Kirkland Consulting, Tadcaster, LS24 0AS, UK.
Cardno ChemRisk, Chicago, IL, USA.
Regul Toxicol Pharmacol. 2021 Jun;122:104892. doi: 10.1016/j.yrtph.2021.104892. Epub 2021 Feb 13.
In 2019, the California Office of Environmental Health Hazard Assessment initiated a review of the carcinogenic hazard potential of acetaminophen, including an assessment of its genotoxicity. The objective of this analysis was to inform this review process with a weight-of-evidence assessment of more than 65 acetaminophen genetic toxicology studies that are of widely varying quality and conformance to accepted standards and relevance to humans. In these studies, acetaminophen showed no evidence of induction of point or gene mutations in bacterial and mammalian cell systems or in in vivo studies. In reliable, well-controlled test systems, clastogenic effects were only observed in unstable, p53-deficient cell systems or at toxic and/or excessively high concentrations that adversely affect cellular processes (e.g., mitochondrial respiration) and cause cytotoxicity. Across the studies, there was no clear evidence that acetaminophen causes DNA damage in the absence of toxicity. In well-controlled clinical studies, there was no meaningful evidence of chromosomal damage. Based on this weight-of-evidence assessment, acetaminophen overwhelmingly produces negative results (i.e., is not a genotoxic hazard) in reliable, robust high-weight studies. Its mode of action produces cytotoxic effects before it can induce the stable, genetic damage that would be indicative of a genotoxic or carcinogenic hazard.
2019 年，加利福尼亚州环境健康危害评估办公室启动了对乙酰氨基酚致癌危害潜力的审查，包括对其遗传毒性的评估。本分析的目的是通过对 65 多项乙酰氨基酚遗传毒理学研究的证据进行评估，为这一审查过程提供信息，这些研究的质量和对接受标准的一致性以及与人类的相关性差异很大。在这些研究中，乙酰氨基酚在细菌和哺乳动物细胞系统或体内研究中均未显示出诱导点突变或基因突变的证据。在可靠的、经过良好控制的测试系统中，只有在不稳定、p53 缺陷的细胞系统中，或者在毒性和/或过高浓度下，才会观察到染色体断裂效应，这些浓度会对细胞过程（例如线粒体呼吸）产生不利影响，并导致细胞毒性。在所有研究中，没有明确的证据表明乙酰氨基酚在没有毒性的情况下会导致 DNA 损伤。在经过良好控制的临床研究中，没有有意义的染色体损伤证据。基于这一证据评估，乙酰氨基酚在可靠、稳健的高权重研究中绝大多数产生阴性结果（即，不是遗传毒性危害）。其作用模式会在诱导稳定的遗传损伤之前产生细胞毒性作用，而稳定的遗传损伤才是遗传毒性或致癌危害的指示。
