Peter P. Egeghy

The exposure data landscape for manufactured chemicals.

The U.S. Environmental Protection Agency is developing chemical screening and prioritization programs to evaluate environmental chemicals for potential risk to human health in a rapid and efficient manner. As part of these efforts, it is important to catalog available information on chemical toxicity and exposure from widely dispersed sources. The main objective of this analysis is to define important aspects of the exposure space and to catalog the available exposure information for chemicals being considered for analysis as part of the U.S. EPA ToxCast™ screening and prioritization program. Publicly available exposure data have been extracted into ACToR (Aggregated Computational Toxicology Resource), which combines information for hundreds of thousands of chemicals from >600 public sources. We use data from ACToR to assess the exposure data landscape for environmental chemicals. Of the roughly 100,000 chemicals that have at least limited toxicity information available, less than one-fifth also have exposure information - and for most of these the information is of limited utility (e.g., production volume). Readily accessible data on concentrations in exposure-related media are only available for a much smaller fraction. Among these, the largest number of chemicals is measured in water with over 1150 unique compounds, followed by 788 substances measured in soil, and 670 in air. These small numbers clearly reflect a focus of resources on those substances previously identified as possibly posing a hazard to human health. Exposure to a much broader number of chemicals will need to be measured in order to fully realize the envisioned goal of using exposure information to guide toxicity testing.

High-throughput models for exposure-based chemical prioritization in the ExpoCast project.

The United States Environmental Protection Agency (U.S. EPA) must characterize potential risks to human health and the environment associated with manufacture and use of thousands of chemicals. High-throughput screening (HTS) for biological activity allows the ToxCast research program to prioritize chemical inventories for potential hazard. Similar capabilities for estimating exposure potential would support rapid risk-based prioritization for chemicals with limited information; here, we propose a framework for high-throughput exposure assessment. To demonstrate application, an analysis was conducted that predicts human exposure potential for chemicals and estimates uncertainty in these predictions by comparison to biomonitoring data. We evaluated 1936 chemicals using far-field mass balance human exposure models (USEtox and RAIDAR) and an indicator for indoor and/or consumer use. These predictions were compared to exposures inferred by Bayesian analysis from urine concentrations for 82 chemicals reported in the National Health and Nutrition Examination Survey (NHANES). Joint regression on all factors provided a calibrated consensus prediction, the variance of which serves as an empirical determination of uncertainty for prioritization on absolute exposure potential. Information on use was found to be most predictive; generally, chemicals above the limit of detection in NHANES had consumer/indoor use. Coupled with hazard HTS, exposure HTS can place risk earlier in decision processes. High-priority chemicals become targets for further data collection.

Determinants of temporal variability in NHEXAS-Maryland environmental concentrations, exposures, and biomarkers

The longitudinal NHEXAS-Maryland study measured metals, PAHs, and pesticides in several media to capture temporal variability. Questionnaires were concurrently administered to identify factors that influenced changes in contaminant levels over time. We constructed mixed-effects regression models for lead, phenanthrene, and chlorpyrifos (including metabolites) in indoor air, dust, dermal wipes, and biological fluids. Significant predictors represented time-varying activities as well as unchanging housing and demographic factors. There was little overlap among the models, with predictors generally reflecting the diverse characteristics of the target compounds. We estimated between- and within-person variance components to evaluate the reliability of the measurements. While only one measurement of lead in blood or chlopyrifos in dust was needed for a dependable estimate of an individuals average level, three to eight measurements were needed for most other compound/exposure medium combinations because of considerable temporal variability. Measurements in biological fluids and dust were generally more consistent than those in indoor air. The significant covariates in the full models preferentially reduced the between-person variance component. Since the regression models explained only 1–37% of the within-person variance, the questionnaires in this study provided only modest insight into the factors responsible for the temporal variability in the contaminant levels.

Organophosphorus and pyrethroid insecticide urinary metabolite concentrations in young children living in a southeastern United States city.

