At the Intersection of Health, Health Care and Policy Cite this article as: Leonardo Trasande Further Limiting Bisphenol A In Food Uses Could Provide Health And Economic Benefits Health Affairs, 33, no.2 (2014):316-323 (published online January 22, 2014; 10.1377/hlthaff.2013.0686)

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Health Affairs is published monthly by Project HOPE at 7500 Old Georgetown Road, Suite 600, Bethesda, MD 20814-6133. Copyright © 2014 by Project HOPE - The People-to-People Health Foundation. As provided by United States copyright law (Title 17, U.S. Code), no part of Health Affairs may be reproduced, displayed, or transmitted in any form or by any means, electronic or mechanical, including photocopying or by information storage or retrieval systems, without prior written permission from the Publisher. All rights reserved.

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Web First By Leonardo Trasande 10.1377/hlthaff.2013.0686 HEALTH AFFAIRS 33, NO. 2 (2014): 316–323 ©2014 Project HOPE— The People-to-People Health Foundation, Inc.

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Leonardo Trasande (Leonardo [email protected]) is an associate professor of pediatrics, environmental medicine, and health policy at the New York University (NYU) School of Medicine, in New York City. He also holds faculty appointments in the Wagner School of Public Service and the Steinhardt School of Culture, Education, and Human Development at NYU.

Further Limiting Bisphenol A In Food Uses Could Provide Health And Economic Benefits There is mounting evidence that bisphenol A (BPA), a chemical used in the production of polycarbonate plastics and the linings of aluminum cans, may have adverse health consequences. The Food and Drug Administration has banned BPA from baby bottles and sippy cups but has deferred further action on other food uses—that is, uses in metalbased food and beverage containers. This article quantifies the potential social costs of childhood obesity and adult coronary heart disease attributable to BPA exposure in the United States in 2008 and models the potential health and economic benefits associated with replacing BPA in all food uses. BPA exposure was estimated to be associated with 12,404 cases of childhood obesity and 33,863 cases of newly incident coronary heart disease, with estimated social costs of $2.98 billion in 2008. Removing BPA from food uses might prevent 6,236 cases of childhood obesity and 22,350 cases of newly incident coronary heart disease per year, with potential annual economic benefits of $1.74 billion (sensitivity analysis: $889 million–$13.8 billion per year). Although more data are needed, these potentially large health and economic benefits could outweigh the costs of using a safer substitute for BPA. ABSTRACT

B

isphenol A (BPA) was first synthesized by Aleksandr Dianin in 1891.1 Its use accelerated in the 1960s, when it was identified as useful in the manufacture of polycarbonate plastics, and it remains a chemical with a high production volume—that is, more than a million pounds are produced annually.2 Exposure to BPA in the United States is nearly ubiquitous: In a nationally representative sample, 92.6 percent of people ages six and older had detectable BPA in their urine.3 Daily consumption of canned soup increased urinary BPA tenfold in a randomized trial.4 Although food is a major source of BPA exposure, dental sealants5 and thermal copy paper6 are also sources of exposure. The Endocrine Society has identified BPA as an endocrine-disrupting chemical (EDC) with 316

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broad public health significance and the potential to alter hormonal systems.7 BPA exposure has been associated with adverse neurobehavioral development,8,9 cancer,10 asthma,11,12 and fertility outcomes.13,14 In addition, laboratory studies identify multiple mechanisms by which BPA promotes obesity, and cross-sectional studies and a more recent longitudinal study show an association between urinary BPA and obesity in children and adults.15–18 Lab studies have identified multiple mechanisms by which BPA may increase cardiovascular risks independent of body mass. For instance, BPA inhibits the release of the protein adiponectin from human adipose tissue that plays a key role in preventing cardiovascular disease.19 BPA may also accelerate “oxidative stress,” in which excess production of free radicals may contribute to formation of plaque and blockages in cor-

