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The importance of information on toxicokinetics for human health risk assessment: specific issues for inhalation exposure

机译：毒物动力学信息对人类健康风险评估的重要性：吸入暴露的特定问题

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Background: Human health risk assessment includes in general a high-to-low dose extrapolation. Experimental animals are usually exposed in toxicity studies using dose levels which vary over one order of magnitude. Moreover, the experimental animal dose levels are in most cases significantly higher than the human exposure levels. Although high-to-low dose extrapolation is a common step in human risk assessment, it introduces various uncertainties. One of these uncertainties is related to the toxicokinetics of the specific chemical. Many kinetic processes such as absorption, metabolism or excretion can be subject to saturation at high dose levels, resulting in disproportionate increases in internal blood or tissue concentration relative to the external dose administered. Objectives: The aim is to emphasize the importance of kinetic information for the determination of a safe exposure in human risk assessment of inhalation exposures assessed by conversion from a high animal exposure to a low exposure in man. Methods: For two selected compounds, i.e. methyl tert-butyl ether and 1,2-dichloroethane, Physiologically Based Toxicokinetic (PBTK) modeling was used to follow the extrapolation and conversion steps as performed in existing risk assessments for these compounds. The modeled human exposure scenarios include both continuous long-term exposure for the general population and occupational exposure for 8h/d for 5 days per week. Both blood Cmax and AUC are considered as internal dose metrics. It is presented how internal exposure might change due to high-to-low dose extrapolation applied on the external exposure. Also, the impact of conversion of an intermittent exposure to continuous exposure on these internal dose metrics is included. Results: In order to reduce the uncertainties related to high-to-low dose extrapolation, information on toxicokinetics is considered essential in order to create an adequate margin of safety at the appropriate dose metric. Human health-based limit values based on an external dose metric without sufficient knowledge on kinetics might be too high to be sufficiently protective. Without insight in the actual internal exposure, the toxic agent, the appropriate dose metric, and whether an effect is related to internal concentration or dose, application of assessment factors on an external dose metric and the conversion to continuous exposure results in an uncertain human health risk assessment of inhalation exposures.
机译：背景：人类健康风险评估通常包括从高剂量到低剂量的推断。在毒性研究中，通常使用超过一个数量级的剂量水平对实验动物进行暴露。此外，在大多数情况下，实验动物的剂量水平明显高于人类的暴露水平。尽管从高剂量到低剂量的外推法是人类风险评估中的常见步骤，但它会带来各种不确定性。这些不确定性之一与特定化学品的毒物动力学有关。许多动力学过程（例如吸收，代谢或排泄）在高剂量水平下可能会饱和，从而导致内部血液或组织浓度相对于所给予的外部剂量不成比例地增加。目标：目的是强调动力学信息对于确定吸入风险的安全暴露的重要性，该风险是通过从高动物暴露水平向低人类暴露水平的转换来评估吸入暴露的。方法：对于两种选定的化合物，即甲基叔丁基醚和1,2-二氯乙烷，使用基于生理学的毒物动力学（PBTK）模型来遵循这些化合物的现有风险评估中执行的外推和转化步骤。模拟的人类暴露情景包括对普通人群的连续长期暴露和每周5天每天8h / d的职业暴露。血液Cmax和AUC均被视为内部剂量指标。本文介绍了由于对外部暴露进行从高到低的剂量外推法，内部暴露可能会如何变化。此外，还包括将间歇性暴露转换为连续暴露对这些内部剂量指标的影响。结果：为了减少与从高到低剂量外推有关的不确定性，为了在适当的剂量标准下创造足够的安全裕度，有关毒代动力学的信息被认为是必不可少的。在没有足够的动力学知识的情况下，基于外部剂量度量的基于人体健康的极限值可能太高而无法起到足够的保护作用。如果不了解实际的内部暴露，有毒物质，适当的剂量标准以及影响是否与内部浓度或剂量有关，将评估因素应用于外部剂量标准以及转换为连续暴露会导致不确定的人类健康吸入暴露的风险评估。

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