Valerie Zartarian

Probabilistic modeling of dietary arsenic exposure and dose and evaluation with 2003-2004 NHANES data.

Background Dietary exposure from food to toxic inorganic arsenic (iAs) in the general U.S. population has not been well studied. Objectives The goal of this research was to quantify dietary As exposure and analyze the major contributors to total As (tAs) and iAs. Another objective was to compare model predictions with observed data. Methods Probabilistic exposure modeling for dietary As was conducted with the Stochastic Human Exposure and Dose Simulation–Dietary (SHEDS-Dietary) model, based on data from the National Health and Nutrition Examination Survey. The dose modeling was conducted by combining the SHEDS-Dietary model with the MENTOR-3P (Modeling ENvironment for TOtal Risk with Physiologically Based Pharmacokinetic Modeling for Populations) system. Model evaluation was conducted via comparing exposure and dose-modeling predictions against duplicate diet data and biomarker measurements, respectively, for the same individuals. Results The mean modeled tAs exposure from food is 0.38 μg/kg/day, which is approximately 14 times higher than the mean As exposures from the drinking water. The mean iAs exposure from food is 0.05 μg/kg/day (1.96 μg/day), which is approximately two times higher than the mean iAs exposures from the drinking water. The modeled exposure and dose estimates matched well with the duplicate diet data and measured As biomarkers. The major food contributors to iAs exposure were the following: vegetables (24%); fruit juices and fruits (18%); rice (17%); beer and wine (12%); and flour, corn, and wheat (11%). Approximately 10% of tAs exposure from foods is the toxic iAs form. Conclusions The general U.S. population may be exposed to tAs and iAs more from eating some foods than from drinking water. In addition, this model evaluation effort provides more confidence in the exposure assessment tools used.

Exposure Assessment in the National Children’s Study: Introduction

The science of exposure assessment is relatively new and evolving rapidly with the advancement of sophisticated methods for specific measurements at the picogram per gram level or lower in a variety of environmental and biologic matrices. Without this measurement capability, environmental health studies rely on questionnaires or other indirect means as the primary method to assess individual exposures. Although we use indirect methods, they are seldom used as stand-alone tools. Analyses of environmental and biologic samples have allowed us to get more precise data on exposure pathways, from sources to concentrations, to routes, to exposure, to doses. They also often allow a better estimation of the absorbed dose and its relation to potential adverse health outcomes in individuals and in populations. Here, we make note of various environmental agents and how best to assess exposure to them in the National Children’s Study—a longitudinal epidemiologic study of children’s health. Criteria for the analytical method of choice are discussed with particular emphasis on the need for long-term quality control and quality assurance measures.

Adoption of an official ISEA glossary

The International Society for Exposure Analysis (ISEA) and its Nomenclature Committee have been involved since the mid-1990s in an intermittent but ongoing effort to develop an official ISEA glossary. Several related activities have stimulated greater interest and discussion nationally and internationally on a common exposure language. Among these activites are a 1997 Journal of Exposure Analysis and Environmental Epidemiology feature article on exposure and dose definitions and a 1999-initiated project of the International Programme on Chemical Safety (IPCS) (WHO/ILO/UNEP) to confront terminology issues hindering harmonization in the area of exposure assessment. Recently, the ISEA members voted in support of adopting the IPCS glossary as the official ISEA glossary, and the ISEA Executive Board agreed to accept this recommendation. In this feature article, we (1) describe the process through which the ISEA adopted the IPCS glossary as the official ISEA glossary, (2) present the joint IPCS/ISEA glossary of terms and their definitions, and (3) discuss plans for how the glossary can be used by ISEA and updated over time by ISEA and IPCS. The glossary is intended to be a living document that reflects the latest usage and maintains international harmonization of exposure terminology that can be practically applied to improve communication in exposure and related fields.

A Probabilistic Arsenic Exposure Assessment for Children who Contact CCA-Treated Playsets and Decks, Part 1: Model Methodology, Variability Results, and Model Evaluation

Concerns have been raised regarding the safety of young children who may contact arsenic residues while playing on and around chromated copper arsenate (CCA)-treated wood playsets and decks. Although CCA registrants voluntarily canceled the production of treated wood for residential use in 2003, the potential for exposure from existing structures and surrounding soil still poses concerns. The EPAs Office of Research and Development developed and applied the probabilistic Stochastic Human Exposure and Dose Simulation model for wood preservatives (SHEDS-Wood) to estimate childrens absorbed dose of arsenic from CCA. Skin contact with, and nondietary ingestion of, arsenic in soil and wood residues were considered for the population of children in the United States who frequently contact CCA-treated wood playsets and decks. Model analyses were conducted to assess the range in population estimates and the impact of potential mitigation strategies such as the use of sealants and hand washing after play events. The results show predicted central values for lifetime annual average daily dose values for arsenic ranging from 10(-6) to 10(-5) mg/kg/day, with predicted 95th percentiles on the order of 10(-5) mg/kg/day. There were several orders of magnitude between lower and upper percentiles. Residue ingestion via hand-to-mouth contact was determined to be the most significant exposure route for most scenarios. Results of several alternative scenarios were similar to baseline results, except for the scenario with greatly reduced residue concentrations through hypothetical wood sealant applications; in this scenario, exposures were lower, and the soil ingestion route dominated. SHEDS-Wood estimates are typically consistent with, or within the range of, other CCA exposure models.