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onary arteries.20 Cross-sectional and longitudinal studies have corroborated concerns from animal studies about the cardiovascular risks of BPA exposure, including associations with cardiovascular diagnoses, newly incident coronary heart disease, low-grade albuminuria (an early marker of coronary heart disease risk), and coronary artery stenosis.21–26 Given that each of the potential public health consequences of BPA exposure is multifactorial, past studies have been rightly cautious about determining causation. Many dose-response relationships do not follow the adage in toxicology that “the dose makes the poison.”27 The need for a paradigm shift has further limited regulatory decision making on BPA and other EDCs,28 despite the fact that nonlinear and U-shaped relationships between exposure and effects are consistent with mechanisms that are known to operate in the case of EDC exposures. The Food and Drug Administration recently banned the use of BPA in baby bottles and sippy cups, but it declined to ban BPA in other food uses—that is, uses in metal-based food and beverage containers—citing the need for further evidence.29 Manufacturers have voluntarily eliminated the use of polycarbonate plastics in food containers. The Institute of Medicine has recommended rigorous methods for quantifying environmentally attributable costs for multifactorial conditions such as obesity.30 The use of these methods makes it possible to compare the costs of ongoing BPA exposure to the potential costs of using alternatives to BPA, which include naturally derived and synthetic linings for food containers such as aluminum cans. To address the gaps in knowledge regarding the health consequences of BPA exposure, this article presents the first estimate of the potential disease burden and costs associated with ongoing exposure to BPA. It then models the potential health and economic benefits associated with the replacement of BPA in food uses.

Study Data And Methods The present analysis followed the approach developed by the Institute of Medicine in assessing the “fractional contribution” of the environment to the causation of illness in the United States.30 This approach is described in detail in the online Appendix.31 This analysis quantifies the health and economic costs of childhood obesity and adult coronary heart disease attributable to BPA in 2008. It then models a counterfactual scenario in which BPA exposure is reduced in the same population by eliminating it from food uses. The article also describes approaches to estimating

the disease burden that is attributable to BPA and the economic costs associated with that burden. Populations At Risk The present analysis was limited to childhood obesity and adult coronary heart disease, both outcomes for which there are relatively plentiful studies and readily available economic data for cost-of-illness analyses. For coronary heart disease, the population at risk was limited to people ages 40–74 because the relevant research used to estimate disease burden and economic costs was limited to that population.23 For childhood obesity, a cohort of twelve-year-old children was selected as the population at risk for obesity in association with exposure to BPA. By that age, obesity is a condition that is difficult to reverse, with resulting cardiovascular and other consequences in adulthood that are independent of exposure to BPA and other substances later in life.32 Disease Rate The calculations of disease rate and costs are described in detail in the Appendix.31 I used nationally representative data from the period 2003–08 to estimate US population exposure to BPA, dividing the cohorts ages 6–19 and 40–74 into four quartiles each, from lowest to highest levels of exposure. Urinary BPA levels were multiplied by the incremental odds of incident coronary heart disease, as identified in the literature,23 to obtain the incremental odds of coronary heart disease attributable to BPA in each of the four quartiles of people ages 40–74. These incremental odds were then multiplied by data from the National Heart, Lung, and Blood Institute on baseline incidence of coronary heart disease to quantify increases in the rates of coronary heart disease attributable to BPA exposure.33 I then calculated the logarithm of the median urinary BPA within each of the quartiles of exposure in the 6–19 age group. To measure increases in the children’s body mass index (BMI) in the two highest quartiles, I multiplied the logarithm of the BPA concentration by the increment in BMI “Z-score”—a measure of the deviation of a specific BMI percentile from the mean of that population—per log unit increase in urinary BPA, using data from the National Health and Nutrition Examination Survey for 2003–08. I assumed that children with levels less than 0:8 ng=mL had no increase in BMI Z-scores.15 Also assuming that body mass in US children is distributed across a normal bell curve, I shifted the bell curve to quantify the increase in percentage of obesity, defined as the 95th percentile of BMI for age and sex based upon the distribution as established by the Centers for Disease Control and Prevention in 2000. Cost Per Case Lifetime cost estimates for incident coronary heart disease were obtained F eb r u a ry 2 0 1 4

