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cell  dets  dose  human airway  internal dose  lung function  lung  n     p     respiratory toxicity  respiratory  toxicity  vitro   
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Preview: Toxicological Sciences - Advance Access

Toxicological Sciences Advance Access

Published: Thu, 23 Nov 2017 00:00:00 GMT

Last Build Date: Thu, 23 Nov 2017 05:50:36 GMT


Local and systemic inflammation may mediate diesel engine exhaust induced lung function impairment in a Chinese occupational cohort


Diesel exhaust (DE) as the major source of vehicle-emitted particle matter in ambient air impairs lung function. The objectives were to assess the contribution of local (e.g., the fraction of exhaled nitric oxide [FeNO] and serum Club cell secretory protein [CC16]) and systemic (e.g., serum C-reaction protein [CRP] and interleukin-6 [IL-6]) inflammation to DE induced lung function impairment using a unique cohort of diesel engine testers (DET, n = 137) and non-DETs (n = 127), made up of current and non-current smokers. Urinary metabolites, FeNO, serum markers, and spirometry were assessed. A 19% reduction in CC16 and a 94% increase in CRP were identified in DETs compared to non-DETs (all P values<10−4), which were further corroborated by showing a dose-response relationship with internal dose for DE exposure (all P values<0.04) and a time-course relationship with DE exposure history (all P values<0.005). Mediation analysis showed that 43% of the difference in FEV1 between DETs and non-DETs can be explained by circulating CC16 and CRP (permuted P < 0.001). An inverse dose-dependent relationship between FeNO and internal dose for cigarette smoke was identified (P = 0.0003). A range of 95% lower bounds of benchmark dose (BMD) of 1.0261 to 1.4513 μg phenanthrols/g creatinine in urine as an internal dose was recommended for regulatory risk assessment. Local and systemic inflammation may be key processes that contribute to the subsequent development of obstructive lung disease in DE-exposed populations.

A 3D human airway model enables prediction of respiratory toxicity of inhaled drugs in vitro


Respiratory tract toxicity represents a significant cause of attrition of inhaled drug candidates targeting respiratory diseases. One of the key issues to allow early detection of respiratory toxicities is the lack of reliable and predictive in vitro systems. Here, the relevance and value of a physiologically relevant 3D human airway in vitro model (MucilAir™) were explored by repeated administration of a set of compounds with (n = 8) or without (n = 7) respiratory toxicity following inhalation in vivo. Predictability for respiratory toxicity was evaluated by readout of cytotoxicity, barrier integrity, viability, morphology, ciliary beating frequency, mucociliary clearance and cytokine release. Interestingly, the data show that in vivo toxicity can be predicted in vitro by studying cell barrier integrity by transepithelial electrical resistance (TEER), and cell viability determined by the Resazurin method. Both read-outs had 88% sensitivity and 100% specificity, respectively, while the former was more accurate with ROC AUC of 0.98 (p = 0.0018) compared to ROC AUC of 0.90 (p = 0.0092). The loss of cell barrier integrity could mainly, but not fully, be attributed to a loss of cell coverage in 6 out of 7 compounds with reduced TEER. Notably, these effects occurred only at 400 µM, at concentration levels significantly above primary target cell potency, suggesting that greater attention to high local lung concentrations should be taken into account in safety assessment of inhaled drugs. Thus, prediction of respiratory toxicity in 3D human airway in vitro models may result in improved animal welfare and reduced attrition in inhaled drug discovery projects.