Bisphenol A (BPA) is the monomer used to manufacture polycarbonate plastic, the resin lining of cans, and other products, with global capacity in excess of 6.4 billion lb/year. Because the ester bonds in these BPA-based polymers are subject to hydrolysis, leaching of BPA has led to widespread human exposure. A recent report prepared by the Harvard Center for Risk Analysis and funded by the American Plastics Council concluded that evidence for low-dose effects of BPA is weak on the basis of a review of only 19 studies; the report was issued after a delay of 2.5 years. A current comprehensive review of the literature reveals that the opposite is true. As of December 2004, there were 115 published in vivo studies concerning low-dose effects of BPA, and 94 of these report significant effects. In 31 publications with vertebrate and invertebrate animals, significant effects occurred below the predicted “safe” or reference dose of 50 μg/kg/day BPA. An estrogenic mode of action of BPA is confirmed by in vitro experiments, which describe disruption of cell function at 10−12 M or 0.23 ppt. Nonetheless, chemical manufacturers continue to discount these published findings because no industry-funded studies have reported significant effects of low doses of BPA, although > 90% of government-funded studies have reported significant effects. Some industry-funded studies have ignored the results of positive controls, and many studies reporting no significant effects used a strain of rat that is inappropriate for the study of estrogenic responses. We propose that a new risk assessment for BPA is needed based on a) the extensive new literature reporting adverse effects in animals at doses below the current reference dose; b) the high rate of leaching of BPA from food and beverage containers, leading to widespread human exposure; c) reports that the median BPA level in human blood and tissues, including in human fetal blood, is higher than the level that causes adverse effects in mice; and d) recent epidemiologic evidence that BPA is related to disease in women.

https://endocrinedisruptors.missouri.edu/pdfarticles/vomsaalHughesEHP2005.pdf

An extensive new literature concerning low-dose effects of bisphenol A shows the need for a new risk assessment.

http://endocrinedisruptors.missouri.edu/pdfarticles/richterbpainvivoreviewrtx2007.pdf

In vivo effects of bisphenol A in laboratory rodent studies

Comparative study of the endocrine-disrupting activity of bisphenol A and 19 related compounds.

Robert E. Chapin, Jane Adams, Kim Boekelheide, L. Earl Gray Jr, Simon W. Hayward, Peter S.J. Lees, Barry S. McIntyre, Kenneth M. Portier, Teresa M. Schnorr, Sherry G. Selevan, John G. Vandenbergh, and Susan R. Woskie Pfizer, Inc., Groton, CT University of Massachusetts, Boston, MA Brown University, Providence, RI U.S. Environmental Protection Agency, Research Triangle Park, NC Vanderbilt University Medical Center, Nashville, TN Johns Hopkins University, Baltimore, MD Schering Plough Research Institute, Summit, NJ American Cancer Society, Atlanta, GA National Institute for Occupational Safety and Health, Cincinnati, OH U.S. Public Health Service (Ret), Silver Spring, MD North Carolina State University, Raleigh, NC University of Massachusetts, Lowell, MA

https://onlinelibrary.wiley.com/doi/pdf/10.1002/bdrb.20147

NTP‐CERHR expert panel report on the reproductive and developmental toxicity of bisphenol A

The estrogenic activities of bisphenol A (BPA) and its major metabolite BPA glucuronide (BPA-G) were assessed in a number of in vitro and in vivo assays. BPA competed with [3H]-17beta-estradiol (E2) for binding to mouse uterine cytosol ER, a glutathione S-transferase (GST)-human ER D, E, and F domain fusion protein (GST-hERalphadef) and full-length recombinant hERbeta. The IC(50) values for E2 were similar for all three receptor preparations, whereas BPA competed more effectively for binding to hERbeta (0.96 microM) than to either mouse uterine cytosol ER (26 microM) or GST-hERalphadef (36 microM). In contrast, BPA-G did not competitively displace [3H]E2 from any of the ER preparations. In MCF-7 cells transiently transfected with Gal4-hERalphadef or Gal4-hERbetadef, BPA induced reporter gene activity with comparable EC(50) values (71 and 39 microM, respectively). No significant induction of reporter gene activity was seen for BPA-G. Cotreatment studies showed that concentrations of (10 microM) BPA and BPA-G did not antagonize E2-induced luciferase mediated through either Gal4-hERalphadef or Gal4-hERbetadef. In vivo, the uterotropic effect of gavage or subcutaneous (sc) administration of 0.002-800 mg of BPA/kg of body weight/day for three consecutive days was examined in immature rats. Dose-related estrogenic effects on the rat uterus were observed at oral doses of 200 and 800 mg/kg and at sc doses of 10, 100, and 800 mg/kg. These results demonstrate that BPA competes more effectively for binding to ERbeta, but induces ERalpha- and ERbeta-mediated gene expression with comparable efficacy. In contrast, BPA-G did not exhibit any in vitro estrogenic activity. In addition, there was a clear route dependency on the ability of BPA to induce estrogenic responses in vivo.

In vitro and in vivo interactions of bisphenol A and its metabolite, bisphenol A glucuronide, with estrogen receptors alpha and beta.

Uterotrophic activity of bisphenol A in the immature mouse.

The potent rat liver carcinogen 6-p-dimethylaminophenylazobenzthiazole (6BT) and its reported noncarcinogenic analogue 5-p-dimethylaminophenylazobenzthiazole (5BT; evaluated for carcinogenicity under the similar limited bioassay conditions used for 6BT) have been studied in order to seek an explanation for their different carcinogenic activities. Both compounds act as DNA-damaging agents to the rat liver, and both have now been shown to induce lacI (-) gene mutations in the liver of Big Blue(trade mark) transgenic rats. Both compounds were mutagenic following ten daily gavage doses or following administration in diet for 10 days. Neither chemical induced cell proliferation in the liver following repeat gavage administrations. In contrast, dietary administration of 6BT, and to a lesser extent of 5BT, induced hepatic cell proliferation. The carcinogen 6BT, but not the noncarcinogen 5BT, caused proliferation of oval stem cells in the livers by both routes of administration. It is possible that mutations induced in oval cells by 6BT are responsible for its potent carcinogenicity, and that the comparative absence of these cells in 5BT-treated livers may account for the carcinogenic inactivity of 5BT. Equally, the proliferation of the oval cells may reflect changes in liver homeostasis associated with the liver toxicity observed at the dose level of 6BT used (which was, nonetheless, the dose level used in the positive cancer bioassays). It is concluded that the new data presented cannot explain the differing carcinogenic activities of 5BT and 6BT, and that the reported noncarcinogen 5BT may also be carcinogenic when adequately assessed for this activity.

A. Soames

Papers

Uterotrophic activity of bisphenol A in the immature mouse.

Hepatic gene mutations induced in Big Blue rats by both the potent rat liver azo-carcinogen 6BT and its reported noncarcinogenic analogue 5BT.

Time course transcriptomic analysis of the 17β-estradiol (17βE2)-regulated transcriptome in mouse uterus