Relationship between chemical structure and the occupational asthma hazard of low molecular weight organic compounds
Relationship between chemical structure and the occupational asthma hazard of low molecular weight organic compounds
复制标题
DOI：
10.1136/oem.2004.016402
复制
发表时间：
2005-04-01
影响因子：
4.9
通讯作者：
Agius, RM
中科院分区：
文献类型：
--
作者：
Jarvis, J;Seed, MJ;Agius, RM
目的：定量研究低分子量（LMW）有机化合物的化学结构与职业性哮喘危害之间的关系;建立并验证哮喘危害与化学结构之间的联系模型;并提出可能解释这种关系的机制假说。方法：一个学习数据集使用了1995年之前文献中报道的78种低分子量化学哮喘，以及301种具有公认职业暴露和呼吸致敏以外危害的对照化合物。哮喘原和对照化合物的化学结构的特征在于存在化学亚结构片段。计算这些片段的比值比，以确定哪些片段与被报告为职业性哮喘原的可能性相关。逻辑回归模型被用来确定这些子结构的独立贡献。一个后1995年设置的21 asthmagens和77个控制被选中外部验证model.Results：含氮或含氧的功能基团，如异氰酸酯，胺，酸酐，羰基与职业性哮喘的危害，特别是当功能组存在两次或两次以上在同一分子。一个逻辑回归模型只使用统计学上显着的独立变量的职业性哮喘危害正确分配90%的模型开发集。结论：虽然多种化学结构与职业性哮喘相关，但双功能反应性在多种化学结构中与职业性哮喘危害密切相关。这表明化学交联是导致职业性哮喘发生的重要分子机制。logistic回归模型可以在互联网上免费获得，并可能提供一个有用的，但廉价的辅助预测职业性哮喘的危害。
Aims: To investigate quantitatively, relationships between chemical structure and reported occupational asthma hazard for low molecular weight (LMW) organic compounds; to develop and validate a model linking asthma hazard with chemical substructure; and to generate mechanistic hypotheses that might explain the relationships.Methods: A learning dataset used 78 LMW chemical asthmagens reported in the literature before 1995, and 301 control compounds with recognised occupational exposures and hazards other than respiratory sensitisation. The chemical structures of the asthmagens and control compounds were characterised by the presence of chemical substructure fragments. Odds ratios were calculated for these fragments to determine which were associated with a likelihood of being reported as an occupational asthmagen. Logistic regression modelling was used to identify the independent contribution of these substructures. A post-1995 set of 21 asthmagens and 77 controls were selected to externally validate the model.Results: Nitrogen or oxygen containing functional groups such as isocyanate, amine, acid anhydride, and carbonyl were associated with an occupational asthma hazard, particularly when the functional group was present twice or more in the same molecule. A logistic regression model using only statistically significant independent variables for occupational asthma hazard correctly assigned 90% of the model development set. The external validation showed a sensitivity of 86% and specificity of 99%.Conclusions: Although a wide variety of chemical structures are associated with occupational asthma, bifunctional reactivity is strongly associated with occupational asthma hazard across a range of chemical substructures. This suggests that chemical cross-linking is an important molecular mechanism leading to the development of occupational asthma. The logistic regression model is freely available on the internet and may offer a useful but inexpensive adjunct to the prediction of occupational asthma hazard.