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December 11 - 12, 2003 SAP meeting Agenda

FIFRA SCIENTIFIC ADVISORY PANEL (SAP)FIFRA SCIENTIFIC ADVISORY PANEL (SAP)
OPEN MEETING
December 11 and 12, 2003
FIFRA SAP WEB SITE http://www.epa.gov/scipoly/sap/
OPP Docket Telephone: (703)305-5805

PHYSIOLOGICALLY-BASED PHARMACOKINETIC/PHARMACODYNAMIC MODELING: PRELIMINARY EVALUATION AND CASE STUDY FOR THE
N-METHYL CARBAMATE PESTICIDES: A CONSULTATION

Thursday, December 11, 2003
Sheraton Crystal City Hotel
1800 Jefferson Davis Highway
Arlington, Virginia 22202
703-486-1111


Please note that all times are approximate.

1. Development of the Preliminary PBPK/PD Model Structure Conceptually, PBPK/PD models offer great promise in cumulative risk assessment, such as the ability to incorporate species, sex, or age-specific information on biological processes and the explicit consideration of pharmacokinetic and mechanistic data. At present time, the appropriate pharmacokinetic data are not available for the majority of N-methyl carbamate pesticides. The Agency has developed preliminary model structure in two computer languages (See Section III.D, Figures 2 and 3) for this common mechanism group based on information available at the present time. Specifically, the structure of the preliminary model is based on: limited available pharmacokinetic data from the literature; AChE inhibition data and rat metabolic profiles from the scientific literature and/or from studies submitted for pesticide registrations; and previous PBPK/PD models developed for organophosphorus chemicals. Question 1.1 Please comment on the proposed PBPK/PD model structure for the N-methyl carbamate pesticides as described in the document, with specific consideration of the biological and mechanistic basis for this structure.
  • 3:15 PM Break
  • 3:30 PM Questions to the Panel (continued)
    2. Data Needs for the N-Methyl Carbamate PBPK/PD Model The document under review describes an iterative process for model development where the model developer and laboratory scientist work collaboratively, first to identify and then to fill in areas where data or information are missing for a particular chemical(s). At the present time, the Agency has developed a preliminary model and has identified areas where pharmacokinetic and/or pharmacodynamic data are not available. These data needs, along with the purpose of the experiment in the modeling effort, are described in the document.
    Question 2.1 Please comment on the adequacy and appropriateness of the data needs identified for the purpose of developing PBPK/PD models for individual N-methyl carbamates and also for developing the PBPK/PD model for the common assessment group as a whole.

    Question 2.2 Typically, parameter estimation is performed using a set of available physiological, pharmacodynamic, and pharmacokinetic data. Data used for model development are not used for evaluating model reliability. Instead, separate data sets are used. Given the considerable resources needed to conduct in vivo pharmacokinetic studies, particularly mixture pharmacokinetic studies, identification of a minimum amount of data needed to achieve an acceptable level of residual uncertainty in the PBPK/PD model for the common assessment group is preferred. Please comment on the types of data needed to evaluate model reliability.
  • 5:30 PM Adjournment

    Friday, December 12, 2003
    Sheraton Crystal City Hotel
    1800 Jefferson Davis Highway
    Arlington, Virginia 22202
    703-486-1111

    Please note that all times are approximate.

  • 8:30 AM Meeting Opening - Stephen M. Roberts, Ph.D. (Chair of the FIFRA SAP)
  • 8:35 AM Introduction of Panel Members - Christopher Portier, Ph.D. (FIFRA SAP Session Chair)
  • 8:40 AM Administrative Procedures by Designated Federal Official - Mrs. Myrta R. Christian
  • 8:45 AM Questions to the Panel

    3. Model Evaluation and Quality Control This document outlines a five-step approach to evaluating a PBPK/PD model for use in cumulative risk assessment. These steps include: 1) determining and stating model purpose, 2) development of model structure based on characterization of the biological and toxicological profiles of the individual members and the common assessment group as a whole; 3) description of the mathematics of the model; 4) implementation in a computer language; and 5) estimation of parameters and evaluation of model fit. Question 3.1 Please comment on this five-step approach to evaluating PBPK/PD models, with particular consideration of their use in regulatory settings. Does this approach encompass the main issues related to model evaluation and quality control? If not, what additional issues need to be considered?
  • 10:30 AM Adjournment
    As noted above, please be advised that agenda times are approximate. For further information, please contact the Designated Federal Official for this meeting, Mrs. Myrta R. Christian, via telephone: (202) 564-8450; fax: (202) 564-8382; or email:christian.myrta@epa.gov
  • FIFRA SCIENTIFIC ADVISORY PANEL (SAP)
    OPEN MEETING


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