Weight-of-the-evidence evaluation of 2,4-D potential for interactions with the estrogen, androgen and thyroid pathways and steroidogenesis

Abstract

A comprehensive weight-of-the-evidence evaluation of 2,4-dichlorophenoxyacetic acid (2,4-D) was conducted for potential interactions with the estrogen, androgen and thyroid pathways and with steroidogenesis. This assessment was based on an extensive database of high quality in vitro, in vivo ecotoxicological and in vivo mammalian toxicological studies. Epidemiological studies were also considered. Toxicokinetic data provided the basis for determining rational cutoffs above which exposures were considered irrelevant to humans based on exceeding thresholds for saturation of renal clearance (TSRC); extensive human exposure and biomonitoring data support that these boundaries far exceed human exposures and provide ample margins of exposure. 2,4-D showed no evidence of interacting with the estrogen or androgen pathways. 2,4-D interacts with the thyroid axis in rats through displacement of thyroxine from plasma binding sites only at high doses exceeding the TSRC in mammals. 2,4-D effects on steroidogenesis parameters are likely related to high-dose specific systemic toxicity at doses exceeding the TSRC and are not likely to be endocrine mediated. No studies, including high quality studies in the published literature, predict significant endocrine-related toxicity or functional decrements in any species at environmentally relevant concentrations, or, in mammals, at doses below the TSRC that are relevant for human hazard and risk assessment. Overall, there is no basis for concern regarding potential interactions of 2,4-D with endocrine pathways or axes (estrogen, androgen, steroidogenesis or thyroid), and thus 2,4-D is unlikely to pose a threat from endocrine disruption to wildlife or humans under conditions of real-world exposures.

Keywords:

• 2,4-Dichlorophenoxyacetic acid
• endocrine
• toxicology
• ecotoxicology
• in vitro
• toxicokinetics
• exposure
• reproduction

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Acknowledgments

The authors thank the four reviewers, selected by the Editor and anonymous to the authors, for their constructive comments that improved its overall quality and clarity of the manuscript.

In memoriam, Barbara Neal, DABT (prepared by James Lamb):

Barbara Neal and I worked together for over 20 years. The response by her colleagues to her passing remind me how valued she was in the field of toxicology. Barbara and I evaluated dozens of various issues in reproductive, developmental and endocrine responses. She approached work and life with a sense of humor and passion that will be missed by me and others in toxicology. Very few will ever match her keen observations and care at interpretation.

Barbara would dig into data more deeply than most. She would find interesting and useful information often missed by others. The paper by Barbara in this issue of Critical Reviews in Toxicology is a perfect example of Barbara?s passion for paying attention to detail. She has analyzed and understood the vast dataset on 2,4-D in a way that no one else could match.

Barbara was a creative and open-minded toxicologist who always looked for more clear ways to describe data, and stronger methods to test a hypothesis. She had no patience with sloppy or convenient interpretations. She would become annoyed with scientists who worked to prove their own pre-existing views, which she felt had become far too common and too adversarial. Barbara always sought an honest answer to an honest question without malice or some hidden agenda. She had no patience for hiding or overlooking results to prove a point.

Barbara worked with her own unique sense of humor. She enjoyed puns and surprising twists in a story. You could often hear her chuckling in a crowd, often at her own joke. She laughed often, even at herself, but never at the expense of others.

Barbara Neal was a special scientist and person who will be deeply missed by many of us in toxicology, which she called home.

Barbara passed away on October 19, 2015, during the final stages of this manuscript preparation. She was a member of the Society of Toxicology and a Diplomate of the American Board of Toxicology, and held the position of Senior Managing Scientist at Exponent, Inc. since 2010. Her career in toxicology extended over 30 years, and included earlier positions at The Weinberg Group, Inc., BBL Sciences, and Battelle Columbus Laboratories.

Declaration of interest

The employment affiliation of the authors is as shown on the cover page. This review was funded by the Industry Task Force II on 2,4-D Research Data [Authors Neal (deceased), Bus, Williams, Staveley and Lamb work for Exponent, which is a consulting company that has performed work for the Industry Task Force II on 2,4-D Research Data, as well as for individual member companies of the Task Force who manufacture 2,4-D. Authors Coady and Marty work for The Dow Chemical Company, which manufactures 2,4-D. On behalf of a previous employer and manufacturer of 2,4-D (The Dow Chemical Company), author Bus has engaged in a single litigation case (defendant deposition).] The review is the exclusive work product of the authors. The professional opinions expressed and the conclusions drawn are those of the authors and not necessarily those of their employers or the sponsors.

Funding

This review was funded by the Industry Task Force II on 2,4-D Research Data.

Supplemental material

Supplemental material for this article is available online here.

Additional information

Funding

This review was funded by the Industry Task Force II on 2,4-D Research Data.