Impact/Purpose:

The overall goal of this work is to reduce the uncertainty in risk assessment. The chemical-specific models developed under this task highlight common methods, analyses, and data requirements for general dose modeling. Specific objectives relate directly to customer needs and contributions to the scientific field.

1)Quantify the relevant dose metrics, and associated uncertainties, under scenarios of regulatory interest.

2)Develop and evaluate methods for species-to-species, age, and route-to-route extrapolation.

3)Evaluate and identify important mechanisms of chemical interaction for cumulative risk assessment.

4)Identify data gaps, and recommend targeted experimental studies to reduce the uncertainties in the dose metric estimates.

5)Provide information on common ADME pathways to recommend enhancements of the general ERDEM dose modeling platform.

6)Develop specific chemical and chemical class PBPK/PD models to support pesticide product registration and re-registration demands through 2008 (EPA Strategic Plan Objective 4.1.1: Reduce exposure to toxic pesticides).

Description:

This project aims to strengthen the general scientific foundation of EPA's exposure and risk assessment processes by developing state-of-the-art exposure to dose computational models. This research will produce physiologically-based pharmacokinetic (PBPK) and pharmacodynamic (PD) models for specific and often times unique applications. The models are expected to provide estimates of relevant dose metrics for diverse exposure scenarios. Source-to-exposure-to-dose models, such as the Exposure Related Dose Estimating Model (ERDEM), provide the essential link between dose-response experimental data and regulatory assumptions and human exposure factors that describe exposure scenarios. Exposure time-histories are used to interpret uptake of chemicals or mixtures of chemicals into the body by multiple routes of entry (e.g., dermal, ingestion, and inhalation). The absorption, distribution, metabolism and excretion (ADME) of parent chemicals and metabolites are simulated, and the pathways where interactions occur are explicitly represented. Adjustments can be made to the modeling framework to account for physiological changes during differing activity levels and to adjust for anatomical and physiological differences during growth and development and aging.

Record Details:

Record Type:PROJECT

Start Date:10/01/2005

Projected Completion Date:10/01/2007

OMB Category:Other

Record ID: 137226

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Project Information:

Progress :This is a new task. However, relevant products to this research are listed under the FY2004 task 3906. The products from FY2004 are listed below; products from previous years are not included here.
ABSTRACT/ORAL
Blancato, J. Use of physiologically based pharmacokinetic models in assessments. Presented at: HEASD Seminar Series, Durham, NC, November 24, 2003.
Date Cleared: 11/23/2003 9:00:00 PM Date Presented: 11/23/2003 9:00:00 PM Peer Review Category: 3
Tracking ID: NERL-RTP-HEASD-03-195
Blancato, J., Dary, C.C., Okino, M.S., Power, F.W., Ruiz, A., and Tornero-Velez, R. Application of ERDEM in risk assessment: health effects division's risk assessor training and certification program. Presented at: Health Effects Division's Risk Assessor Training and Certification Program, Washington, DC, August 11-12, 2004.
Date Cleared: 8/9/2004 9:00:00 PM Date Presented: 8/10/2004 9:00:00 PM Peer Review Category: 3
Tracking ID: NERL-RTP-HEASD-04-105
Evans, M.V., Power, F.W., Dary, C.C., Knaak, J.B., Tornero-Velez, R., and Blancato, J. Application of the exposure dose estimating model (ERDEM) to assessment of dermal exposure in the rat to malathion. Presented at: Society of Toxicology, Baltimore, MD, March 22-26, 2004. Date Cleared: 3/24/2004 9:00:00 PM Date Presented: 3/24/2004 9:00:00 PM Peer Review Category: 3
Tracking ID: NERL-RTP-HEASD-04-038
Kryak, D.D. Demonstration of human exposure tools. Presented at: EPA Science Forum 2004, Washington, DC, June 1-3, 2004.
Date Cleared: 4/22/2004 9:00:00 PM Date Presented: 6/1/2004 9:00:00 PM Peer Review Category: 3
Tracking ID: NERL-RTP-HEASD-04-062
Lowit, A., Dary, C.C., Power, F.W., Blancato, J., Setzer, R.W., Conolly, R., and Seaton, M. Physiologically-based pharmacokinetic/pharmacodynamic modeling and cumulative risk assessment: case study for the n-methyl carbamate pesticides. Presented at: EPA Science Forum 2004, Washington, DC, June 1-3, 2004.
Date Cleared: 5/27/2004 9:00:00 PM Date Presented: 6/1/2004 9:00:00 PM Peer Review Category: 3
Tracking ID: NERL-RTP-HEASD-04-080(b)
Lowit, A., Dary, C.C., Power, F.W., Blancato, J., Setzer, R.W., Conolly, R., and Seaton, M. Physiologically-based pharmacokinetics/pharmacodynamic modeling and cumulative risk assessment: case study for the n-methyl carbmate pesticides. Presented at: EPA Science Forum 2004, Washington, DC, June 1-3, 2004.
Date Cleared: 5/27/2004 9:00:00 PM Date Presented: 6/1/2004 9:00:00 PM Peer Review Category: 3
Tracking ID: NERL-RTP-HEASD-04-080(a)
Okino, M.S., Power, F.W., Blancato, J.N., Chiu, W., Chen, C., and Lipscomb, J. Harmonization and communication of PBPK models using the exposure related dose model (ERDEM) system: trichloroethylene. Presented at: EPA Science Forum 2004, Washington, DC, June 1-3, 2004.
Date Cleared: 4/8/2004 9:00:00 PM Date Presented: 6/1/2004 9:00:00 PM Peer Review Category: 3
Tracking ID: NERL-RTP-HEASD-04-050(a)
Okino, M.S., Power, F.W., Blancato, J., Chiu, W., Chen, CW, and Lipscomb, J. Harmonization and communication of PBPK models using the exposure related dose estimation model (ERDEM) system: trichloroethylene. Presented at: EPA Science Forum 2004, Washington, DC, June 1-3, 2004.
Date Cleared: 5/12/2004 9:00:00 PM Date Presented: 6/1/2004 9:00:00 PM Peer Review Category: 3
Tracking ID: NERL-RTP-HEASD-04-050(b)
Ross, M.K., Tornero-Velez, R., Granville, C., Gold , A., Evans, M.V., and DeMarini, D. M. Metabolism of 1,1- and 1,3- dichloropropene: a mechanism of bioactivation by glutathione. Presented at: International Society for the Study of Xenobiotics, Vancouver, Canada, August 29-September 2, 2004.
Date Cleared: 4/25/2004 9:00:00 PM Date Presented: 8/30/