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Web First from the American Heart Association’s 2008 report on costs of cardiovascular disease.34,35 For childhood obesity, data from the Nationwide Inpatient Sample and Medical Expenditure Panel Survey were used to estimate annual emergency department, prescription drug, outpatient, and hospitalization costs per obese child.32,36,37 These costs were updated using medical care data from the Consumer Price Index.38 Data on the persistence of obesity from childhood to adulthood were used to estimate the cases of obesity in adulthood that could be attributed to obesity due to BPA exposure in childhood.39 Annual adult obesity-associated health care costs were obtained from the Medical Expenditure Panel Survey40 and were assumed to accrue over thirty-five years for each obese adult. Quality-adjusted life-year (QALY) losses per obese adult from previously published estimates41 were then applied to quantify QALY losses that were attributable to increases in BMI Z-score associated with previous exposure to BPA. For each QALY a $50,000 value was applied and discounted for thirty-five years. A 3 percent annual interest rate was applied to bring future costs into the present, weighing the time value of money in the base case analysis against future costs.42 Benefit Estimates To quantify potential benefits produced by the removal of BPA from food uses, reductions in urinary BPA were identified from intervention studies that quantified changes in exposure. The reductions were applied to each quartile of children and adults to identify urinary levels in a counterfactual scenario. As a base-case estimate for the effects of the intervention, I multiplied pre-intervention BPA levels by 66 percent, which is the reduction in geometric mean urinary BPA that was observed following a dietary intervention in children and adults that reduced BPA exposure.43 I then repeated the analyses to quantify disease burden and economic costs in a scenario in which the identical 2008 population did not ingest food contaminated by BPA. The difference in disease burden and economic costs from the preintervention model yielded an estimate of potential health and economic benefits produced by the removal of BPA from food uses. Sensitivity Analyses Recognizing uncertainty in a number of data inputs, I performed a series of sensitivity analyses. First, to develop alternative estimates of BPA exposure I measured the mean of urinary BPA in each quartile (an approach that generally produces higher estimates than the median because BPA distributions can be positively skewed) and the lower bounds of each quartile as inputs to modeling health effects. 318

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These estimates provide a sense of the trade-offs involved with continuing BPA food uses.

Second, although $50,000 is generally considered to be the value of a QALY, I used a broader range of ratios ($20,000–$200,000 per QALY).44 Third, I applied a range of 0–5 percent interest rates to bring future values into the present when considering the time value of money.42 Finally, a 92 percent decrease in urinary BPA was modeled as a higher bound of the effect of eliminating BPA contamination in food, based on the literature.4 Limitations There remain substantial gaps in knowledge about BPA exposure through food and the effects of that exposure on humans. The online Appendix31 provides a detailed discussion of the resulting uncertainties in modeling BPA reductions and the approach used to account for them. The extent to which the urinary BPA concentration reflects current versus chronic exposure is uncertain. The few adult pharmacokinetic studies to date suggest that BPA is excreted within twenty-four hours.45 However, recent data from adults suggest that urinary BPA may not decrease rapidly with fasting time.46 Most human studies have examined the relationship of health effects to a urinary BPA concentration at a single time point, with reverse causation and residual confounding as alternative explanations. Animal studies have shown divergent relationships between BPA and body mass, with the factors contributing to that variability including dose, sex, exposure window, and timing of body mass measures.47 Few studies have examined exposure to BPA in early life,18 which is more likely than exposures later in life to cause permanent disturbances in human metabolism that lead to childhood obesity. The degree to which BPA contributes to coronary heart disease in adults also remains uncertain. Again, human studies22–26 have examined the relationship of health outcomes to a urinary BPA concentration at a single point in time. The mechanisms by which exposure to BPA causes cardiovascular disease also are in need of further study.

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Exhibit 1 Estimated Health And Economic Consequences Of Childhood Obesity Attributable To Bisphenol A (BPA), 2008 Quartile of exposure 3 2 2.00a 0a 0a 0a 0a 0a

4

Outcome Median urinary BPA, ng/mL Increase in obesity prevalence, % Increase in number of obese 12-year-olds BPA-attributable child health care expenditures (millions) Increased number of obese adults BPA-attributable adult health care expenditures (millions)

1 0.8a 0a 0a 0a 0a 0a

Base case 3.8 0.49 4,879 $10.9 3,708 $192.3

BPA-attributable childhood obesity Direct costs (millions) QALY losses Indirect costs (millions) Total costs (millions)

All quartiles $517 ($283.8, $1,040) 54,677b (44,134, 56,337)c $972 ($160, $11,300) $1,488 ($443, $12,300)

SA (2.80, 3.82) (0.40, 0.49) (3,999, 4,894) ($8.4, $12.1) (3,039, 3,719) ($105.0, $386.4)

Base case 9.3 0.75 7,525 $16.8 5,719 $296.6

SA (5.6, 10.49) (0.60, 0.79) (6,013,7,887) ($12.6, $19.5) (4,570, 5,994) ($157.9, $622.7)

SOURCE Author’s analysis. NOTES People in quartile 1 had the lowest exposure, and those in quartile 4 the highest. Inputs for and outputs of sensitivity analyses (SA) are shown in parentheses. All dollar amounts are in 2008 dollars. Numbers may not sum to totals because of rounding. QALY is quality-adjusted life-year. aBecause no effects were modeled for either of the two lower quartiles, inputs and outputs were not provided. bValue of QALY: $17,769. cValue of QALY, SA: ($9,064, $200,000).

