EPA731-N-94-002
       f      UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
        *                     WASHINGTON, DC  20460
                               August  24,  1994
                                                                     OFFICE OF
                                                                PREVENTION, PESTICIDES
                                                                 AND TOXIC SUBSTANCES
             PESTICIDE REGULATION (PR) NOTICE 94-5
          NOTICE TO REGISTRANTS OF PESTICIDE PRODUCTS


ATTENTION:    Persons Responsible For Registration of
              Pesticide Products

SUBJECT:      Requests for Re-considerations of Carcinogenicity
              Peer Review Decisions Based on Changes in Pathology
              Diagnose-s.

     -This notice sets forth a procedure to be followed for
submission of pathology re-reads to the Agency.


I.   BACKGROUND

From time to time the Office of Pesticide Programs receives requests for
re-consideration of Peer Review decisions based on re-evaluations of the
pathology readings.  These re-evaluations reflect voluntary activity on the
part of the registrants, and are not the result of a requirement imposed by
the Agency.  The Agency is then asked to disregard the original readings and
base its evaluation on the most recent ones.  As a result the Agency may have
two  (or at times even more) "pathological diagnoses for the same study.


Since this situation is occurring more and more frequently, the Agency is _
instituting a procedural requirement  for any voluntary submissions of revised
pathology diagnoses. This procedure will require a comprehensive peer review
process, similar to the one used by the National Toxicology Program (NTP) .
                                 (NTP) has a protoco Flfor^quality assurance* in
pathology,  involving  a quality  assessment (peer review) pathologist and a
Pathology Working Group  (PWG) which  is used to resolve differences in
diagnoses between the laboratory (study) pathologist and the peer review
pathologist.   The PWG consists  of  a  chair, the peer review pathologist and
other pathologists  (to include  the study pathologist), all of whom are
experienced in rodent toxicologic  pathology.  This group examines the tissues
without  knowledge of  dose  groups or  previously rendered diagnoses.  When the
PWG  consensus  differs from the  opinion of the study pathologist, the diagnosis
is changed.  Thus,  the final  diagnoses represent  a consensus of study, peer
review,  and consultant pathologists  on the PWG.   This procedure is described
in the NTP  Technical  Reports  under the section: "Clinical Examinations and
Pathology."  EPA believes that the  use of a PWG, similar to one used by NTP,
should be part of every  pathology  re-evaluation.
                                                       Printed on Recycled Paper

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II.  POLIC5T AND RATIONALE

The Agency believes that a procedure for obtaining consensus in
pathology re-reads will improve the quality of decision-making in
classifying pesticide chemicals having carcinogenic potential.  The Agency has
determined that unless .the re-reads have been conducted using a Peer Review
procedure, the Agency will base its evaluations upon the original readings.

The following will be required:                                     '  ,

For any target tissue which is being re-evaluated, all slides containing that
tissue in all dose groups, as well as the controls, must be re-read by the
peer review pathologist.  This is to include slides previously classified by
the study pathologist as within normal limits, in addition to those having
tumors, hyperplasia, hypertrophy, foci of cellular alteration or other
non-neoplastic lesions.

The pathology reports from both the study and peer review pathologist and the
original slides are to be submitted to a Pathology Working Group (PWG) similar
to that described in the NTP Technical Reports under the section: "Clinical
Examinations and Pathology."  The PWG will review, as a minimum,  all slides
about which there were significantly differing diagnoses between the study and
peer review pathologists.

Finally, the Agency should be provided with a detailed pathology
report, which presents the PWG findings and includes the original
diagnosis and the new diagnosis for each slide read, and a comment
column to note any discrepancies, missing slides,  etc.

The Agency also is considering including the requirement for
review by a PWG for all original submissions in the future.  This
present Notice deals only with re-reads.
III. EFFECTIVE DATE

     This policy notice is effective immediately.  If you have
questions, contact Esther Rinde at (703) 305-7492.
                                    ^^
                                             -/a,
                                          H~ "
                                 Penelope A. Fenner-Crisp,
                                 Deputy Director (Acting)
                                Office of Pesticide Programs

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