Bisphenol A and Risk of Metabolic Disorders

Abstract

IN THIS ISSUE OF JAMA, LANG AND COLLEAGUES 1 REPORT the results of the first major epidemiologic study to examine the health effects associated with the ubiquitous estrogenic chemical bisphenol A (BPA). This compound is the base chemical (monomer) used to make polycarbonate plastic food and beverage containers, the resin lining of cans, and dental sealants; it also is found in “carbonless” paper used for receipts as well as a wide range of other common household products. Based on their analysis of data from the National Health and Nutrition Examination Survey 2003-2004, Lang et al report a significant relationship between urine concentrations of BPA and cardiovascular disease, type 2 diabetes, and liver-enzyme abnormalities in a representative sample of the adult US population. This report, suggesting links between BPA and some of the most significant and economically burdensome human diseases, is based on a cross-sectional study and therefore cannot establish causality; follow-up longitudinal studies should thus be a high priority. Yet many peer-reviewed published studies report on related adverse effects of BPA in experimental animals, and cell culture studies identify the molecular mechanisms mediating these responses. These experimental findings add biological plausibility to the results reported by Lang et al. Based on this background information, the study by Lang et al, while preliminary with regard to these diseases in humans, should spur US regulatory agencies to follow the recent action taken by Canadian regulatory agencies, which have declared BPA a “toxic chemical” requiring aggressive action to limit human and environmental exposures. Alternatively, Congressional action could follow the precedent set with the recent passage of federal legislation designed to limit exposures to another family of compounds, phthalates, also used in plastic. Like BPA, phthalates are detectable in virtually everyone in the United States. This bill moves US policy closer to the European model, in which industry must provide data on the safety of a chemical before it can be used in products. Subsequent to an unexpected observation in 1997, numerous laboratory animal studies have identified lowdose drug-like effects of BPA at levels less than the dose used by the US Food and Drug Administration (FDA) and the Environmental Protection Agency to estimate the current human acceptable daily intake dose (ADI) deemed safe for humans. These studies have shown adverse effects of BPA on the brain, reproductive system, and—most relevant to the findings of Lang et al—metabolic processes, including alterations in insulin homeostasis and liver enzymes. However, no prior studies examining BPA for effects on cardiovascular function have been conducted in laboratory animals or humans. Epidemiologists are informed by animal studies that identify potential human health hazards when the animal models and exposure levels are relevant and effects are mediated via response mechanisms present in humans. For example, when adult rats were fed a 0.2-μg/kg per day dose of BPA for 1 month (a dose 250 times lower than the current ADI), BPA significantly decreased the activities of antioxidant enzymes and increased lipid peroxidation, thereby increasing oxidative stress. When adult mice were administered a 10-μg/kg dose of BPA once a day for 2 days (a dose 5 times lower than the ADI), BPA stimulated pancreatic cells to release insulin. After administration of 100 μg/kg per day of BPA via injection or feeding for 4 days, mice developed insulin resistance and postprandial hyperinsulinemia. Follow-up studies showed that stimulation of mouse -cell insulin production and secretion by between 0.1 to 1 nM of estradiol or BPA (23-230 pg/mL of BPA) is mediated by activation of the extracellular signal-related protein kinase 1/2 pathway by binding of BPA to estrogen receptor and that via this nonclassical estrogen-response mechanism, BPA and estradiol have equal potency and efficacy. BPA and estradiol are also equipotent at inhibiting adiponectin release from human adipocytes at 1 nM, further implicating BPA at current human exposure levels in insulin resistance and the metabolic syndrome.