Towards a paradigm shift in environmental health decision-making: a case study of oxybenzone.

BACKGROUND: Technological advancements make lives safer and more convenient. Unfortunately, many of these advances come with costs to susceptible individuals and public health, the environment, and other species and ecosystems. Synthetic chemicals in consumer products represent a quintessential example of the complexity of both the benefits and burdens of modern living. How we navigate this complexity is a matter of a society's values and corresponding principles. OBJECTIVES: We aimed to develop a series of ethical principles to guide decision-making within the landscape of environmental health, and then apply these principles to a specific environmental chemical, oxybenzone. Oxybenzone is a widely used ultraviolet (UV) filter added to personal care products and other consumer goods to prevent UV damage, but potentially poses harm to humans, wildlife, and ecosystems. It provides an excellent example of a chemical that is widely used for the alleged purpose of protecting human health and product safety, but with costs to human health and the environment that are often ignored by stakeholders. DISCUSSION: We propose six ethical principles to guide environmental health decision-making: principles of sustainability, beneficence, non-maleficence, justice, community, and precautionary substitution. We apply these principles to the case of oxybenzone to demonstrate the complex but imperative decision-making required if we are to address the limits of the biosphere's regenerative rates. We conclude that both ethical and practical considerations should be included in decisions about the commercial, pervasive application of synthetic compounds and that the current flawed practice of cost-benefit analysis be recognized for what it is: a technocratic approach to support corporate interests.

Endocrine disruptors and the future of toxicology testing - lessons from CLARITY-BPA.

Five years ago, an ambitious collaboration, the Consortium Linking Academic and Regulatory Insights on Toxicity of BPA (CLARITY-BPA; henceforth CLARITY), was launched by three US agencies. The goal was to provide a definitive evaluation of bisphenol A (BPA) and explain disparities between traditional regulatory studies and findings from independent investigators. BPA or vehicle-treated rats from an FDA facility were used in a guideline study and animals and/or tissues were provided to academic researchers for analysis. An interim summary released in February 2018 by the FDA concluded that currently authorized uses of BPA continue to be safe. We disagree. In this Perspectives, we summarize the goals, design and problems of CLARITY. We conclude that, despite its flaws, CLARITY provides important insight and, taken together, the data provide compelling evidence that low-dose BPA exposure induces marked adverse effects. Indeed, the greatest number of effects were observed at doses 20,000 times lower than the current 'safe' dose of BPA for humans.

Nonmonotonic Dose-Response Curves Occur in Dose Ranges That Are Relevant to Regulatory Decision-Making.

Non-monotonic dose response curves (NMDRCs) occur in cells, tissues, animals and human populations in response to nutrients, vitamins, pharmacological compounds, hormones and endocrine disrupting chemicals (EDCs). Yet, regulatory agencies have argued that NMDRCs are not common, are not found for adverse outcomes, and are not relevant for regulation of EDCs. Under the linear dose response model, high dose testing is used to extrapolate to lower doses that are anticipated to be 'safe' for human exposures. NMDRCs that occur below the toxicological no-observed-adverse-effect level (NOAEL) would falsify a fundamental assumption, that high dose hazards can be used to predict low dose safety. In this commentary, we provide examples of NMDRCs and discuss how their presence in different portions of the dose response curve might affect regulatory decisions. We provide evidence that NMDRCs do occur below the NOAEL dose, and even below the 'safe' reference dose, for chemicals such as resveratrol, permethrin, chlorothalonil, and phthalates such as DEHP. We also briefly discuss the recent CLARITY-BPA study, which reported mammary adenocarcinomas only in rats exposed to the lowest BPA dose. We conclude our commentary with suggestions for how NMDRCs should be acknowledged and utilized to improve regulatory toxicity testing and in the calculation of reference doses that are public health protective.

Prenatal Exposure to Unconventional Oil and Gas Operation Chemical Mixtures Altered Mammary Gland Development in Adult Female Mice.

Unconventional oil and gas (UOG) operations, which combine hydraulic fracturing (fracking) and directional drilling, involve the use of hundreds of chemicals, including many with endocrine-disrupting properties. Two previous studies examined mice exposed during early development to a 23-chemical mixture of UOG compounds (UOG-MIX) commonly used or produced in the process. Both male and female offspring exposed prenatally to one or more doses of UOG-MIX displayed alterations to endocrine organ function and serum hormone concentrations. We hypothesized that prenatal UOG-MIX exposure would similarly disrupt development of the mouse mammary gland. Female C57Bl/6 mice were exposed to ~3, ~30, ~ 300, or ~3000 µg/kg/d UOG-MIX from gestational day 11 to birth. Although no effects were observed on the mammary glands of these females before puberty, in early adulthood, females exposed to 300 or 3000 µg/kg/d UOG-MIX developed more dense mammary epithelial ducts; females exposed to 3 µg/kg/d UOG-MIX had an altered ratio of apoptosis to proliferation in the mammary epithelium. Furthermore, adult females from all UOG-MIX-treated groups developed intraductal hyperplasia that resembled terminal end buds (i.e., highly proliferative structures typically seen at puberty). These results suggest that the mammary gland is sensitive to mixtures of chemicals used in UOG production at exposure levels that are environmentally relevant. The effect of these findings on the long-term health of the mammary gland, including its lactational capacity and its risk of cancer, should be evaluated in future studies.

Developmental origins of health and disease: a paradigm for understanding disease cause and prevention.

PURPOSE OF REVIEW: Although diseases may appear clinically throughout the lifespan, it is clear that many diseases have origins during development. Altered nutrition, as well as exposure to environmental chemicals, drugs, infections, or stress during specific times of development, can lead to functional changes in tissues, predisposing those tissues to diseases that manifest later in life. This review will focus on the role of altered nutrition and exposures to environmental chemicals during development in the role of disease and dysfunction. RECENT FINDINGS: The effects of altered nutrition or exposure to environmental chemicals during development are likely because of altered programming of epigenetic marks, which persist across the lifespan. Indeed some changes can be transmitted to future generations. SUMMARY: The evidence in support of the developmental origins of the health and disease paradigm is sufficiently robust and repeatable across species, including humans, to suggest a need for greater emphasis in the clinical area. As a result of these data, obesity, diabetes, cardiovascular morbidity, and neuropsychiatric diseases can all be considered pediatric diseases. Disease prevention must start with improved nutrition and reduced exposure to environmental chemicals during development.