National Exposure Research Laboratory Research Abstract. Government Performance Results Act (GPRA) Goal #4.5 Annual Performance Measure #32

Transcription

1 United States Environmental Protection Agency National Exposure Research Laboratory Research Abstract Office of Research and Development Government Performance Results Act (GPRA) Goal #4.5 Annual Performance Measure #32 Significant Research Findings: Exposure Related Dose Estimating Model (ERDEM): A Physiologically-Based Pharmacokinetic and Pharmacodynamic (PBPK/PD) model for Assessing Human Exposure and Risk Scientific Problem and Policy Issues Research Approach The U.S. EPA, as part of its mission to protect human health and the environment, develops tools (methods, measures and models) that can be readily used to improve risk and exposure assessments. Risk assessments are used at EPA to predict potential adverse effects that may result from exposure to environmental agents. As with any predictive approach, there is often considerable uncertainty associated with the assessment. To reduce this uncertainty and to increase confidence in risk assessments supporting policy decisions, the Agency seeks to ensure that its assessments incorporate the best and most-up-to-date science. Current approaches include the use of state-of-the-science predictive models to describe the physical, chemical, and biological processes that may be impacted by an exposure to a chemical of concern. In particular, scientists often need to describe, estimate, and predict the dose of foreign chemicals within the body that results from an environmental exposure. This requires the knowledge of many biological processes and chemical factors both inside and outside of the body. Predictive mathematical models, which can accurately describe the biology and chemistry within the human body, are used to estimate and predict the dose. By improving such models and their predictions of dose, risk assessors can better predict the possible health impacts and can assure that the Agency s risk management decisions are founded on high quality science. Over recent years, the Agency and others have used physiologically based pharmacokinetic (PBPK) models to better describe internal doses resulting from human exposures to chemicals in the environment. PBPK models are mathematical descriptions of how chemicals enter the body, are transported in the body, are eliminated from the body, and stored in the body. More recently the Agency has sought to develop and use physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) models. The PBPK/PD models not only describe the disposition of a chemical in the body, but they also attempt to mathematically describe how some normal biologic processes are altered (and might lead to disease) as a result of the chemical in the body. PBPK/PD models developed within the National Exposure Research Laboratory s Exposure Related Dose Estimating Model (ERDEM) platform hold great promise for evaluating, estimating, and predicting measures of toxicologically relevant doses within the body. PBPK/PD models may be essential for predicting actual organ level exposures to chemicals producing cancer and non-cancer effects, especially as

2 they may occur as mixtures in the environment. ERDEM is a PC-based modeling framework that allows for using existing models and for building new PBPK and PBPK/PD models to address specific science questions. The ERDEM framework provides a modeling tool for characterizing exposures of children and other groups and calculating estimated internal doses. This framework consists of two parts: the model engine, built in Advanced Continuous Simulation Language (ACSL), and a user friendly front-end for creating and executing models. The model engine contains the mathematical descriptions of the PBPK and PBPK/PD models. ERDEM has recently been updated to improve the way it handles important pollutants. Improvements include improved dermal uptake modeling and the inclusion of intracellular processes in the model. Special attention was paid to developing accurate descriptions for absorption into the body. Gastrointestinal absorption can be modeled as simple absorption from the stomach and intestine into the blood flowing to the liver. The user may also model absorption across the membranes of several sections of the small intestine. Each absorption path allows for gall bladder activity and for fecal elimination. Dermal absorption is also modeled in more than one way. One approach assumes a rapid and direct absorption across the skin: it is used for vapors and chemicals in water where exposure would normally occur during showering and bathing. A second approach allows for chemicals to be deposited on the skin, either as a result of occupational practices or simply from the activities of daily life, and then slowly absorbed across the dermal barrier. Absorption of pesticides has been modeled in this fashion. In addition, absorption from inhalation is also modeled in ERDEM. For the user, ERDEM requires no special software other than the basic Windows environment commonly used on PCs. Results and Impact Recent improvements in ERDEM have allowed the model to be applied more rigorously to a variety of chemicals, including trichloroethylene, methyl tertiary butyl ether (MTBE), malathion, and the N-methyl carbamates. Highlights of recent research and technical transfer activities are provided below: Trichloroethylene Revised Risk Assessment: ERDEM was used to develop a PBPK model of trichloroethylene uptake and distribution throughout the human body. This effort was central to the development of a revised risk assessment based upon recent developments in the field and upon NAS comments on the 2001 draft risk assessment. This work served as an example for the use of PBPK models in investigating scientific uncertainties in risk assessment. The ERDEM-based approach was described in a white paper delivered to the NAS panel "Issues in Trichloroethylene Pharmacokinetics" (EPA/600/R-05/022). Findings from the work have also been presented at the EPA 2004 Science Forum (Okino et al. "Harmonization and Communication of PBPK Models using the Exposure Related Dose Estimation Model (ERDEM) System: Trichloroethylene") and submitted to Environmental Health Perspectives in 2005 for publication (Chiu et al. "Issues in the Pharmacokinetics of Trichloroethylene and Its Metabolites". Methyl-Tertiary Butyl Ether (MTBE). ERDEM was used to estimate the human exposure related concentrations of MTBE in human tissues and excreta that were equivalent to doses used in animal tests. The model was also used to estimate body burden for a range of exposures and age groups. Sensitivity and Monte Carlo analyses were performed. Model runs were performed for risk

