1. Does bisphenol-A Cause Obesity in Humans? Xuan Du ‘16 and Lidia Henderson ‘16 ES366: The Environment and Human Health, Environmental Studies Program, Colby College Introduction Since the 1960s, bisphenol-A (BPA) has been used as an industrial chemical to make polycarbonate plastics and epoxy resins. Present in many food storage containers, water bottles, baby bottles, receipt paper, and the tops of jars and linings of cans, BPA can leach into food (1). Over eight billion pounds of BPA are produced annually (2), and it is in the top two percent of high- production-volume chemicals in the U.S. (3). The primary path BPA enters the body is through ingestion, but people can also be exposed to the chemical via skin contact and inhalation. BPA acts as an endocrine disruptor by mimicking estrogen, and it has been linked to many serious health issues, including obesity (2). Our project aims to analyze the relationship between BPA exposure and obesity by looking at toxicological and epidemiological research. (See Data section to the right) Policy Table 1. Proposed and passed federal BPA policies (4). States are more proactive and lead the way for more comprehensive BPA laws. Eleven states have passed BPA restrictions: California, Connecticut, Delaware, Maine, Maryland, Massachusetts, Minnesota, New York, Vermont, Washington, and Wisconsin (5). Data Toxicological data In one study, pregnant CD-1 mice were fed BPA at doses ranging from 5-50,000 μg/kg/day, which is ten-fold below the currently estimated reference dose and ten-fold above the estimated NOAEL. The male offspring were studied and monitored every week from day of birth to week 19. The BPA-500 males were heavier than the negative controls and significantly heavier than the BPA-50,000 males. When exposed to BPA doses at or below the estimated NOAEL (5000 μg/kg/day), male mice experienced a significant increase in postnatal body weight gain, adipocyte number and volume, and total amount of abdominal fat. In comparison, male offspring with fetal exposure to high BPA doses had minimal metabolic disruption. These outcomes occurred at BPA doses at or below the NOAEL, which suggests that “the dose does NOT make the poison” (6). Figure 1 illustrates body mass increase in mice fed with tocopherol-stripped corn oil that contained dissolved BPA, administered subcutaneously on days 9-16 of gestation. This study found that three months after delivery, BPA treated mice showed an increase in body weight. After four months, the mice continued to gain weight even though there was no measured difference in food intake. Lower doses of BPA had considerable effects on glucose homeostasis and altered nutrient metabolism in the mice, which are both metabolic functions associated with obesity and weight gain. To test the in utero effects, the offspring of all mice groups were studied and it was found that BPA offspring measured 3% heavier at birth and 7% heavier at weaning (7). Epidemiologica l data An epidemiological study used cross-sectional analysis to show that higher BPA exposure (measured by urinary BPA concentrations) is associated with obesity (measured by both BMI and waist circumference) among adults in the U.S. Six years of NHANES data (2003-2008) were used to examine the association between urinary BPA levels and obesity. The association between BPA levels and obesity was present in both genders and across all major U.S. racial/ethnic groups. The association was not affected by other factors such as age, education, drinking, smoking, and physical activity (9). Conclusions Detectable levels of BPA are found in 93% of Americans over the age of five (1). BPA is an ubiquitous chemical that is linked to many health concerns, including heart disease, diabetes, cancer, and obesity. The studies summarized in this project strongly suggest that BPA exposure causes obesity. The FDA claims that there are no low dose effects of BPA, but research shows otherwise (13). It is particularly concerning that exposure to low BPA doses may have a greater effect on weight gain than exposure to high BPA doses, especially when so many people are exposed to the chemical in minute doses. Also, with the prevalent issue of childhood obesity in the U.S. and worldwide, increased adipogenesis and adipose storage due to perinatal BPA exposure is worrisome. If BPA is programming cells to be fat cells, this has many implications for future generations. Future Research and Action Both in vivo and in vitro data are important for understanding the mechanism linking BPA exposure to obesity. Future studies should evaluate whether there are synergistic effects between type of diet and BPA exposure for obesity onset. The timing of BPA exposure and dose levels are also