AGENDA  

Federal Insecticide, Fungicide, and Rodenticide Act

Scientific Advisory Panel Open Meeting

May 21-23, 2013

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

EPA Docket Number: EPA-HQ-OPP-2013-0075

Potomac Yard One South

2777 Crystal Drive

Arlington, VA 22202

Scientific Review of the Endocrine Disruptor Screening Program (EDSP);
Tier I Assay and Battery Performance 

Please note that all times are approximate.  (See note at the end of the
Agenda).

Tuesday, May 21, 2013

9:00 A.M.	Opening of Meeting and Administrative Procedures, Fred
Jenkins, Ph.D., Designated Federal Official, Office of Science
Coordination and Policy, EPA

9:05 A.M. 	Introduction and Identification of Panel Members, Daniel
Schlenk, Ph.D., Chair FIFRA Scientific Advisory Panel 

9:15 A.M.	Opening Remarks, David Dix, Ph.D., Acting Director, Office of
Science Coordination and Policy, EPA: Steve Bradbury, Ph.D., Director,
Office of Pesticide Programs, EPA

EDSP Program Overview, Mary Manibusan, Director, Exposure Assessment
Coordination and Policy Division, Office of Science Coordination and
Policy, EPA

10:00 A.M. 	Background: Current Validated EDSP Tier 1 Screening Assays
and Battery, Leslie Touart, Ph.D., Exposure Assessment Coordination and
Policy Division, Office of Science Coordination and Policy, EPA

10:30 A.M.	Break

Scientific Review of Tier 1 Assay and Battery Performance

10:45 A.M.	In Vitro Assays, Gregory Akerman, Ph.D., Health Effects
Division, Office of Pesticide Programs, EPA

11:30 A.M.	In Vivo Mammalian Assays, John Liccione, Ph.D., Health
Effects Division, Office of Pesticide Programs, EPA

12:00 P.M.	Lunch

1:00 P.M.	Fish Assay, Amy Blankinship, M.S., Environmental Fate and
Effects Division, Office of Pesticide Programs, EPA

1:30 P.M.	Frog Assay, Catherine Aubee, M.P.A., Environmental Fate and
Effects Division, Office of Pesticide Programs, EPA

2:00 P.M.	Battery Performance, Tom Steeger, Ph.D, Catherine Aubee,
M.P.A, Amy Blankinship, M.S., Gregory Akerman, Ph.D., Office of
Pesticide Programs, EPA

2:45 P.M. 	Break

3:00 P.M.	Summary of Assay and Battery Review, Tom Steeger, Ph.D.,
Environmental Fate and Effects Division, Office of Pesticide Programs,
EPA

3:15 P.M.	Adjournment 

Wednesday, May 22, 2013

9:00 A.M.	Opening of Meeting and Administrative Procedures, Fred
Jenkins, Ph.D., Designated Federal Official, Office of Science
Coordination and Policy, EPA

9:05 A.M.	Follow-up from Previous Day’s Meeting, Daniel Schlenk,
Ph.D., Chair, FIFRA Scientific Advisory Panel

9:20 A.M.	 Public Comments 

10:30 A.M.	Break

10:45 A.M.	Public Comments (Cont’d)

12:15 P.M.	Lunch

1:15 P.M.	Panel Discussion of Charge Questions

 Charge Question 1. Based on the analysis of the data presented in
Section III, please comment on the proficiency of the contributing
laboratories to execute each assay in accordance with the test
guidelines and achieve the performance criteria.

2:15 P.M. 

Charge Question 2. The performance criteria for each in vitro assay are
clearly stated in the test guidelines for the ER binding (OCSPP
890.1250), AR binding (OCSPP 890.1150), ERα Transcriptional Activation
(OCSPP 890.1300, OECD 455), H295R steroidogenesis (OCSPP 890.1550) and
aromatase human recombinant (OCSPP 890.1200) assays.  Although
contributing laboratories did not always demonstrate that results were
within the specified boundaries of the performance criteria, the
majority of the deviations were still close to the performance criteria.
 In this regard, the EPA concluded that the data were still adequate for
use.  Please comment on the EPA’s conclusion.  Please comment on when
a deviation from the recommended performance criteria would render the
study unreliable.

3:15 P.M. 

Charge Question 3. Unlike the Hershberger and Uterotrophic assays, a
positive control is not required in the male (OCSPP 890.1500) and female
(OCSPP 890.1450) pubertal assays.  For these in vivo assays with rats,
coefficient of variation (CV) limits are specified in the test
guidelines for most endpoints.  Submissions from different laboratories
sometimes fell short of meeting all the test guideline-recommended CV
limits for the endpoints evaluated.  However, in most cases these
shortcomings were considered of minor importance to the overall results,
and EPA concluded that the data are still adequate for endocrine
screening.  Please comment on the EPA’s conclusion. Please comment on
when a deviation from the recommended CV limits would render the study
unreliable.

4:15 P.M.

Charge Question 4. The test guidelines for the six in vivo assays
(Hershberger assay - OCSPP 890.1400, OECD 441; Uterotrophic assay- OCSPP
890.1600, OECD 440; Male Pubertal assay- OCSPP 890.1500; Female Pubertal
assay - OCSPP 890.1450; FSTRA - OCSPP 890.1350, OECD 229 and AMA - OCSPP
890.1100) offer some guidance on setting the dose/concentration range
when testing for specific effects on the E, A, or T signaling pathways. 
In some of the in vivo assays, overt toxicity was noted based on effects
on growth, other sublethal effects, and even mortality at the highest
dose/concentration tested.  Positive Tier 1 findings indicating the
potential for endocrine activity can be difficult to interpret in the
presence of overt toxicity.

