Toxicology & Environmental Research and Consulting, The Dow Chemical Company , Midland, MI , USA.
Crit Rev Toxicol. 2014 May;44 Suppl 2:45-62. doi: 10.3109/10408444.2014.910752.
Sulfoxaflor (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. Sulfoxaflor induced these effects 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 offspring. 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 confidence, that the sulfoxaflor-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 differences in sulfoxaflor agonism on the rat versus the human muscle nAChR. Specifically, sulfoxaflor does not cause agonism on either the human fetal- or adult-type muscle nAChR.
（甲砜霉素）是一种新型的具有杀虫特性的活性物质，通过其对高度丰富的昆虫烟碱型乙酰胆碱受体（nAChR）的激动作用来介导。在发育和生殖毒性研究中，妊娠暴露导致胎儿畸形（主要是肢体挛缩），并降低了高剂量饮食暴露后的新生大鼠的存活率，但对兔子没有影响。（甲砜霉素）通过一种新型作用模式（MoA）诱导这些作用，该模式由胎儿型肌肉 nAChR 介导，具有以下关键事件：（1）与受体结合，（2）在受体上激动，导致（3）在近胎期胎儿和新生后代中持续的肌肉收缩。这种持续的肌肉收缩导致四肢畸形、锁骨弯曲和膈肌功能降低，从而在新生大鼠出生时损害呼吸，降低其存活率。本综述根据布拉德福·希尔标准评估了这种 MoA 的证据权重，包括在各种体外、离体和体内研究设计中应用和内剂量的交叉比较，检查了替代的 MoA，并应用人类相关性框架（HRF）来确定这种大鼠 MoA 的人类风险。该综述表明，在高置信度水平上，（甲砜霉素）诱导的大鼠胎儿畸形和新生死亡是通过单一的 MoA 发生的，该 MoA 包括对大鼠胎儿型肌肉 nAChR 的持续激活，导致持续的肌肉收缩。鉴于（甲砜霉素）对大鼠和人类肌肉 nAChR 的激动作用存在根本性的定性差异，这种 MoA 被认为与人类无关。具体而言，（甲砜霉素）不会引起人类胎儿型或成人型肌肉 nAChR 的激动作用。
