Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
Gilead Sciences, Inc., Foster City, California 94404, United States.
Chem Res Toxicol. 2022 Jun 20;35(6):1011-1022. doi: 10.1021/acs.chemrestox.2c00031. Epub 2022 May 9.
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 , and 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, - 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.
肽偶联剂(也称为酰胺键形成试剂或偶联试剂)广泛应用于有机化学合成,特别是在制药行业。然而,与这类化学物质相关的职业健康危害在很大程度上尚未得到探索,鉴于这些化合物的固有反应性,这令人感到不安。有几项涉及职业暴露的案例研究报告了呼吸道和皮肤健康受到不良影响的情况,这为化学致敏提供了初步证据。为了解决毒理学数据不足的问题,成立了一个制药跨行业工作组,以评估和评估这些化合物引起眼睛和皮肤刺激以及腐蚀性和皮肤致敏的潜力。我们工作的目标是向健康和安全专业人员以及制药和有机化学家通报与这类化学物质相关的职业健康危害。为此,选择了 25 种最常用的肽偶联剂和 5 种水解产物进行皮肤致敏和眼睛刺激测试。我们的研究结果证实,皮肤致敏是此类化学物质的一个关注点,25 种肽偶联剂中有 21 种呈皮肤致敏阳性,其中 15 种为强/极强致敏剂。我们还发现,皮肤腐蚀和刺激(25 种中有 8 种)以及眼睛刺激(25 种中有 9 种)是与肽偶联剂及其水解产物相关的健康危害(其中 4 种是皮肤刺激物或腐蚀性,4 种是眼睛刺激物)。综合这些结果以告知肽偶联剂选择的决策,并实现对工人进行数据驱动的危害沟通。这包括协调危害分类、适当的处理建议和准确的安全数据表,这些都支持工业卫生控制策略和风险评估的层次结构。我们的研究展示了综合的、 - 分析的优点,在这里,使用计算机辅助发现和重新设计(CADRE)和 Derek Nexus 程序应用于皮肤致敏终点。我们表明,实验数据可以通过填补现有数据空白来改进预测模型,同时为关键引发事件提供计算见解,并阐明导致不良健康影响的化学结构特征。这种互动的、跨学科的方法符合绿色化学原则,该原则旨在改善工业过程和应用中更具危害性试剂的选择和设计。