Delic J I, Lilly P D, MacDonald A J, Loizou G D
Toxicology Unit, Health Directorate, Health and Safety Executive, Bootle, Liverpool, L20 3QZ, United Kingdom.
Regul Toxicol Pharmacol. 2000 Oct;32(2):144-55. doi: 10.1006/rtph.2000.1419.
Occupational exposure limits (OELs) for individual substances are established on the basis of the available toxicological information at the time of their promulgation, expert interpretation of these data in light of industrial use, and the framework in which they sit. In the United Kingdom, the establishment of specific OELs includes the application of uncertainty factors to a defined starting point, usually the NOAEL from a suitable animal study. The magnitude of the uncertainty factors is generally determined through expert judgment including a knowledge of workplace conditions and management of exposure. PBPK modeling may help in this process by informing on issues relating to extrapolation between and within species. This study was therefore designed to consider how PBPK modeling could contribute to the establishment of OELs. PBPK models were developed for chloroform (mouse and human) and carbon tetrachloride (rat and human). These substances were chosen for examination because of the extent of their toxicological databases and availability of existing PBPK models. The models were exercised to predict the rate (chloroform) or extent (carbon tetrachloride) of metabolism of these substances, in both rodents and humans. Monte Carlo analysis was used to investigate the influence of variability within the human and animal model populations. The ratio of the rates/extent of metabolism predicted for humans compared to animals was compared to the uncertainty factors involved in setting the OES. Predictions obtained from the PBPK models indicated that average rat and mouse metabolism of carbon tetrachloride and chloroform, respectively, are much greater than that of the average human. Application of Monte Carlo analysis indicated that even those people who have the fastest rates or most extensive amounts of metabolism in the population are unlikely to generate the levels of metabolite of these substances necessary to produce overt toxicity in rodents. This study highlights the value that the use of PBPK modeling may add to help inform and improve toxicological aspects of a regulatory process.
单个物质的职业接触限值（OELs）是根据其发布时可用的毒理学信息、结合工业用途对这些数据的专业解读以及相关框架来确定的。在英国，特定OELs的制定包括将不确定系数应用于一个确定的起始点，通常是来自合适动物研究的无观察到有害作用水平（NOAEL）。不确定系数的大小一般通过专家判断来确定，包括对工作场所条件和接触管理的了解。生理药代动力学（PBPK）模型可能有助于这一过程，通过提供有关种间和种内外推问题的信息。因此，本研究旨在探讨PBPK模型如何有助于OELs的制定。针对氯仿（小鼠和人类）和四氯化碳（大鼠和人类）开发了PBPK模型。选择这些物质进行研究是因为它们毒理学数据库的完善程度以及现有PBPK模型的可获得性。运用这些模型来预测这些物质在啮齿动物和人类体内的代谢速率（氯仿）或代谢程度（四氯化碳）。采用蒙特卡罗分析来研究人类和动物模型群体内变异性的影响。将预测的人类与动物代谢速率/程度的比值与设定职业接触限值（OES）所涉及的不确定系数进行比较。从PBPK模型获得的预测结果表明，四氯化碳在大鼠体内以及氯仿在小鼠体内的平均代谢分别比人类的平均代谢快得多。蒙特卡罗分析的应用表明，即使是人群中代谢速率最快或代谢量最大的人，也不太可能产生在啮齿动物中产生明显毒性所需的这些物质的代谢物水平。本研究强调了使用PBPK模型可能为监管过程的毒理学方面提供信息并加以改进所具有的价值。