3 assessment and applied in route-to-route applications. The results will be reviewed by a National Academy of Sciences (NAS) panel in the near future and incorporated into IRIS where they will become publicly available. This research is a collaborative effort between the client office, NCEA, and the National Computational Toxicology Center (NTCT), the NHEERL, and the NERL (points of contact, Dr. Jerry N. Blancato, Dr. Marina Evans, and Mr. Fred Power, respectively). Malathion. Malathion was modeled in ERDEM as a formulation in shampoo to kill lice. The model assumed the user places the shampoo on the scalp and allows it to remain on the scalp for 12 hours. A given percentage is absorbed through the scalp and the hair roots before the shampoo is then washed off. The amount of modeled enzyme inhibition was very small, although it lasted for up to three days. The results indicated that, if consumers use such over the counter preparations as directed on the label, there is little or no chance of an adverse event. N-methyl Carbamate Cumulative Risk Assessment: A PBPK/PD model of carbaryl demonstrated how NERL and ORD can help estimate relevant dose and inform risk assessments. This work also serves as an example for further work in the area of cumulative risk assessment for other compounds of regulatory interest. The ERDEM model and results were presented at a FIFRA Scientific Advisory Panel (SAP) Open Meeting, February 15-18, 2005, Docket Number: OPP , Washington DC as a presentation and companion report "Assessment Of Carbaryl Exposure Following Turf Application Using A Physiologically Based Pharmacokinetic Model The SAP panel gave favorable reviews to the PBPK/PD modeling approach, including the development, documentation and communication of the model in the ERDEM platform. The model provided estimates of target tissue dose in brain and blood with concomitant estimates of acetylcholinesterase (AChE) inhibition. These findings were accepted by the Office of Pesticide Programs (OPP) as a proof of concept, although the OPP made the decision not to directly incorporate the PBPK/PD results in the N-methyl carbamate risk assessment. Most substantively, the OPP accepted the SAP comments as guidance in future cumulative risk assessments that will use PBPK/PD models. U.S.-Mexico Border 2012: ERDEM was used to develop a PBPK model for chlorpyrifos, and to extrapolate the animal and adult models to children. The child model was implemented to evaluate exposure to pesticides based on previously collected urinary biomarker concentrations "Urinary Biomarker Data Analysis and Study Design for Children Along the U.S.-Mexico Border" ( ysis_and_study_design_for_children.html). Results for estimated exposure levels were presented at the 2005 ISEA meeting (Okino et al. "Use of Pharmacokinetic Models to Assess Occupational and Residential Pesticide Exposure"). The dynamic model provides a platform to quantitatively investigate the uncertainties associated with biomarker interpretation. Training to the Office of Pesticide Programs (OPP): ERDEM developers and users provided training to OPP on the uses of PBPK models in risk assessment. The session "PBPK Modeling in Risk Assessment" was part of a twoday training session as part of the OPP Health Effects Division Risk Assessor Training and Certification program, August 10-11, 2004, Washington DC. The training described the use of the ERDEM platform, illustrated by examples of ERDEM applications.

