Abstract

Background:

Naphthalene is a polycyclic aromatic hydrocarbon that has been associated with health effects, including cancer. As the state of the science on naphthalene toxicity continues to evolve, updated toxicity reference value(s) may be required to support human health risk assessment.

Objectives:

We present a systematic evidence map of studies that could be used to derive toxicity reference value(s) for naphthalene.

Methods:

Human and animal health effect studies and physiologically based pharmacokinetic (PBPK) models were identified from a literature search based on populations, exposures, comparators, and outcomes (PECO) criteria. Human and animal studies meeting PECO criteria were refined to a smaller subset considered most informative for deriving chronic reference value(s), which are preferred for assessing risk to the general public. This subset was evaluated for risk of bias and sensitivity, and the suitability of each study for dose–response analysis was qualitatively assessed. Lowest observed adverse effect levels (LOAELs) were extracted and summarized. Other potentially relevant studies (e.g., mechanistic and toxicokinetic studies) were tracked as supplemental information but not evaluated further. Existing reference values for naphthalene are also summarized.

Results:

We identified 26 epidemiology studies and 16 animal studies that were considered most informative for further analysis. Eleven PBPK models were identified. The available epidemiology studies generally had significant risk of bias and/or sensitivity concerns and were mostly found to have low suitability for dose–response analysis due to the nature of the exposure measurements. The animal studies had fewer risk of bias and sensitivity concerns and were mostly found to be suitable for dose–response analysis.

Conclusion:

Although both epidemiological and animal studies of naphthalene provide weight of evidence for hazard identification, the available animal studies appear more suitable for reference value derivation. PBPK models and mechanistic and toxicokinetic data can be applied to extrapolate these animal data to humans, considering mode of action and interspecies metabolic differences. https://doi.org/10.1289/EHP7381

中文翻译：

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萘暴露对健康的影响：系统证据图和剂量反应评估潜在考虑因素分析

摘要

背景：

萘是一种多环芳烃，与包括癌症在内的健康影响有关。随着萘毒性科学状况的不断发展，可能需要更新的毒性参考值来支持人类健康风险评估。

目标：

我们提出了一个系统的研究证据图，可用于得出萘的毒性参考值。

方法：

人类和动物健康影响研究和基于生理学的药代动力学 (PBPK) 模型是根据人群、暴露、比较和结果 (PECO) 标准从文献检索中确定的。符合 PECO 标准的人类和动物研究被细化为一个较小的子集，被认为对于得出慢性参考值最具信息性，这对于评估公众的风险是首选的。对这个子集的偏倚风险和敏感性进行了评估，并对每项研究进行剂量反应分析的适合性进行了定性评估。提取并总结了观察到的最低不良反应水平 (LOAEL)。其他潜在相关的研究（例如，机制和毒代动力学研究）被作为补充信息进行跟踪，但没有进一步评估。还总结了萘的现有参考值。

结果：

我们确定了 26 项流行病学研究和 16 项动物研究，这些研究被认为最有利于进一步分析。确定了 11 个 PBPK 模型。现有的流行病学研究通常存在显着的偏倚风险和/或敏感性问题，并且由于暴露测量的性质，大多数发现不适合剂量反应分析。动物研究的偏倚风险和敏感性问题较少，并且大多适合剂量反应分析。

结论：

尽管萘的流行病学和动物研究都为危害识别提供了重要的证据，但现有的动物研究似乎更适合参考值推导。考虑到作用模式和种间代谢差异，PBPK 模型以及机制和毒代动力学数据可用于将这些动物数据外推到人类。https://doi.org/10.1289/EHP7381