A geospatial modeling approach to quantifying the risk of exposure to environmental chemical mixtures via a common molecular target

In the real world, individuals are exposed to chemicals from sources that vary over space and time. However, traditional risk assessments based on in vivo animal studies typically use a chemical-by-chemical approach and apical disease end-points. New approach methodologies (NAMs) in toxicology, such as in vitro high-throughput (HTS) assays generated in Tox21 and ToxCast, can more readily provide mechanistic chemical hazard information for chemicals with no existing data than in vivo methods. In this paper, we establish a workflow to assess the joint action of 41 modeled ambient chem-ical exposures in the air from the USA-wide National Air Toxics Assessment by integrating human exposures with hazard data from curated HTS (cHTS) assays to identify counties where exposure to the local chemical mixture may perturb a common biological target. We exemplify this proof-of-concept using CYP1A1 mRNA up-regulation. We first estimate in-ternal exposure and then convert the inhaled concentration to a steady state plasma concentration using physiologically based toxicokinetic modeling parameterized with county-specific information on ages and body weights. We then use the estimated blood plasma concentration and the concentration-response curve from the in vitro cHTS assay to deter-mine the chemical-specific effects of the mixture components. Three mixture modeling methods were used to estimate the joint effect from exposure to the chemical mixture on the activity levels, which were geospatially mapped. Finally, a Monte Carlo uncertainty analysis was performed to quantify the influence of each parameter on the combined effects. This workflow demonstrates how NAMs can be used to predict early-stage biological perturbations that can lead to ad-verse health outcomes that result from exposure to chemical mixtures. As a result, this work will advance mixture risk assessment and other early events in the effects of chemicals.