Dorne J L C M
Clinical Pharmacology Group, University of Southampton, Biomedical Sciences Building, Bassett Crescent East, Southampton, SO16 7PX, UK.
Fundam Clin Pharmacol. 2004 Dec;18(6):609-20. doi: 10.1111/j.1472-8206.2004.00292.x.
Safety evaluation aims to assess the dose-response relationship to determine a dose/level of exposure for food contaminants below which no deleterious effect is measurable that is 'without appreciable health risk' when consumed daily over a lifetime. These safe levels, such as the acceptable daily intake (ADI) have been derived from animal studies using surrogates for the threshold such as the no-observed-adverse-effect-level (NOAEL). The extrapolation from the NOAEL to the human safe intake uses a 100-fold uncertainty factor, defined as the product of two 10-fold factors allowing for human variability and interspecies differences. The 10-fold factor for human variability has been further subdivided into two factors of 10(0.5) (3.16) to cover toxicokinetics and toxicodynamics and this subdivsion allows for the replacement of an uncertainty factor with a chemical-specific adjustment factor (CSAF) when compound-specific data are available. Recently, an analysis of human variability in pharmacokinetics for phase I metabolism (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, hydrolysis, alcohol dehydrogenase), phase II metabolism (N-acetyltransferase, glucuronidation, glycine conjugation, sulphation) and renal excretion was used to derive pathway-related uncertainty factors in subgroups of the human population (healthy adults, effects of ethnicity and age). Overall, the pathway-related uncertainty factors (99th centile) were above the toxicokinetic uncertainty factor for healthy adults exposed to xenobiotics handled by polymorphic metabolic pathways (and assuming the parent compound was the proximate toxicant) such as CYP2D6 poor metabolizers (26), CYP2C19 poor metabolizers (52) and NAT-2 slow acetylators (5.2). Neonates were the most susceptible subgroup of the population for pathways with available data [CYP1A2 and glucuronidation (12), CYP3A4 (14), glycine conjugation (28)]. Data for polymorphic pathways were not available in neonates but uncertainty factors of up to 45 and 9 would allow for the variability observed in children for CYP2D6 and CYP2C19 metabolism, respectively. This review presents an overview on the history of uncertainty factors, the main conclusions drawn from the analysis of inter-individual differences in metabolism and pharmacokinetics, the development of pathway-related uncertainty factors and their use in chemical risk assessment.
安全性评估旨在评估剂量 - 反应关系，以确定食品污染物的剂量/暴露水平，在该水平以下，当在一生中每日食用时，不会出现可测量的有害影响，即“没有明显健康风险”。这些安全水平，如每日允许摄入量（ADI），是通过动物研究得出的，使用无观察到有害作用水平（NOAEL）等阈值替代指标。从NOAEL外推至人类安全摄入量时使用100倍的不确定系数，该系数定义为两个10倍系数的乘积，分别考虑人类变异性和种间差异。人类变异性的10倍系数进一步细分为两个10(0.5)（3.16）的系数，以涵盖毒代动力学和毒效动力学，当有化合物特异性数据时，这种细分允许用化学特异性调整因子（CSAF）替代不确定系数。最近，对人类群体（健康成年人、种族和年龄的影响）中I相代谢（CYP1A2、CYP2A6、CYP2C9、CYP2C19、CYP2D6、CYP2E1、CYP3A4、水解、乙醇脱氢酶）、II相代谢（N - 乙酰转移酶、葡萄糖醛酸化、甘氨酸结合、硫酸化）和肾脏排泄的药代动力学个体差异进行了分析，以得出相关途径的不确定系数。总体而言，对于通过多态代谢途径处理的外源性物质（假设母体化合物是最接近的毒物），如CYP2D6慢代谢者（26）、CYP2C19慢代谢者（52）和NAT - 2慢乙酰化者（5.2），健康成年人的相关途径不确定系数（第99百分位数）高于毒代动力学不确定系数。对于有数据的途径，新生儿是人群中最敏感的亚组[CYP1A2和葡萄糖醛酸化（12）、CYP3A4（14）、甘氨酸结合（28）]。新生儿中多态途径的数据不可用，但高达45和9的不确定系数分别考虑了儿童中CYP2D6和CYP2C19代谢中观察到的变异性。本综述概述了不确定系数的历史、代谢和药代动力学个体差异分析得出的主要结论、相关途径不确定系数的发展及其在化学风险评估中的应用。
