28 July 2016

In recent years, there has been significant discussion around low-dose effects (LDEs) and non-monotonic dose-response (NMDR) curves, particularly relative to endocrine disruption. For example, there are claims that crop protection products are associated with LDEs and NMDRs, which question whether current human exposure limits are adequate. These claims present an opportunity for increased dialogue on the relevance of LDEs and NMDRs for chemical risk assessment and regulatory decision-making.

The focus on LDE and NMDR relevance has to be shifted to a different level of thinking and involve 1) clarification on the definition of low dose, 2) recognition of current testing guidelines and risk assessment standards for crop protection products, 3) strength of evidence for LDEs/NMDRs and the relationship to adversity of effect, 4) temporality of dose-response relationships, and 5) placement of any observed LDEs or NMDRs in the context of related endpoints examined in affected system(s) (e.g., endocrine), other systemic endpoints, other available data and the relevance to human and wildlife exposure. The discussion needs to progress from debating whether LDEs or NMDRs exist to their relevance for risk assessment and protection of environmental and human health. What constitutes low dose and what might be termed an effect to some may be different from the perspective of a regulatory scientist who considers an effect in the context of the following: a weight-of-evidence evaluation of available scientific data, determination of whether an effect is adverse or adaptive,[1] where the effect falls relative to the no observed adverse effect level/concentration used for establishment of acceptable exposure levels, and finally, how the effective dose compares to actual human exposure.

Crop protection products are regulated globally and testing requirements span the range of exposures from frank (high) toxicity levels to thresholds (no effect levels/concentrations) below which no adverse effects are observed. A number of crop protection products were the first candidate chemicals to undergo Tier 1 screening with 11 endocrine-sensitive assays under the U.S. Endocrine Disruptor Screening Program.[2] Using a weight-of-evidence approach, there is no indication that toxicologically meaningful LDEs or NMDRs influenced the United States Environmental Protection Agency’s (EPA) recommendations for Tier 2 testing. Tier 2 testing, in comparison with Tier 1 screening, is more comprehensive, longer-term testing that is intended to characterize the dose response of endocrine mediated (and non-endocrine mediated) effects in whole organisms.

In 2013, the EPA published a draft report, “State of the Science Evaluation: Nonmonotonic Dose Responses as They Apply to Estrogen, Androgen, and Thyroid Pathways and EPA Testing and Assessment Procedures.[3]” While criticized for methodological issues,[4] the EPA reached a number of conclusions from their evaluation that are, to date, generally supported. It stated that while NMDRs do occur, they are not commonly identified in vivo and are rarely seen when identifying adverse effects in whole-organism studies after either low-dose or long-term exposure. The EPA also concluded “there is currently no reproducible evidence that the early key events involved in the expression of NMDRs that are identified at low dose are predictive of adverse outcomes that may be seen in humans or wildlife populations for estrogen, androgen or thyroid endpoints.” At present, regulatory agencies globally have not modified their testing approaches or requirements in response to charges that they fail to adequately address either LDEs or NMDRs.

The tenets and first principles of pharmacology and toxicology, including “the dose makes the poison” and potency, need to enter this discussion. For example, there are drug treatments that exert endocrine activity (e.g., birth control pills, estrogen replacement therapy) with therapeutic benefits based on traditional dose-response and relative potency. If LDEs and NMDRs are common within biological systems, and if they result in adversity to a living system without being adequately identified in toxicological testing during chemical and drug development, then testing approaches and regulatory oversight need to be reconsidered. Finally, while the current focus of LDEs and NMDRs relates primarily to exogenous, synthetic chemicals, these phenomena and this discussion should extend and include any/all natural chemicals and constituents of food and other products as the human body does not distinguish chemistry – whether naturally occurring or man-made – to which it is being exposed.

Daland Juberg, Ph.D., is a Fellow of the Academy of Toxicological Sciences and global leader, Human Health Assessment, at Dow AgroSciences LLC in Indianapolis, Ind., USA. Sue Marty, Ph.D., is a Diplomate of the American Board of Toxicology and TERC science leader at The Dow Chemical Company in Midland, Mich., USA.

^* The views expressed in this article are those of the authors and do not necessarily reflect the views of Dow AgroSciences or The Dow Chemical Company.

[1] Keller DA, Juberg DR, Catlin N, Farland WH, Hess FG, Wolf DC, Doerrer NG. 2012. Identification and characterization of adverse effects in 21^st century toxicology. Toxicol Sci. 126(2):291-97.

[2] United States Environmental Protection Agency. 2015. Endocrine Disruptor Screening Program tier 1 assessments. https://www.epa.gov/ingredients-used-pesticide-products/endocrine-disruptor-screening-program-tier-1-assessments (accessed July 11, 2016).

[3] Office of Research and Development and Office of Chemical Safety and Pollution Prevention, United States Environmental Protection Agency. 2013. State of the science evaluation: Nonmonotonic dose responses as they apply to estrogen, androgen, and thyroid pathways and EPA testing and assessment procedures – V7.

[4] National Research Council, National Academies of Sciences, Engineering, and Medicine. 2013. Review of the Environmental Protection Agency’s state-of-the-science evaluation of nonmonotonic dose-response relationships as they apply to endocrine disrupters (2014). The National Academies Press, Washington, D.C.