AGENDA

FIFRA SCIENTIFIC ADVISORY PANEL (SAP)

OPEN MEETING

August 16-17, 2007

FIFRA SAP WEB SITE http://www.epa.gov/scipoly/sap/

OPP Docket Telephone: (703) 305-5805

Docket Number: EPA-HQ-OPP-2007-0388

U.S. Environmental Protection Agency

Conference Center - Lobby Level

One Potomac Yard (South Bldg.)

2777 S. Crystal Drive, Arlington, VA 22202

Assessing Approaches for the Development of PBPK Models of Pyrethroid
Pesticides

Thursday, August 16, 2007

8:30 A.M.	Introduction and Identification of Panel Members – Steven G.
Heeringa, Ph.D. (FIFRA SAP Chair)  

8:40 A.M.	Administrative Procedures by Designated Federal Official –
Mr. Steven Knott, Office of Science Coordination and Policy, EPA

8:45 A.M.	Welcome and Opening Remarks – Debbie Edwards, Ph.D.,
Director, Office of Pesticide Programs, EPA

8:50 A.M.	Opening Remarks - Tina Levine, Ph.D., Director, Health Effects
Division, Office of Pesticide Programs, EPA

8:55 A.M.	Introduction – Anna Lowit, Ph.D., Office of Pesticide
Programs, Health Effects Division, EPA

9:10 A.M.	Pharmacokinetics of Pyrethroid Pesticides and Potential Dose
Metrics – Michael F. Hughes, Ph.D., Office of Research and
Development, The National Health and Environmental Effects Research
Laboratory, EPA 

9:35 A.M.	Metabolism of Pyrethroid Pesticides in Rodents and Humans –
Edward Scollon, Ph.D., Michael DeVito, Ph.D., Office of Research and
Development, The National Health and Environmental Effects Research
Laboratory, EPA

10:00 A.M.	Approaches to Pharmacokinetic Modeling of Pyrethroids –
Rogelio Tornero-Velez, Ph.D., Office of Research and Development, The
National Exposure Research Laboratory, EPA

10:30 A.M.	Statistical Approaches to PBPK Models – R. Woodrow Setzer,
Ph.D., Office of Research and Development, National Center for
Computational Toxicology, EPA

10:40 A.M.	Break

10:55 A.M.	Public Comments 

12:00 P.M.	Lunch

1:15 P.M.	Charge to Panel – Issue 1: 

The Agency’s issue paper describes different aspects of the
pharmacokinetic (PK) properties of pyrethroid pesticides. The Agency
believes that the important PK properties relevant for PBPK modeling are
common among all or most members of this class, such that a
‘generic’ or family model structure with chemical specific
adjustments, as needed, can be used. 

Please comment on the evidence which does and does not support the
concept of using a generic model structure for the pyrethroid
pesticides.

3:00 P.M.	Break

3:15 P.M.	Charge to Panel – Issue 2: 

In the development of PBPK models in vivo and in vitro data are acquired
and used to calibrate and optimize the model. The predictions of the
PBPK model are then evaluated against additional in vivo data sets. In
the case of pyrethroids, there are limited human data available to
calibrate and assess the human PBPK models. The Agency plans to develop
a family modeling approach to address this issue. This approach assumes
that because pyrethroids share many physical chemical and biological
properties, a common model structure can be used for all pyrethroids.
The family model approach allows for the assessment of the overall model
structure with each iteration. The more iterations through this process,
the more confidence is gained in the models’ predictive abilities.
Thus, the rat deltamethrin model is not only assessed by data from
deltamethrin, but is assessed by model fits to data for every other
pyrethroid. As our confidence in the rodent family model increases
across pyrethroids, our confidence in the use of this modeling approach
for rodent to human extrapolation also increases. The Agency is planning
to develop equivalent rodent and human in vitro databases for metabolic
and physiological parameters. The rodent in vitro parameters will be
assessed by comparing model predictions to in vivo data. It is likely
that scaling factors will be used in order to incorporate these in vitro
parameters into the rodent model. When calibrating the human data, the
scaling factors used in the rodent models will be used in the human
models. 

Please comment on this approach and other approaches that could be taken
to calibrate and assess these models for use in human risk assessment.

5:00 P.M. 	Adjournment

AGENDA

FIFRA SCIENTIFIC ADVISORY PANEL (SAP)

OPEN MEETING

August 16-17, 2007

FIFRA SAP WEB SITE http://www.epa.gov/scipoly/sap/

OPP Docket Telephone: (703) 305-5805

Docket Number: EPA-HQ-OPP-2007-0388

U.S. Environmental Protection Agency

Conference Center - Lobby Level

One Potomac Yard (South Bldg.)

2777 S. Crystal Drive, Arlington, VA 22202

Assessing Approaches for the Development of PBPK Models of Pyrethroid
Pesticides

Friday, August 17, 2007

8:30 A.M.	Introduction and Identification of Panel Members - 

		Steven G. Heeringa, Ph.D. (FIFRA SAP Chair)  

8:40 A.M.	Administrative Procedures by Designated Federal Official - 

		Mr. Steven Knott, Office of Science Coordination and Policy, EPA

8:45 A.M.	Follow-up from Previous Day’s Discussion 

9:00 A.M.	Charge to Panel – Issue 3:

The Agency’s issue paper and data provided in Appendix C show that
blood and brain concentrations of parent compound in the rat correlate
with pyrethroid toxicity as measured by motor activity. At the present
time, the Agency plans to evaluate additional metrics (e.g., area under
the curve) with additional pyrethroids. Moreover, the Agency plans to
test other behavioral measures (e.g., startle response). 

Please comment on the available database to assess the dose metric for
pyrethroids. Please also comment on what additional experiments, if any,
could further inform the dose metric.

10:15 A.M.	Break

10:30 A.M.	Charge to Panel – Issue 3 continued

11:00 A.M.	Charge to Panel – Issue 4:

Pyrethroids may have one or more chiral centers resulting in potentially
multiple stereoisomers. Some products, such as deltamethrin, are
relatively pure single stereoisomers. Others such as cypermethrin may
contain as many as eight stereoisomers. There is limited information on
the toxicity and pharmacokinetics of the different stereoisomers. The
Agency is proposing to evaluate three modeling assumptions. The first
approach combines all stereoisomers as one chemical. The second approach
includes modeling all the diastereomers and ignores the enantiomers; the
third approach includes only the toxic stereoisomers. To evaluate these
approaches, the Agency is using permethrin as a model chemical. 

Please comment on these three approaches. Are there additional modeling
assumptions or approaches that the Agency should consider or that could
simplify the modeling?

12:00 P.M.	Lunch

1:15 P.M.	Charge to Panel – Issue 4 continued

2:00 P.M.	Adjournment

Please be advised that agenda times are approximate; when the discussion
for one topic is completed, discussions for the next topic will begin. 
For further information, please contact the Designated Federal Official
for this meeting, Mr. Steven Knott, via telephone:  (202) 564-0103; fax:
 (202) 564-8382; or email: knott.steven@epa.gov

DRAFT 7/30/2007

