Exponent Inc, Alexandria, VA, 22314, USA.
BASF Corporation, Research Triangle Park, NC, 27709, USA.
Regul Toxicol Pharmacol. 2020 Jun;113:104644. doi: 10.1016/j.yrtph.2020.104644. Epub 2020 Mar 16.
Afidopyropen is an insecticide that acts as a TRPV channel modulator in chordotonal organs of target insects and has been assessed for a wide range of toxicity endpoints including developmental toxicity in rats and rabbits. The GLP developmental toxicity study in rabbits did not produce evidence of maternal or fetal toxicity at the highest dose tested (32 mg/kg/day) but pharmacokinetics (PK) in pregnant rabbits in this study exhibited onset of PK nonlinearity from 5 mg/kg/day on, as measured by plasma C and AUC. The NOAEL (32 mg/kg/day) is 9000X higher than maximum expected human dietary exposures to afidopyropen; the dose range where nonlinear PK were observed (5-15 mg/kg/day) is 1400-4200X higher. As nonlinearity occurred between 5 and 15 mg/kg/day, 32 mg/kg/day is concluded to be a sufficiently high dose (kinetically derived maximum dose) for a prenatal developmental toxicity study. As recognized by regulatory dose-selection guidance, onset of saturated PK is evidence of excessive biological stress to test animals rendering any effects at such doses of questionable relevance for human risk assessment. These data demonstrate that consideration of PK is critical for improving the dose-selection in developmental toxicity studies to enhance human relevance of animal toxicity studies.
阿弗地平是一种杀虫剂，它在靶标昆虫的听毛器官中作为 TRPV 通道调节剂发挥作用，已评估了包括大鼠和兔的发育毒性在内的广泛毒性终点。在兔中进行的 GLP 发育毒性研究在最高测试剂量（32mg/kg/天）下未产生母体或胎儿毒性的证据，但本研究中妊娠兔的药代动力学（PK）表现出从 5mg/kg/天开始出现 PK 非线性，这是通过血浆 C 和 AUC 来衡量的。NOAEL（32mg/kg/天）是人类最大预期膳食暴露于阿弗地平的 9000 倍；观察到非线性 PK 的剂量范围（5-15mg/kg/天）是 1400-4200 倍。由于非线性发生在 5 至 15mg/kg/天之间，因此可以得出结论，32mg/kg/天是进行产前发育毒性研究的足够高剂量（从 PK 角度推导的最大剂量）。正如监管剂量选择指南所承认的，饱和 PK 的出现表明试验动物承受了过度的生物压力，使得此类剂量下的任何影响对于人类风险评估都具有可疑的相关性。这些数据表明，考虑 PK 对于提高发育毒性研究中的剂量选择至关重要，以增强动物毒性研究对人类的相关性。
