investigators do not provide any estimates of dose in the article; instead there seems to be the implicit assumption that the concentrations in urine are accurate surrogates of dose. The implicit rationale behind this assumption is critical to the conclusions of the study. For such an assumption to hold, the ratio between the dose of BPA (amount of BPA ingested per body weight of exposed individual), and the concentration in the urine, must be the same in all groups of individuals. This implies that the biotransformation of BPA in the human body is the same in all subgroups in the study.
However, it is well established that the biotransformation of xenobiotics can be affected by a number of factors including diseases, such as diabetes, and by nutritional status (4). It is clear that disease status varies among the groups and it is not unreasonable to believe that nutritional status may vary among individuals with greatly different body mass indexes. Without data on possible variations in biotransformation among the different subgroups of the population under study, it is impossible to accurately calculate doses for those with or without disease. Without dose measurements, it is impossible to demonstrate dose-response and so to draw toxicologically valid conclusions.
Thus, this article fails to provide persuasive evidence to support the contention that BPA at any dose causes adverse effects in humans. Because of deficiencies in the study design, it also does not convincingly support the conclusion that there is an association between urinary BPA and medical conditions and laboratory abnormalities. Thus, the authors' call for additional epidemiological studies appears premature at this time.
1. Iain A. Lang, Tamara S. Galloway, Alan Scarlett, William E. Henley, Michael Depledge, Robert B. Wallace, David Melzer. (2008) Association of Urinary Bisphenol A Concentration with Medical Disorders and Laboratory Abnormalities in Adults. JAMA 300(11): 1303-1310.
2. Lee DH, Lee IK, Song K; et al. (2006) A strong dose-response relation between serum concentrations of persistent organic pollutants and diabetes: results from the National Health and Examination Survey 1999-2002. Diabetes Care. 29(7):1638-1644.
3. Vasiliu O, Cameron L, Gardiner J, Deguire P, Karmaus W. Polybrominated biphenyls, polychlorinated biphenyls, body weight, and incidence of adult-onset diabetes mellitus. (2006) Epidemiology. 17(4):352-359
4. Timbrell, J.A. (1991) Principles of Biochemical Toxicology, 2nd Edition. Taylor and Francis, Washington, D.C.
Michael Kamrin, Ph.D., is a Professor Emeritus at Michigan State University's Institute for Environmental Toxicology and an ACSH Advisor.
Castle (November 8, 2008)
I think what is most disturbing about this is that somehow this paper made it past peer-review. How can such a flawed experimental design and over(mis?)-interpretation of results be ignored by the scientists who were asked to review this paper? What hope does the scientific community have of educating the public about real risk, when we will allow such questionable results to be put out for the world to see? It is hard enough to explain that scienctific results are rarely, if ever, as simple as a "yes" or "no," but now try explaining to the average person why the conclusions drawn by this paper are not as clear-cut as they would have us believe--better yet, try explaining that to the mass media that will likely run with this story as "proof" that BPA is dangerous. As a young, and perhaps too idealistic, scientist, I would hope that scientists who are asked to review papers would see it not as a burden that must be done, but rather as part of their greater obligation to educate the public. And as such, I would hope they would take the time necessary to critically review all papers that come across their desks.
|
