Provocation of occupational asthma by non-specific irritation and its relevance for the classification of chemicals as respiratory allergens: a case study of methyl methacrylate

Allergic sensitisation of the respiratory tract by chemicals, commonly associated with asthma, is an important adverse health effect. However, the accurate identification of true chemical respiratory allergens remains problematic. In the absence of fully validated predictive test methods, or a universally agreed adverse outcome pathway, it is commonly the case that regulatory classification of chemicals as respiratory allergens relies solely upon clinical data that frequently fails to distinguish between irritant-provoked bronchial responses and true allergic sensitisation. Here this issue is explored using as a case study methyl methacrylate (MMA). In a regulatory context this chemical has been proposed for classification as a respiratory sensitiser on the basis of specific inhalation challenge data in humans. A review of the clinical data on which the proposal is based reveals that they are unsuitable for accurate discrimination between allergic and non-specific irritant mechanisms. Furthermore, the available information supports that MMA lacks respiratory sensitising activity. This conclusion is supported by review of experimental data, derived from both animal studies, and recently published in vitro assessments, that individually and collectively indicate that MMA is not a respiratory sensitiser. It is concluded that accurate regulatory classification of chemical respiratory allergens cannot rely solely on clinical studies. • Distinguishing new asthma from exacerbation of existing asthma is important • Human data rarely distinguish non-specific irritation from respiratory sensitisation • In vitro assays for KEs in the AOP for Respiratory sensitisation are recommended • Asthma triggered by non-specific irritations is not a basis for classifications