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Sunday, March 9, 2014

#NEOTAME SWEETENER - MEGA-CLONE OF #ASPARTAME IS IN ETHICAL VIOLATION OF #FDA GUIDELINES


Friday, February 28, 2014

Serious #Kidney Damage Including Cancer From #Aspartame Ingestion


Damage to Kidneys, etc. from Methanol 
[wood alcohol]:

Renal changes [Table - 3] such as varying degrees of renal tubular degeneration (severe cloudy or vacuolar change) with patchy necrosis were seen in all the cases. Severe congestion of peritubular capillaries (71.42%), moderate glomerular capillary dilatation and congestion (78.57%), mild endothelial swelling (35.7%) and mild mesangial proliferation (35.7%) was the other significant renal findings.


Approximately 3-10% of administered dose of methanol is excreted unchanged by the kidneys[2]. Highest concentration of formaldehyde has been found in the kidney, liver and gastro-intestinal tract by studies using C[14] labelled methanol. Considering that both methanol and its toxic metabolites are concentrated in the kidneys it is not difficult to explain the severe degenerative changes in the renal tubules and peritubular capillaries. Glomerular changes too rescmble the early changes seen in cases of viper bites, Haemolytic uracmic syndrome and toxacmia of pregnancy, all of which have a known toxic aetiology.
Thus changes in the various organs were probably of toxic aetiology, either mediated through the direct toxic action of the metabolite formaldehyde or the metabolic acidosis due to formic acid production. 

::   References  
1. Bade LK, Snore DP. Methyl alcohol poisoning, Medical News, Medicine and Law as quoted by Ravichandran et a1[8]. 1981; 12:106-108.      
2. Barriers GR. Combustion of C[14] labeled methanol in intact rat and its isolated tissues. Amer J Physiol 1950; 163:614-618.      
3. Bonnets IL Jr, Cony FH, Mitchell GL Jr, Cooper MN. Acute methyl alcohol poisoning: a review based on experiences in an outbreak of 323 cases. Medicine 1953; 32:431-463.      
4. Gender A, Manly H, Churchill D, Hollomby D. Hemodialysis for methanol intoxication. Amer J Med 1978; 64:749-758.      
5. Lurid A. Excretion of methanol and formic acid in man after methanol consumption. Quoted by Gender et al[4]. Acta Phamacol Toxicol 1948; 4:205.      
6. Kaplan K. Methyl alcohol poisoning. Amer J Med Sci 1962; 244:170-174.      
7. Orthner H. Die Methylalkohol vergiftung, as quoted by Gender er al[4]. Berlin: Springer Verlag; 1950.      
8. Ravichandran R, Dudani RA, Alongside AE, Chamber KP, Acharya VN. Methyl alcohol poisoning (experience of an outbreak in Bombay). J Postgrad Med 1974; 30:69-74.      
9. Zimmerman HJ, Ishak KG. In: Pathology of the Liver." MacSween RNM, Anthony PP, Pscheuer PJ, editors. 1st ed., Edinburgh: Churchill Livingstone; 1979, pp 337.   

Below from FDA's Jerome Bressler Report:

 ORGAN WEIGHTS

 Organ Weights were entered on the gross pathology sheets at the time of
 autopsy.  We compared all of the individual organ weights on appendix
 table 5 in the submission to FDA (Vol 1, pp. 222-226) with the original
 data on the gross pathology sheets.  A total of eleven (11) errors were
 noted in transcribing the raw data from the pathology sheets, to the
 tables in the submission to FDA.

 The errors are tabulated below:

                                 Wt. Shown In          Wt. Recorded on
 Animal No.       Organ          Submission      Original Pathology Sheet

 A12CM            Kidneys           3.75 G             3.45 G
 L28LM            Ven. Prostrate    747 mg.            474.7 mg.
 C0lMM            Kidneys           9.40 G             9.219 G.
 C02HM            Kidneys           1.46 G             4.259 G
 E14HM            Kidneys           11.74 G            4.746 G
 J12HM            Pituitary         3.0 mg.            3.3 mg.
 J30HM            Ven. Prostrate    444 mg.            444.8 mg.
 F17CF            Ovaries           36.7 mg.           233.5 & 36.7 mg.
 H30CF            Liver             9.4 G              9.493 G
 B20HF            Uterus            1115 mg.           1155 mg.
 K11HF            Adrenals          799.1 mg.          797.1 mg.
_________________________________________________________________

 NO evidence was obtained that any attempts were made to determine
    whether or not DKP could interfere with any of the clinical lab-
    oratory tests conducted.  For that matter no information was made
    available to us as to whether DKP itself or related compounds did
    appear in the blood or the urine of rats fed diet containing this
    compound.

teletype sheets referred to previously.  In reference to the
    low BUN values, Page 29 of the submission contains the following
    statement: "BUN" values for the control males at treatment
    day 189 were unusually low and may possibly be related to
    a technical artefact; as a result, the group mean values for
    all treated males at this interval were significantly higher
    but, in fact, these values were in the normal range.  BUN values
    both in control and all treated male groups at treatment
    day 364 were unusually low;  this again reflects a possible
    technical artefact."

                          (55)

 GROSS PATHOLOGY

 The pathologists responsible for the microscopic examination (Rudolph
 Stejskal and Joseph smith) did not perform the necropsies.  Necropsies
 were performed by Tony Martinez, David Kie and Robert Spaet, with the two
 pathologists avilable for consultation.