Study Results The twelve-year-old children in the two highest quartiles of exposure to BPA were estimated to have BMI Z-scores that were, on average, 0.041 and 0.063 standard deviation units higher than the scores for the remainder of the population. This resulted in 4,879 and 7,525 additional cases of obesity for the third and fourth quartiles, respectively (Exhibit 1). In 2008 dollars, these additional cases resulted in $27.7 million in additional child health care expenditures. Of the additional 12,404 obese children, 9,427 were estimated to remain obese as adults, with an additional $489 million in associated increased health care expenditures in adulthood and 54,676 QALYs lost. Applying a value of $50,000 to each QALY and adjusting for bringing future costs into the present, the lost QALYs cost an additional $972 million, for a total of $1.49 billion in costs for BPA-attributable childhood obe-

sity. In the sensitivity analyses, the estimated total costs ranged from $443 million to $12.3 billion. Exhibit 2 presents estimates of health and economic consequences of coronary heart disease attributable to BPA in 2008. The adults ages 40– 74 in the three highest quartiles of BPA exposure were estimated to have 15.17 percent, 6.2 percent, and 3.1 percent greater odds of coronary heart disease, respectively, compared with the lowest quartile. There were an estimated 33,863 cases of newly incident coronary heart disease attributable to BPA in the three highest quartiles, with associated costs of $1.50 billion (Exhibit 2). Sensitivity analyses suggested that the cost of BPA-attributable coronary heart disease could range from $935 million to $2.29 billion. Combining the estimated costs of BPA-attributable childhood obesity and adult coronary

Exhibit 2 Estimated Health And Economic Consequences Of Coronary Heart Disease Associated With Bisphenol A (BPA), 2008 Quartile of exposure 1

2

Outcome Median urinary BPA, ng/mL Increase in number of CHD cases

1 0.4a —b

Base case 1.30 4,233

Lifetime cost of BPA-attributable CHD Per case Total (millions)

All quartiles $44,177a $1,496 ($935, $2,286)

3 SA (0.80, 1.47) (2,605, 4,786)

4

Base case 2.60 8,466

SA (1.90, 2.91) (6,187, 9,475)

Base case 6.50 21,164

SA (3.80, 11.51) (12,373, 37,477)

SOURCE Author’s analysis. NOTES People in quartile 1 had the lowest exposure, and those in quartile 4 the highest. Inputs for and outputs of sensitivity analyses (SA) are shown in parentheses. All dollar amounts are in 2008 dollars. Numbers may not sum to totals because of rounding. CHD is coronary heart disease. aBecause no effects were modeled for the lowest quartile, inputs and outputs were not provided. bNo sensitivity analyses were performed for this input.

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Web First heart disease produced a cost of $2.98 billion in 2008. According to the sensitivity analyses, the figure could be between $1.4 billion and $14.6 billion. This represents an annual cost that will accrue each year that exposure to BPA continues unabated in the US population. In the counterfactual scenarios, urinary BPA was reduced 66–92 percent as a result of eliminating BPA from food uses. In the baseline scenario, 6,236 fewer twelve-year-olds were obese in 2008, and 22,350 cases of newly incident coronary heart disease were prevented (Exhibit 3). The resulting savings were $748 million and $987 million, respectively, with a total economic benefit of $1.74 billion. The lower-bound estimate of the counterfactual scenarios suggested economic benefits of $889 million, while the upper-bound estimate suggested $13.8 billion.

Discussion

◀

2.98 billion

$

Annual costs This analysis suggests that $2.98 billion in annual costs are attributable to BPA-associated childhood obesity and adult coronary heart disease.

This analysis suggests that $2.98 billion in annual costs are attributable to BPA-associated childhood obesity and adult coronary heart disease. The $1.49 billion in childhood obesity costs are the first environmentally attributable costs of obesity in childhood to be documented, and they can be added to the estimated $76.6 billion in environmentally attributable costs of US childhood disease in 2008.48 It is useful to compare the estimated $1.74 billion annual economic benefit of removing BPA from food uses with the costs of replacing BPA with an alternative that might not produce health consequences similar to those attributable to BPA. One proposed alternative is oleoresin, a mixture of oil and resin extracted from various plants. If an oleoresin lining for an aluminum can costs 2.2 cents more than a BPA lining, as some reports suggest,49 and 100 billion aluminum cans are produced annually,50 then the incremental cost of replacing BPA would be $2.2 billion each year.

