An Extensive New Literature Concerning Low-Dose Effects of Bisphenol A Shows the Need for a New Risk Assessment

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. Originally published Environmental Health Perspectives, Vol. 113, No. 8, Aug 200

Good Laboratory Practices Are Not Synonymous with Good Scientific Practices, Accurate Reporting, or Valid Data

Reproduced with permission from Environmental Health Perspectives. DOI:10.1289/ehp.0901495In her commentary, Tyl (2009) responded to our criticism (Myers et al. 2009) of her bisphenol A (BPA) research (Tyl et al. 2008), and she defended the reliance on Good Laboratory Practices (GLP) in animal studies concerning risks posed by chemicals. Her commentary, however, provides additional evidence that her research on BPA is flawed and that GLP can be unreliable

A Clash of Old and New Scientific Concepts in Toxicity, with Important Implications for Public Health

Background A core assumption of current toxicologic procedures used to establish health standards for chemical exposures is that testing the safety of chemicals at high doses can be used to predict the effects of low-dose exposures, such as those common in the general population. This assumption is based on the precept that “the dose makes the poison”: higher doses will cause greater effects. Objectives We challenge the validity of assuming that high-dose testing can be used to predict low-dose effects for contaminants that behave like hormones. We review data from endocrinology and toxicology that falsify this assumption and summarize current mechanistic understanding of how low doses can lead to effects unpredictable from high-dose experiments. Discussion Falsification of this assumption raises profound issues for regulatory toxicology. Many exposure standards are based on this assumption. Rejecting the assumption will require that these standards be reevaluated and that procedures employed to set health standards be changed. The consequences of these changes may be significant for public health because of the range of health conditions now plausibly linked to exposure to endocrine-disrupting contaminants. Conclusions We recommend that procedures to establish acceptable exposure levels for endocrine-disrupting compounds incorporate the inability for high-dose tests to predict low-dose results. Setting acceptable levels of exposure must include testing for health consequences at prevalent levels of human exposure, not extrapolations from the effects observed in high-dose experiments. Scientists trained in endocrinology must be engaged systematically in standard setting for endocrine-disrupting compounds

Meeting Report: Batch-to-Batch Variability in Estrogenic Activity in Commercial Animal Diets—Importance and Approaches for Laboratory Animal Research

We report information from two workshops sponsored by the National Institutes of Health that were held to a) assess whether dietary estrogens could significantly impact end points in experimental animals, and b) involve program participants and feed manufacturers to address the problems associated with measuring and eliminating batch-to-batch variability in rodent diets that may lead to conflicting findings in animal experiments within and between laboratories. Data were presented at the workshops showing that there is significant batch-to-batch variability in estrogenic content of commercial animal diets, and that this variability results in differences in experimental outcomes. A combination of methods were proposed to determine levels of total estrogenic activity and levels of specific estrogenic constituents in soy-containing, casein-containing, and other soy-free rodent diets. Workshop participants recommended that researchers pay greater attention to the type of diet being used in animal studies and choose a diet whose estrogenic activity (or lack thereof) is appropriate for the experimental model and end points of interest. Information about levels of specific phytoestrogens, as well as estrogenic activity caused by other contaminants and measured by bioassay, should be disclosed in scientific publications. This will require laboratory animal diet manufacturers to provide investigators with information regarding the phytoestrogen content and other estrogenic compounds in commercial diets used in animal research

