Silver nanoparticles (AgNP) are one of the 84,000 chemicals regulated by the U.S. Environmental Protection Agency’s (US EPA) Toxic Substances Control Act (TSCA) that have yet to be tested for potential respiratory toxicity. AgNP are used in multiple applications but primarily in the manufacturing of many antimicrobial products and are thus exposures in occupational settings that are of concern to public health. Interactions between host genetic and acquired factors, or gene Ã environment interactions (GÃ E), may play a defining role in identifying sensitive populations to AgNP exposures in occupational settings. Host genetic factors, such as sex, genotype, or polymorphism, contribute to variation in certain genes that may increase an individual’s sensitivity to occupational exposures. Host acquired factors, such as pre-existing chronic respiratory diseases, including asthma, acute bronchitis, and chronic obstructive pulmonary disease (COPD), collectively affect 16% of the total United States population; these contribute to impairing host defense mechanisms, such as barrier function and immune regulation, mucocilliary clearance and permeability, as well as enzymatic and non-enzymatic oxidative stress regulation, and may also increase an individual’s sensitivity to occupational exposures. Few previous studies have characterized GÃ E effects on AgNP toxicity. Understanding GÃ E effects is important for identifying sensitive populations, whose underlying genetics or diseases could directly modify their response to AgNP exposures. Typically, these studies have used young, healthy animals or cell lines cultured toward a “Normal” phenotype and thus did not address the possibility of increased AgNP toxicity in asthmatics. In the present studies, we used organotypic cultures derived from murine tracheal epithelial cells (MTEC) as a high-content in vitro model of the conducting airway to characterize GÃ E effects, or in this case—the effects of genotype Ã phenotype interaction (GÃ P), in order to identify determinants of sensitivity and help define both regulatory and mechanistic bases for these effects on AgNP toxicity. In our first study, we used organotypic cultures 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 genotypes, phenotypes, and exposures to understand GÃ P effects on AgNP toxicity. The “Type 2 (T2)-Skewed” phenotype was characterized as an in vitro model of chronic respiratory diseases and experienced an increased sensitivity to AgNP toxicity, suggesting that asthmatics could be a sensitive population to AgNP exposures in occupational settings. In our second study, we used organotypic cultures to characterize global, differential, and targeted gene expression, canonical pathway enrichment, and upstream transcriptional regulation to understand GÃ P effects on transcriptional response to AgNP toxicity. We pursued a targeted analysis to characterize dose, genotype, and phenotype effects on expression patterns of genes involved in the secreted factors canonical pathway that were also associated with T1, pro-T2, T2, and T17 responses to AgNP toxicity. We observed the “T2-Skewed” phenotype was marked by increased pro-inflammatory T17 responses to AgNP toxicity, which are significant predictors of neutrophilic/difficult-to-control asthma and suggests that asthmatics could be a sensitive population to AgNP exposures in occupational settings. In our third study, we utilized mechanistic information from in vitro and in vivo studies to highlight how key events (KE) can be modified by host genetic and host acquired factors at acute, subacute, and subchronic exposures, and identified two categories of knowledge gaps in order to more directly prioritize future research needs. Taken together, our results highlight the importance of considering dosimetry as well as GÃ P effects when screening and prioritizing potential respiratory toxicants. This suggests the importance of considering other host factors, such as age, gender, and epigenetic effects when screening and prioritizing potential respiratory toxicants. This is challenging and important for engineered nanomaterials (ENM), since their mode of action (MoA) have been shown to differ considerably but are still used in hundreds of consumer products. Prior to anticipating potential adverse organism responses arising from ENM toxicity, ensuring safe development of the consumer products in which they are used will be the most critical and necessary step toward safeguarding public health.