Relevance :Exposure related physiologically-based pharmacokinetic (PBPK) and pharmacodynamic (PBPD) models as developed in ERDEM hold the very real promise of aiding risk assessors and policy experts in making informed judgements about the scientific validity of safety factors, reference doses (RfD), and margin of exposure (MOE). As a matter of policy, pesticide cumulative risk assessments rely on a ?weight of the evidence? approach (U.S. EPA, http://www.epa.gov/pesticides/cumulative/). Recently, the Office of Pesticide Programs (OPP) FIFRA science advisory panel (SAP) recognized the usefulness of computational software for the assessment of aggregate exposure and cumulative risk to pesticides having a common mechanism of toxicity (Federal Register. 4/17/2002; Federal Register. 10/22/2003; http://www.epa.gov/scipoly/sap/). The 10/222003 FIFRA SAP commended U.S. EPA for the initiative to develop a much needed methodology and tool for refining health risk in general and cumulative risk in particular. The SAP acknowledged the urgent need for PBPK/PD model development for use in cumulative risk assessment. The report, ?Physiologically-based pharmacokinetic (PBPK) and pharmacodynamic (PBPD) modeling: Preliminary evaluation and case study for the N-methyl carbamate pesticides: A consultation?, (FIFRA SAP 12/11-12, 2003) stated that EPA is on the right track to find a workable, manageable and acceptable solution to a pressing issue in risk assessment. For these reasons, external advisors to NCEA and OPPTS/OPP have recommended the use of PBPK models in risk assessments, in conjunction with ?weight-of- the-evidence? procedures, to formulate state-of-the science analyses. Moreover, it is simply not practical for the Agency to collect data to address every aspect of the exposure to risk paradigm. This is particularly true for exposures involving multiple chemicals or mixtures. It is therefore prudent and necessary to enable PBPK/PD models to predict risk to diverse populations for exposure scenarios where a multiplicity of pathways impose ponderous uncertainties upon non-computational ?weight-of- the-evidence? procedures.

Clients :OPPTS, OPP, OSWER, ORD, NERL, NCEA, NHEERL, Scientific Community

Project IDs:

ID Code :20709

Project type :OMIS