For decades, studies of endocrine-disrupting chemicals (EDCs) have challenged traditional concepts in toxicology, in particular the dogma of “the dose makes the poison,” because EDCs can have effects at low doses that are not predicted by effects at higher doses. Here, we review two major concepts in EDC studies: low dose and nonmonotonicity. Low-dose effects were defined by the National Toxicology Program as those that occur in the range of human exposures or effects observed at doses below those used for traditional toxicological studies. We review the mechanistic data for low-dose effects and use a weight-of-evidence approach to analyze five examples from the EDC literature. Additionally, we explore nonmonotonic dose-response curves, defined as a nonlinear relationship between dose and effect where the slope of the curve changes sign somewhere within the range of doses examined. We provide a detailed discussion of the mechanisms responsible for generating these phenomena, plus hundreds of examples from...

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Hormones and endocrine-disrupting chemicals: Low-dose effects and nonmonotonic dose responses

Synthetic chemicals currently used in a variety of industrial and agricultural applications are leading to widespread contamination of the environment. Even though the intended uses of pesticides, plasticizers, antimicrobials, and flame retardants are beneficial, effects on human health are a global concern. These so-called endocrine-disrupting chemicals (EDCs) can disrupt hormonal balance and result in developmental and reproductive abnormalities. New in vitro, in vivo, and epidemiological studies link human EDC exposure with obesity, metabolic syndrome, and type 2 diabetes. Here we review the main chemical compounds that may contribute to metabolic disruption. We then present their demonstrated or suggested mechanisms of action with respect to nuclear receptor signaling. Finally, we discuss the difficulties of fairly assessing the risks linked to EDC exposure, including developmental exposure, problems of high- and low-dose exposure, and the complexity of current chemical environments.

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Endocrine Disruptors: From Endocrine to Metabolic Disruption

http://blumberg-serv.bio.uci.edu/reprints/grun_MCE-2009.pdf

Endocrine disrupters as obesogens.

The incidence and/or prevalence of health problems associated with endocrine-disruption have increased. Many chemicals have endocrine-disrupting properties, including bisphenol A, some organochlorines, polybrominated flame retardants, perfluorinated substances, alkylphenols, phthalates, pesticides, polycyclic aromatic hydrocarbons, alkylphenols, solvents, and some household products including some cleaning products, air fresheners, hair dyes, cosmetics, and sunscreens. Even some metals were shown to have endocrine-disrupting properties. Many observations suggesting that endocrine disruptors do contribute to cancer, diabetes, obesity, the metabolic syndrome, and infertility are listed in this paper. An overview is presented of mechanisms contributing to endocrine disruption. Endocrine disruptors can act through classical nuclear receptors, but also through estrogen-related receptors, membrane-bound estrogen-receptors, and interaction with targets in the cytosol resulting in activation of the Src/Ras/Erk pathway or modulation of nitric oxide. In addition, changes in metabolism of endogenous hormones, cross-talk between genomic and nongenomic pathways, cross talk with estrogen receptors after binding on other receptors, interference with feedback regulation and neuroendocrine cells, changes in DNA methylation or histone modifications, and genomic instability by interference with the spindle figure can play a role. Also it was found that effects of receptor activation can differ in function of the ligand.

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Endocrine-Disrupting Chemicals: Associated Disorders and Mechanisms of Action

Since the 1970s, an increasing number of regulations have expanded the use of brominated and chlorinated flame retardants. Many of these chemicals are now recognized as global contaminants and are associated with adverse health effects in animals and humans, including endocrine and thyroid disruption, immunotoxicity, reproductive toxicity, cancer, and adverse effects on fetal and child development and neurologic function. Some flame retardants such as polybrominated diphenyl ethers (PBDEs) have been banned or voluntarily phased out by manufacturers because of their environmental persistence and toxicity, only to be replaced by other organohalogens of unknown toxicity. Despite restrictions on further production in some countries, consumer products previously treated with banned retardants are still in use and continue to release toxic chemicals into the environment, and the worldwide use of organohalogen retardants continues to increase. This paper examines major uses and known toxic effects of commonly-used organohalogen flame retardants, replacements for those that have been phased out, their combustion by-products, and their effectiveness at reducing fire hazard. Policy and other solutions to maintain fire safety while reducing toxicity are suggested. The major conclusions are: (1) Flammability regulations can cause greater adverse environmental and health impacts than fire safety benefits. (2) The current options for end-of-life disposal of products treated with organohalogens retardants are problematic. (3) Life-cycle analyses evaluating benefits and risks should consider the health and environmental effects of the chemicals, as well as their fire safety impacts. (4) Most fire deaths and most fire injuries result from inhaling carbon monoxide, irritant gases, and soot. The incorporation of organohalogens can increase the yield of these toxic by-products during combustion. (5) Fire-safe cigarettes, fire-safe candles, child-resistant lighters, sprinklers, and smoke detectors can prevent fires without the potential adverse effects of flame retardant chemicals. (6) Alternatives to organohalogen flame retardant chemicals include using less flammable materials, design changes, and safer chemicals. To date, before evaluating their health and environmental impacts, many flame retardant chemicals have been produced and used, resulting in high levels of human exposure. As a growing literature continues to find adverse impacts from such chemicals, a more systematic approach to their regulation is needed. Before implementing new flammability standards, decision-makers should evaluate the potential fire safety benefit versus the health and environmental impacts of the chemicals, materials, or technologies likely to be used to meet the standard. Reducing the use of toxic or untested flame retardant chemicals in consumer products can protect human and animal health and the global environment without compromising fire safety.

Halogenated flame retardants: do the fire safety benefits justify the risks?

OBJECTIVE —Chlorinated persistent organic pollutants (POPs), endocrine disruptors accumulated in adipose tissue, were associated with diabetes and metabolic syndrome. Brominated flame retardants (BFRs), such as polybrominated diphenyl ethers (PBDEs) or polybrominated biphenyls (PBBs), are another class of POPs for which body burden is increasing. Cross-sectional associations of serum concentrations of BFRs with diabetes and metabolic syndrome were studied.

RESEARCH DESIGN AND METHODS —In the National Health and Nutrition Examination Survey 2003–2004, 1,367 adults were examined with respect to diabetes status. Five PBDEs and one PBB were selected, detectable in ≥60% of participants. For the outcome metabolic syndrome, we restricted the analysis to 637 participants with a morning fasting sample.

RESULTS —Compared with subjects with serum concentrations below the limit of detection, prevalent diabetes had differing dose-response associations with serum concentrations of PBB-153 and PBDE-153. Adjusted odds ratios across quartiles of serum concentrations for PBB-153 or PBDE-153 were 1.0, 0.7, 1.4, 1.6, and 1.9 ( P for trend <0.01) and 1.0, 1.6, 2.6, 2.7, and 1.8 ( P for quadratic term <0.01), respectively. PBB-153 was also positively associated with the prevalence of metabolic syndrome with adjusted odds ratios of 1.0, 1.5, 3.1, 3.1, and 3.1 ( P for trend<0.01). As in its association with diabetes, PBDE-153 showed an inverted U-shaped association with metabolic syndrome.

CONCLUSIONS —Pending confirmation in prospective studies, lipophilic xenobiotics, including brominated POPs stored in adipose tissue, may be involved in the pathogenesis of diabetes and metabolic syndrome.

https://care.diabetesjournals.org/content/diacare/31/9/1802.full.pdf

Ji-Sun Lim

Papers

Association of Brominated Flame Retardants With Diabetes and Metabolic Syndrome in the U.S. Population, 2003–2004