# Presentation: 164375

## 6

**Computer Models to Estimate Real-World Aggregate and Cumulative Exposures and Doses**
- Edwin J. Furtaw, Jr. (NERL-Las Vegas), Valerie Zartarian (NERL-R1), Fred Power (NERL-Las Vegas),
- Tom McCurdy (NERL-RTP), Zhishi Guo (NRMRL-RTP), and Chris Saint (NCER-DC)
- U.S. Environmental Protection Agency, Office of Research and Development

- ORD’s human exposure and dose models serve multiple purposes.  In the research field, they help scientists understand the transport and fate of chemicals both in various environmental media and within humans, and the relative importance of various factors in contributing to exposure, dose, and risk.  The improved understanding from the use of the models helps to prioritize additional research.  In the regulatory arena, the models provide risk assessors and managers with tools for helping to understand the effects of the pollutants on health risks, the need for regulatory controls on the use of chemicals, and the likely effectiveness of various possible regulatory actions.

- ORD’s exposure and dose models have been used by EPA’s Office of Pesticide Programs (e.g., exposure of children to chromated copper arsenate-treated wood playsets; use of malathion for head-lice treatment) and by its National Center for Environmental Assessment (e.g., dose assessments for several volatile organic compounds) to conduct exposure and dose assessments that contribute important scientific information to risk assessments that in turn inform risk-management decisions.

- The development, improvement, and application of ORD’s exposure-related models is an ongoing activity.  Future research activities in this area include:

- Bennett, D.H. and Furtaw, E.J.Jr. (2004). Fugacity-Based Indoor Residential Pesticide Fate Model. *Environ. Sci. Technol.* 38(7): 2142 - 2152.
- Bennett, D.H., Furtaw, E.J.Jr., and McKone, T.E. (2002). A fugacity-based indoor residential pesticide fate model. Proceedings: Indoor Air 2002, July 2002, Monterey, CA.
- Guo, Z. (2002). Review of indoor emission source models – part 1. overview. *Environmental Pollution*, Vol. 120, pp 533-549.
- Guo, Z. and Roache, N. F. (2003). Overall mass transfer coefficient for pollutant emissions from small water pools under simulated indoor environmental conditions.* The Annals of Occupational Hygiene*, Vol. 47, pp 279-286.
- Sparks, L. E., Tichenor, B. A., Chang, J., and Guo, Z (1996). Gas-phase mass transfer model for predicting volatile organic compound (VOC) emission rates from indoor pollutant sources. *Indoor Air*, Vol. 6, pp 31-40.
- US EPA (1996). *IAQ Model for Windows, RISK Version 1.0, User Manual*, U.S. Environmental Protection Agency, National Risk Management Research Laboratory, Research Triangle Park, NC, EPA-600/R-96-037 (NTIS PB96-501929), March 1996. (The most recent version – 1.9 – is available at EPA website http://www.epa.gov/appcdwww/iemb/risk.htm).
- US EPA (2000). *Simulation Tool Kit for Indoor Air Quality and Inhalation Exposure (IAQX) Version 1.0 User’s Guide*, U.S. Environmental Protection Agency, National Risk Management Research Laboratory, Research Triangle Park, NC, Report No. EPA-600/R-00-094 (NTIS PB2001-101221), 76 pp.
- U.S. EPA (2002).  Exposure Related Dose Estimating Model (ERDEM) for Assessing Human Exposure and Dose. EPA/600/X-04/060.
- US EPA (2005). *Program PARAMS User’s Guide*, National Risk Management Research Laboratory, Research Triangle Park, NC; 49 pp. (In press).
- McCurdy, T. and Graham, S. (2003). Using human activity data in exposure models: Analysis of discriminating factors. _J. Exp. Anal. Env. Epi._  13: 294-317.
- McCurdy, T. and Xue, Z. (submitted). Meta-analysis of Physical Activity Level (PAL) data for US children and adolescents. _J. Children’s Health_.
- Xue, J., McCurdy, T., Spengler, J. and Özkaynak, H. (2004). Understanding variability in time spent in selected locations for 7-12-year old children. _J. Exp. Anal. Env. Epi._ 14: 222-233.
- Zartarian, V.G., Özkaynak H., Burke J.M., Zufall M.J., Rigas M.L., Furtaw Jr. E.J., (2000), “A Modeling Framework For Estimating Children's Residential Exposure and Dose to Chlorpyrifos Via Dermal Residue Contact and Non-Dietary Ingestion,” *Environmental Health Perspectives*, 108(6): 505-514.
- Zartarian, V.G., Xue J.,  Özkaynak H., Dang W., Glen G., Smith L., Stallings C. (2003), “ Pro-babilistic Exposure Assessment for Children Who Contact CCA-Treated Playsets and Decks Using the Stochastic Human Exposure and Dose Simulation Model for the Wood Preservative Exposure Scenario (SHEDS-Wood),” Draft Preliminary Report, prepared for EPA Office of Pesticide Programs FIFRA (Federal Insecticide, Fungicide, Rodenticide Act) Science Advisory Panel (SAP) meeting, December 3-5, 2003.

