Large effects from small exposures. I. Mechanisms for endocrine-disrupting chemicals with estrogenic activity.

By W. Welshons, K. Thayer, Barbara Judy, Julia A. Taylor, E. Curran, F. V. vom Saal. Environmental Health Perspectives, 2003

912 citations recorded by the source corpus.

Information concerning the fundamental mechanisms of action of both natural and environmental hormones, combined with information concerning endogenous hormone concentrations, reveals how endocrine-disrupting chemicals with estrogenic activity (EEDCs) can be active at concentrations far below those currently being tested in toxicological studies. Using only very high doses in toxicological studies of EEDCs thus can dramatically underestimate bioactivity. Specifically: a) The hormonal action mechanisms and the physiology of delivery of EEDCs predict with accuracy the low-dose ranges of biological activity, which have been missed by traditional toxicological testing. b) Toxicology assumes that it is valid to extrapolate linearly from high doses over a very wide dose range to predict responses at doses within the physiological range of receptor occupancy for an EEDC; however, because receptor-mediated responses saturate, this assumption is invalid. c) Furthermore, receptor-mediated responses can first increase and then decrease as dose increases, contradicting the assumption that dose-response relationships are monotonic. d) Exogenous estrogens modulate a system that is physiologically active and thus is already above threshold, contradicting the traditional toxicological assumption of thresholds for endocrine responses to EEDCs. These four fundamental issues are problematic for risk assessment methods used by regulatory agencies, because they challenge the traditional use of extrapolation from high-dose testing to predict responses at the much lower environmentally relevant doses. These doses are within the range of current exposures to numerous chemicals in wildlife and humans. These problems are exacerbated by the fact that the type of positive and negative controls appropriate to the study of endocrine responses are not part of traditional toxicological testing and are frequently omitted, or when present, have been misinterpreted.

Subfields: Cancer Research, Health, Toxicology and Mutagenesis

View Paper: https://www.semanticscholar.org/paper/a7b1db8af6ff970543113d7f3e0c3e524df64522

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

In Health, Toxicology and Mutagenesis

Citations in the corpus

Teratogenic Effects of Glyphosate-Based Herbicides: Divergence of Regulatory Decisions from Scientific Evidence (2012, background): “A large body of evidence indicates that for some compounds, toxic effects are found at low doses but not at higher doses, and that different toxic effects can be found at different doses [28-31].”
EDC-2: The Endocrine Society's Second Scientific Statement on Endocrine-Disrupting Chemicals. (2015, background): “For example, the MCF7 breast cancer cell line proliferates in response to estrogen until high doses are reached (10 5 to 10 4 M) where it is cytotoxic, resulting in cell death (137).”
Components of plastic: experimental studies in animals and relevance for human health (2009, background): “Numerous reviews have been published discussing the assumptions used in estimating safe exposure levels for endocrine-disrupting chemicals such as BPA (vom Saal & Sheehan 1998; Markey et al. 2003; Welshons et al. 2003, 2006; vom Saal & Hughes 2005; Myers & vom Saal 2008).”
Chapel Hill bisphenol A expert panel consensus statement: integration of mechanisms, effects in animals and potential to impact human health at current levels of exposure. (2007, neutral): “reported for BPA (reviewed in: [18, 23, 24].”
The role of animal behaviour in the study of endocrine-disrupting chemicals (2004, positive): “Increased awareness of the problem of nonlinear dose– response relationships has led to calls for more studies that test a range of physiologically active doses and that are more attentive to positive and negative controls (Welshons et al. 2003).”
Large effects from small exposures. III. Endocrine mechanisms mediating effects of bisphenol A at levels of human exposure. (2006, methodology): “Until recently, BPA had been considered to be a very weak environmental estrogen, because in some bioassays (for example, in the uterus of some rats and mouse strains or for some responses in human breast cancer cells), BPA can be 10,000- to 100,000-fold less potent than estradiol (7).”
Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses. (2012, positive): “Because of shared receptor-mediated mechanisms, EDCs that mimic natural hormones have been proposed to follow the same rules and therefore have biological effects at low doses (38, 118).”
An Extensive New Literature Concerning Low-Dose Effects of Bisphenol A Shows the Need for a New Risk Assessment (2005, background): “…or, at best, considered to be rare, just for BPA there are currently 11 in vivo and in vitro examples of unique effects seen at low doses but not at higher doses (e.g., Endocrine Disruptors Group 2005; Oehlmann et al. 2000; Wetherill et al. 2002; Welshons et al. 2003; Wozniak et al. 2005).”
In vivo effects of bisphenol A in laboratory rodent studies. (2007, background): “BPA has been demonstrated in both in vivo and in vitro xperiments to act as an endocrine disrupting chemical (EDC) reviewed in [5,6]).”
Farmers’ Exposure to Pesticides: Toxicity Types and Ways of Prevention (2016, background): “Some endocrine disrupting pesticides show toxic effects that decrease as the dose decreases, until, at very low doses (often as low as parts per billion or even parts per trillion), their effects increase [19].”
Depression as a disease of modernity: explanations for increasing prevalence (2012, background): “Do somatic depressive symptoms associate more with health status and non-somatic symptoms with the social milieu? How do these lifestyle factors differentially affect risk by age and gender? How do subcutaneous versus visceral adipose tissues influence the relationship between obesity and depression”
Endocrine Disrupting Chemicals and Disease Susceptibility (2011, background): “In summary, making predictions about the safety of chemicals by testing at moderate or high doses is not appropriate when very low doses of endocrine disruptors can alter biochemical and morphological endpoints in a manner that is not necessarily predicted by exposures at much higher doses [31].”