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.

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Available from: Lindsay Sawyer, Aug 18, 2015
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    • ") and other species which transform by decomposition, isomerization, or hydrolysis, leading to the formation of oxygenated compounds, such as alcohols, carbonyls , carboxylic acids, and hydroxycarbonyls (Atkinson and Arey, 2003; Finlayson-Pitts and Pitts, 2000; Forester et al., 2007; Kroll and Seinfeld, 2008; Orlando and Tyndall, 2012; Orlando et al., 2003; Wells, 2005). Oxygenated organics formed by O 3 or OH reactions can be acute or chronic irritants, and they can sorb to surfaces, oxidize further, contribute to aerosol formation, or be removed by air exchange (Aalto-Korte et al., 2005; Anderson et al., 2007, 2012; Bein and Leikauf, 2011; Jakubowski and Czerczak, 2010; Jarvis et al., 2005; Kroll and Seinfeld, 2008; Weschler, 2011). The quantification of OH indoors is challenging, but OH has been predicted or measured at ~10 À7 e10 À5 ppb (Carslaw, 2007; Sarwar et al., 2002; Weschler and Shields, 1996, 1997). "
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    ABSTRACT: Indoor chemistry may be initiated by reactions of ozone (O3), the hydroxyl radical (OH), or the nitrate radical (NO3) with volatile organic compounds (VOC). The principal indoor source of O3 is air exchange, while OH and NO3 formation are considered as primarily from O3 reactions with alkenes and nitrogen dioxide (NO2), respectively. Herein, we used time-averaged models for residences to predict O3, OH, and NO3 concentrations and their impacts on conversion of typical residential VOC profiles, within a Monte Carlo framework that varied inputs probabilistically. We accounted for established oxidant sources, as well as explored the importance of two newly realized indoor sources: (i) the photolysis of nitrous acid (HONO) indoors to generate OH and (ii) the reaction of stabilized Criegee intermediates (SCI) with NO2 to generate NO3. We found total VOC conversion to be dominated by reactions both with O3, which almost solely reacted with d-limonene, and also with OH, which reacted with d-limonene, other terpenes, alcohols, aldehydes, and aromatics. VOC oxidation rates increased with air exchange, outdoor O3, NO2 and d-limonene sources, and indoor photolysis rates; and they decreased with O3 deposition and nitric oxide (NO) sources. Photolysis was a strong OH formation mechanism for high NO, NO2, and HONO settings, but SCI/NO2 reactions weakly generated NO3 except for only a few cases.
    Atmospheric Environment 04/2015; 106:382-391. DOI:10.1016/j.atmosenv.2014.06.062 · 3.28 Impact Factor
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    • "A chemical was considered a respiratory nonsensitizer when it was either present in the 1994 edition of the U.K. Health and Safety Executive's document OELs and no cases of OA were reported in the United Kingdom (Enoch et al., 2012; Jarvis et al., 2005 and references therein; see Supplementary Table 1), or if a substance tested negative for human allergic contact skin sensitizing ability (Graham et al., 1997). The first criterion is based on the assumptions that (1) the presence of an OEL is evidence that humans have had fairly extensive industrial inhalational exposure and (2) a lack of reports on OA due to exposure to these chemicals therefore suggests a lack of respiratory sensitizing potential (Enoch et al., 2012; Jarvis et al., 2005). The second criterion is based on the mechanistic assumption that human skin nonsensitizers will also not be able to induce respiratory sensitization (Cunningham et al., 2005; Graham et al., 1997). "
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    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; 142(2). DOI:10.1093/toxsci/kfu188 · 4.48 Impact Factor
    • "Its gastrointestinal toxicity to humans was also documented (Sawada et al., 1988; Talbot et al., 1991; Tominack et al., 1991; Menkes et al., 1991; Temple and Smith, 1992). According to the SAR (structure–activity relationships) model of Jarvis et al. (2005), the hazard index value of glyphosate is 0.6257, which evidently supports the hazardous nature of glyphosate and its possible role in inducing asthmatic symptoms. However, the inhalational effects of glyphosate particularly its effect on development of asthma was not entirely explored. "
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