Slama et al. (2016) recently published a paper on issues relevant to setting regulations for endocrine disrupting substances in the European Union.1 The authors discuss options associated with these issues, briefly described as use of interim criteria, or use of the World Health Organization definition of endocrine disruption by itself or with additional categories of strength of evidence or chemical potency.
We agree with several points of the authors, but we also found some errors. The European Union is said to be the first major authority to develop a strategy for the regulation of endocrine disrupting chemicals. Not so. The U.S. Environmental Protection Agency (1980)2 and the World Health Organization,3 developed strategies for defining “safe” doses for chemicals on the basis of reviewing data and applying factors 30 or so years earlier to account for uncertainty in what those data tell us. The strategy, still in force and still evolving,4 protects against the adverse effect a chemical produces at the lowest level of exposure and all other effects that the chemical may cause at higher exposure. Using this strategy, numerous chemicals have been regulated with “safe” doses based on endocrine disruption, as can be seen in a review of the International Toxicity Estimates for Risk (ITER) or the Integrated Risk Information System (IRIS) on the U.S. National Library of Medicine’s Toxnet web database.5 Thus, endocrine disruption is not a new kind of hazard as the authors say, and as already mentioned.6
The authors also state that potency of a chemical “is not well defined,” and then go on to show in a series of figures why potency is not helpful in an evaluation of endocrine disruption. But potency, the strength of a chemical in causing its effects, is actually well defined in numerous toxicology textbooks,7 and simple examples can be easily shown to discount their concern.
For example, consider the chemicals perchlorate and dihydrogen monoxide. These chemicals are both disruptors of different endocrine systems, but they differ greatly in potency or strength of effect. Perchlorate disrupts thyroid hormones at tiny doses, ug/kg body weight-day (essentially 1 sugar grain per day from a 1gram sugar packet). In huge contrast, dihydrogen monoxide disrupts kidney and adrenal hormones at grams/kg body weight-day (essentially 5 to 7 quarts per day). So if potency is not considered in the evaluation of these two chemicals for endocrine disruption, how does one make a distinction in managing their potential risk?
Slama et al. might suggest that it does not make any difference, or that a distinction should be made on what is considered to be negligible exposure. This latter choice won’t work, however, as daily exposure to dihydrogen monoxide is enormous (one to two quarts per day), whereas for perchlorate the exposure is virtually zero. Many authorities regulate perchlorate, the thyroid disrupting chemical with extremely low, near zero exposure, but do not regulate water, (that is, dihydrogen monoxide), for disrupting kidney and adrenal hormones.
The authors’ call for additional research is reasonable, but funding of such research needs to be scientifically based. The current strategy focuses on determining safe doses of chemical, including doses that would protect against endocrine disruption. The challenge of current findings on endocrine disruption is to assure that such protection is occurring.
This article was written in collaboration with several authors: Dr. Michael Dourson, Dr. Sam Kacew, Dr. Rita Schoeny, Dr. Wallace Hayes, Dr. Penny Fenner-Crisp, and Dr. Ray York.
1 Rémy Slama, Jean-Pierre Bourguignon, Barbara Demeneix, Richard Ivell, Giancarlo Panzica, Andreas Kortenkamp, and Thomas Zoeller. 2016. Scientific issues relevant to setting regulatory criteria to identify endocrine disrupting substances in the European Union. Environmental Health Perspectives. Doi.org/10.1289/EHP217.
2 U.S. EPA (U.S. Environmental Protection Agency). 1980. Guidelines and methodology used in the preparation of health effects assessment chapters of the consent decree water quality criteria. Fed Regist. 45: 79347-79357.
3 See, for example: https://en.wikipedia.org/wiki/Acceptable_daily_intake.
4 A partial list of references includes:
Barnes, D.G. and M.L. Dourson. 1988. Reference dose (RfD): Description and use in health risk assessments. Regul Toxicol Pharmacol. 8: 471-486.
Boobis AR, Doe JE, Heinrich-Hirsch B, Meek ME, Munn S, Ruchirawat M, Schlatter J, Seed J, Vickers C. 2008. IPCS framework for analyzing the relevance of a noncancer mode of action for humans. Crit Rev Toxicol. 2008;38(2):87-96. doi: 10.1080/10408440701749421.
Crump, K.S. 1984. A new method for determining allowable daily intakes. Fund. Appl. Toxicol. 4: 854-871.
Dourson, M.L. and J.F. Stara. 1983. Regulatory history and experimental support of uncertainty (safety) factors. Regul Toxicol Pharmacol. 3: 224-238.
Dourson, M.L., L.A. Knauf, and J.C. Swartout. 1992. On Reference Dose (RfD) and Its Underlying Toxicity Data Base. Toxicology and Industrial Health. 8(3): 171-189.
Dourson, M.L., S.P. Felter, and D. Robinson. 1996. Evolution of science-based uncertainty factors in noncancer risk assessment. Regul Toxicol Pharmacol. 24: 108-120.
Dourson, M.L., G. Charnley, and R. Scheuplein. 2002. Differential Sensitivity of Children and Adults to Chemical Toxicity: II. Risk and Regulation. Regul Toxicol Pharmacol. 35: 448-467.
Elder, L., Poirier, K. Dourson, M., Kleiner, J., Mileson, B., Nordmann, H., Renwick, A., Slob, W., Walton, K., and G. Wurtzen. 2002. Mathematical modeling and quantitative methods. Food and Chem. Toxicol. 40: 283-326.
IPCS (International Programme on Chemical Safety). 2005. Chemical-specific adjustment factors for Interspecies differences and human variability: Guidance document for use of data in dose/concentration-response assessment. Geneva Swittzerland. Available at www.who.int/ipcs/methods/harmonization/areas/uncertainty/en/index.html
M. E. (Bette) Meek, Christine M. Palermo, Ammie N. Bachman, Colin M. North and R. Jeffrey Lewis. 2013. Mode of action human relevance (species concordance) framework: Evolution of the Bradford Hill considerations and comparative analysis of weight of evidence. Journal of Applied Toxicology. DOI 10.1002/jat.2984.
5 See http://toxnet.nlm.nih.gov.
6 Herman Autrup, Frank A. Barile, Bas J. Blaauboer, Gisela H. Degen,Wolfgang Dekant, Daniel Dietrich, Jose L. Domingo, Gio Batta Gori, Helmuth Greim, Jan G. Hengstler, Sam Kacew, Hans Marquardt, Olavi Pelkonen, Kai Savolainen, and Nico P. Vermeulen. 2015. Principles of Pharmacology and Toxicology Also Govern Effects of Chemicals on the Endocrine System. TOXICOLOGICAL SCIENCES, 1–5.
7 See, for example, Cassarett and Doull, 1996, page 25, and all subsequent editions.