Pesticide metabolites are routinely measured in the urine of children in the United States. Although the sources of these metabolites are believed to include residues in food from agricultural applications and residues from applications in everyday environments (e.g., homes), few studies have been able to demonstrate an association between indoor residential pesticide applications and pesticide metabolite concentrations. To better quantify the effects of potential risk factors related to demographics, household characteristics, occupation, and pesticide use practices on urinary biomarker levels, we performed a study in a city (Jacksonville, Florida) previously determined to have elevated rates of pesticide use. We enrolled a convenience sample of 203 children ranging in age from 4 to 6 years; their caregivers completed a questionnaire and the children provided a urine sample, which was analyzed for a series of organophosphorus and pyrethroid insecticide metabolites. The questionnaire responses substantiated much higher pesticide use for the study participants as compared to other studies. Urinary metabolite concentrations were approximately an order of magnitude higher than concentrations reported for young children in other studies. Few statistically significant differences (at the p<0.05 level) were observed, however, several trends are worth noting. In general, mean urinary pesticide metabolite concentrations were higher for males, Caucasians, and those children living in homes with an indoor pesticide application occurring within the past four weeks. Comparing the urinary pesticide metabolite concentrations in this study to those reported in the NHANES and GerES studies showed that the children living in Jacksonville had substantially higher pyrethroid pesticide exposures than the general populations of the United States and Germany. Further research is needed in communities where routine pesticide use has been documented to obtain information on the most important routes and pathways of exposure and to develop the most effective strategies for reducing pesticide exposures for children.

An assessment of the exposure of Americans to perfluorooctane sulfonate: A comparison of estimated intake with values inferred from NHANES data

To better understand human exposure to perfluorinated compounds (PFCs), a model that assesses exposure to perfluorooctane sulfonate (PFOS) and its precursors from both an intake and a body burden perspective and combines the two with a simple pharmacokinetic (PK) model is demonstrated. Exposure pathways were modeled under “typical” and “contaminated” scenarios, for young children and adults. A range of intakes was also estimated from serum concentrations of PFOS reported in the National Health and Nutrition Examination Survey (NHANES) using a first-order 1-compartment PK model. Total PFOS intakes (medians summed over all pathways) were estimated as: 160 and 2200u2009ng/day for adults and 50 and 640u2009ng/day for children under typical and contaminated scenarios, respectively. Food ingestion appears to be the primary route of exposure in the general population. For children, the contribution from dust ingestion is nearly as great as from food ingestion. Pathway-specific contributions span several orders of magnitude and exhibit considerable overlap. PK modeling suggests central tendency PFOS intakes for adults range between 1.6 and 24.2u2009ng/kg-bw/day, and the forward-based intake estimates are within this range. The favorable comparison reported between the forward-modeled and the back-calculated range of intake predictions lends validity to the proposed framework.

Aggregating data for computational toxicology applications: The U.S. Environmental Protection Agency (EPA) Aggregated Computational Toxicology Resource (ACToR) System.

Computational toxicology combines data from high-throughput test methods, chemical structure analyses and other biological domains (e.g., genes, proteins, cells, tissues) with the goals of predicting and understanding the underlying mechanistic causes of chemical toxicity and for predicting toxicity of new chemicals and products. A key feature of such approaches is their reliance on knowledge extracted from large collections of data and data sets in computable formats. The U.S. Environmental Protection Agency (EPA) has developed a large data resource called ACToR (Aggregated Computational Toxicology Resource) to support these data-intensive efforts. ACToR comprises four main repositories: core ACToR (chemical identifiers and structures, and summary data on hazard, exposure, use, and other domains), ToxRefDB (Toxicity Reference Database, a compilation of detailed in vivo toxicity data from guideline studies), ExpoCastDB (detailed human exposure data from observational studies of selected chemicals), and ToxCastDB (data from high-throughput screening programs, including links to underlying biological information related to genes and pathways). The EPA DSSTox (Distributed Structure-Searchable Toxicity) program provides expert-reviewed chemical structures and associated information for these and other high-interest public inventories. Overall, the ACToR system contains information on about 400,000 chemicals from 1100 different sources. The entire system is built using open source tools and is freely available to download. This review describes the organization of the data repository and provides selected examples of use cases.

High Throughput Heuristics for Prioritizing Human Exposure to Environmental Chemicals

The risk posed to human health by any of the thousands of untested anthropogenic chemicals in our environment is a function of both the hazard presented by the chemical and the extent of exposure. However, many chemicals lack estimates of exposure intake, limiting the understanding of health risks. We aim to develop a rapid heuristic method to determine potential human exposure to chemicals for application to the thousands of chemicals with little or no exposure data. We used Bayesian methodology to infer ranges of exposure consistent with biomarkers identified in urine samples from the U.S. population by the National Health and Nutrition Examination Survey (NHANES). We performed linear regression on inferred exposure for demographic subsets of NHANES demarked by age, gender, and weight using chemical descriptors and use information from multiple databases and structure-based calculators. Five descriptors are capable of explaining roughly 50% of the variability in geometric means across 106 NHANES chemicals for all the demographic groups, including children aged 6-11. We use these descriptors to estimate human exposure to 7968 chemicals, the majority of which have no other quantitative exposure prediction. For thousands of chemicals with no other information, this approach allows forecasting of average exposure intake of environmental chemicals.