5:15 PM	Adjourn 



Thursday, May 23, 2013

9:00 A.M.	Opening of Meeting and Administrative Procedures, Fred
Jenkins, Ph.D., Designated Federal Official, Office of Science
Coordination and Policy, EPA

9:05 A.M.	Follow-up from Previous Day’s Meeting, Daniel Schlenk,
Ph.D., Chair, FIFRA Scientific Advisory Panel 

9:20 A.M.	Panel Discussion of Charge Questions (Cont’d)

Charge Question 5. Spinal curvature, usually manifesting as “bent
tail” in X. laevis tadpoles, was reported in 15 of 18 AMA studies
reviewed thus far.  The anomaly appears to be first observed several
days after study initiation, and prevalence increases with time. 
Overall, the prevalence of spinal curvature in these studies ranged from
“a few per replicate” to 92% of a given treatment group by test
termination.  Experimental work by the EPA Office of Research and
Development suggests that overfeeding can be a primary cause of spinal
curvature in their Xenopus test populations; however, spinal curvature
remained prevalent (range: 16-92%) in the five industry AMA studies in
which feed was reduced by 50% compared to guideline recommendations.

Overall, the incidence of spinal curvature appears to be highly
variable.  From a qualitative review of the data, there appear to be no
consistent differences in the incidence or variability of spinal
curvature when studies using guideline versus reduced feeding regimes
are compared.  Please comment on whether the presence or prevalence of
spinal curvature in test specimens, including controls, compromises the
utility or validity of an AMA submission.  If so, when does the
prevalence of spinal curvature render the study unreliable?  What
technical guidance may be useful for laboratories in reducing the
occurrence of spinal curvature and determining if, or at what point
within the study, a study may be compromised because of this phenomenon?

10:20 A.M.	Break

10:30 A.M.	

Charge Question 6. With the exception of thyroid gross pathology
findings (thyroid gland atrophy and hypertrophy) in the AMA, severity
grades are generally assigned based on comparison to “normal” X.
laevis thyroid findings depicted in the guidance or based on the
professional opinion of the pathologist conducting the assessment; they
are not assigned in comparison to concurrent control findings from a
given study.  (Please refer to Section III.2.f in the document entitled
“Interpreting Amphibian Thyroid Histopathology Diagnoses” and
supporting documents, OECD Guidance Document on Amphibian Thyroid
Histology No. 82, 2007 and Grim et al., 2009).

In one study, the pathologist’s report identified a lower incidence
and severity of follicular cell hypertrophy when compared to the
incidence and severity of this trait in control specimens.  Similar
trends have been observed in other studies.  In this case, the
pathologist concluded that the finding was potentially consistent with
treatment-related delay of metamorphosis because thyroid follicular
cells normally increase in height during tadpole development.  Please
comment on the validity of this conclusion.

11:30 A.M.

What guidance may be given to better distinguish between histological
changes in the thyroid associated with the normal progression of
metamorphosis and treatment-related effects?  Are there certain lesions
or diagnoses which may, by their absence or lessened severity as
compared to controls, be indicative of treatment-related HPT effects
such as delayed metamorphosis?

12:30 P.M.	Lunch

1:30 P.M.	

Charge Question 7. In 2008, the SAP acknowledged that the in vivo assays
included in the Tier 1 battery provide both redundancy and
complementarity for evaluating interactions with the E, A, or T
signaling pathways.  The panel also noted that all of the Tier 1 assays
and the broad range of endpoints appeared to be necessary to
“discriminate positive and negative results”.

a.	Please comment on the battery performance with respect to the
anticipated complementary nature of the more complex, multi-parameter in
vivo assays in the context of the observed responses with the case
studies.  Please comment separately on the E-, A-, and T-related assays
and endpoints.

2:30 P.M.	Break

2:45 P.M.	

Please comment on the battery performance with respect to the
anticipated redundancy across the 11 assays in the context of the
observed responses with the case studies.  Please comment separately on
the E-, A-, and T-related assays and endpoints.

3:45 P.M.

The EPA concluded that the battery has performed as anticipated by the
2008 SAP.  Please comment on this conclusion.

4:45 P.M.	

Charge Question 8. The EPA is committed to minimizing animal usage in
the screening battery while maintaining the effectiveness of the battery
to answer the question of whether a chemical has the “potential” to
interact with the endocrine system.

a.	In 1998, the EDSTAC described the conceptual framework for Tier 1
assays and recommended the strategy to “require the minimal number of
screens and tests necessary to make sound decisions, thereby reducing
the time needed to make these decisions”, and that the screens should
be conducted at a minimal cost necessary to make decisions.  Based on
the preliminary battery performance evaluation, to what extent can the
current Tier 1 battery of 11 assays be modified to reduce animal usage
and/or lower cost while adequately ensuring the EPA’s ability to
answer the question of “whether a chemical has the potential to
interact with the endocrine system?”  More specifically, please
comment on whether the Uterotrophic and Hershberger assays provide
necessary redundancies in the Tier 1 battery based on this preliminary
analysis.  Please include in your comments what information may be lost
and what uncertainties may be introduced by absence of either or both of
these assays.

Please comment on the scientific criteria the Agency should consider in
evaluating necessary redundancies and eliminating assays from the
current battery.

5:45 P.M.	Closing Remarks, Daniel Schlenk, Ph.D., Chair FIFRA Scientific
Advisory Panel; 

	Fred Jenkins, Ph.D., Designated Federal Official, Office of Science
Coordination and Policy, EPA

6:00 P.M.	Adjournment

Note:	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, Dr. Fred Jenkins, via telephone:
(202) 564-3327; fax: (202) 564-8382; or email: jenkins.fred@epa.gov.

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