A critical review of neonicotinoid insecticides for developmental neurotoxicity

• Published in: Critical reviews in toxicology 2016-02, Vol.46 (2), p.153-190
• Main Authors: Sheets, Larry P., Li, Abby A., Minnema, Daniel J., Collier, Richard H., Creek, Moire R., Peffer, Richard C.
• Format: Article
• Language: English
• Subjects: acetamiprid; Animals; Central Nervous System - drug effects; Central Nervous System - pathology; clothianidin; developmental neurotoxicity; Disease Models, Animal; Dose-Response Relationship, Drug; Guanidine - analogs & derivatives; Guanidine - toxicity; Guanidines - toxicity; Humans; imidacloprid; Imidazoles - toxicity; Insecta - drug effects; insecticide; Insecticides - toxicity; Neonicotinoid; Neonicotinoids; nicotinic receptor; Nitro Compounds - toxicity; Oxazines - toxicity; Pyridines - toxicity; Randomized Controlled Trials as Topic; Receptors, Nicotinic - metabolism; Reflex, Startle - drug effects; Review; Risk Assessment; Thiamethoxam; Thiazines - toxicity; Thiazoles - toxicity; United States; United States Environmental Protection Agency
• ISSN: 1040-8444; 1547-6898
• DOI: 10.3109/10408444.2015.1090948

A comprehensive review of published and previously unpublished studies was performed to evaluate the neonicotinoid insecticides for evidence of developmental neurotoxicity (DNT).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.