Benefits of soy-based feeds for fetal estrogen levels and obesity in adulthood

Abstract only availableWe examined the effect of maternal exposure to naturally occurring estrogenic chemicals in diets on circulating levels of estradiol in mouse fetuses. An animal's specific response to estrogen can vary according to the time of exposure. The time when the fetus is sensitive to permanent “programming” effects of estrogen is called a “critical period” in development of organ systems. An important factor in the regulation of estrogen in the fetus is the composition of the mother's diet. Our hypothesis was that if a diet that was fed to pregnant mice during the fetal critical period contained estrogenic chemicals, these chemicals would “estrogenize” the fetus. In contrast to this prediction, a casein-based diet with virtually no estrogenic chemicals led to significantly higher levels of endogenous estradiol relative to a soy-based diet with very high levels of estrogenic chemicals. In a follow-up experiment we compared a soy-based diet containing estrogenic chemicals with a soy-based diet from which these estrogenic chemicals were extracted. The complete soy diet resulted in estrodiol levels of 60 pg/ml in fetal serum, while the extracted soy diet dramatically increased serum estradiol by over 50%. This finding shows that the naturally occurring estrogens in soy (phytoestrogens) fed to pregnant mice reduce endogenous estradiol levels in the fetuses. This is important since elevated levels of estradiol during fetal life "program" certain characteristics into the animal later on in adulthood. One of these characteristics is obesity. Obesity is associated with Type II diabetes, and the mice with elevated fetal estradiol levels show evidence of impaired glucose tolerance in later adulthood. These effects are relevant since obesity and diabetes are abnormalities in humans that are increasing.Life Sciences Undergraduate Research Opportunity Progra

Exposure to a low dose of bisphenol A during fetal life or in adulthood alters maternal behavior in mice.

Maternal behavior in mammals is the result of a complex interaction between the lactating dam and her developing offspring. Slight perturbations of any of the components of the mother-infant interaction may result in alterations of the behavior of the mother and/or of the offspring. We studied the effects of exposure of female CD-1 mice to the estrogenic chemical bisphenol A (BPA) during fetal life and/or in adulthood during the last part of pregnancy on subsequent maternal behavior. Pregnant females were fed daily doses of corn oil (controls) or 10 microg/kg body weight BPA during gestation days 14-18. As adults, the prenatally treated female offspring were time-mated and again fed either corn oil (controls) or the same doses of BPA on gestation days 14-18, resulting in four treatment groups: controls, prenatal BPA exposure, adult BPA exposure, and both prenatal and adult BPA exposure. Maternal behavior was then observed on postnatal days 2-15 and reflex responses were examined in the offspring. Dams exposed to BPA either as fetuses or in adulthood spent less time nursing their pups and more time out of the nest compared with the control group. Females exposed to BPA both as fetuses and in adulthood did not significantly differ from controls. No alterations in postnatal reflex development were observed in the offspring of the females exposed to BPA. The changes seen in maternal behavior may be the result of a direct effect of BPA on the neuroendocrine substrates underlying the initiation of maternal behavior

Exposure to a Low Dose of Bisphenol A during Fetal Life or in Adulthood Alters Maternal Behavior in Mice

Reproduced with permission from Environmental Health Perspectives.Maternal behavior in mammals is the result of a complex interaction between the lactating dam and her developing offspring. Slight perturbations of any of the components of the mother-infant interaction may result in alterations of the behavior of the mother and/or of the offspring. We studied the effects of exposure of female CD-1 mice to the estrogenic chemical bisphenol A (BPA) during fetal life and/or in adulthood during the last part of pregnancy on subsequent maternal behavior. Pregnant females were fed daily doses of corn oil (controls) or 10 μg/kg body weight BPA during gestation days 14-18. As adults, the prenatally treated female offspring were timemated and again fed either corn oil (controls) or the same doses of BPA on gestation days 14-18, resulting in four treatment groups: controls, prenatal BPA exposure, adult BPA exposure, and both prenatal and adult BPA exposure. Maternal behavior was then observed on postnatal days 2-15 and reflex responses were examined in the offspring. Dams exposed to BPA either as fetuses or in adulthood spent less time nursing their pups and more time out of the nest compared with the control group. Females exposed to BPA both as fetuses and in adulthood did not significantly differ from controls. No alterations in postnatal reflex development were observed in the offspring of the females exposed to BPA. The changes seen in maternal behavior may be the result of a direct effect of BPA on the neuroendocrine substrates underlying the initiation of maternal behavior.This research was supported by grants from NIEHS, NIH (ES08293), to F.V.S. and from the Italian Ministry of University and Scientific Research (MURST-COFIN2000), the University of Parma, and CNR (National Council for Research) to P.P