Abstract
The aim of the study was to develop an in vitro model that mimics the alveolar-capillary barrier and that allows assessment of the respiratory sensitizing potential of respiratory sensitizers. The 3D in vitro model cultured at the air liquid interface consists of alveolar type II epithelial cells (A549), endothelial cells (EA.hy926), macrophage-like cells (PMA-differentiated THP-1) and dendritic-like cells (non-differentiated THP-1). This alveolar model was exposed apically to nebulized chemical respiratory sensitizers (Phthalic Anhydride (PA) and TriMellitic Anhydride (TMA)) or irritants (Methyl Salicylate (MeSa) and Acrolein (Acr)) at concentrations inducing at maximum 25% of cytotoxicity. The exposure to respiratory sensitizers induced dendritic cells activation and a specific cytokine release pattern, while the irritants did not. In addition, the cell surface marker OX40L was determined for dendritic like cells activation to identify high molecular weight allergens. With this in vitro model we can postulate a set of promising markers based on the studied compounds that allow the discrimination of chemical respiratory sensitizers from irritants.
Highlights
Due to their peculiar toxicity and systemic effects, respiratory sensitizers are receiving increasing attention within toxicity evaluation studies and risk assessment
The inclusion of a substance on the European Chemicals Agency (ECHA) list for substances of very high concern (SVHC) does not translate to a ban of the substance, but it implies that additional documentation and authorizations are required prior to the placing on the market, use, or import of the substance, which is associated with high expenditure for the company and high potential socioeconomic impact
In this work we investigated the in vitro effects of respiratory sensitizers (LMW: phthalic anhydride (PA) and trimellitic anhydride (TMA); HMW: Bet v1 purified protein and house dust mite (HDM) extract) and irritants (methyl salicylate (MeSa) and acrolein (Acr)) at the lung-blood barrier using a novel 3D in vitro coculture model developed by our group on the basis of the lung in vitro model for respiratory irritation developed by Klein et al (Klein et al, 2013, 2017; Fizeșan et al, 2018) (Fig. 1B)
Summary
Due to their peculiar toxicity and systemic effects, respiratory sensitizers are receiving increasing attention within toxicity evaluation studies and risk assessment. As stated in Article 57 of the EU REACH Regulation, respiratory sensitizers can be considered substances of very high concern (SVHC) following the principle of equivalent level of concern to carcinogens, mutagens, substances toxic for reproduction, PBT substances (persistent, bio-accumulative, and toxic), and vPvB (very persistent and very bio-accumulative) substances (EC, 2006). Respiratory sensitization to chemical (or low molecular weight; LMW) compounds mostly occurs at the workplace, leading to the development of occupational allergies such as allergic asthma, rhinitis, and conjunctivitis (Kimber et al, 2010). Around a hundred chemicals were described to act as respiratory sensitizers (Bloemen et al, 2009), among which different chemical classes such as acid anhydrides, diisocyanates, and chloroplatinate salts were identified
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