No abstract

Sulfoxaflor (X11422208), a novel agricultural molecule, induced fetal effects (forelimb flexure, hindlimb rotation, and bent clavicle) and neonatal death in rats at high doses (≥ 400 ppm in diet); however, no such effects occurred in rabbit dietary studies despite achieving similar maternal and fetal plasma exposure levels. Mode-of-action (MoA) studies were conducted to test the hypothesis that the effects in rats had a single MoA induced by sulfoxaflor agonism on the fetal rat muscle nicotinic acetylcholine receptor (nAChR). The studies included cross-fostering and critical windows of exposure studies in rats, fetal ((α1)(2)β1γδ) and adult ((α1)(2)β1δε) rat and human muscle nAChR in vitro agonism experiments, and neonatal rat phrenic nerve-hemidiaphragm contracture studies. The weight of evidence from these studies supported a novel MoA where sulfoxaflor is an agonist to the fetal, but not adult, rat muscle nAChR and that prolonged agonism on this receptor in fetal/neonatal rats causes sustained striated muscle contracture resulting in concomitant reduction in muscle responsiveness to physiological nerve stimulation. Fetal effects were inducible with as little as 1 day of exposure at the end of gestation, but were rapidly reversible after birth, consistent with a pharmacological MoA. With respect to human relevance, sulfoxaflor was shown to have no agonism on human fetal or adult muscle nAChRs. Taken together, the data support the hypothesis that the developmental effects of sulfoxaflor in rats are mediated via sustained agonism on the fetal muscle nAChR during late fetal development and are considered not relevant to humans.

Sulfoxafl or, a novel active substance that targets sap-feeding insects, induced rodent hepatotoxicity when administered at high dietary doses. Specifi cally, hepatocellular adenomas and carcinomas increased after 18 months in male and female CD-1 mice at 750 and 1250 ppm, respectively, and hepatocellular adenomas increased after 2 years in male F344 rats at 500 ppm. Studies to determine the mode of action (MoA) for these liver tumors were performed in an integrated and prospective manner as part of the standard battery of toxicology studies such that the MoA data were available prior to, or by the time of, the completion of the carcinogenicity studies. Sulfoxafl or is not genotoxic and the MoA data support the following key events in the etiology of the rodent liver tumors: (1) CAR nuclear receptor activation and (2) hepatocellular proliferation. The MoA data were evaluated in a weight of evidence approach using the Bradford Hill criteria for causation and were found to align with dose and temporal concordance, biological plausibility, coherence, strength, consistency, and specifi city for a CAR-mediated MoA while excluding other alternate MoAs. The available data include: activation of CAR, Cyp2b induction, hepatocellular hypertrophy and hyperplasia, absence of liver eff ects in KO mice, absence of proliferation in humanized mice, and exclusion of other possible mechanisms (e.g., genotoxicity, cytotoxicity, AhR, or PPAR activation), and indicate that the identifi ed rodent liver tumor MoA for sulfoxafl or would not occur in humans. In this case, sulfoxafl or is considered not to be a potential human liver carcinogen.

No abstract

There are currently several factors driving a move away from the reliance on in vivo toxicity testing for the purposes of chemical safety assessment. Progress has started to be made in the development and validation of non-animal methods. However, recent advances in the biosciences provide exciting opportunities to accelerate this process and to ensure that the alternative paradigms for hazard identification and risk assessment deliver lasting 3Rs benefits, whilst improving the quality and relevance of safety assessment. The NC3Rs, a UK-based scientific organisation which supports the development and application of novel 3Rs techniques and approaches, held a workshop recently which brought together over 20 international experts in the field of chemical safety assessment. The aim of this workshop was to review the current scientific, technical and regulatory landscapes, and to identify key opportunities towards reaching these goals. Here, we consider areas where further strategic investment will need to be focused if significant impact on 3Rs is to be matched with improved safety science, and why the timing is right for the field to work together towards an environment where we no longer rely on whole animal data for the accurate safety assessment of chemicals.