A Probabilistic Arsenic Exposure Assessment for Children Who Contact Chromated Copper Arsenate (CCA)‐Treated Playsets and Decks, Part 2: Sensitivity and Uncertainty Analyses

A probabilistic model (SHEDS-Wood) was developed to examine childrens exposure and dose to chromated copper arsenate (CCA)-treated wood, as described in Part 1 of this two-part article. This Part 2 article discusses sensitivity and uncertainty analyses conducted to assess the key model inputs and areas of needed research for childrens exposure to CCA-treated playsets and decks. The following types of analyses were conducted: (1) sensitivity analyses using a percentile scaling approach and multiple stepwise regression; and (2) uncertainty analyses using the bootstrap and two-stage Monte Carlo techniques. The five most important variables, based on both sensitivity and uncertainty analyses, were: wood surface residue-to-skin transfer efficiency; wood surface residue levels; fraction of hand surface area mouthed per mouthing event; average fraction of nonresidential outdoor time a child plays on/around CCA-treated public playsets; and frequency of hand washing. In general, there was a factor of 8 for the 5th and 95th percentiles and a factor of 4 for the 50th percentile in the uncertainty of predicted population dose estimates due to parameter uncertainty. Data were available for most of the key model inputs identified with sensitivity and uncertainty analyses; however, there were few or no data for some key inputs. To evaluate and improve the accuracy of model results, future measurement studies should obtain longitudinal time-activity diary information on children, spatial and temporal measurements of residue and soil concentrations on or near CCA-treated playsets and decks, and key exposure factors. Future studies should also address other sources of uncertainty in addition to parameter uncertainty, such as scenario and model uncertainty.

Modeled estimates of soil and dust ingestion rates for children.

Daily soil/dust ingestion rates typically used in exposure and risk assessments are based on tracer element studies, which have a number of limitations and do not separate contributions from soil and dust. This article presents an alternate approach of modeling soil and dust ingestion via hand and object mouthing of children, using EPAs SHEDS model. Results for children 3 to <6 years old show that mean and 95th percentile total ingestion of soil and dust values are 68 and 224 mg/day, respectively; mean from soil ingestion, hand-to-mouth dust ingestion, and object-to-mouth dust ingestion are 41 mg/day, 20 mg/day, and 7 mg/day, respectively. In general, hand-to-mouth soil ingestion was the most important pathway, followed by hand-to-mouth dust ingestion, then object-to-mouth dust ingestion. The variability results are most sensitive to inputs on surface loadings, soil-skin adherence, hand mouthing frequency, and hand washing frequency. The predicted total soil and dust ingestion fits a lognormal distribution with geometric mean = 35.7 and geometric standard deviation = 3.3. There are two uncertainty distributions, one below the 20th percentile and the other above. Modeled uncertainties ranged within a factor of 3-30. Mean modeled estimates for soil and dust ingestion are consistent with past information but lower than the central values recommended in the 2008 EPA Child-Specific Exposure Factors Handbook. This new modeling approach, which predicts soil and dust ingestion by pathway, source type, population group, geographic location, and other factors, offers a better characterization of exposures relevant to health risk assessments as compared to using a single value.

Quantifying children's aggregate (dietary and residential) exposure and dose to permethrin: application and evaluation of EPA's probabilistic SHEDS-Multimedia model

Reliable, evaluated human exposure and dose models are important for understanding the health risks from chemicals. A case study focusing on permethrin was conducted because of this insecticides widespread use and potential health effects. SHEDS-Multimedia was applied to estimate US population permethrin exposures for 3- to 5-year-old children from residential, dietary, and combined exposure routes, using available dietary consumption data, food residue data, residential concentrations, and exposure factors. Sensitivity and uncertainty analyses were conducted to identify key factors, pathways, and research needs. Model evaluation was conducted using duplicate diet data and biomonitoring data from multiple field studies, and comparison to other models. Key exposure variables were consumption of spinach, lettuce, and cabbage; surface-to-skin transfer efficiency; hand mouthing frequency; fraction of hand mouthed; saliva removal efficiency; fraction of house treated; and usage frequency. For children in households using residential permethrin, the non-dietary exposure route was most important, and when all households were included, dietary exposure dominated. SHEDS-Multimedia model estimates compared well to real-world measurements data; this exposure assessment tool can enhance human health risk assessments and inform childrens health research. The case study provides insights into childrens aggregate exposures to permethrin and lays the foundation for a future cumulative pyrethroid pesticides risk assessment.

