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Key Event-Informed Risk Models for Benzene-induced Acute Myeloid Leukaemia
Toxicology Letters ( IF 3.5 ) Pub Date : 2021-04-01 , DOI: 10.1016/j.toxlet.2021.01.003
Colin M. North , A. Robert Schnatter , Martijn Rooseboom , Neslihan Aygun Kocabas , Abigail Dalzell , Stephen D. Williams

Occupational exposure to benzene at levels of 10 ppm or more has been associated with increased risk of acute myeloid leukaemia (AML). The mode of action (MOA) for AML development leading to mortality is anticipated to include multiple earlier key events, which can be observed in hematotoxicity and genetic toxicity in peripheral blood of exposed workers. Prevention of these early events would lead to prevention of the apical, adverse outcomes, the morbidity and mortality caused by the myelodysplastic syndromes (MDS) and AML. Incorporation of key event information should modify the risk model, but few modification approaches have been suggested. To that end, two approaches to risk model modification are described that use sub-linear and segmented linear increases in risk below key events, while maintaining a linear increase in AML mortality risk beginning at 2 ppm, the lowest observed adverse effect concentration (LOAEC) identified for hemato- and geno- toxicity in high quality studies of human occupational exposure. Below 2 ppm two different modification approaches to quantitative risk models were applied: a continuously decreasing slope model and a segmented modification in slope. These two approaches provide greater flexibility to incorporate MOA information in risk model development and selection.

中文翻译:

苯诱导的急性髓系白血病的关键事件知情风险模型

职业暴露于 10 ppm 或更高水平的苯与急性髓性白血病 (AML) 的风险增加有关。预计导致死亡的 AML 发展的作用模式 (MOA) 包括多个早期关键事件,这些事件可以在暴露工人外周血的血液毒性和遗传毒性中观察到。预防这些早期事件将导致预防由骨髓增生异常综合征 (MDS) 和 AML 引起的根尖不良结果、发病率和死亡率。关键事件信息的合并应该修改风险模型,但很少提出修改方法。为此,描述了两种风险模型修改方法,它们使用关键事件下风险的次线性和分段线性增加,在维持 AML 死亡风险从 2 ppm 开始线性增加的同时,在人类职业暴露的高质量研究中确定的血液和基因毒性的最低观察到的不良反应浓度 (LOAEC)。低于 2 ppm 时,应用了两种不同的定量风险模型修正方法:连续下降的斜率模型和斜率分段修正。这两种方法为将 MOA 信息纳入风险模型开发和选择提供了更大的灵活性。连续递减坡度模型和坡度分段修正。这两种方法为将 MOA 信息纳入风险模型开发和选择提供了更大的灵活性。连续递减坡度模型和坡度分段修正。这两种方法为将 MOA 信息纳入风险模型开发和选择提供了更大的灵活性。
更新日期:2021-04-01
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