Simmons Jane Ellen, Evans Marina V, Boyes William K
National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, USA.
J Toxicol Environ Health A. 2005;68(11-12):927-50. doi: 10.1080/15287390590912586.
The potential human health risk(s) from chemical exposure must frequently be assessed under conditions for which adequate human or animal data are not available. The default method for exposure-duration adjustment, based on Haber's rule, C (external exposure concentration) or C(n) (the ten Berge modification) x t (exposure duration) = K (a constant toxic effect), has been criticized for prediction errors. A promising alternative approach to duration adjustment is based on equivalence of internal dose, that is, target-tissue dose levels, across different exposure durations. A proposed methodology for dose-duration adjustments for acute exposure guideline levels (AEGLs) based on physiologically based pharmacokinetic (PBPK) estimates of dose is illustrated with trichloroethylene (TCE). Steps in this methodology include: (1) selection and evaluation, or development and evaluation, of an appropriate PBPK model; (2) determination of an appropriate measure of internal dose; (3) estimation with the PBPK model of the tissue dose (the target tissue dose) resulting from the external exposure conditions (concentration, duration) of the critical effect; (4) estimation of the external exposure concentrations required to achieve tissue doses equivalent to the target tissue dose at exposure durations of interest; and (5) evaluation of sources of variability and uncertainty. For TCE, this PBPK modeling approach has allowed determination of dose metrics predictive of the acute neurotoxic effects of TCE and dose-duration adjustments based on estimates of internal dose.
在缺乏充分的人体或动物数据的情况下，必须经常评估化学物质暴露对人类健康的潜在风险。基于哈伯法则（Haber's rule）的暴露持续时间调整默认方法，即C（外部暴露浓度）或C(n)（ten Berge修正值）×t（暴露持续时间）=K（恒定毒性效应），已因预测误差而受到批评。一种有前景的暴露持续时间调整替代方法是基于不同暴露持续时间下内部剂量的等效性，即靶组织剂量水平。以三氯乙烯（TCE）为例，说明了一种基于生理学基础的药代动力学（PBPK）剂量估计对急性暴露指导水平（AEGLs）进行剂量-持续时间调整的拟议方法。该方法的步骤包括：（1）选择和评估，或开发和评估合适的PBPK模型；（2）确定合适的内部剂量测量方法；（3）用PBPK模型估计由关键效应的外部暴露条件（浓度、持续时间）产生的组织剂量（靶组织剂量）；（4）估计在感兴趣的暴露持续时间下达到与靶组织剂量等效的组织剂量所需的外部暴露浓度；以及（5）评估变异性和不确定性的来源。对于TCE，这种PBPK建模方法已能够确定预测TCE急性神经毒性效应的剂量指标，并基于内部剂量估计进行剂量-持续时间调整。
