Kristin Isaacs

Linking high resolution mass spectrometry data with exposure and toxicity forecasts to advance high-throughput environmental monitoring

There is a growing need in the field of exposure science for monitoring methods that rapidly screen environmental media for suspect contaminants. Measurement and analysis platforms, based on high resolution mass spectrometry (HRMS), now exist to meet this need. Here we describe results of a study that links HRMS data with exposure predictions from the U.S. EPAs ExpoCast™ program and in vitro bioassay data from the U.S. interagency Tox21 consortium. Vacuum dust samples were collected from 56 households across the U.S. as part of the American Healthy Homes Survey (AHHS). Sample extracts were analyzed using liquid chromatography time-of-flight mass spectrometry (LC-TOF/MS) with electrospray ionization. On average, approximately 2000 molecular features were identified per sample (based on accurate mass) in negative ion mode, and 3000 in positive ion mode. Exact mass, isotope distribution, and isotope spacing were used to match molecular features with a unique listing of chemical formulas extracted from EPAs Distributed Structure-Searchable Toxicity (DSSTox) database. A total of 978 DSSTox formulas were consistent with the dust LC-TOF/molecular feature data (match score≥90); these formulas mapped to 3228 possible chemicals in the database. Correct assignment of a unique chemical to a given formula required additional validation steps. Each suspect chemical was prioritized for follow-up confirmation using abundance and detection frequency results, along with exposure and bioactivity estimates from ExpoCast and Tox21, respectively. Chemicals with elevated exposure and/or toxicity potential were further examined using a mixture of 100 chemical standards. A total of 33 chemicals were confirmed present in the dust samples by formula and retention time match; nearly half of these do not appear to have been associated with house dust in the published literature. Chemical matches found in at least 10 of the 56 dust samples include Piperine, N,N-Diethyl-m-toluamide (DEET), Triclocarban, Diethyl phthalate (DEP), Propylparaben, Methylparaben, Tris(1,3-dichloro-2-propyl)phosphate (TDCPP), and Nicotine. This study demonstrates a novel suspect screening methodology to prioritize chemicals of interest for subsequent targeted analysis. The methods described here rely on strategic integration of available public resources and should be considered in future non-targeted and suspect screening assessments of environmental and biological media.

SHEDS-HT: an integrated probabilistic exposure model for prioritizing exposures to chemicals with near-field and dietary sources.

United States Environmental Protection Agency (USEPA) researchers are developing a strategy for high-throughput (HT) exposure-based prioritization of chemicals under the ExpoCast program. These novel modeling approaches for evaluating chemicals based on their potential for biologically relevant human exposures will inform toxicity testing and prioritization for chemical risk assessment. Based on probabilistic methods and algorithms developed for The Stochastic Human Exposure and Dose Simulation Model for Multimedia, Multipathway Chemicals (SHEDS-MM), a new mechanistic modeling approach has been developed to accommodate high-throughput (HT) assessment of exposure potential. In this SHEDS-HT model, the residential and dietary modules of SHEDS-MM have been operationally modified to reduce the user burden, input data demands, and run times of the higher-tier model, while maintaining critical features and inputs that influence exposure. The model has been implemented in R; the modeling framework links chemicals to consumer product categories or food groups (and thus exposure scenarios) to predict HT exposures and intake doses. Initially, SHEDS-HT has been applied to 2507 organic chemicals associated with consumer products and agricultural pesticides. These evaluations employ data from recent USEPA efforts to characterize usage (prevalence, frequency, and magnitude), chemical composition, and exposure scenarios for a wide range of consumer products. In modeling indirect exposures from near-field sources, SHEDS-HT employs a fugacity-based module to estimate concentrations in indoor environmental media. The concentration estimates, along with relevant exposure factors and human activity data, are then used by the model to rapidly generate probabilistic population distributions of near-field indirect exposures via dermal, nondietary ingestion, and inhalation pathways. Pathway-specific estimates of near-field direct exposures from consumer products are also modeled. Population dietary exposures for a variety of chemicals found in foods are combined with the corresponding chemical-specific near-field exposure predictions to produce aggregate population exposure estimates. The estimated intake dose rates (mg/kg/day) for the 2507 chemical case-study spanned 13 orders of magnitude. SHEDS-HT successfully reproduced the pathway-specific exposure results of the higher-tier SHEDS-MM for a case-study pesticide and produced median intake doses significantly correlated (p<0.0001, R2=0.39) with medians inferred using biomonitoring data for 39 chemicals from the National Health and Nutrition Examination Survey (NHANES). Based on the favorable performance of SHEDS-HT with respect to these initial evaluations, we believe this new tool will be useful for HT prediction of chemical exposure potential.

