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

Human exposure to bisphenol A (BPA).

Plastics debris in the marine environment, including resin pellets, fragments and microscopic plastic fragments, contain organic contaminants, including polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons, petroleum hydrocarbons, organochlorine pesticides (2,2′-bis(p-chlorophenyl)-1,1,1-trichloroethane, hexachlorinated hexanes), polybrominated diphenylethers, alkylphenols and bisphenol A, at concentrations from sub ng g–1 to µg g–1. Some of these compounds are added during plastics manufacture, while others adsorb from the surrounding seawater. Concentrations of hydrophobic contaminants adsorbed on plastics showed distinct spatial variations reflecting global pollution patterns. Model calculations and experimental observations consistently show that polyethylene accumulates more organic contaminants than other plastics such as polypropylene and polyvinyl chloride. Both a mathematical model using equilibrium partitioning and experimental data have demonstrated the transfer of contaminants from plastic to organisms. A feeding experiment indicated that PCBs could transfer from contaminated plastics to streaked shearwater chicks. Plasticizers, other plastics additives and constitutional monomers also present potential threats in terrestrial environments because they can leach from waste disposal sites into groundwater and/or surface waters. Leaching and degradation of plasticizers and polymers are complex phenomena dependent on environmental conditions in the landfill and the chemical properties of each additive. Bisphenol A concentrations in leachates from municipal waste disposal sites in tropical Asia ranged from sub µg l–1 to mg l–1 and were correlated with the level of economic development.

/pdf/transport-and-release-of-chemicals-from-plastics-to-the-2a1psxlca9.pdf

Transport and release of chemicals from plastics to the environment and to wildlife

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

Effect of inoculum conditioning on hydrogen fermentation and pH effect on bacterial community relevant to hydrogen production.

Estrogenic activity and estrogenic chemicals in landfill leachate were investigated by yeast two-hybrid assay and chemical analysis. Leachate sample extracted by liquid–liquid extraction with dichloromethane at pH 7.0 showed a higher dose–response curve than sample extracted at pH 3.0, or than sample extracted by solid phase extraction at either pH 7.0 or 3.0. The fraction extracted at pH 3.0 specifically inhibited not only growth of yeast but also estrogenic activity in this assay, suggesting that it contained anti-estrogenic chemicals. The greatest contributor to estrogenic activity among the chemicals identified in leachate extract was bisphenol A, with an estimated contribution ratio of 84%. The contribution ratios of 4-nonyl phenol (4-np) and 4-tert-octyl phenol (4-t-op) were estimated at 1.0% and 0.1%, respectively, while natural estrogens such as 17β-estradiol or estrone were below detection limit, so that their contribution ratio was estimated at no more than 10%. The estrogenic activity of leachate was decreased by aeration treatment alone after 7 days, and was no longer detected after 22 days. Concentrations of bisphenol A, 4-np and 4-t-op likewise decreased with aeration.

Yukiko Fujita

Papers

Effect of inoculum conditioning on hydrogen fermentation and pH effect on bacterial community relevant to hydrogen production.

Estrogenic chemicals and estrogenic activity in leachate from municipal waste landfill determined by yeast two-hybrid assay