- 3A. Source-to-effects modeling
- ORD researchers have developed a variety of computer models to simulate how pollutants enter and move through the environment, and how they contact, enter, and move through exposed humans.  For pesticides, several models have been developed and are being used for exposure and risk assessments.  These models span the “source-to-effects” continuum of processes whereby chemicals are introduced into the environment, move through multiple environmental media, are contacted and absorbed into humans, and have effects on biological systems that can in turn lead to health effects.  Use of such models will enable risk assessors to answer questions about the sources, pathways, and factors that contribute to aggregate and cumulative exposures and risk.

- 3B. Indoor Fugacity Model for
-       Pesticides
- Working with colleagues in academia, ORD researchers have developed a model to simulate the indoor fate and transport of low-volatility pesticides (Bennett et al., 2002, 2004). This model uses the chemical principle of fugacity to estimate the reversible movement of pesticides between indoor air and household surfaces such as carpets and vinyl, and incorporates ventilation rates to show the gradual exhausting of the chemicals to the outdoors.  The indoor fugacity model is being linked to ORD’s Stochastic Human Exposure and Dose Simulation (SHEDS) model for pesticides.  This model is one of several indoor fate and transport models that ORD has developed.

- 3D. Stochastic Human Exposure and Dose       (SHEDS) Models
- SHEDS inputs include air and surface concentrations from the indoor fugacity model, human activity data extracted from ORD’s Consolidated Human Activity Database (CHAD), and other exposure factors data as compiled in the EPA Exposure Factors Handbooks (see Moya et al. poster) and collected through ORD measurement studies (see Egeghy et al. poster).  SHEDS utilizes probabilistic modeling to estimate distributions of multiple-pathway (aggregate) exposure and absorbed dose for user-selected segments of the population.  The outputs from SHEDS represent the inherent variabilities of exposure and dose that result from varying environmental conditions and human behavior, as well as the uncertainty surrounding those estimates.  SHEDS has been applied for numerous pollutants of interest to the USEPA, including chlorpyrifos (Zartarian et al. 2000), arsenic and chromium from Chromated Copper Arsenate-treated wood products (Zartarian et al. 2003), air toxics, and airborne Particulate Matter (PM).

- 3F. Exposure-Related Dose-Estimating       (ERDEM) Models
- ORD scientists have developed the Exposure-Related Dose-Estimating Model (ERDEM), a physiologically-based pharmacokinetic (PBPK) model to simulate the human organism and its ability to absorb, distribute, metabolize, and eliminate chemicals.  ERDEM has been used to simulate the reaction of multiple (cumulative) pesticides and their metabolites with cholinesterase enzymes in the nervous system, and will be interfaced with SHEDS for enhanced dose estimates.

_**Exposure Pathways Considered in SHEDS**_

- 3E. Consolidated Human Activity       Database (CHAD)
- ORD’s National Exposure Research Laboratory (NERL) is making a concerted effort to develop and evaluate human activity data used in its SHEDS model, and in program office exposure models, such as APEX and HAPEM.  Among other things, NERL is exploring how representative are the data in CHAD with respect to literature from the exercise physiology and clinical nutrition disciplines.  One recent investigation evaluated age/gender differences in Physical Activity Level (PAL) obtained in children and adolescents, a factor found in McCurdy & Graham (2003) to be highly correlated with the time spent outdoors by that population subgroup.
- In another analysis, NERL staff investigated how many days of activity data were required from an individual over a year time period in order to be reasonably assured that their time spent in important locations of interest from an exposure assessment viewpoint was well-characterized (Xue et al., 2004).  Using the criterion of reducing the reciprocal of the intraclass correlation coefficient–a metric that incorporates both intra- and inter-individual variability–to a reasonable level, requires that around 27 days of data for each person be obtained.
- These projects are examples of work being done by NERL staff relating to the understanding and evaluation of human activity data used in its exposure models, and eventually trying to incorporate this knowledge into updates of the CHAD database.

_**Compartments in the Indoor Fugacity Model for Pesticides**_

- Can computer models be developed and applied to estimate the human exposure and dose of various pollutants on humans exposed via multiple routes and pathways (e.g., inhalation, dietary, dermal contact)?  What models are available to perform these assessments?

- The development of models for use in exposure and risk assessments serves several purposes:
- Improve our understanding of the sources, environmental fate and transport, human exposure and dose, and health effects of environmental pollutants;
- Understand the various factors that affect the above processes so that researchers can prioritize those factors that most need additional study;
- Provide tools for exposure and risk assessors to give a better mechanistic understanding of the pathways of exposure and the effects of pollutant doses;
- Enable risk managers to make better-informed decisions on the appropriate uses of chemicals and levels that can prevent environmental and human health problems.