Estimating Sobol sensitivity indices using correlations

Sensitivity analysis is a crucial tool in the development and evaluation of complex mathematical models. Sobols method is a variance-based global sensitivity analysis technique that has been applied to computational models to assess the relative importance of input parameters on the output. This paper introduces new notation that describes the Sobol indices in terms of the Pearson correlation of outputs from pairs of runs, and introduces correction terms to remove some of the spurious correlation. A variety of estimation techniques are compared for accuracy and precision using the G function as a test case.

A review of air exchange rate models for air pollution exposure assessments.

A critical aspect of air pollution exposure assessments is estimation of the air exchange rate (AER) for various buildings where people spend their time. The AER, which is the rate of exchange of indoor air with outdoor air, is an important determinant for entry of outdoor air pollutants and for removal of indoor-emitted air pollutants. This paper presents an overview and critical analysis of the scientific literature on empirical and physically based AER models for residential and commercial buildings; the models highlighted here are feasible for exposure assessments as extensive inputs are not required. Models are included for the three types of airflows that can occur across building envelopes: leakage, natural ventilation, and mechanical ventilation. Guidance is provided to select the preferable AER model based on available data, desired temporal resolution, types of airflows, and types of buildings included in the exposure assessment. For exposure assessments with some limited building leakage or AER measurements, strategies are described to reduce AER model uncertainty. This review will facilitate the selection of AER models in support of air pollution exposure assessments.

GPS-based microenvironment tracker (MicroTrac) model to estimate time–location of individuals for air pollution exposure assessments: Model evaluation in central North Carolina

A critical aspect of air pollution exposure assessment is the estimation of the time spent by individuals in various microenvironments (ME). Accounting for the time spent in different ME with different pollutant concentrations can reduce exposure misclassifications, while failure to do so can add uncertainty and bias to risk estimates. In this study, a classification model, called MicroTrac, was developed to estimate time of day and duration spent in eight ME (indoors and outdoors at home, work, school; inside vehicles; other locations) from global positioning system (GPS) data and geocoded building boundaries. Based on a panel study, MicroTrac estimates were compared with 24-h diary data from nine participants, with corresponding GPS data and building boundaries of home, school, and work. MicroTrac correctly classified the ME for 99.5% of the daily time spent by the participants. The capability of MicroTrac could help to reduce the time–location uncertainty in air pollution exposure models and exposure metrics for individuals in health studies.

Identifying housing and meteorological conditions influencing residential air exchange rates in the DEARS and RIOPA studies: development of distributions for human exposure modeling

Appropriate prediction of residential air exchange rate (AER) is important for estimating human exposures in the residential microenvironment, as AER drives the infiltration of outdoor-generated air pollutants indoors. AER differences among homes may result from a number of factors, including housing characteristics and meteorological conditions. Residential AER data collected in the Detroit Exposure and Aerosol Research Study (DEARS) and the Relationships of Indoor, Outdoor and Personal Air (RIOPA) study were analyzed to determine whether the influence of a number of housing and meteorological conditions on AER were consistent across four cities in different regions of the United States (Detroit MI, Elizabeth NJ, Houston TX, Los Angeles, CA). Influential factors were identified and used as binning variables for deriving final AER distributions for the use in exposure modeling. In addition, both between-home and within-home variance in AER in DEARS were quantified with the goal of identifying reasonable AER resampling frequencies for use in longitudinal exposure modeling efforts. The results of this analysis indicate that residential AER is depended on ambient temperature, the presence (or not) of central air conditioning, and the age of the home. Furthermore, between-home variability in AER accounted for the majority (67%) of the total variance in AER for Detroit homes, indicating lower within-home variability. These findings are compared with other previously published AER distributions, and the implications for exposure modeling are discussed.

