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

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.

Disposition of glycolic acid into rat and rabbit embryos in vitro.

High dose gavage administration of ethylene glycol (EG) induces teratogenicity in rodents, but not in rabbits, resulting from saturation of intermediate EG metabolism and glycolic acid (GA) accumulation. In vivo, rat embryos sequester GA 2-4-fold higher than maternal blood, a phenomenon absent in rabbits and proposed not to occur in humans. This research explored the mechanisms of GA disposition into rat and rabbit conceptuses using whole embryo culture (WEC).

Incorporating new technologies into toxicity testing and risk assessment: moving from 21st century vision to a data-driven framework.

Based on existing data and previous work, a series of studies is proposed as a basis toward a pragmatic early step in transforming toxicity testing. These studies were assembled into a data-driven framework that invokes successive tiers of testing with margin of exposure (MOE) as the primary metric. The first tier of the framework integrates data from high-throughput in vitro assays, in vitro-to-in vivo extrapolation (IVIVE) pharmacokinetic modeling, and exposure modeling.

Prediction of late disease recurrence and extended adjuvant letrozole benefit by the HOXB13/IL17BR biomarker.

Background: Biomarkers to optimize extended adjuvant endocrine therapy for women with estrogen receptor (ER)-positive breast cancer are limited. The HOXB13/IL17BR (H/I) biomarker predicts recurrence risk in ER-positive, lymph node-negative breast cancer patients. H/I was evaluated in MA.