important for determining its relationship to obesity. Furthermore, before BPA alternatives are introduced to the marketplace, they should be thoroughly tested for any health risks. More generally, the U.S. chemical regulation system needs an overhaul. Under TSCA, chemicals are presumed safe until proven otherwise, but with hazardous chemicals such as BPA and its unsafe alternatives, we cannot take that risk and need to adopt a precautionary approach. A main issue clouding BPA risk assessment is a matter of scientific credibility; industry-funded studies tend to promote their own self-interests. Thus, more independent scientists should be on EPA and FDA panels to limit industry’s influence on government and to ensure that regulatory decisions on BPA are unbiased. It is important for policymakers to keep the consumers’ interests before industry’s interests. The plastics and chemical industries have a lot of money and thus political sway, but as shown by numerous scientific studies, BPA is a public health concern and needs to be properly regulated. BPA Alternatives Does a BPA-free label guarantee a safer product? Not necessarily. Some of the alternative chemicals are just as bad, or worse, than BPA. Under the Toxic Substances Control Act, the U.S.’s chemical regulation law, chemicals are assumed to be safe until proven otherwise, and companies are rarely required to collect or disclose chemical safety data. Here are two of many BPA alternatives that have not been thoroughly tested for health risks (10): Tritan- heat-resistant plastic introduced in 2007; one of its ingredients, triphenyl phosphate, may even be more estrogenic than BPA BPS- chemical cousin of BPA with similar effects (structure determines function); common uses include food service components, lighting fixtures, and medical devices Figure 3. Structure of BPA (11). Figure 4. Structure of BPS (12). PolicyDescription BPA-Free Kids Act of 2008 (S.2928) Not passed -Deemed hazardous any consumer product with a detectable amount of BPA that is used by children seven years old and younger -Allowed state laws that provide equal or greater protection BPA-Free Kids Act of 2009 (S.753/H.R.4456) Not passed -Required any children’s food and drink container composed of BPA to be treated as a banned hazardous substance -Required testing by manufacturers BPA Consumer Information Act of 2009 (H.R.4341) Not passed -Deemed a food to be misbranded if its container was composed of BPA, could leach BPA, or if container lacked proper warning labeling Ban Poisonous Additives Act of 2011 (S.136) Not passed -Deemed food containers for children younger than four, bottles for children younger than four, and containers of infant formula adulterated if came into contact with BPA -Required the Secretary of Health and Human Services to produce a revised safety assessment for food containers that contain BPA and to determine, with relative certainty, that aggregate BPA exposure will not cause harm FDA ban, 2012 Passed -Banned BPA from baby bottles and sippy cups Food Packaging Right to Know Act, 2013 (S.1124) Proposed -Requires the labeling of containers that contain BPA -Requires the Secretary of Health and Human Services to determine that aggregate BPA exposure will not cause harm Ban Poisonous Additives Act of 2013 (H.R.2248) Proposed -Deems a food item to be contaminated if its container is composed of BPA or can leach BPA into food -Requires the Secretary of Health and Human Services to review substances to determine that aggregate exposure will lead to no harm -Requires manufacturers to determine that low- dose exposures to the substance do not cause adverse health effects Figure 1. Body weight of F1- C, F1-BPA10, and F1- BPA100 mice. Mean body weight (A) and percentage of control weight (B) from birth to weaning for males and females combined. (C, D) Mean body weight from weaning to adulthood (22 through 180 days of age) for males (C) and females (D). Another study examined the effects of perinatal exposure to BPA on adipogenesis and adipose storage at weaning. The rats were exposed to BPA via the placenta and milk, and both male and female offspring that were prenatally exposed to BPA had significantly higher body weights relative to the controls, as shown in Figure 2. At weaning, when the offspring were exposed to BPA via milk, the females continued to have higher body weights relative to the controls. Perinatal exposure to low doses of BPA increased adipogenesis and adipose storage in females at weaning. This study suggests that adult body weight may be programmed during early life (8). Figure 2. Effect of perinatal exposure to 1 mg/L BPA on body weight of rat pups at PND1 (A, males; B, females) and PND21 (C, males; D, females).