Innovative Strategies for Agrochemical Safety Assessments: Use of Toxicokinetic Data for ArylexTM and RinskorTM

摘要

Integrating toxicokinetics (TK) into toxicity studies, without use of additional animals, provides valuable data on metabolism, systemic exposure and dose response for observed toxicity. Guidance documents, such as the OECD GD 116, highlight the importance of TK for dose level selection. Increasingly, TK data are being used to provide insights on MoA, study design, and in vitro to in vivo extrapolation in human health risk assessments. Described here are case studies, with the herbicides, ArylexTM (Halauxifen-methyl) and RinskorTM (XDE-848 Benzyl Ester), highlighting the use of integrated TK approaches in novel testing strategies to explore a MoA, or implement kinetically-derived maximum dose (KMD) strategies, respectively. In the MoA case study, Halauxifen-methyl is rapidly hydrolyzed in rodent liver to a single primary metabolite, Halauxifen-acid, and induces rodent liver effects via nuclear receptor (NR) activation. Halauxifen-acid does not activate NR and in vitro assays in rat and human blood, liver S9, and gastric fluid evaluated species differences in hydrolysis rates. TK and hydrolysis data were incorporated into a PBPK model for rat and human systemic exposure to Halauxifen-methyl, and supported non-human relevance of the Halauxifen-methyl liver MoA. In the KMD case study, XDE-848 Benzyl Ester is hydrolyzed to a single primary metabolite, XDE-848 acid, which displays non-linear kinetics based on integrated TK from 28- to 90-day toxicity studies. Interestingly, these studies indicated no toxicity up to the limit dose (1000 mg/kg/day) and the TK data provided strong justification for use of a KMD approach on the OECD 453 and 416 studies in the rat, and 1-year chronic toxicity study in the dog. A high dose of 300 mg/kg/day was chosen in contrast to traditional toxicity testing paradigms using a maximum tolerated dose approach where the limit dose is chosen as the high dose in the absence of toxicity. Taken together, integration of TK into guideline toxicity studies can increase understanding of the intrinsic properties of a molecule to develop human health risk assessments that utilize the best available science.