Inconvenient Toxicology Truths Part 1. Endocrine disrupters -- A prime example of the "cherchez la femme!" fallacy.

Anything Greenpiss don't want discussed has got to be near the top of the Pundit's to-do list. 

So here is a quote from a superb 2013 opinion piece/review "Endocrine disruption: fact or urban legend?"  by Gerhard Nohynek and colleagues in Toxicology Letters:

Paradoxically, our society and its regulators appear to be quite tolerant towards potent substances that are confirmed Endocrine Disrupters and are taken orally by a large number of humans. These examples show how the focus on purported man-made, endocrine disrupting chemicals (EDCs) distracts from potential health risks of human exposure to other substances with far greater potential for hormonal activity. Perhaps the entire issue of purported health risks of chemical Endocrine Disrupters is just another version of the trivial dichotomy natural is good versus man-made is bad...
 ...Overall, it appears weird how the supporters of the Endocrine Disrupter hypothesis appear to be mesmerised by the idea that a handful of weakly acting chemicals that involve produce little or negligible human exposure must be somehow responsible for a range of hypothetical adverse effects on human reproduction or other human health problems. About 150 years ago, Alexandre Dumas coined the phrase cherchez la femme! - meaning that, in every human crime, there is always a woman involved who plays a key role [Translation of the complete phrase: There is a woman in every case; as soon as they bring me a report, I say, ‘Look for the woman!’ (Dumas, 1871)]. Today, this view may strike us as somewhat naïve and sexist. In contrast, today’s popular belief rather appears to be: cherchez le produit chimique! (Translation: look for the chemical!) - expressing the belief that, in every human health problem, man-made, synthetic chemicals must play a key role. Would this not be equally naïve?

Gerhard J. Nohynek, Christopher J. Borgert, Daniel Dietrich, Karl K. Rozman Toxicol Lett. 2013 Dec 16;223(3):295-305. doi: 10.1016/j.toxlet.2013.10.022. Epub 2013 Oct 28.

 Scientific summary

Endocrine disruptors (EDs) are substances that cause adverse health effects via endocrine-mediated mechanisms in an intact organism or its progeny or (sub) populations. Purported EDCs in personal care products include 4-MBC (UV filter) or parabens that showed oestrogenic activity in screening tests, although regulatory toxicity studies showed no adverse effects on reproductive endpoints.
Hormonal potency is the key issue of the safety of EDCs. Oestrogen-based drugs, e.g. the contraceptive pill or the synthetic oestrogen DES, possess potencies up to 7 orders of magnitude higher than those of PCP ingredients; yet, in utero exposure to these drugs did not adversely affect fertility or sexual organ development of offspring unless exposed to extreme doses. Additive effects of EDs are unlikely due to the multitude of mechanisms how substances may produce a hormone-like activity; even after uptake of different substances with a similar mode of action, the possibility of additive effects is reduced by different absorption, metabolism and kinetics. This is supported by a number of studies on mixtures of chemical EDCs. Overall, despite of 20 years of research a human health risk from exposure to low concentrations of exogenous chemical substances with weak hormone-like activities remains an unproven and unlikely hypothesis.

Explanatory notes

1. The Pundit has been drawn to blog more about "Endocrine Disrupter" chemicals by the discovery that it ranks with GMOs as a topic about which the EU's anti-technology NGOs such as Greenpiss need and want the general public to wildly confused.

Greenpiss need Endocrine Disrupters as much as they need GMOs to protect their cash flow.

That's why they thought EU scientific advisor Anne Glover had to go. They demonstrated this inthe freedom of information requests that emerged during their attacks on the former science advisor position held by Anne Glover. 

And anything Greenpiss don't want discussed has got to be near the top of the Pundit's to-do list. 

Besides that, the subject of Endocrine Disrupters provides lots of scope to explain generally useful principles of toxicology to a wider readership. So thanks Greenpiss for the such a fine fine lede to a series of Inconvenient Toxicology Truths posts at GMO Pundit.

2. One article cited by Nohynek and colleagues is mentioned below. The full article is open access at the journal website provided as a link.

Commentary

Low-dose effects and nonmonotonic dose–responses of endocrine disrupting chemicals: Has the case been made?

Lorenz R. Rhomberg, , Julie E. Goodman

http://www.sciencedirect.com/science/journal/02732300/64/1

Regulatory Toxicology and Pharmacology

Volume 64, Issue 1, October 2012, Pages 130–133 (Open Access)

Vandenberg et al.

► claim low-dose effects and nonmonotonicity of endocrine disrupting chemicals.

► They do not provide sufficient evidence to support their conclusions.

► They overlook evidence contrary to their conclusions.

► They do not evaluate whether exposures are truly low-dose and relevant to humans.

