# Presentation: 331851

## Overview of Source-to Effects Modeling for Susceptible (Children) Populations

- Halûk Özkaynak1, Hugh Barton2, Bob Sonawane3
- U.S. Environmental Protection Agency, Office of Research and Development, 1National Exposure Research Laboratory;
- 2National Health and Environmental Effects Research Laboratory; 3National Center for Environmental Assessment

- Assessment of chemical-specific risk for children requires several types of information on exposures and effects occurring during early life stages. In particular, chemical risk assessments now rely upon an analytical framework, which includes characterization of exposure, pharmacokinetics (or toxicokinetics) and pharmacodynamics (or toxicodynamics) and response (cf. Barton 2004, Ginsberg et al. 2004a, Barton* et al.* 1998). In order to evaluate the basis of differential risk to children from environmental stressors, ORD researchers are implementing an interdisciplinary research program that attempts to address all the four components  of this framework.
- The critical science questions that were identified by ORD under the source-to-effects modeling for susceptible populations, including children, were:
- 1) How can we improve the linkage between emissions, exposure and dose estimation for predicting target tissue response or biologically effective dose response for children?
- 2) What are the best approaches for developing physiologically-based pharmacokinetics models and evaluating potential health risks to children, either using human studies data, or by extrapolating across species using animal toxicity data that involve exposures at early life stages?

**Research Goals**

**Methods/Approach**

**Impact and Outcomes**

**Results/Conclusions**

**Future Directions**

**Science Question**

- In order to understand potential health risks to children from exposures to environmental chemicals of concern, it is necessary to investigate quantitative relationships between exposure, absorbed dose and the biologically effective dose. The main goals of the ORD’s current source-to-effects modeling research program for children under the susceptible subpopulations area, are to:
-  identify and quantify routes and pathways of   exposures of concern for children,
-  develop new tools that can describe the biological basis for differential sensitivity in children, and
-  develop and apply scientifically robust human exposure and risk analysis framework that incorporates models, databases and analytical tools in estimating exposure, dose and health risks to children.
- This information is being provided to risk assessors and policy-makers both within the Agency and elsewhere, so that appropriate source and exposure mitigation strategies can be considered, in order to reduce risks to children exposed to environmental stressors.

- ORD had significant success in generating basic information and models that would support study of children’s exposures to a number of chemicals of regulatory concern. For example, the SHEDS-Wood model developed by ORD was used by the Office of Pesticides Program in their regulatory evaluation of exposures and risks to children from contacting CCA treated wood on playsets and decks. The research in the area of toxicokinetic modeling for children is ongoing in ORD with related efforts at other institutions (e.g., CIIT Centers for Health Sciences, ILSI, Clark University, Connecticut Department of Health).  ORD scientists have presented and organized workshops at professional society meetings (e.g., 2005 Society of Toxicology Annual Meeting) to promote generation of needed information and methods by the toxicology community to support early life pharmacokinetic modeling. More reliable source-to-effects models will allow the Agency to replace or revise the default uncertainty factors typically used in its current risk assessments for children and to make informative risk management decisions.

- ORD is in the process of extending the exposure and dose-response modeling tools to study cumulative risks resulting from exposures to mixtures or multiple chemicals, such as the pyrethroid or n–methyl carbamate pesticides. Using animal or adult human data for extrapolation to different life stages have been informative and helpful for constructing chemical-specific PBTK models. However, applicability of these models to other chemicals of interest remains to be determined through future research. Additional research is being performed to determine whether children may be more susceptible than adults due to toxicokinetic or due to toxicodynamic differences, or both. On-going and future research planned by the ORD under the Computational Toxicology Program and in the exposure and PBPK modeling areas should improve cross-species extrapolation of effects and the prediction of health risks to children, resulting from exposures to chemicals of concern.

