Exploring regrettable substitution: replacements for bisphenol A
Authors: Leonardo Trasande
Journal: The Lancet Planetary Health (2017)

Bisphenols are used in the polymerisation of polycarbonate plastics and production of epoxy resins. Bisphenol A (BPA) was first synthesised by Alexander Dianin in 1891, and was considered for use as a pharmaceutical oestrogen for pregnant women, but was not sufficiently potent, and eventually diethylstilbestrol was used instead.1Vandenberg LN Maffini MV Sonnenschein C Rubin BS Soto AM Bisphenol-A and the great divide: a review of controversies in the field of endocrine disruption.Endocr Rev. 2009; 30: 75-95Crossref PubMed Scopus (1086) Google Scholar Increasing evidence from the past two decades suggest that synthetic chemicals represent an underrecognised third key factor in the obesity epidemic worldwide, alongside diet and physical activity.2Lind L Lind PM Lejonklou MH et al.Uppsala Consensus Statement on environmental contaminants and the global obesity epidemic.Environ Health Perspect. 2016; 124: A81-A83Crossref PubMed Scopus (30) Google Scholar Bisphenols are one major category of chemicals now recognised as obesogens. Laboratory studies have documented that BPA makes fat cells bigger and inhibits function of adiponectin.3Trasande L Attina TM Blustein J Association between urinary bisphenol A concentration and obesity prevalence in children and adolescents.JAMA. 2012; 308: 1113-1121Crossref PubMed Scopus (355) Google Scholar Cross-sectional and longitudinal human studies3Trasande L Attina TM Blustein J Association between urinary bisphenol A concentration and obesity prevalence in children and adolescents.JAMA. 2012; 308: 1113-1121Crossref PubMed Scopus (355) Google Scholar, 4Philips EM Jaddoe VW Trasande L Effects of early exposure to phthalates and bisphenols on cardiometabolic outcomes in pregnancy and childhood.Reprod Toxicol. 2017; 68: 105-118Crossref PubMed Scopus (49) Google Scholar, 5Song Y Hauser R Hu FB Franke AA Liu S Sun Q Urinary concentrations of bisphenol A and phthalate metabolites and weight change: a prospective investigation in US women.Int J Obes. 2014; 38: 1532-1537Crossref PubMed Scopus (92) Google Scholar have also associated BPA exposure with obesity in children and adults. Notably, human studies have not consistently identified the key periods of susceptibility. Differences in results between studies might be the result of leveraging a limited number of spot urine samples in pregnancy as a proxy of exposure. Given that the half-life of BPA is generally 24–48 h, use of a modest number of spot samples introduces exposure imprecision that can influence statistical results. Obesity is not the only concern documented for BPA. Epidemiological studies have identified neurocognitive effects of BPA6Braun JM Kalkbrenner AE Calafat AM et al.Impact of early-life bisphenol A exposure on behavior and executive function in children.Pediatrics. 2011; 128: 873-882Crossref PubMed Scopus (444) Google Scholar and newly incident coronary artery disease,7Melzer D Osborne NJ Henley WE et al.Urinary bisphenol a concentration and risk of future coronary artery disease in apparently healthy men and women.Circulation. 2012; 125: 1482-1490Crossref PubMed Scopus (210) Google Scholar and laboratory studies strongly suggest BPA is an ovarian toxicant.8Peretz J Vrooman L Ricke WA et al.Bisphenol A and reproductive health: update of experimental and human evidence, 2007–2013.Environ Health Perspect. 2014; 122: 775-786Crossref PubMed Scopus (388) Google Scholar The rapidly rising evidence of adverse effects has prompted manufacturers to substitute BPA with various bisphenols (BPS, BPP, BPZ, and BPF, to name a few). These chemicals were not required to be proven as safer alternatives because of the Toxic Substances Control Act, which, until June, 2016, when President Obama signed legislation updating the law, presumed chemicals to be innocent until proven guilty in terms of toxicity in the USA, requiring little toxicity testing data before approval for widespread use by the Environmental Protection Agency.9Trasande L Updating the toxic substances control act to protect human health.JAMA. 2016; 315: 1565-1566Crossref PubMed Scopus (10) Google Scholar What little we know about one BPA replacement, BPS, suggests serious concerns. BPS has been found to be as oestrogenic in laboratory studies10Trasande L Further limiting bisphenol a in food uses could provide health and economic benefits.Health Aff. 2014; 33: 316-323Crossref Scopus (38) Google Scholar and as toxic to embryos as BPA,11Crump D Chiu S Williams KL Bisphenol S alters embryonic viability, development, gallbladder size, and mRNA expression in chicken embryos exposed via egg injection.Environ Toxicol Chem. 2016; 35: 1541-1549Crossref PubMed Scopus (29) Google Scholar and even more persistent in the environment.10Trasande L Further limiting bisphenol a in food uses could provide health and economic benefits.Health Aff. 2014; 33: 316-323Crossref Scopus (38) Google Scholar Is it obesogenic in humans? In The Lancet Planetary Health, Buyun Liu and colleagues12Liu B Lehmler H-J Sun Y et al.Bisphenol A substitutes and obesity in US adults: analysis of a population-based, cross-sectional study.Lancet Planet Health. 