Relationship between chemical structure and the occupational asthma hazard of low molecular weight organic compounds.

University Computing Services, The University of Edinburgh, UK.
Occupational and environmental medicine (Impact Factor: 3.23). 05/2005; 62(4):243-50. DOI: 10.1136/oem.2004.016402
Source: PubMed

ABSTRACT 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.
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.
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%.
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.

  • Archives des Maladies Professionnelles et de l Environnement 06/2012; 73(3):419-421. · 0.09 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Low molecular weight (LMW) respiratory sensitizers can cause occupational asthma but due to a lack of adequate test methods, prospective identification of respiratory sensitizers is currently not possible. This paper presents the evaluation of Structure-Activity Relationship models (SARs) as potential methods to prospectively conclude on the sensitization potential of LMW chemicals. The predictive performance of the SARs calculated from their training sets was compared to their performance on a dataset of newly identified respiratory sensitizers and non-sensitizers, derived from literature. The predictivity of the available SARs for new substances was markedly lower than their published predictive performance. For that reason, no single SAR model can be considered sufficiently reliable to conclude on potential LMW respiratory sensitization properties of a substance. The individual applicability domains of the models were analyzed for adequacies and deficiencies. Based on these findings, a tiered prediction approach is subsequently proposed. This approach combines the two SARs with the highest positive and negative predictivity taking into account model specific chemical applicability domain issues. The tiered approach provided reliable predictions for one third of the respiratory sensitizers and non-sensitizers of the external validation set compiled by us. For these chemicals, a positive predictive value of 96% and a negative predictive value of 89% was obtained. The tiered approach was not able to predict the other two thirds of the chemicals, meaning that additional information is required and that there is an urgent need for other test methods, e.g. in chemico or in vitro, to reach a reliable conclusion.
    Toxicological Sciences 09/2014; · 4.48 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Several low weight molecules have often been implicated in the induction of occupational asthma. Glyphosate, a small molecule herbicide, is widely used in the world. There is a controversy regarding a role of glyphosate in developing asthma and rhinitis among farmers, the mechanism of which is unexplored. The aim of this study was to explore the mechanisms of glyphosate induced pulmonary pathology by utilizing murine models and real environmental samples. C57BL/6, TLR4−/−, and IL-13−/− mice inhaled extracts of glyphosate-rich air samples collected on farms during spraying of herbicides or inhaled different doses of glyphosate and ovalbumin. The cellular response, humoral response, and lung function of exposed mice were evaluated. Exposure to glyphosate-rich air samples as well as glyphosate alone to the lungs increased: eosinophil and neutrophil counts, mast cell degranulation, and production of IL-33, TSLP, IL-13, and IL-5. In contrast, in vivo systemic IL-4 production was not increased. Co-administration of ovalbumin with glyphosate did not substantially change the inflammatory immune response. However, IL-13-deficiency resulted in diminished inflammatory response but did not have a significant effect on airway resistance upon methacholine challenge after 7 or 21 days of glyphosate exposure. Glyphosate-rich farm air samples as well as glyphosate alone were found to induce pulmonary IL-13-dependent inflammation and promote Th2 type cytokines, but not IL-4 for glyphosate alone. This study, for the first time, provides evidence for the mechanism of glyphosate-induced occupational lung disease.
    Toxicology 11/2014; · 3.75 Impact Factor

Full-text (2 Sources)

Available from
May 30, 2014