► Many of their examples are not widely endorsed by the scientific community.

3. A second recent article cited by Nohynek and crew:

Endocrine effects of chemicals: aspects of hazard identificationand human health risk assessment. Dekant W, Colnot T.

Highlights

•Hazard assessment for chemicals with hormonal activity needs to rely on induction of adverse effects.

•Approaches to risk assessment of chemicals with hormonal activity are discussed.

•“Inverted U-shaped” dose–response curves for chemicals with hormonal activity are not supported.

Hazard and risk assessment of chemicals with endocrine activity is hotly debated due to claimed non-monotonous dose-response curves in the low-dose region. In hazard identification a clear definition of "endocrine disruptors" (EDs) is required; this should be based on the WHO/IPCS definition of EDs and on adverse effects demonstrated in intact animals or humans. Therefore, endocrine effects are a mode of action potentially resulting in adverse effects; any classification should not be based on a mode of action, but on adverse effects. In addition, when relying on adverse effects, most effects reported in the low-dose region will not qualify for hazard identification since most have little relation to an  adverse effect. Non-monotonous dose-response curves that had been postulated from limited, exploratory studies could also not be reproduced in targeted studies with elaborate quality assurance. Therefore, regulatory agencies or advisory bodies continue to apply the safety-factor method or the concept of "margin-of-exposure" based on no observed adverse effect levels (NOAELs) in the risk assessment of chemicals with weak hormonal activity. Consistent with this approach, tolerable levels regarding human exposure have been defined for such chemicals. To conclusively support non-monotonous dose-response curves, targeted  experiments with a sufficient number of animals, determination of adverse endpoints, adequate statistics and quality control would be required.

Toxicol Lett. 2013 Dec 16;223(3):280-6. doi: 10.1016/j.toxlet.2013.03.022. Epub 2013 Mar 28.  Endocrine effects of chemicals: aspects of hazard identification and human health risk assessment. 

Key Quote from Dekant and Colnot 2013:

4. Issues with low-dose effects
Low dose effects have been reported with several chemicals with hormonal activity and have been explained as indicative for non-monotonous dose–response relationships (e.g. “inverted U-shapes” of the dose–response curve) ( Vandenberg et al., 2012). The presence of “inverted U-shapes” in dose ranges well below those covered by toxicity studies and below tolerable human exposures that have been derived for chemicals with weak endocrine activity from guideline toxicity studies using the safety factor methodology have been attributed to specific properties of the interaction of hormonally active chemicals with the endocrine system and specific features of the receptor response ( Vandenberg et al., 2012 and Zoeller et al., 2012). If confirmed, “inverted U-shape” dose response curves may have a specific impact on the testing of chemicals for adverse effects (e.g. use of more then 3 dose levels spanning a very wide dose range) and for the risk assessment process. However, despite the reporting of low-dose effects in a number of studies and interpretation of the toxicology database on chemicals with hormonal activity as frequently indicative of non-linear dose–responses ( Vandenberg et al., 2012), regulatory authorities have not endorsed the presence of “inverted U-shaped” or other non-linear dose–responses for chemicals with hormonal activity. This is due to a number of shortcomings in studies reporting low-dose effects. These shortcomings include the use of only single dose level in a study, low numbers of animals per dose group, determination of small changes in endpoints with significant variability, issues of confounding, inappropriate statistical evaluation, use of endpoints with questionable relation to adversity, and the failure to separate interacting dose–response curves such as the interaction between hormone-induced cell proliferation and cytotoxicity ( Ashby, 2003, EFSA, 2010, Goodman et al., 2006, Goodman et al., 2009,Melnick et al., 2002, Tyl, 2009 and Tyl et al., 2008). Moreover, studies with adequate quality control spanning a wide dose range could not confirm “inverted U-shaped” dose–response curves or other non-linear dose–response relationships or low-dose effects in general ( EFSA, 2010, FDA, 2008a and Goodman et al., 2009) and the overall database on “low-dose effects” is inconsistent. For example, low-dose effects were not observed in rodents exposed to a wide range of concentrations of bisphenol A in guideline compliant developmental toxicity studies and in comprehensive biochemical analyses of the receptor-mediated effects of TCDD in hepatocytes. The studies with bisphenol A covered six dose levels ranging from 0.018 to 600 mg/kg bw/day in mice and 0.001 to 500 mg/kg bw/day in rats. The analyses of TCDD-induced protein expression in hepatocytes used 11 concentration levels between 0.0001 and 100 nM ( Black et al., 2012 and Budinsky et al., 2010). In these studies, clear effect thresholds with no evidence of non-monotonous concentration response curves were observed. Therefore, “inverted U-shapes” or other non-monotonous dose–response curves for EDs cannot be considered as established.