However, oleoresins are not appropriate for all canned foods, especially acidic ones. Polyester linings have been used in Japan since the 1990s, and acrylic coatings and low-density polyethylene paperboard are other alternatives. However, acrylics can be more brittle than BPA, and polyester coatings are not ideal for acidic foods, either.51 Additional costs of removing BPA from food uses include the costs of premarket testing to rule out toxicity. The analysis reported here could not quantify the costs of the other alternatives or premarket testing, but the estimates in the analysis are still useful. They provide a sense of the trade-offs involved with continuing BPA food uses. It is important to note that the cost of replacing BPA would be borne by food manufacturers and incorporated in the price of food sold to purchasers such as parents, whereas the costs of obesity and coronary heart disease attributable to BPA are borne by multiple sectors of society. These sectors include state and federal governments, since Medicaid and Medicare pay for associated treatment costs. There is still ambiguity about the nature of the exposure-outcome relationship and the residual confounding in childhood obesity and coronary heart disease related to BPA exposure. However, this article presents conservative estimates of the public health and economic burden of childhood obesity and coronary heart disease. In the two highest quartiles of exposure, this analysis could have adopted the higher increment in BMI Zscore that was identified in the literature in relationship to BPA quartile15 instead of the increment computed assuming a linear relationship of urinary BPA to BMI Z-score. The analysis also assumed a threshold at which increases in obesity occurred in association with BPA exposure. However, no level of BPA exposure has been identified as safe. If these assumptions are incorrect, this study will have

Exhibit 3 Estimated Health And Economic Benefits Associated With The Removal Of Bisphenol A (BPA) From Food Uses, 2008 Outcome

Base-case scenario

Sensitivity analysis

Reduction in urinary BPA, ng/mL

66%

(66%, 92%)

Cases of BPA-attributable childhood obesity prevented Cases of BPA-attributable adult CHD prevented

6,236 22,350

(6,131, 12,148) (13,968, 47,600)

Costs of BPA-associated childhood obesity saved (millions)

$748

($272, $11,699)

Costs of BPA-associated adult CHD saved (millions)

$987

($617, $2,103)

Total economic benefits (millions)

$1,736

($889, $13,801)

SOURCE Author’s analysis. NOTES Inputs for and outputs of sensitivity analyses are shown in parentheses. All dollar amounts are in 2008 dollars. Numbers may not sum to totals because of rounding. CHD is coronary heart disease.

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Regulatory agencies should consider the potential toxicity of as-yet-untested substitutes for BPA.

underestimated the number of cases of BPAattributable childhood obesity and the number of cases prevented by eliminating BPA from food uses. Finally, I modeled the benefits of obesity prevention for a single age cohort (twelve-yearolds), although in practice multiple age cohorts (for example, people ages 6–19) might experience reductions in obesity. Given the potential role of BPA in insulin resistance independent of obesity,52–54 the analysis might also have underestimated the cardiovascular costs. The estimated burden of disease and costs attributable to BPA is also likely to be conservative since substantial evidence supports attributing to BPA exposure the estimated burden of disease for other conditions such as asthma;11,12 decrements in cognitive potential;8 cancers; and adverse reproductive and fertility outcomes.13 This analysis suggests that regulatory action to reduce BPA exposure could produce net benefits to society. It also emphasizes the need for a more rational system of regulating environmental chemicals. There are thousands of chemicals in commercial use for which there are few or no regulatory data. Absent premarket testing of chemicals, decades of epidemiologic data are typically required before it can be determined whether or not they cause chronic conditions.55 In the case of BPA, the need for faster regulatory action came to public attention only after a large number of cell-culture, experimental animal, and epidemiologic studies had been published.8,9,11,15,19,20 The costs of BPA exposure will likely be borne by society for decades. Newer economic models are also needed to