Benzene and naphthalene in air and breath as indicators of exposure to jet fuel

Aims: To estimate exposures to benzene and naphthalene among military personnel working with jet fuel (JP-8) and to determine whether naphthalene might serve as a surrogate for JP-8 in studies of health effects. Methods: Benzene and naphthalene were measured in air and breath of 326 personnel in the US Air Force, who had been assigned a priori into low, moderate, and high exposure categories for JP-8. Results: Median air concentrations for persons in the low, moderate, and high exposure categories were 3.1, 7.4, and 252 µg benzene/m3 air, 4.6, 9.0, and 11.4 µg benzene/m3 breath, 1.9, 10.3, and 485 µg naphthalene/m3 air, and 0.73, 0.93, and 1.83 µg naphthalene/m3 breath, respectively. In the moderate and high exposure categories, 5% and 15% of the benzene air concentrations, respectively, were above the 2002 threshold limit value (TLV) of 1.6 mg/m3. Multiple regression analyses of air and breath levels revealed prominent background sources of benzene exposure, including cigarette smoke. However, naphthalene exposure was not unduly influenced by sources other than JP-8. Among heavily exposed workers, dermal contact with JP-8 contributed to air and breath concentrations along with several physical and environmental factors. Conclusions: Personnel having regular contact with JP-8 are occasionally exposed to benzene at levels above the current TLV. Among heavily exposed workers, uptake of JP-8 components occurs via both inhalation and dermal contact. Naphthalene in air and breath can serve as useful measures of exposure to JP-8 and uptake of fuel components in the body.

Pilot scale application of a method for the analysis of perfluorinated compounds in surface soils

A growing number of studies now indicate that perfluorinated compounds (PFCs) are globally distributed in the environment. Their widespread distribution and presence in remote locations has led to questions about the importance of atmospheric and oceanic transport. Describing their distribution in surface soils is also an essential but neglected element in developing a comprehensive understanding of their occurrence in the environment. Soils are the critical link between global atmospheric and hydrologic processes where both local and distant contaminants can accumulate and be released into aquatic and terrestrial communities. Because PFC concentrations in soils will influence ground and surface water, wildlife, and crops, methods to accurately measure PFCs in soil are clearly needed. To help answer this need, we developed a method for the analysis of nine perfluorinated carboxylic acids and four perfluorinated sulfonic acids in soil. Samples from six nations (n=10 per nation) were analyzed by LC-MS/MS to demonstrate the method performance parameters and to make preliminary observations about the occurrence of the PFCs in soils in different parts of the world. The resulting method shows acceptable performance characteristics for the target compounds in most soils while documenting the widespread occurrence of PFCs in surface soils.

Flame retardant exposures in California early childhood education environments

Infants and young children spend as much as 50h per week in child care and preschool. Although approximately 13 million children, or 65% of all U.S. children, spend some time each day in early childhood education (ECE) facilities, little information is available about environmental exposures in these environments. We measured flame retardants in air and dust collected from 40 California ECE facilities between May 2010 and May 2011. Low levels of six polybrominated diphenyl ether (PBDE) congeners and four non-PBDE flame retardants were present in air, including two constituents of Firemaster 550 and two tris phosphate compounds [tris (2-chloroethyl) phosphate (TCEP) and tris (1,3-dichloroisopropyl) phosphate (TDCIPP)]. Tris phosphate, Firemaster 550 and PBDE compounds were detected in 100% of the dust samples. BDE47, BDE99, and BDE209 comprised the majority of the PBDE mass measured in dust. The median concentrations of TCEP (319 ng g(-1)) and TDCIPP (2265 ng g(-1)) were similar to or higher than any PBDE congener. Levels of TCEP and TDCIPP in dust were significantly higher in facilities with napping equipment made out of foam (Mann-Whitney p-values<0.05). Child BDE99 dose estimates exceeded the RfD in one facility for children<3 years old. In 51% of facilities, TDCIPP dose estimates for children<6 years old exceeded age-specific No Significant Risk Levels (NSRLs) based on California Proposition 65 guidelines for carcinogens. Given the overriding interest in providing safe and healthy environments for young children, additional research is needed to identify strategies to reduce indoor sources of flame retardant chemicals.