Department of Risk-Benefit Assessment, Swedish National Food Agency, SE-75126 Uppsala, Sweden.
Department of Energy and Technology, Swedish University of Agricultural Sciences, SE-75007 Uppsala, Sweden.
Toxicol Sci. 2018 Sep 1;165(1):74-89. doi: 10.1093/toxsci/kfy124.
Risk assessment of chemical hazards is typically based on single critical health effects. This work aims to expand the current approach by characterizing the dose-related sequence of the development of multiple (lower- to higher-order) toxicological health effects caused by a chemical. To this end a "reference point profile" is defined as the relation between benchmark doses for considered health effects, and a standardized severity score determined for these effects. For a given dose of a chemical or mixture the probability for exceeding the reference point profile, thereby provoking lower- to higher-order effects, can be assessed. The overall impact at the same dose can also be derived by integrating contributions across all health effects following severity-weighting. In its generalized form the new impact metric relates to the probability of response for the most severe health effects. Reference points (points of departure) corresponding to defined levels of response can also be estimated. The proposed concept, which is evaluated for dioxin-like chemicals, provides an alternative for characterizing the low-dose region below the reference point for a severe effect like cancer. The shape and variability of the reference point profile add new dimensions to risk assessment, which for example extends the characterization of chemical potency, and the concept of acceptable effect sizes for individual health effects. Based on the present data the method shows high stability at low doses/responses, and is also robust to differences in severity categorization of effects. In conclusion, the novel method proposed enables risk-based integration of multiple dose-related health effects. It provides a first step towards a more comprehensive characterization of chemical toxicity, and suggests a potential for improved low-dose risk assessment.
化学危害风险评估通常基于单一关键健康影响。本工作旨在通过描述化学物质引起的多种（低阶到高阶）毒理学健康影响的发展的剂量相关序列来扩展当前方法。为此，定义了“参考点分布”作为考虑的健康影响的基准剂量与为此类影响确定的标准化严重程度评分之间的关系。对于给定剂量的化学物质或混合物，可以评估超过参考点分布从而引发低阶到高阶影响的概率。通过对所有健康影响进行严重程度加权的积分，可以得出相同剂量下的总体影响。在其广义形式中，新的影响度量与最严重健康影响的反应概率有关。也可以估计对应于定义的反应水平的参考点（出发点）。所提出的概念针对类二恶英化学物质进行了评估，为在癌症等严重影响的参考点以下的低剂量区域的特征提供了替代方法。参考点分布的形状和可变性为风险评估增加了新的维度，例如扩展了化学效力的特征描述，以及单个健康影响的可接受影响大小的概念。基于目前的数据，该方法在低剂量/反应时显示出很高的稳定性，并且对影响严重程度分类的差异也具有稳健性。总之，所提出的新方法能够基于风险整合多种剂量相关的健康影响。它为更全面地描述化学毒性迈出了第一步，并为改进低剂量风险评估提供了潜力。