A Pharmacokinetic Model of cis- and trans-Permethrin Disposition in Rats and Humans With Aggregate Exposure Application

Permethrin is a broad-spectrum pyrethroid insecticide and among the most widely used insecticides in homes and crops. Managing the risks for pesticides such as permethrin depends on the ability to consider diverse exposure scenarios and their relative risks. Physiologically based pharmacokinetic models of delta methrin disposition were modified to describe permethrin kinetics in the rat and human. Unlike formulated deltamethrin which consists of a single stereoisomer, permethrin is formulated as a blend of cis- and trans-diastereomers. We assessed time courses for cis-permethrin and trans-permethrin in several tissues (brain, blood, liver, and fat) in the rat following oral administration of 1 and 10mg/kg permethrin (cis/trans: 40/60). Accurate simulation of permethrin in the rat suggests that a generic model structure is promising for modeling pyrethroids. Human in vitro data and appropriate anatomical information were used to develop a provisional model of permethrin disposition with structures for managing oral, dermal, and inhalation routes of exposure. The human permethrin model was used to evaluate dietary and residential exposures in the U.S. population as estimated by EPAs Stochastic Human Exposure and Dose Simulation model. Simulated cis- and trans-DCCA, metabolites of permethrin, were consistent with measured values in the National Health and Nutrition Examination Survey, indicating that the model holds promise for assessing population exposures and quantifying dose metrics.

Biologically based modeling of multimedia, multipathway, multiroute population exposures to arsenic

This article presents an integrated, biologically based, source-to-dose assessment framework for modeling multimedia/multipathway/multiroute exposures to arsenic. Case studies demonstrating this framework are presented for three US counties (Hunderton County, NJ; Pima County, AZ; and Franklin County, OH), representing substantially different conditions of exposure. The approach taken utilizes the Modeling ENvironment for TOtal Risk studies (MENTOR) in an implementation that incorporates and extends the approach pioneered by Stochastic Human Exposure and Dose Simulation (SHEDS), in conjunction with a number of available databases, including NATA, NHEXAS, CSFII, and CHAD, and extends modeling techniques that have been developed in recent years. Model results indicate that, in most cases, the food intake pathway is the dominant contributor to total exposure and dose to arsenic. Model predictions are evaluated qualitatively by comparing distributions of predicted total arsenic amounts in urine with those derived using biomarker measurements from the NHEXAS — Region V study: the population distributions of urinary total arsenic levels calculated through MENTOR and from the NHEXAS measurements are in general qualitative agreement. Observed differences are due to various factors, such as interindividual variation in arsenic metabolism in humans, that are not fully accounted for in the current model implementation but can be incorporated in the future, in the open framework of MENTOR. The present study demonstrates that integrated source-to-dose modeling for arsenic can not only provide estimates of the relative contributions of multipathway exposure routes to the total exposure estimates, but can also estimate internal target tissue doses for speciated organic and inorganic arsenic, which can eventually be used to improve evaluation of health risks associated with exposures to arsenic from multiple sources, routes, and pathways.

A meta-analysis of children's object-to-mouth frequency data for estimating non-dietary ingestion exposure.

To improve estimates of non-dietary ingestion in probabilistic exposure modeling, a meta-analysis of childrens object-to-mouth frequency was conducted using data from seven available studies representing 438 participants and ∼1500 h of behavior observation. The analysis represents the first comprehensive effort to fit object-to-mouth frequency variability and uncertainty distributions by indoor/outdoor location and by age groups recommended by the US Environmental Protection Agency for assessing childhood exposures. Weibull distributions best fit the observed data from studies with no statistical differences, and are presented by study, age group, and location. As age increases, both indoor and outdoor object-to-mouth frequencies decrease. Object-to-mouth frequency is significantly greater indoors (2–32 contacts/h) than outdoors (average 1–9 contacts/h). This paper compares results to a similar hand-to-mouth frequency meta-analysis. Children who tend to mouth hands indoors also tend to mouth hands outdoors; children who tend to mouth objects indoors tend to mouth objects outdoors. However, children who tend to mouth objects do not necessarily have a tendency to mouth hands. Unlike for hand-to-mouth frequency, a statistical difference was found among the various studies for object-to-mouth frequency. This could be due to different definitions for object mouthing across the studies considered. The analysis highlights the need for additional object-to-mouth data (indoors and especially outdoors) for various age groups using standardized collection and analysis.