4 Research Collaboration and Research Products As an exposure-to-dose modeling tool, ERDEM, has been used to identify quality assurance features that are critical for verification of model structure to test the reasonableness of regulatory default assumptions, such as the OPP residential standard operating procedures that have been previously set in the absence of data. The ability of ERDEM to interpret children s aggregate exposure and cumulative risk assisted in identifying critical data gaps in important risk assessments. These included critical windows of susceptibility during the prenatal and childhood development stages. PBPK/PD models have the ability to examine animal systems as a means of predicting different human life stage susceptibility and to explore modes of action of chemicals/pesticides. Details of ERDEM and how it has been applied to address key scientific issues are outlined in a variety of reports, presentations, and publications. Examples of recent publications from this study include: Power FW, Knaak JB, Okino MS, Tornero-Velez R, Lowit A, Blancato JN, Dary CC. Use of Exposure-Related Dose Estimating Model (ERDEM) for Assessment of Aggregate Exposure of Infants and Children to N-Methyl Carbamate Insecticides. At the 44th Annual Meeting of the Society of Toxicology (SOT), New Orleans, LA, March 6-10, Okino MS, Power FW, Knaak JB, Tornero-Velez R, Lunchick C, Lowit A, Blancato JN, Dary CC. Use of a Physiologically-Based Pharmacokinetic Model to Estimate Absorbed Carbaryl Dose in Children after Turf Application. At the 44th Annual Meeting of the Society of Toxicology (SOT), New Orleans, LA, March 6-10, Okino MS, Power FW, Tornero-Velez R, Blancato JN, Dary CC. Assessment Of Carbaryl Exposure Following Turf Application Using A Physiologically Based Pharmacokinetic Model. FIFRA Scientific Advisory Panel (SAP) Open Meeting, Docket Number: OPP , Washington, DC, February 15-18, Knaak, JB, Dary, CC, Power, F, Thompson, C, Blancato, JN. Review of Physicochemical and Biological Data available for the Development of Predictive Organophosphorus Pesticide QSARs and PBPK/PD Models for Human Risk Assessment. Critical Reviews in Toxicology, 34 (2): , Ruiz A., Tsang A., Power F.W., Lucitra J., Blancato J.N., Dary C.C., and Evans M.V. Comprehensive PBPK Modeling Approach Using the Exposure Dose Estimating Model (ERDEM). At the 43rd Annual Meeting of the Society of Toxicology (SOT), Baltimore, MD, March 21-25, Evans M.V., Power F.W., Dary C.C., Tornero-Velez R., and Blancato J.N. Application of the Exposure Dose Estimating Model (ERDEM) to the Assessment of Dermal Exposure in the Rat to Malathion. At the 43rd Annual Meeting of the Society of Toxicology (SOT), Baltimore, MD, March 21-25, Tornero-Velez R., Nichols H., Evans M.V., DeVito M., Dary C.C., and Blancato J.N. Towards a Generic PBPK Model of Pyrethoid Pesticides: Modeling Deltamethrin and Permethrin in the Rat. At the 43rd Annual Meeting of the Society of Toxicology (SOT), Baltimore, MD, March 21-25, Knaak, JB, Dary, CC, Patterson, GT, Blancato, JN. Worker Hazard Posed by Reentry into Pesticide-Treated Foliage: Reassessment of Reentry Levels/Intervals Using Foliar Residue Transfer- Percutaneous Absorption PBPK/PD Models, with Emphasis on Isofenphos and Parathion. In Human and Ecological Risk Assessment: Theory and Practice, Paustenbach, DJ, ed., John Wiley & Sons, Inc Wilkes, C, Blancato, J, Hern, S, Power, F, and Olin, S. Integrated Probabilistic and Deterministic Modeling Techniques in Estimating Exposure to Water-Borne Contaminants: Part 1: Exposure

5 Modeling. Proceedings: 9th International Conference on Indoor Air Quality and Climate, Monterey, California, June 30-July 5, Blancato, J., Power, F., Wilkes, C., Tsang, A., Hern, S., and Olin, S. Integrated Probabilistic and Deterministic Modeling Techniques in Estimating Exposure to Water-Borne Contaminants: Part 2: Pharmacokinetic Modeling. Proceedings: 9th International Conference on Indoor Air Quality and Climate, Monterey, California, June 30-July 5, Knaak J.B., Power F.W., Blancato J.N. and Dary C.C. Poster presentation, Use of Exposure- Related Dose Estimating Model (ERDEM) for Assessment of Aggregate Exposure of Infants and Children to Organophosphorus Insecticides. At the 40th Annual Meeting of the Society of Toxicology (SOT), San Francisco, CA, Abstract (#84). In: the Toxicologist, Volume 60 (1) 17, March 25-29, Knaak J.B.