2017; 1: e114-e122Summary Full Text Full Text PDF Scopus (93) Google Scholar examine data from the 2013–14 National Health and Nutrition Examination Survey to study cross-sectional associations of urinary concentrations of BPA, BPF, and BPS with obesity in adults. Their analysis confirms persistent associations of BPA with obesity, despite lower exposures than previously studied. Although associations of urinary BPF or BPS with body-mass index or obesity were not significant, Liu and colleagues' analyses raise more questions than answers about whether non-A bisphenols are obesogenic. The authors used statistical models to examine effects of each bisphenol independent of the other; however, no potency data are available to aggregate effects of model relationships in aggregate across the bisphenols, and examination of interactions to evaluate synergy or antagonism were not done. Exposures to BPF and BPS were much lower and less prevalent than BPA and the cross-sectional evaluation of adult obesity is an important limitation of the study design given the known life-course origins, especially early life exposures that can have a big impact on adult obesity.4Philips EM Jaddoe VW Trasande L Effects of early exposure to phthalates and bisphenols on cardiometabolic outcomes in pregnancy and childhood.Reprod Toxicol. 2017; 68: 105-118Crossref PubMed Scopus (49) Google Scholar Longitudinal studies are needed, especially to examine pregnancy and early childhood exposures, as are studies that assess the period after the introduction of BPA. Most longitudinal cohort studies of BPA exposure are limited by missing measurements of non-A bisphenols and missing associations could be caused by imprecision in the measurement of bisphenol exposure. Although these issues complicate interpretation of human studies, they exemplify the problem of so-called regrettable substitution. The economic benefits of substituting BPA in the linings of aluminium cans with an alternative free of health effects (US$1·74 billion per year) were found to nearly outweigh the costs of a natural alternative oleoresin ($2·2 billion per year), and this analysis was limited to benefits associated with reductions in BPA-attributable childhood obesity and coronary artery disease.10Trasande L Further limiting bisphenol a in food uses could provide health and economic benefits.Health Aff. 2014; 33: 316-323Crossref Scopus (38) Google Scholar Oleoresin is not necessarily a feasible alternative for all canned foods, but substitution of BPA with BPF, BPS, or another bisphenol might result in the same associations with adverse health outcomes as BPA, after years of studies in the laboratory and human beings. The European Commission has the opportunity to set the platform for a stronger regulatory framework for bisphenols and other endocrine disrupting chemicals (EDCs) that necessitate the use of safer alternatives when laboratory and other studies suggest that they cause adverse effects. The stakes are high; EDC-associated diseases and disabilities extend well beyond bisphenols to a broader array of synthetic chemicals, with effects including adverse neurodevelopmental outcomes, diabetes, cardiovascular disease, and male and female reproductive disorders. The costs of EDC exposures are estimated to be €163 billion in the European Union and $340 billion in the USA.13Attina TM Hauser R Sathyanarayana S et al.Exposure to endocrine-disrupting chemicals in the USA: a population-based disease burden and cost analysis.Lancet Diabetes Endocrinol. 2016; 4: 996-1003Summary Full Text Full Text PDF PubMed Scopus (147) Google Scholar Although these estimates are based on known exposures, they suggest the large, potential societal benefits of proactive and thorough screening of new chemicals before they can be introduced into the market, and reconsidering the use of non-A bisphenols and other potentially regrettable substitutes. I acknowledge support from National Institutes of Health. This content is solely the responsibility of the author and does not represent the official views of the National Institutes of Health. Bisphenol A substitutes and obesity in US adults: analysis of a population-based, cross-sectional studyWhereas there were significant associations of BPA exposure with general and abdominal obesity, concentrations of BPF or BPS were not significantly associated with obesity in US adults at current exposure levels. Continued biomonitoring of these bisphenols and further investigation into their health effects on human beings are warranted. Full-Text PDF Open Access