Saghir Shakil Ahmed
Smithers Avanza Toxicology Services, 11B Firstfield Road, Gaithersburg, MD 20878, United States.
Regul Toxicol Pharmacol. 2015 Jul;72(2):423-8. doi: 10.1016/j.yrtph.2015.05.009. Epub 2015 May 14.
The guidelines for risk assessment of plant protection products (PPPs) and other non-pharmaceuticals were developed over three decades ago and have generally not been updated to incorporate advancements in toxicology and exposure sciences. These guidelines recommend using maximum-tolerated-dose (MTD) even when human relevance of such high doses is mostly limited due to orders of magnitude margin-of-exposure. Conducting animal studies at such high doses often requires further mode-of-action (MoA) studies elucidating human relevance. In order to improve data, ILSI/HESI-ACSA technical committee proposed a tiered approach with emphasis on determining systemic dose of parent and/or metabolite(s) in test animals as biological effects are reflective of systemic rather than administered dose. Any deviation from linearity in systemic dose (saturation of absorption or elimination) in animal studies may have profound toxic effect(s) not expected to occur in likely human exposure scenarios and should be avoided. Toxicity studies should ideally be conducted at kinetically linear doses or slightly above the point of departure from linearity or kinetically-derived maximum dose (KMD) as the systemic dose nonlinearity is a more sensitive parameter occurring much earlier than the MTD endpoints. Therefore, determining systemic dose, especially KMD, in study animals is an improvement to hazard assessment of PPPs and other non-pharmaceuticals allowing toxicologists to better understand findings in animals at systemically linear as well as nonlinear doses to likely human exposures which can easily be accomplished using core study animals as outlined below. Determining systemic dose in studies will also increase the understanding of initial potential MoA of a PPPs and other non-pharmaceuticals and reduce the use of animals by avoiding unnecessary additional MoA studies.
植物保护产品（PPPs）及其他非药品的风险评估指南是三十多年前制定的，总体上尚未更新以纳入毒理学和暴露科学的进展。这些指南建议使用最大耐受剂量（MTD），即使由于暴露量的数量级差异，如此高剂量与人类的相关性大多有限。在如此高剂量下进行动物研究通常需要进一步的作用模式（MoA）研究来阐明与人类的相关性。为了改进数据，国际生命科学研究所/健康与环境科学学会-农药科学咨询委员会（ILSI/HESI-ACSA）技术委员会提出了一种分层方法，重点是确定试验动物体内母体和/或代谢物的全身剂量，因为生物学效应反映的是全身剂量而非给药剂量。动物研究中全身剂量的任何线性偏差（吸收或消除的饱和）可能会产生在可能的人类暴露场景中预计不会出现的深远毒性作用，应予以避免。毒性研究理想情况下应在动力学线性剂量下进行，或略高于线性偏离点或动力学推导的最大剂量（KMD），因为全身剂量非线性是一个比MTD终点出现更早的更敏感参数。因此，确定研究动物的全身剂量，尤其是KMD，是对PPPs和其他非药品危害评估的改进，使毒理学家能够更好地理解动物在全身线性和非线性剂量下对可能的人类暴露的研究结果，这可以使用如下所述的核心研究动物轻松实现。确定研究中的全身剂量还将增加对PPPs和其他非药品初始潜在作用模式的理解，并通过避免不必要的额外作用模式研究减少动物的使用。
