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Highlights • The most robust endpoint of acute lung edema in animals is lung gravimetry. • Protein in bronchoalveolar lavage is a poor predictor of pulmonary fluid imbalance. • Surrogate endpoints for lung edema in rats match increased extravascular lung water in humans. • Relative to dogs, rats are biased to overestimate edema formation. • Dogs appear to be the species of choice for setting human thresholds for pulmonary edema. Abstract Phosgene-induced acute lung injury (ALI) is characterized by a concentration x time (Cxt)-dependent increased pulmonary vascular permeability, phenotypically manifested as potentially life-threatening acute lung edema. In contemporary animal bioassays, the quantification of protein in bronchoalveolar lavage fluid (BAL) is taken as an unequivocal endpoint suggestive of disruption of alveolar barrier function. However, extravasated protein can only be a surrogate endpoint for assessing the extravascular fluid dynamics of the lung. This pathophysiological hallmark of ALI is diagnosed and quantified in vivo in humans by assessing the accumulation of excess extravascular lung water (EVLW). The Point of Departure (POD) of the Cxt relationship of this adverse outcome pathway should also constitute the basis for setting safe occupational and emergency response values. Unlike the EVLW approach, toxicology-based animal models utilize postmortem analyses of total protein in BAL and lung weights as the basis for human risk assessment. With either approach, it remains difficult to unequivocally evaluate pulmonary edema in terms of etiopathology and specificity, i.e., cardiogenic and hydrostatic versus increased permeability edema. The objective of this paper is to retrospectively analyze the clinical scoring of the severity grades of in vivo EVLWs from humans with the respective postmortem biomarkers BAL protein and collagen versus wet lung weights in rats and dogs exposed by inhalation to phosgene gas. Despite the different methodological approaches taken in humans and animals, the EVLW-based predicted thresholds for the onset of pulmonary edema and potentially life-threatening severe pulmonary edema were in remarkable agreement. Data from dogs appear to more aptly reflect the human etiopathology and should be given preference over data from rodents. Especially in rats, elevations in BAL protein may lead to a marked overestimation of the edematous potency of phosgene due to secreted protein into airways. In summary, increased lung weight in rats and dogs scaled favorably with the human-EVLW and was shown to be the biomarker of choice for the scaling lung edema. Caution is advised when using BAL protein in isolation as a surrogate endpoint of pulmonary edema. [ABSTRACT FROM AUTHOR]

This paper compares two previously published 13-week inhalation studies with poorly soluble, low-toxicity particles (PSLTs) in rats to identify the unifying key metric of kinetic lung overload. The PSLTs compared are Multi-Walled Carbon Nanotubes (MWCNT) and black iron oxide (Fe 3 O 4 , magnetite). Their material densities and related displacement volumes differ approximately 30-fold. This offers an opportunity for analyzing the impact of the PSLT-density of agglomerates on endpoints currently conceived to be involved in kinetic lung overload. Corpuscular volumes and counts of cells retrieved by bronchoalveolar lavage (BAL) are analyzed to interrelate modeled cumulative lung burdens of solid aerosol to predict the no observed adverse effect concentration (NOAEC) and range of conditions causing various degrees of kinetic lung overload up to and beyond the maximum tolerated cumulative dose (MTD). Both descriptors are a reflection of accumulated lung burdens and, by design, bracket repeated exposure inhalation studies with PSLTs. This comparative analysis of high- and low-density PSLTs reveals that the leading adverse outcome pathway (AOP) is caused by a markedly increased pool-size of BAL-cells rather than any increased corpuscular volume of cells. The overload-related increased pool-size of BAL-cells is shown to be the dependent variable for the prorated increased elimination half-time of PSLTs. This interrelationship was used to predict the exposure concentrations for attaining a NOAEC and MTD of guideline-based repeated exposure inhalation studies with PSLTs. Earlier approaches suggesting a loss of the migratory capabilities of particle-laden, enlarged alveolar macrophages to be the cause for any increased elimination half-time of PSLTs could not be confirmed. In summary, kinetic modeling provides a versatile means to predict the cornerstones of repeated inhalation studies with PSLTs on rats. Such possibilities leverage adjustment of studies from different sources to identical degrees of kinetic overload. They also facilitate and foster AOP-facilitated read-across approaches. The course taken enables risk assessors to better differentiate lung pathologies caused by generic lung overload and substance-specific pathologies. [ABSTRACT FROM AUTHOR]

Catechol-O-methyltransferase (COMT) inhibitors are widely used as an add-on treatment to levodopa in adults with Parkinson's disease. It has been evidenced that the second-generation COMT inhibitors entacapone and tolcapone are potent inhibitors on human UDP-glucosyltransferases (UGTs), while the effect of the third-generation COMT inhibitor opicapone on human UGTs activities is unclear. The purpose of this study is to systemically investigate the effects of opicapone on human UGTs activities, and also to assess the potential risk of drug-drug interactions (DDIs) associated with opicapone. Our results indicated that opicapone is a broad-spectrum inhibitor of UGTs. Particularly, opicapone exhibited potent inhibition against UGT1A1, 1A7, 1A8, 1A9, and 1A10, with a range of inhibition constant K i values of 1.31–10.58 µM. Furthermore, the DDI risk was quantitatively predicted by using the in vitro-in vivo extrapolation (IVIVE). The prediction suggested that co-administration of opicapone at 25 mg/day or 50 mg/day with drugs primarily cleared by hepatic UGT1A9 or intestinal UGT1A1, 1A7, 1A8, 1A9, or 1A10 might result in potential DDI via inhibition of intestinal or hepatic UGTs. [Display omitted] • Opicapone is a potent inhibitor for UGT1A1, 1A7, 1A8, 1A9, and 1A10. • Opicapone is likely to cause a significant DDIs via inhibition of hepatic UGT1A9. • Combination of opicapone with intestinal UGTs substrates may cause clinical DDIs. [ABSTRACT FROM AUTHOR]

Highlights: [•] Fibrogenic changes in lung is accompanied by Nrf2 suppression and oxidative stress. [•] BLM interferes with Nrf2 activation in lung fibroblasts via ERK. [•] Suppressed Nrf2-tuned antioxidant system stimulating cellular ROS promotes fibrogenesis in lung fibroblasts. [•] Nrf2 activator attenuates BLM-induced fibrogenesis in lung fibroblasts. [Copyright &y& Elsevier]