**References**

- The EPA’s Office of Research and Development (ORD) has been developing and applying source-to-effect models to estimate children’s exposures to environmental pollutants and formulating appropriate physiologically based pharmacokinetic (PBPK) models for evaluating risks to children at various early life-stages. Figure 1 shows the main elements of ORD’s source-to effects modeling framework that is being applied to the study of children’s risks resulting from exposures to environmental chemicals.
_**Modeling Exposures and Dose**_
- In the area of developing models to estimate exposures of young children to pollutants, ORD has been developing a state-of-the-art aggregate exposure and dose model, the Stochastic Human Exposure and Dose Simulation (SHEDS) model (see Figure 2 for a model flow diagram for SHEDS-Air Toxics) to examine children’s exposure to a variety of inhalation and multi-media multi-pathway pollutants, such as air toxics, a number of the organophosphate pesticides, and arsenic from contact with CCA treated wood (e.g., Zartarian et al. 2003). The SHEDS model is designed to interface with more sophisticated source-to-concentration (e.g., the indoor fugacity model for pesticides) and exposure-to-dose (e.g., ERDEM or the Exposure Related Dose Estimation Model) models (see also Agg/Cum Risk topic). In the development, evaluation and dissemination of the exposure and dose models, ORD has been collaborating with various academic partners (e.g. Rutgers and Harvard University) and with several private and public organizations, for example, the International life Sciences Institute (ILSI), the Cumulative and Aggregate Risk Evaluation System (CARES) model group, World Health Organization’s International Program on Chemical Safety (WHO/IPCS).
_**Formulating PBPK Models for Children**_
- In formulating appropriate PBPK models for children, ORD has been evaluating both human and animal data sets that are relevant to chemicals and exposure scenarios of concern for children. Two major approaches are being used for evaluating potential risks from early life exposures, each of which has strengths and limitations (Barton 2004). The first approach is to extrapolate from adults to children based upon quantifiable differences in exposure, pharmacokinetics, and pharmacodynamics leading to potential pharmacological activity or toxicity (Ginsberg et al. 2004b). The second approach is to extrapolate across species from animal toxicity studies that involve exposures at early life stages.  Such studies include developmental toxicity  (in utero exposure), one- or two-generation reproductive and developmental toxicity, and neurotoxicity studies.
_**Developing PK Parameters for Children**_
- ORD researchers have been conducting research using the first approach for evaluating and incorporating child/adult toxicokinetic differences in assessing risk to several environmental toxicants. Specific research questions addressed under this research are: 1) Are there differences in toxicokinetics (TK) of xenobiotics between children and adults due to physiological changes and the immaturity of enzyme systems and clearance mechanisms? 2) How these differences can be incorporated into PBTK models that simulate fate of environmental toxicants in both children and adults? While there are very little PBTK data for environmental agents in children, there are much more abundant data for therapeutic drugs used in pediatric practice. Using published literature, a children’s PK database has been compiled by ORD-sponsored research that compares PK parameters between children and adults for 45 pharmaceutical agents.
_**Extrapolation from Animal Toxicity Studies Involving Early Lifestage Exposures**_
- The second approach evaluates risks at early ages by conducting cross-species extrapolation from animal studies that involve exposures at early life-stages (Figure 3). However, a major challenge for modeling these life stages is how to obtain datasets for model parameterization (i.e. choices of physiological and chemical-specific parameters), calibration (i.e. assignment of values to the parameters), and testing (i.e. using an independent dataset to evaluate the success of the model beyond the original data). Pregnancy and very limited lactational models have been developed previously.  Therefore, postnatal development has been the major focus of recent ORD research.  Physiological parameters for growing rats have been compiled in an electronic database; this has been contributed to an ORD sponsored and ILSI-organized collaborative effort among government Agencies, academics, and industry to evaluate the state of knowledge for physiological parameters for modeling growing mice, rats, and humans.  Chemical-specific parameters can be estimated using *in vitro* or *in vivo* studies.  In collaboration with ORD and the Air Force Research Laboratory, the age-dependency of partition coefficients for volatile organic compounds with a range of physicochemical properties are being determined in rat and human blood and tissues.