account for uncertainty in disease causation, so that trade-offs involved in decisions such as whether to remove BPA from food uses can be weighed more carefully in spite of incomplete understanding of the health consequences. These newer approaches will be especially important in informing regulations of endocrinedisrupting chemicals. Information on the costs of their ongoing use, however incomplete, is needed because of the broad public health effects of these chemicals. In spite of the absence of regulatory action, BPA is already being replaced to some extent with a synthetic alternative—bisphenol S (BPS)—that has an identical chemical structure.56,57 The current regulatory framework does not require new chemicals such as BPS to be compared with older chemicals such as BPA for similarity in structure-function relationships and potential toxicity.58 Therefore, much less is known about BPS than BPA regarding the public health consequences of exposure. The few studies that have been done on BPS have found that it is similar to BPA in genotoxicity and estrogenicity—that is, the capacity to cause mutations and affect sex hormones59–64— and that it breaks down more slowly in the environment than BPA does.65,66 Substituting BPS for BPA, therefore, may fail to reap the potential disease prevention and economic benefits described in this article. Regulatory agencies should consider the potential toxicity of as-yetuntested substitutes for BPA in deciding how to further restrict BPA in food uses.

Conclusion Exposure to BPA is associated with substantial child and adult morbidity that comes with a large economic burden, potentially greater than the estimated cost of replacing BPA with an alternative substance. From an economic perspective, it might make sense for the Food and Drug Administration to require that an additive free of obesogenic and cardiovascular risks be substituted for BPA. However, premarket testing of potential substitutes is needed to prevent the use of another synthetic chemical instead of BPA that may lead to the same or worse health consequences. ▪

The author thanks Teresa Attina and Jan Blustein for their support in prior work that informed the writing of this article, and Justin Trogdon for clarifying cost estimates for coronary heart disease in the American Heart Association report. [Published online January 22, 2014.]

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Web First NOTES 1 Dianin AP. Condensation of ketones with phenols. Zhurnal Russkago Fiziko-Khimicheskago Obshchestva. 1891;23:488–517, 523–46, 601–11. 2 Environmental Protection Agency. Bisphenol A (BPA) action plan summary [Internet]. Washington (DC): EPA; [last updated 2013 Feb 11; cited 2013 Dec 18]. Available from: http://www.epa.gov/opptintr/ existingchemicals/pubs/action plans/bpa.html 3 Calafat AM, Ye X, Wong LY, Reidy JA, Needham LL. Exposure of the U.S. population to bisphenol A and 4tertiary-octylphenol: 2003–2004. Environ Health Perspect. 2008; 116(1):39–44. 4 Carwile JL, Ye X, Zhou X, Calafat AM, Michels KB. Canned soup consumption and urinary bisphenol A: a randomized crossover trial. JAMA. 2011;306(20):2218–20. 5 Fleisch AF, Sheffield PE, Chinn C, Edelstein BL, Landrigan PJ. Bisphenol A and related compounds in dental materials. Pediatrics. 2010; 126(4):760–8. 6 Schwartz AW, Landrigan PJ. Bisphenol A in thermal paper receipts: an opportunity for evidence-based prevention. Environ Health Perspect. 2012;120(1):a14–5. 7 Diamanti-Kandarakis E, Bourguignon JP, Giudice LC, Hauser R, Prins GS, Soto AM, et al. Endocrine-disrupting chemicals: an Endocrine Society scientific statement. Endocr Rev. 2009;30(4):293–342. 8 Braun JM, Kalkbrenner AE, Calafat AM, Yolton K, Ye X, Dietrich KN, et al. Impact of early-life bisphenol A exposure on behavior and executive function in children. Pediatrics. 2011;128(5):873–82. 9 Sathyanarayana S, Braun JM, Yolton K, Liddy S, Lanphear BP. Case report: high prenatal bisphenol A exposure and infant neonatal neurobehavior. Environ Health Perspect. 2011;119(8):1170–5. 10 Fillon M. Getting it right: BPA and the difficulty proving environmental cancer risks. J Natl Cancer Inst. 2012;104(9):652–5. 11 Donohue KM, Miller RL, Perzanowski MS, Just AC, Hoepner LA, Arunajadai S, et al. Prenatal and postnatal bisphenol A exposure and asthma development among innercity children. J Allergy Clin Immunol. 2013;131(3):736–42. 12 Spanier AJ, Kahn RS, Kunselman AR, Hornung R, Xu Y, Calafat AM, et al. Prenatal exposure to bisphenol A and child wheeze from birth to 3 years of age. Environ Health Perspect. 2012;120(6):916–20. 13 Meeker JD, Calafat AM, Hauser R. Urinary bisphenol A concentrations in relation to serum thyroid and reproductive hormone levels in men from an infertility clinic. Environ Sci

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