Human relevance framework evaluation of a novel rat developmental toxicity mode of action induced by sulfoxaflor

Abstract

Sulfoxafl or (CAS# 946578-00-3) is a novel active substance with insecticidal properties mediated via its agonism on the highly abundant insect nicotinic acetylcholine receptor (nAChR). In developmental and reproductive toxicity studies, gestational exposure caused fetal abnormalities (primarily limb contractures) and reduced neonatal survival in rats, but not rabbits, following high-dose dietary exposure. Sulfoxafl or induced these eff ects via a novel mode of action (MoA) mediated by the fetal-type muscle nAChR with the following key events: (1) binding to the receptor, (2) agonism on the receptor, causing (3) sustained muscle contracture in the near-term fetus and neonatal off spring. This sustained muscle contracture results in misshapen limbs, bent clavicles, and reduced diaphragm function, which compromises respiration in neonatal rats at birth, reducing their survival. This review evaluates the weight of evidence for this MoA based upon the Bradford Hill criteria, includes a cross-comparison of applied and internal doses in a variety of in vitro , ex vivo , and in vivo study designs, examines alternative MoAs, and applies a Human relevance framework (HRF) to ascertain human risk for this rat MoA. The review indicated, with a high level of confi dence, that the sulfoxafl or-induced fetal abnormalities and neonatal death in rats occur via a single MoA comprising sustained activation of the rat fetal-type muscle nAChR resulting in a sustained muscle contracture. This MoA is considered not relevant to humans, given fundamental qualitative diff erences in sulfoxafl or agonism on the rat versus the human muscle nAChR. Specifi cally, sulfoxafl or does not cause agonism on either the human fetal-or adult-type muscle nAChR.

In Vivo Effects of Neonicotinoid-Sulfoximine Insecticide Sulfoxaflor on Acetylcholinesterase Activity in the Tissues of Zebrafish (Danio rerio)

“…No studies regarding the environmental concentration in water bodies of sulfoxaflor or its metabolites have been conducted until this time. Similar to neonicotinoids, sulfoxaflor has a variable half-life ranging from 37–88 days in aquatic systems under aerobic conditions and ranging from 103–382 days under anaerobic conditions [ 2 ]. It is obvious that interactions between sulfoxaflor and the environment have not been well revealed.…”

“…Sufoxaflor[methyl(oxo){1-[6-(trifluoromethyl)-3-pyridyl]ethyl}-λ6-sulfanylidene]cyanamide (IUPAC) (Chemical Abstracts Service No. 946578-00-3) is one of the newly developed neonicotinoid-sulfoximine insecticides [ 1 ] and it acts as a nicotinic acetylcholine receptor (nAChR) agonist in insects [ 2 ]. Sulfoxaflor has a unique structure–activity relation when compared with other neonicotinoids, since it contains the sulfoximine group.…”

Maternal residential exposure to agricultural pesticides and birth defects in a 2003 to 2005 North Carolina birth cohort

“…Developmental toxicants disrupt growth and organ formation. Prenatal exposure to sulfoxaflor, a chemical with insecticide properties, has been implicated in limb defects (limb contracture: forelimb flexure, hindlimb rotation, and bent/misshapen clavicle bones) in rats by binding with aChR receptor during fetal development (Ellis‐Hutchings et al, ). Other potential mechanisms of pesticide action in chronic diseases may also play a role, such as: genetic or germ cell damage or epigenetic changes from preconception exposures; inhibition of electron chain transport activity or mitochondrial dysfunction; oxidative stress; or protein regulation (Mostafalou and Abdollahi, ).…”

A critical review of neonicotinoid insecticides for developmental neurotoxicity

“…Given the fundamental qualitative differences in sulfoxaflor agonism on the rat versus the human muscle nAChR, this mode of action is not relevant to, or at least very unlikely to occur, in humans (Ellis-Hutchings et al. 2014 ). Therefore, sulfoxaflor is a developmental toxicant in the rat but it does not result in neurotoxicity in the adult rat or other mammalian species, due to its specificity in interaction with the fetal nAChR.…”