Silver nanoparticles (AgNP) are used in multiple applications but primarily in the manufacturing of antimicrobial products. AgNP toxicity in the respiratory system is well characterized, but few in vitro or in vivo studies have evaluated the effects of interactions between host genetic and acquired factors or gene × environment interactions (G × E) on AgNP toxicity in the respiratory system. The primary goal of this article is to review host genetic and acquired factors identified across in vitro and in vivo studies and prioritize those necessary for defining exposure limits to protect all populations. The impact of these exposures and the work being done to address the current limited protections are also discussed. Future research on G × E effects on AgNP toxicity is warranted and will assist with informing regulatory or recommended exposure limits that enforce special protections for all populations to AgNP exposures in occupational settings.

Silver nanoparticles (AgNP) are used in multiple applications but primarily in the manufacturing of antimicrobial products. Previous studies have identified AgNP toxicity in airway epithelial cells, but no in vitro studies to date have used organotypic cultures as a high-content in vitro model of the conducting airway to characterize the effects of interactions between host genetic and acquired factors, or gene × phenotype interactions (G×P), on AgNP toxicity. In the present study, we derived organotypic cultures from primary murine tracheal epithelial cells (MTEC) to characterize nominal and dosimetric dose-response relationships for AgNP-induced barrier dysfunction, glutathione (GSH) depletion, reactive oxygen species (ROS) production, lipid peroxidation, and cytotoxicity across two genotypes (A/J and C57BL/6J mice), two phenotypes ("Normal" and "Type 2[T2]-Skewed"), and two exposures (an acute exposure of 24 h and a subacute exposure of 4 hours, every other day, over 5 days [5×4 h]). We characterized the "T2-Skewed" phenotype as an in vitro model of chronic respiratory diseases, which was marked by increased sensitivity to AgNP-induced barrier dysfunction, GSH depletion, ROS production, lipid peroxidation, and cytotoxicity, suggesting that asthmatics are a sensitive population to AgNP exposures in occupational settings. This also suggests that exposure limits, which should be based upon the most sensitive population, should be derived using in vitro and in vivo models of chronic respiratory diseases. This study highlights the importance of considering dosimetry as well as G×P effects when screening and prioritizing potential respiratory toxicants. Such in vitro studies can be used to inform regulatory policy aimed at special protections for all populations.

Exposure estimates that do not account for time in-transit may underestimate exposure to traffic-related air pollution, but exact contributions have not been studied directly. We conducted two-week monitoring, including novel in-vehicle sampling, in a subset of the Multi-Ethnic Study of Atherosclerosis and Air Pollution cohort in two cities. Participants spent the majority of their time indoors and only 4.4% of their time (63 min/day) in-vehicle, on average. The mean ambient-source NO2 concentration was 5.1 ppb indoors and 32.3 ppb in-vehicle during drives. On average, indoor exposure contributed 69% and in-vehicle exposure contributed 24% of participants’ ambient-source NO2 exposure. For participants in the highest quartile of time in-vehicle (≥1.3 hrs/day), indoor and in-vehicle contributions were 60% and 31%, respectively. Incorporating infiltrated indoor and measured in-vehicle NO2 produced exposure estimates 5.6 ppb lower, on average, than using only outdoor concentrations. The indoor microenvironment accounted for the largest proportion of ambient-source exposure in this older population, despite higher concentrations of NO2 outdoors and in vehicles than indoors. In-vehicle exposure was more influential among participants who drove most and for participants residing in areas with lower outdoor air pollution. Failure to characterize exposures in these microenvironments may contribute to exposure misclassification in epidemiologic studies.

Silver nanoparticles (AgNP) are used in multiple applications but primarily in the manufacturing of antimicrobial products. Previous studies have identified AgNP toxicity in airway epithelial cells, but no in vitro studies to date have used organotypic cultures as a high-content in vitro model of the conducting airway to characterize the effects of interactions between host genetic and acquired factors, or gene × phenotype interactions (G×P), on AgNP toxicity. In the present study, we derived organotypic cultures from primary murine tracheal epithelial cells (MTEC) to characterize nominal and dosimetric dose-response relationships for AgNP-induced barrier dysfunction, glutathione (GSH) depletion, reactive oxygen species (ROS) production, lipid peroxidation, and cytotoxicity across two genotypes (A/J and C57BL/6J mice), two phenotypes ("Normal" and "Type 2[T2]-Skewed"), and two exposures (an acute exposure of 24 h and a subacute exposure of 4 hours, every other day, over 5 days [5×4 h]). We characterized the "T2-Skewed" phenotype as an in vitro model of chronic respiratory diseases, which was marked by increased sensitivity to AgNP-induced barrier dysfunction, GSH depletion, ROS production, lipid peroxidation, and cytotoxicity, suggesting that asthmatics are a sensitive population to AgNP exposures in occupational settings. This also suggests that exposure limits, which should be based upon the most sensitive population, should be derived using in vitro and in vivo models of chronic respiratory diseases. This study highlights the importance of considering dosimetry as well as G×P effects when screening and prioritizing potential respiratory toxicants. Such in vitro studies can be used to inform regulatory policy aimed at special protections for all populations.