A new method of longitudinal diary assembly for human exposure modeling.

Human exposure time-series modeling requires longitudinal time–activity diaries to evaluate the sequence of concentrations encountered, and hence, pollutant exposure for the simulated individuals. However, most of the available data on human activities are from cross-sectional surveys that typically sample 1 day per person. A procedure is needed for combining cross-sectional activity data into multiple-day (longitudinal) sequences that can capture day-to-day variability in human exposures. Properly accounting for intra- and interindividual variability in these sequences can have a significant effect on exposure estimates and on the resulting health risk assessments. This paper describes a new method of developing such longitudinal sequences, based on ranking 1-day activity diaries with respect to a user-chosen key variable. Two statistics, “D” and “A”, are targeted. The D statistic reflects the relative importance of within- and between-person variance with respect to the key variable. The A statistic quantifies the day-to-day (lag-one) autocorrelation. The user selects appropriate target values for both D and A. The new method then stochastically assembles longitudinal diaries that collectively meet these targets. On the basis of numerous simulations, the D and A targets are closely attained for exposure analysis periods >30 days in duration, and reasonably well for shorter simulation periods. Longitudinal diary data from a field study suggest that D and A are stable over time, and perhaps over cohorts as well. The new method can be used with any cohort definitions and diary pool assignments, making it easily adaptable to most exposure models. Implementation of the new method in its basic form is described, and various extensions beyond the basic form are discussed.

Computational Exposure Science: An Emerging Discipline to Support 21st-Century Risk Assessment.

Background: Computational exposure science represents a frontier of environmental science that is emerging and quickly evolving. Objectives: In this commentary, we define this burgeoning discipline, describe a framework for implementation, and review some key ongoing research elements that are advancing the science with respect to exposure to chemicals in consumer products. Discussion: The fundamental elements of computational exposure science include the development of reliable, computationally efficient predictive exposure models; the identification, acquisition, and application of data to support and evaluate these models; and generation of improved methods for extrapolating across chemicals. We describe our efforts in each of these areas and provide examples that demonstrate both progress and potential. Conclusions: Computational exposure science, linked with comparable efforts in toxicology, is ushering in a new era of risk assessment that greatly expands our ability to evaluate chemical safety and sustainability and to protect public health. Citation: Egeghy PP, Sheldon LS, Isaacs KK, Özkaynak H, Goldsmith M-R, Wambaugh JF, Judson RS, Buckley TJ. 2016. Computational exposure science: an emerging discipline to support 21st-century risk assessment. Environ Health Perspect 124:697–702; http://dx.doi.org/10.1289/ehp.1509748

Characterization and prediction of chemical functions and weight fractions in consumer products

Highlights • Functional role of thousands of chemicals is analyzed.• These data are combined with chemical weight fractions in personal care products.• Empirical compositions for products are developed based on function.• Classifier models for function and weight fraction are built.• These methods can fill data gaps for consumer product exposure models.

Statistical properties of longitudinal time-activity data for use in human exposure modeling

Understanding the longitudinal properties of the time spent in different locations and activities is important in characterizing human exposure to pollutants. The results of a four-season longitudinal time-activity diary study in eight working adults are presented, with the goal of improving the parameterization of human activity algorithms in EPA’s exposure modeling efforts. Despite the longitudinal, multi-season nature of the study, participant non-compliance with the protocol over time did not play a major role in data collection. The diversity (D)—a ranked intraclass correlation coefficient (ICC)— and lag-one autocorrelation (A) statistics of study participants are presented for time spent in outdoor, motor vehicle, residential, and other-indoor locations. Day-type (workday versus non-workday, and weekday versus weekend), season, temperature, and gender differences in the time spent in selected locations and activities are described, and D & A statistics are presented. The overall D and ICC values ranged from approximately 0.08–0.26, while the mean population rank A values ranged from approximately 0.19–0.36. These statistics indicate that intra-individual variability exceeds explained inter-individual variability, and low day-to-day correlations among locations. Most exposure models do not address these behavioral characteristics, and thus underestimate population exposure distributions and subsequent health risks associated with environmental exposures.