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.

This study outlines how mechanistic organic chemistry related to covalent bond formation can be used to rationalize the ability of low molecular weight chemicals to cause respiratory sensitization. The results of an analysis of 104 chemicals which have been reported to cause respiratory sensitization in humans showed that most of the sensitizing chemicals could be distinguished from 82 control chemicals for which no clinical reports of respiratory sensitization exist. This study resulted in the development of a set of mechanism-based structural alerts for chemicals with the potential to cause respiratory sensitization. Their potential for use in a predictive algorithm for this purpose alongside an externally validated quantitative structure-activity relationship model is discussed.

ObjectivesExposure to cleaning products has been associated with adverse respiratory outcomes. This study aimed to investigate the medically reported incidence, trends in incidence and occupational determinants of work-related respiratory disorders attributed to cleaning agents and to explore the role of ‘Quantitative Structure Activity Relationships’ (QSAR) in corroborating the identification of chemical respiratory sensitisers.MethodsRespiratory diagnoses attributed to cleaning agents were extracted from The Health and Occupation Research (THOR) surveillance network, 1989–2017. Incidence, trends in incidence and incidence rate ratios by occupation were investigated. Agents were classified by chemical type and QSAR hazard indices were determined for specific organic chemicals.ResultsApproximately 6% (779 cases) of the (non-asbestos) THOR respiratory cases were attributed to cleaning agents. Diagnoses were predominantly asthma (58%) and inhalation accidents (27%) with frequently reported chemical categories being aldehydes (30%) and chlorine/its releasers (26%). No significant trend in asthma incidence (1999–2017) was observed (annual average change of −1.1% (95% CI −4.4 to 2.4)). This contrasted with a statistically significant annual decline in asthma incidence (−6.8% (95% CI −8.0 to −5.6)) for non-cleaning agents. There was a large variation in risk between occupations. 7 of the 15 organic chemicals specifically identified had a QSAR generated hazard index consistent with being a respiratory sensitiser.ConclusionSpecific occupations appear to be at increased risk of adverse respiratory outcomes attributed to cleaning agents. While exposure to agents such as glutaraldehyde have been addressed, other exposures, such as to chlorine, remain important. Chemical features of the cleaning agents helped distinguish between sensitising and irritant agents.

The most pragmatic as well as valid approach for screening large numbers of industrial chemicals for respiratory sensitization hazard is likely to consist of an algorithm starting with quantitative structure-activity relationship models. Further corroboration from animal or human data, however, may be required for chemicals with a positive result by quantitative structure-activity relationship.