The first phase of Dr. Frith's review consisted of the examination of the tissues of 25 of the surviving control females and 11 of the non-surviving control females for a total of 36 animals.  All of the slides were examined for each animal and the results were compared to the microscopic reports provided by Searle Laboratories.  The inconsistencies (findings that differed from those reported by Searle) are listed below:

In most cases the inconsistencies represent findings that were not diagnosed or reported by Searle.  Copies of Searle's microscopic pathology reports for each of the animals listed below are attached as exhibit #60.

Female Rat No. F13CF  (Path. No. 95617)

Small Intestine - Diverticulum with mucosal necrosis and cellular inflammatory infiltrate.

Female Rat No. F15CF  (Path No. 95618)

Pancreas - Focal hyperplasia

Female Rat No. F16CF  (Path No. 95619)

Heart - Focal Fibrosis.

Kidney - Mild chronic nephritis.

Female Rat No. H10CF (Path 95624)

Ovary - Neoplasm - probably granulosa cell tumor.

Female Rat No. H19CF  (Path. No. 95626)

Kidney - Focal calcification.

Ovary  - Neoplasm - probably granulosa cell tumor.

Female Rat No. H30CF (Path. No. 95628)

Kidney - Focal calcification.

Female Rat - No. K25CF (Path No. 95630)

Kidney  - Focal calcification.

Female Rat No. K29CF (Path No. 95631)

Heart   - Focal fibrosis

Kidney  - Focal calcification

Female Rat No. M4CF  (Path No. 95632)

Liver   - Focal hyperplasia

Female Rat No. M10CF  (Path No. 95634)

Kidney  - Focal calcification.

Pituitary - Adenoma

Ovary   - Fibrosis and Pigmentation.

Female Rat No. M15CF  (Path No. 95635)

Pituitary   - Adenoma.

Ovary       - Cyst.

Female Rat No. B30CF  (Path No. 95801)

Kidney      - Focal calcification.

Female Rat D29CF  (Path No. 95803)

Urinary Bladder (1)  Chronic diffuse inflammation. (2)  Diffuse mild hyperplasia.

The second phase of the review consisted of the microscopic examination of all tissues from the high dose females - a total of 36 animals.  The inconsistencies are listed below:

Female Rat No. B14HF  (Path. No. 95657)

Eye was reported as not examined but eye was present and normal.

Female Rat No. F25HF (Path. No. 95823)

Urinary Bladder - Mild diffuse hyperplasia.

Female Rat No. H7HF (Path No. 95623)

Ovary - Neoplasm - probably granulosa cell tumor.

Female Rat No. H9HF (Path No. 95665)

Heart - Focal fibrosis.

Urinary Bladder - Mild focal hyperplasia.

Female Rat No. H15HF  (Path No. 95665)

Lymph Node - The diagnosis of lymphoma, benign, was present on the Searle microscopic report.  According to Dr. Frith, lymphoma is generally not considered to be benign and he would diagnose lympphosarcoma.

Female Rat NO. H18HF  (Path No. 95667)

Pituitary - Adenoma.

Brain - Mild bilateral hydrocephalus.

Female Rat No. K18HF (Path No. 95824)

Pituitary - Adenoma

Female Rat No. K24HF (Path. No. 95671)

Mass noted grossly - nothing consistent with mass reported microscopically.

Female Rat No. - M2HF  (Path. No. 95672)

Uterus - Chronic mild endometritis.

Female Rat No. M30HF  (Path. No. 95343)

Kidney - Focal calcification.

Uterus - Chronic mild endometritis.

Female Rat No. M30HF  (Path. No. 95675)

Pancreas - Focal hyperplasia.

The third phase of this review consisted of microscopic verification of all masses reported grossly at necropsy from all female animals not examined in phases 1 and 2 and included a total of 73 animals.  The inconsistencies are listed below:

Female Rat No. D10Lf (Path No. 92521)

Subcutaneous mass was diagnosed as an angiofibroma on Searle report.  The lesion is more consistent with an angiosarcoma.

Female Rat No. K9MF (Path. No. 95707)

Uterus - Polyp.

Female Rat No. M1LF (Path. No. 95844)

Tissue mass seen grossly was reported as missing and not available for microscopic examination.  The tissue was present and was a mammary fibroadenoma.

In summary, Dr. Frith reviewed:

1)   All 36 high dose females (all slides) including 3 that had been excluded from the study due to autolysis.

2)   36 (one-half) of the control females (all slides) including 1 animal that had been excluded from the study due to autolysis.

