An Evaluation of the Occupational Health Hazards of Peptide Couplers.
An Evaluation of the Occupational Health Hazards of Peptide Couplers.
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DOI：
10.1021/acs.chemrestox.2c00031
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发表时间：
2022-06-20
影响因子：
4.1
通讯作者：
Schmitz, Matthew
中科院分区：
文献类型：
--
作者：
Graham, Jessica C.;Trejo-Martin, Alejandra;Chilton, Martyn L.;Kostal, Jakub;Bercu, Joel;Beutner, Gregory L.;Bruen, Uma S.;Dolan, David G.;Gomez, Stephen;Hillegass, Jedd;Nicolette, John;Schmitz, Matthew
多肽偶联剂(又称酰胺成键试剂或偶联剂)广泛应用于有机合成，特别是在制药工业中。然而，与这类化学物质相关的职业健康危害在很大程度上还没有被探索出来，这是令人不安的，因为这些化合物具有内在的反应性。几个涉及职业暴露的案例研究报告了对呼吸道和皮肤健康的不利影响，提供了化学致敏的初步证据。为了解决毒理学数据匮乏的问题，成立了一个跨行业的制药特别工作组，以评估和评估这些化合物对眼睛和皮肤刺激以及腐蚀性和皮肤敏化的潜力。我们工作的目标是告知健康和安全专业人员以及药物和有机化学家与这种化学类别相关的职业健康危害。为此，选择了25种最常用的多肽偶联剂和5种水解物进行体内、体外和电子测试。我们的发现证实了皮肤致敏是这类化学物质的一个问题，21/25个多肽偶联剂的皮肤致敏检测呈阳性，其中15个是强/极端致敏剂。我们还发现，皮肤腐蚀和刺激(8/25)以及眼睛刺激(9/25)是与多肽偶联剂及其水解物(4/5是皮肤刺激性或腐蚀性，4/5是眼刺激性)相关的健康危害。结果被综合起来，为多肽偶联剂选择的决策提供信息，并使工人能够进行数据驱动的危险交流。后者包括统一的危险分类、适当的处理建议和准确的安全数据表，这支持控制战略和风险评估的工业卫生等级。我们的研究使用计算机辅助发现和重新设计(CADRE)和Derek Nexus程序，展示了集成的在体硅胶分析的优点，在这里应用于皮肤敏化终点。我们表明，实验数据可以通过填补现有的数据空白来改进预测模型，同时提供对关键启动事件的计算见解，并阐明导致不利健康影响的化学结构特征。这种交互的、跨学科的方法符合绿色化学原则，该原则寻求改善工业过程和应用中危害较小的试剂的选择和设计。
Peptide couplers (also known as amide bond-forming reagents or coupling reagents) are broadly used in organic chemical syntheses, especially in the pharmaceutical industry. Yet, occupational health hazards associated with this chemical class are largely unexplored, which is disconcerting given the intrinsic reactivity of these compounds. Several case studies involving occupational exposures reported adverse respiratory and dermal health effects, providing initial evidence of chemical sensitization. To address the paucity of toxicological data, a pharmaceutical cross-industry task force was formed to evaluate and assess the potential of these compounds to cause eye and dermal irritation as well as corrosivity and dermal sensitization. The goal of our work was to inform health and safety professionals as well as pharmaceutical and organic chemists of the occupational health hazards associated with this chemical class. To that end, 25 of the most commonly used peptide couplers and five hydrolysis products were selected for in vivo, in vitro, and in silico testing. Our findings confirmed that dermal sensitization is a concern for this chemical class with 21/25 peptide couplers testing positive for dermal sensitization and 15 of these being strong/extreme sensitizers. We also found that dermal corrosion and irritation (8/25) as well as eye irritation (9/25) were health hazards associated with peptide couplers and their hydrolysis products (4/5 were dermal irritants or corrosive and 4/5 were eye irritants). Resulting outcomes were synthesized to inform decision making in peptide coupler selection and enable data-driven hazard communication to workers. The latter includes harmonized hazard classifications, appropriate handling recommendations, and accurate safety data sheets, which support the industrial hygiene hierarchy of control strategies and risk assessment. Our study demonstrates the merits of an integrated, in vivo -in silico analysis, applied here to the skin sensitization endpoint using the Computer-Aided Discovery and REdesign (CADRE) and Derek Nexus programs. We show that experimental data can improve predictive models by filling existing data gaps while, concurrently, providing computational insights into key initiating events and elucidating the chemical structural features contributing to adverse health effects. This interactive, interdisciplinary approach is consistent with Green Chemistry principles that seek to improve the selection and design of less hazardous reagents in industrial processes and applications.
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影响因子：
3.6
作者：
McKnelly, Kate J.;Sokol, William;Nowick, James S.
通讯作者：
Nowick, James S.
影响因子：
4.1
作者：
Kostal, Jakub;Voutchkova-Kostal, Adelina
通讯作者：
Voutchkova-Kostal, Adelina
影响因子：
3.3
作者：
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通讯作者：
Parakhia, Rahul
影响因子：
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作者：
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通讯作者：
Maertens, Alexandra
影响因子：
4.1
作者：
Kostal, Jakub;Voutchkova-Kostal, Adelina
通讯作者：
Voutchkova-Kostal, Adelina