**Future Directions**

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- 3C.  NRMRL’s Indoor Air Quality Modeling Research
- ORD’s National Risk Management Research Laboratory (NRMRL) has unique research facilities for characterizing indoor pollution sources and other indoor air related problems such as pollutant penetration and surface adsorption/desorption.  The facilities include a small chamber lab, a room-sized well-mixed chamber, a plug-flow chamber for particulate matter, a dual-chamber system for pollutant penetration, and a well-equipped research house.  Data generated from these facilities have been used to develop source models and indoor air quality (IAQ) and exposure models.
- Over 50 indoor source models have been developed by researchers worldwide. Ten of them were developed by NRMRL researchers (Guo, 2002). NRMRL is also actively involved in developing dynamic sink models, which describe pollutants’ adsorption and desorption from interior surfaces.  The Langmuir sink model developed by NRMRL is the most widely used sink model in IAQ simulation.
- In the area of IAQ modeling, NRMRL has developed two Windows-based IAQ simulation software packages: RISK and IAQX.  Both are available to the public.  Initially published in 1996 (Sparks, 1996), RISK has undergone several revisions.  The current version (v 1.9) is a multiple-pollutant IAQ model developed by using the experimental data from test chambers and research house.  It takes into consideration building features, indoor-outdoor air exchange, heating and air-conditioning system, indoor sources, outdoor sources, indoor sinks, and air filtration and cleaning, and computes indoor pollutant concentration over time, inhalation exposure, and individual health risks.  Simulation package IAQX (Guo, US EPA, 2000) consists of 5 stand-alone simulation programs: a general-purpose IAQX simulation program and four special-purpose programs for applications such as petroleum-based interior paint or building materials.  The two packages combined have more than 500 registered users in over 20 countries.  These programs have been used by indoor air professionals for risk management and IAQ investigation, by emergency response personnel for emergency planning, by manufacturers for product stewardship, and by universities  for teaching IAQ courses.
- One of the major difficulties in developing physically based exposure models is to develop methods for estimating model parameters independently. NRMRL has been developing such methods to support ORD’s development of exposure and risk models.  Examples of such research outputs include the development of a method for estimating the gas-phase mass-transfer coefficient for the indoor environment (Sparks et al., 1996), and a method for estimating the overall mass-transfer coefficient for pollutant emissions from aqueous solutions applied to interior surfaces (Guo and Roache, 2003).  As part of this effort, NRMRL is also involved in developing modeling tools.  A recent product in this area is a Windows-based computer program, PARAMS 1.0, that implements 30 existing methods for parameter estimation.

- 2005Feb HH Program Review (Modeling) Poster EFurtaw.PPT

- 3G. Model Development by Grantees
- In addition to these ORD-developed models, other exposure-related models have been developed by academic researchers working under Science To Achieve Results (STAR) grants from ORD’s National Center for Environmental Research (NCER).  Examples include:

*Development of a Physiologically-Based Pharmacokinetic/Pharmacodynamic Model to Quantitate Biomarkers of Exposure for Organophosphate Insecticides*, Charles Timchalk, Battelle Memorial Institute (STAR Grantee - **R828608**)
*Biomarkers of Human Exposure to Pesticides Utilizing a New PBPK/PD Model and Kinetic Data on Pesticide Metabolism in Humans*, James Olson and James Knaak, SUNY Buffalo (STAR Grantee - **R830683**)
*Measurements and Models of Longitudinal Dietary Intake of Pyrethroid and Organophosphate Insecticides by Children, *Barry Ryan, Emory University (STAR Grantee **R829396**)
*Lumped Chemical Approach for Fate and Transport Modeling of Organic Pollutant Mixtures, *Kenneth Reardon, Colorado State University (STAR Grantee **R829355**)

- Linking environmental, exposure, dose, and effects models
- Developing improved methods for modeling variability and uncertainty
- Developing advanced computational models of organs and other biological systems
- Develop robust mass transfer models for pollutant emissions from aqueous solutions
- Evaluate existing sink models with experimental data and recommend practically useful sink models for use in exposure models
- Develop IAQX Version 2, which includes 8 to 9 stand-alone simulation programs and supporting programs.  We hope that, with minor modifications, some of these programs can be used as front-end modules for NERL’s exposure models
- Continued SHEDS-Pesticides model evaluation will be conducted in-house on the dietary module and on the aggregate estimates of SHEDS-Pesticides version 2 (for chlorpyrifos) using available measurements data
- SHEDS-Pesticides version 3 will be applied to an aggregate exposure assessment case study, accounting for co-occurences in space and time for the pesticide permethrin (using outputs from the indoor residential fugacity model)
- SHEDS-Pesticides version 4 will be developed and applied to a cumulative exposure assessment case study, accounting for co-occurences in space and time for multiple pyrethroid chemicals

_**Schematic Diagram of ERDEM**_