3)   Remaining 73 female animals with grossly observed masses. (sufficient slides were reviewed to substantiate the masses)

4)   5 additional animals selected by the investigators (A1HM,  A9HM, A29HM, C2CM, C24HM).

The slides reviewed in the first two categories above constituted 20% of the total animals on the study.  Dr. Frith reviewed these slides blindly and then compared his findings with the Searle microscopic reports. According to Dr. Frith, his findings were in agreement with those of SEarle, for the most part.  In his opinion, some of the lesions that he reported as inconsistencies were small, and might be considered insignificant by some pathologists.  Dr. Frith did feel, however, that the ovarian neoplasms (animals H10CF, H19CF, and H7HP, and chronic cystitis and diffuse hyperplasia (animal D29CF) should have been reported.

Dr. Frith also considered two other discrepancies to be significant.  They were:

1)  The reporting of a mass (by Searle) as missing which was actually present (MlLF).

2)  The finding of a polyp of the uterus which was not diagnosed by Searle (K9MF)

The second of the above two discrepancies assumes even more significance in view of the following:

The Histopathologic Summary table (table 11) in Volume I of the submission to FDA lists the following incidence of Uterine Polyps on page 87:

Incidence of Uterine Polyps

       Controls         Low             Medium           High

       1 of 69          1 of 34         4 of 34          6 of 33

         (1%)             (3%)           (12%)            (18%)

The finding of one additional uterine polyp by Dr. Frith (in animal K9MF) increases the incidence in the mid dose to 5 of 34 (15%).

On page 82 of Volume I of the submission to FDA, is the statement: "other sporadic findings is included endometrial hyperplasia, polyp, cyst, congestion and squamous metaplasia."  The term "sporadic findings" was used to characterize the incidence of uterine polyps, in spite of the fact that Searle had done a statistical analysis of these findings.

When this study was reviewed by the Bureau of Foods in l975, the dose-related incidence of uterine polyps was noted.  The appropriate slides were requested by FDA at that time and were reviewed by three groups of pathologists:  1.)  The Division of Pathology, Bureau of Foods, 2.) Armed Forces Institute of Pathology, 3.) Massachusetts Institute of Technology.  Copies of the reports submitted by the 3 groups and related correspondence were obtained and are attached as exhibits #43-45.

Dr. Rudolph Stejskal was responsible for the microscopic findings and accuracy on these findings in the submission to FDA.  Only Dr. Stejskal's name appears on the submission.  However, a Dr. Joseph H. Smith, M.D. also read slides for this study and his initials appear on some of the microscopic examination sheets.  Dr. Frith questioned some of the terminology used in describing tissues.  Dr. Stejskal stated that Dr. Smith had come directly to SEarle from a hospital situation.  Due to his human pathology background, his description of animal tissues was somewhat different than that used by veterinary pathologists.

Dr. Stejskal joined SEarle in July of l973, therefore, he had no input into the pathology protocol, since E-77/78 was initiated in November of l971.

No microscopic worksheets or other "raw data" relating to microscopic pathology could be found for study E-77/78.  We were told by Searle personnel that the original microscopic findings were dictated by the pathologists (Stejskal & Smith) onto belts, and then typed onto sheets which were placed in a binder.  The belts were then discarded and apparently the bound microscopic pathology sheets were either discarded or lost, after the study report was written.  Therefore our verification of the microscopic findings submitted to FDA was limited to a complete inventory of the slides and tissue blocks and microscopic examination of a representative number of slides by Dr. Frith.

Our inventory of the slides and tissue blocks for each animal included a complete list on the tissues sectioned, the number of slides made from each tissue, and a complete count of the total number of slides and blocks for each animal.  We also checked the identification numbers on every slide and tissue block.  We examined a total of 7,872 slides and 7,360  tissue blocks.  The average number of organs submitted for tissue processing was 20 per animal.  No errors in slide identification were noted, although in many cases the number of organs submitted for sectioning was less than specified in the protocol.  A detailed dis cussion of this can be found under the heading PROTOCOL.

In addition to the discrepancies noted by Dr. Frith, some other errors were noted in the submission to FDA.  A mammary tumor found in rat F27CF was described as a papillary cystadenoma on the individual pathology sheet (page 105, Volume II of the submission to FDA) and as an adenocarcinoma on the summary table 12, page 96, Volume I of the submission to FDA.

Page 92, Volume I of the submission to FDA (a summary table) reports that animal J23CM was found dead after 754 days on study, while the individual pathology sheet for this animal (page 56, Volume II of the submission to FDA) reported that the animal was found dead after 620 days on study. The correct figure is 620 days, since J23CM was placed on the study on 11/17/72 and was found dead on 7/29 /73.