A critical review of neonicotinoid insecticides for developmental neurotoxicity

Abstract

A comprehensive review of published and previously unpublished studies was performed to evaluate the neonicotinoid insecticides for evidence of developmental neurotoxicity (DNT). These insecticides have favorable safety profiles, due to their preferential affinity for nicotinic receptor (nAChR) subtypes in insects, poor penetration of the mammalian blood–brain barrier, and low application rates. Nevertheless, examination of this issue is warranted, due to their insecticidal mode of action and potential exposure with agricultural and residential uses. This review identified in vitro, in vivo, and epidemiology studies in the literature and studies performed in rats in accordance with GLP standards and EPA guidelines with imidacloprid, acetamiprid, thiacloprid, clothianidin, thiamethoxam, and dinotefuran, which are all the neonicotinoids currently registered in major markets. For the guideline-based studies, treatment was administered via the diet or gavage to primiparous female rats at three dose levels, plus a vehicle control (≥20/dose level), from gestation day 0 or 6 to lactation day 21. F1 males and females were evaluated using measures of motor activity, acoustic startle response, cognition, brain morphometry, and neuropathology. The principal effects in F1 animals were associated with decreased body weight (delayed sexual maturation, decreased brain weight, and morphometric measurements) and acute toxicity (decreased activity during exposure) at high doses, without neuropathology or impaired cognition. No common effects were identified among the neonicotinoids that were consistent with DNT or the neurodevelopmental effects associated with nicotine. Findings at high doses were associated with evidence of systemic toxicity, which indicates that these insecticides do not selectively affect the developing nervous system.

Keywords:

• Neonicotinoid
• insecticide
• developmental neurotoxicity
• nicotinic receptor
• acetamiprid
• imidacloprid
• clothianidin
• thiamethoxam

Acknowledgements

The authors want to acknowledge Alan Hoberman (Charles River Laboratories), Robert Garman (Consultants in Veterinary Pathology, Inc.), Mark Nemec and Melissa Beck (formerly with WIL Laboratories), Eddie Sloter (WIL Labs), Edmund Lau and Steave Su (Exponent, Inc.), Sandra Allen and Gill Milburn (Regulatory Science Associates, formerly at Syngenta Central Toxicology Laboratory), and Barry Stuart (formerly with Bayer CropScience) for their involvement in the guideline DNT studies cited in this review or further analysis of the findings. We also acknowledge the assistance of Edward Scollon (Syngenta Crop Protection) and Gabriele Schmuck (Bayer HealthCare, Animal Health) for reviewing studies reported in the literature.

Declaration of interest

The authors are employed or funded by companies that manufacture and sell the neonicotinoid insecticides that were evaluated in this review. The authors are experts on the toxicology of these insecticides, with responsibility for addressing regulatory toxicology issues and reviews. RHC is involved in litigation for dinotefuran; however, the subject of litigation does not pertain to DNT and EPA concluded dinotefuran had no effect in the DNT study, as reflected in this review. None of the other authors is involved in litigation for the neonicotinoid insecticides reviewed in this paper. This review is premised upon the publically-available literature, the publically-available EPA reviews of the DNT studies and the DNT study reports and data analysis. All authors contributed to the conception, design, data analysis and interpretation, drafting and critically revising this review paper, including sections unrelated to the insecticide produced by the company for which they worked. At the end of the review and drafting process and immediately prior to submission of the manuscript, a copy of the final draft was sent to company representatives for comment. Revisions made in response to comments and suggested edits were minor and did not alter or contribute to the opinions and conclusions. Thus, the analysis, interpretation and conclusions presented herein are solely those of the authors.