scholarly journals Hormones and Endocrine-Disrupting Chemicals: Low-Dose Effects and Nonmonotonic Dose Responses

2012 ◽  
Vol 33 (3) ◽  
pp. 378-455 ◽  
Author(s):  
Laura N. Vandenberg ◽  
Theo Colborn ◽  
Tyrone B. Hayes ◽  
Jerrold J. Heindel ◽  
David R. Jacobs ◽  
...  
Keyword(s):  
Dose Response ◽  
Low Dose ◽  
Endocrine Disrupting Chemicals ◽  
Low Doses ◽  
Response Curves ◽  
Toxicological Studies ◽  
Endocrine Disrupting ◽  
Dose Effects ◽  
Dose Response Curves ◽  
Low Dose Effects

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 the cell culture, animal, and epidemiology literature. We illustrate that nonmonotonic responses and low-dose effects are remarkably common in studies of natural hormones and EDCs. Whether low doses of EDCs influence certain human disorders is no longer conjecture, because epidemiological studies show that environmental exposures to EDCs are associated with human diseases and disabilities. We conclude that when nonmonotonic dose-response curves occur, the effects of low doses cannot be predicted by the effects observed at high doses. Thus, fundamental changes in chemical testing and safety determination are needed to protect human health.

Reproductive stimulation by low doses of xenoestrogens contrasts with the view of hormesis as an adaptive response

2005 ◽  
Vol 24 (9) ◽  
pp. 431-437 ◽  
Author(s):  
Lennart Weltje ◽  
Frederick S vom Saal ◽  
Jörg Oehlmann
Keyword(s):  
Risk Assessment ◽  
Adaptive Response ◽  
Low Dose ◽  
Threshold Model ◽  
Endocrine Disrupting Chemicals ◽  
Environmental Chemicals ◽  
Low Doses ◽  
Response Curves ◽  
Endocrine Disrupting ◽  
High Doses

We discuss the similarities and differences of two types of effects that occur at low but not high doses of chemicals: hormesis and stimulation by oestrogenic endocrine-disrupting chemicals or xenoestrogens. While hormesis is a general phenomenon evoked by many compounds, oestrogenic stimulation occurs for specific chemicals that disrupt actions of endogenous oestrogen. Both types of phenomena can induce an inverted-U dose-response curve, from low-dose stimulation of response, and thus challenge current methods of risk assessment. Hormesis is generally thought to be caused by an over-reaction of detoxification mechanisms, which is considered an adaptive response that should protect an organism from subsequent stress. One view of the hormetic low-dose stimulatory response, i.e., increased performance, is that it is beneficial. In contrast, we propose that for manmade xenoestrogens this is never the case. This is demonstrated with examples for low doses of the oestrogenic environmental chemicals bisphenol A and octylphenol, and the oestrogenic drug-response curves is underestimated by the current threshold model used in risk assessment, and this is likely to apply to other endocrine-disrupting chemicals.

scholarly journals Nonmonotonic Dose–Response Curves Occur in Dose Ranges That Are Relevant to Regulatory Decision-Making

Dose-Response ◽  
2018 ◽  
Vol 16 (3) ◽  
pp. 155932581879828 ◽  
Author(s):  
Corinne E. Hill ◽  
J. P. Myers ◽  
Laura N. Vandenberg
Keyword(s):  
Dose Response ◽  
Endocrine Disrupting Chemicals ◽  
Toxicity Testing ◽  
Adverse Outcomes ◽  
High Dose ◽  
Human Populations ◽  
Response Curves ◽  
Regulatory Decision ◽  
Adverse Effect Level ◽  
Dose Response Curves

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.

Choice of animal feed can alter fetal steroid levels and mask developmental effects of endocrine disrupting chemicals

2011 ◽  
Vol 2 (1) ◽  
pp. 36-48 ◽  
Author(s):  
R. L. Ruhlen ◽  
J. A. Taylor ◽  
J. Mao ◽  
J. Kirkpatrick ◽  
W. V. Welshons ◽  
...  
Keyword(s):  
Low Dose ◽  
Animal Feed ◽  
Endocrine Disrupting Chemicals ◽  
In Utero ◽  
High Dose ◽  
Serum Estradiol ◽  
Toxicological Studies ◽  
Endocrine Disrupting ◽  
Health And Disease ◽  
Daily Sperm Production

Exposure of fetuses to endocrine disrupting chemicals (EDCs), such as the estrogenic drug diethylstilbestrol (DES), disrupts development of the reproductive system and affects other aspects of adult phenotype including diseases, consistent with the developmental origins of health and disease hypothesis. To determine whether diet could influence the effects of DES, we compared mice fed a commonly used combination of soy-based Purina 5008 (breeding and lactation) and 5001 (post-weaning) with mice fed soy-based Purina 5002 throughout life. We exposed fetal CD-1 mice (F1) in utero on different feeds to a 0 (controls), low (0.1 μg/kg/day) or high (50 μg/kg/day) dose of DES via feeding the dam (F0) on gestation days 11–17. Compared to 5008, 5002 feed significantly increased serum estradiol in control fetuses. On 5008 (but not 5002) feed, DES significantly increased fetal serum estradiol at a low dose and reduced it at a high dose. Diet influenced the effects of in utero DES on F1 female onset of puberty and the uterine response to estradiol (an inverted-U dose–response relationship seen for DES on uterine weight with 5008/5001 feed was not observed with 5002). Both low- and high-dose DES reduced daily sperm production (DSP) in adult F1 males on 5008/5001 feed, whereas males fed 5002 showed no DES-induced reduction in DSP. Thus, we observed a number of low-dose effects of in utero DES exposure on Purina 5008/5001 feed that were not observed using Purina 5002, a feed commonly used in industry-funded toxicological studies conducted for regulatory purposes.

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