Pelekis M, Gephart L A, Lerman S E
Toxicology and Environmental Sciences Division, ExxonMobil Biomedical Sciences, Inc., 1545 Route 22 East, Annandale, New Jersey 08801-0971, USA.
Regul Toxicol Pharmacol. 2001 Feb;33(1):12-20. doi: 10.1006/rtph.2000.1436.
The intraspecies uncertainty factor (UF(HH)=10x) is used in the determination of the reference dose or reference concentration and accounts for the pharmacokinetic and pharmacodynamic heterogeneity within the human population. The Food Quality Protection Act of 1996 mandated the use of an additional uncertainty factor (UF(HC)=10x) to take into account potential pre- and postnatal toxicity and lack of completeness of the data with respect to exposure and toxicity to children. There is no conclusive experimental or theoretical justification to support or refute the magnitude of the UF(HH) and UF(HC) nor any conclusive evidence to suggest that a factor of 100 is needed to account for intrahuman variability. This study presents a new chemical-specific method for estimating the pharmacokinetic (PK) component of the interspecies uncertainty factor (UF(HH-PK) and UF(HC-PK)) for volatile organic compounds (VOCs). The approach utilizes validated physiological-based pharmacokinetic (PBPK) models and simplified physiological-model-based algebraic equations to translate ambient exposure concentration to tissue dose in adults and children the ratio of which is the UF(HH-PK) and UF(HC-PK). The results suggest that: (i) the UF(HH-PK) and UF(HC-PK) are chemical specific; (ii) for the chemicals used in this study there is no significant difference between UF(HH-PK) and UF(HC-PK); (iii) the magnitude of UF(HH-PK) and UF(HC-PK) varies between 0.033 and 2.85 with respect to tissue and blood concentrations; (iv) the body weight, the rate of ventilation, the fraction of cardiac output flowing to the liver, the blood : air partition coefficient, and the hepatic extraction ratio are the only parameters that play a critical role in the variability of tissue and blood doses within species; and (v) the magnitude of the UF(HH-PK) and UF(HC-PK) obtained with the simplified steady-state equations is essentially the same with that obtained with PBPK models. Overall, this study suggests that no adult-children differences in the parent chemical concentrations of the VOCs are likely to be observed during inhalation exposures. The physiological-model-based approaches used in the present study to estimate the UF(HH-PK) and UF(HC-PK) provide a scientific basis for their magnitude. They can replace the currently used empirical default approaches to provide chemical-specific UF(HH-PK) in future risk assessments.
种内不确定性因子（UF(HH)=10 倍）用于确定参考剂量或参考浓度，反映了人群中药代动力学和药效学的异质性。1996 年的《食品质量保护法》规定使用额外的不确定性因子（UF(HC)=10 倍），以考虑潜在的产前和产后毒性以及儿童暴露和毒性数据的不完整性。目前尚无确凿的实验或理论依据支持或反驳 UF(HH) 和 UF(HC) 的量级，也没有确凿证据表明需要 100 倍的因子来解释人群内部的变异性。本研究提出了一种新的化学物质特异性方法，用于估算挥发性有机化合物（VOCs）种间不确定性因子（UF(HH-PK) 和 UF(HC-PK)）的药代动力学（PK）成分。该方法利用经过验证的基于生理学的药代动力学（PBPK）模型和基于简化生理模型的代数方程，将环境暴露浓度转换为成人和儿童体内的组织剂量，二者的比值即为 UF(HH-PK) 和 UF(HC-PK)。结果表明：（i）UF(HH-PK) 和 UF(HC-PK) 具有化学物质特异性；（ii）对于本研究中使用的化学物质，UF(HH-PK) 和 UF(HC-PK) 之间无显著差异；（iii）相对于组织和血液浓度，UF(HH-PK) 和 UF(HC-PK) 的量级在 0.033 至 2.85 之间变化；（iv）体重、通气率、流向肝脏的心输出量分数、血 - 气分配系数和肝脏提取率是影响种内组织和血液剂量变异性的关键参数；（v）用简化稳态方程得到的 UF(HH-PK) 和 UF(HC-PK) 量级与 PBPK 模型得到的基本相同。总体而言，本研究表明在吸入暴露期间，不太可能观察到成人和儿童体内 VOCs 母体化学物质浓度的差异。本研究中用于估算 UF(HH-PK) 和 UF(HC-PK) 的基于生理模型的方法为其量级提供了科学依据。它们可以取代目前使用的经验性默认方法，在未来的风险评估中提供化学物质特异性的 UF(HH-PK)。
