Pelekis Michael, Nicolich Mark J, Gauthier Joseph S
The Pelekis Group, Nazateth, PA 18064, USA.
Risk Anal. 2003 Dec;23(6):1239-55. doi: 10.1111/j.0272-4332.2003.00398.x.
Human health risk assessments use point values to develop risk estimates and thus impart a deterministic character to risk, which, by definition, is a probability phenomenon. The risk estimates are calculated based on individuals and then, using uncertainty factors (UFs), are extrapolated to the population that is characterized by variability. Regulatory agencies have recommended the quantification of the impact of variability in risk assessments through the application of probabilistic methods. In the present study, a framework that deals with the quantitative analysis of uncertainty (U) and variability (V) in target tissue dose in the population was developed by applying probabilistic analysis to physiologically-based toxicokinetic models. The mechanistic parameters that determine kinetics were described with probability density functions (PDFs). Since each PDF depicts the frequency of occurrence of all expected values of each parameter in the population, the combined effects of multiple sources of U/V were accounted for in the estimated distribution of tissue dose in the population, and a unified (adult and child) intraspecies toxicokinetic uncertainty factor UFH-TK was determined. The results show that the proposed framework accounts effectively for U/V in population toxicokinetics. The ratio of the 95th percentile to the 50th percentile of the annual average concentration of the chemical at the target tissue organ (i.e., the UFH-TK) varies with age. The ratio is equivalent to a unified intraspecies toxicokinetic UF, and it is one of the UFs by which the NOAEL can be divided to obtain the RfC/RfD. The 10-fold intraspecies UF is intended to account for uncertainty and variability in toxicokinetics (3.2x) and toxicodynamics (3.2x). This article deals exclusively with toxicokinetic component of UF. The framework provides an alternative to the default methodology and is advantageous in that the evaluation of toxicokinetic variability is based on the distribution of the effective target tissue dose, rather than applied dose. It allows for the replacement of the default adult and children intraspecies UF with toxicokinetic data-derived values and provides accurate chemical-specific estimates for their magnitude. It shows that proper application of probability and toxicokinetic theories can reduce uncertainties when establishing exposure limits for specific compounds and provide better assurance that established limits are adequately protective. It contributes to the development of a probabilistic noncancer risk assessment framework and will ultimately lead to the unification of cancer and noncancer risk assessment methodologies.
人体健康风险评估使用点值来得出风险估计值，从而赋予风险一种确定性特征，而从定义上讲，风险是一种概率现象。风险估计值是基于个体计算得出的，然后使用不确定性因子（UFs）外推至具有变异性特征的人群。监管机构建议通过应用概率方法来量化风险评估中变异性的影响。在本研究中，通过将概率分析应用于基于生理学的毒代动力学模型，开发了一个用于处理人群中靶组织剂量的不确定性（U）和变异性（V）定量分析的框架。用概率密度函数（PDFs）描述了决定动力学的机制参数。由于每个PDF描绘了人群中每个参数所有预期值的出现频率，因此在人群组织剂量的估计分布中考虑了U/V多种来源的综合影响，并确定了一个统一的（成人和儿童）种内毒代动力学不确定性因子UFH-TK。结果表明，所提出的框架有效地考虑了人群毒代动力学中的U/V。靶组织器官处化学物质年平均浓度的第95百分位数与第50百分位数之比（即UFH-TK）随年龄而变化。该比值等同于一个统一的种内毒代动力学UF，并且是可用于将无观察到有害作用水平（NOAEL）相除来获得参考浓度（RfC）/参考剂量（RfD）的UFs之一。10倍的种内UF旨在考虑毒代动力学（3.2倍）和毒效动力学（3.2倍）中的不确定性和变异性。本文专门探讨UF的毒代动力学组成部分。该框架为默认方法提供了一种替代方案，其优势在于毒代动力学变异性的评估基于有效靶组织剂量的分布，而非应用剂量。它允许用源自毒代动力学数据的值替代默认的成人和儿童种内UF，并为其大小提供准确的化学物质特异性估计值。结果表明，在为特定化合物确定接触限值时，正确应用概率和毒代动力学理论可以减少不确定性，并更好地确保所确定的限值具有充分的保护作用。它有助于开发概率性非癌症风险评估框架，并最终将导致癌症和非癌症风险评估方法的统一。