- Figure 1. Elements of Source-to-Effects Modeling

- ORD has recently prepared a draft document entitled “Framework for Children’s Health Risk Assessment” (see Children’s Risk Assessment topic). This internal document is now being revised following an internal review in October 2004. Soon to be sent for external peer-review, this document describes ORD’s approach for assessing children’s risk from exposures to environmental pollutants. ORD’s source-to-effects modeling research, which supports this effort, has identified key age-dependent factors that influence exposures and toxicokinetics and toxicodynamics of select classes or types of chemicals that children may come in contact with during different periods of early development.
**The SHEDS exposure and dose model** was applied to the organophosphate (chlorpyrifos) and wood preservative (arsenic) case studies of regulatory interest to EPA (Zartarian et al 2003). These applications demonstrated the important contributions of hand-to mouth and hand-to-object-to-mouth exposure pathways for infant and young children’s exposures to multimedia pollutants. Likewise, the ERDEM model has also been applied to chlorpyrifos and to malathion and selected volatile organic compounds (e.g. trichloroethylene) in air and water (see Agg/Cum Risk topic). ORD also developed a case study for malathion PBPK model for children.
**The children’s PK data base** complied by ORD has enabled comparison of child and adult PK function across a number of cytochrome P450 (CYP) pathways, as well as certain Phase II conjugation reactions and renal elimination (Hattis et al. 2003). The database provides an opportunity for calibrating and validating PBTK models for various chemicals, using examples as theophylline and caffeine (Ginsberg et al. 2004b). These drugs are particularly useful case studies because the clearance mechanism in neonates and infants is considerably different (slower) than adults.
**The physiological parameters database** for growing rats has already been compiled in an electronic form. The chemical-specific tissue partitioning data, which has been assembled by ORD and the Air Force Laboratory, demonstrate only minor differences across age groups.  By contrast, modeling of serum protein binding for estrogenic compounds demonstrates substantial differences across ages and species due to high affinity binding to alpha-fetoprotein (rats) and serum hormone binding globulin (humans), while lower affinity albumin binding is age, but not species, dependent. Thus, determinants of tissue distribution must be carefully considered in the analysis of pharmacokinetic and pharmacodynamic linkages and potency of a compound by lifestage. Conazole fungicides are now the subject of an integrated toxicokinetic and toxicodynamic research effort in ORD (see Harmonization topic).

- Barton, H.A. Computational Pharmacokinetics during Developmental Windows of Susceptibility. J Toxicol Environ  A (in press).
- Barton, H. A., Andersen, M. E., and Clewell, H. J., III 1998. Harmonization: developing consistent guidelines for applying mode of action and dosimetry information to cancer and noncancer risk assessment. Human EcolRisk Assess 4:75-115.
- Ginsberg, G., Slikker, W., Bruckner J. and Sonawane, B. 2004a. Incorporating children’s toxicokinetics into a risk framework. Environmental Health Perspect. 112:272-283.
- Ginsberg, G., Hattis, D., Russ, A., and Sonawane, B. 2004b. Physiologically based pharmacokinetic (PBPK) modeling of caffeine and theophylline in neonates and adults: implications for assessing children's risks from environmental agents. J Toxicol Environ Health A 67:297-329.
- Hattis, D., Ginsberg, G., Sonawane, B., Smolenski, S., Russ, A., Kozlak, M., and Goble, R. 2003. Differences in pharmacokinetics between children and adults. II. Children’s variability in drug elimination half-lives and in some parameters needed for physiologically-based pharmacokinetic modeling. Risk Analysis 23:117-142.
- Zartarian,V.G., Xue J.,  Özkaynak H., Dang W., Glen G., Smith L., Stallings C. 2003. Probabilistic 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.  Reviewed at the EPA Office of Pesticide Programs FIFRA (Federal Insecticide, Fungicide, Rodenticide Act) Science Advisory Panel (SAP) meeting, December 3-5, 2003.   EPA/600/X-04/089

- Figure 2. SHEDS-Air Toxics Model Flow

- Figure 3. Life Stage and Species Extrapolations