 The submission to FDA (Vol 1, p. 7) reported that "Rats found dead during
 the study were autopsied immediately whenever possible.  In cases where
 the ncropsy could not be performed promptly, the thoracic and abdominal
 cavities of dead rats were opened and the entire animal was immersed in
 neutral buffered formalin fixative for subsequent gross examination and
 dissection".

 Our examination of gross pathology records showed that 98 of the 196
 animals that died during the study were fixed in toto and autopsied at
 some later date, in some cases more than one year later.

 A total of 20 animals were excluded from the study due to excessive
 autolysis.  Of these, 17 had been fixed in toto and autopsied at a later
 date.  Following are the twenty animals excluded from the study:

 Animal No               Date Found Dead             Date Autopsied

 C21CM                      7/3/73                      1/11/74
 G16CM                      9/21/73                     1/11/74
 G18CM                      8/11/73                     10/4/73
 G26CM                      4/2/73                      1/11/74

 J2CM                       5/21/73                     1/11/74
 J5CM                       10/30/72                    11/8/72
 L10CM                      3/29/73                     1/11/74
 L15/CM                     9/9/73                      1/11/74
 L21CM                      4/13/73                     1/11/74
 L11LM                      5/6/73                      1/9/74
 A14MM                      5/21/73                     1/9/74
 G28MM                      1/5/74                      1/7/74
 J25MM                      5/24/73                     5/24/73
 A3HN                       6/17/73                     1/9/74
 C15HM                      1/7/74                      1/7/74

                            (56)

 Animal No                  Date Found Dead            Date Autopsied

 G13HM                          7/25/73                   **1/9/74
 H24CF                          4/29/73                     1/11/74
 D4HF                           7/11/73                     7/11/73
 D16HF                          *4/2/73                     1/8/74
 F6HF                           1/5/74                      1/7/74

 *Although the date found dead was listed as 4/12/73 on the gross pathology
  sheet, the "Tissue Masses & Deaths" book listed this date as 4/1/73.

 **Although the date found dead was listed as 1/9/74 on the gross pathology
  sheet, the "Tissue Masses & Deaths" book listed this date as 7/25/73.

 The gross pathology sheet for one of the above animals, F6HF, described a
 tissue mass measuring 5.0 X 4.5X2.5 cm.  This tissue mass was first
 observed on 8/24/73 according to the pathology sheet (Exhibit #79), the
 observation records (Exhibit #70), and the palpation record in the "Tissue
 Masses and Deaths" book (Exhibit #65).  The submission to FDA (Exhibit #8)
 reported no tissue mass and the animal was excluded from the study due to
 marked autolysis.

 In addition to the above twenty animals that were excluded from the study,
 many other animals exhibited marked autolysis.  For example, D27LF, M25CF,
 and H12CF are all described grossly in the submission to FDA as follows;
 "all organs examined grossly were markedly autolyzed".

 Records for approximately 30 animals showed substantial differences
 between gross observations on pathology sheets, when compared with the
 individual pathology summaries submitted to FDA.  Following is a detailed
 comparison of ten of these.  (Copies of all the gross pathology sheets,
 and the pathology summaries submitted to FDA are attached as Exhibits #78,
 #79, and #86).

 A2CM

 Submission to FDA:

   Lung         - Focal adhesion
   Adrenal      - Moderately enlarged

                            (57)

 All other organs examined grossly were unremarkable.

 Original Pathology Sheet:

 Pituitary - Missing
 Lung      - Left, mid-portion adheres to the medial area of
             the rib cage by a "fibrous" type of tissue.  (Sub-
             mitted together with relevant portion of the rib cage).

 Right, post-caval lobe has undergone consolidation.  Contains
 grayish-yellowish nodules measuring 2 x 2 mm.  (Entire lung
 submitted in toto)

  Lymph NOdes, Pancreatic - Slightly enlarged

 Adrenal   - Left, moderately enlarged.  Right and left, covered
             with tiny yellow spots measuring 1.0 x 1.0 mm.

 Lymph Nodes, Mesenteric - moderately enlarged.
 Mass - previously described on 8/20/73 has since then regressed.
 Prostate - Marked atrophy, all lobes
 Seminal Vesicles - Marked atrophy, bilaterally

 All other organs examined were grossly normal and unremarkable.

 M15CF

 Submission:

   Mammary gland   - subcutaneous mass located in mid-thoracic
                     region measuring 7 x 6 x 2.5 cm.

   Urinary bladder - papillary growth in the lumen.

   All other organs examined grossly were unremarkable.

 Original:

   Mass #1 - Previously described in the left inguinal region
             on 2/9/73 has since then regressed.

                            (58)

   Masses #2 and # - Located in the mid-axillary-cervical regions
                     are all on mass now measuring 7.0 x 6.0 x 2.5 cm
                     and may be described as irregular in shape, multi-
                     nodular, smooth-surfaced, non-glistening,
   No Spinal Cord    yellowish-purpulish in color, non-adherent to the
        VL           underlying muscle and containing a whitish-yellowish
                     firm tissue within.  (Submitted in toto together with
                     remainder of tissue).

 Heart             - Left Ventricle - dilitation and walls thin.
 Spleen            - Slightly enlarged
 Liver             - Prominent lobular architecture.
 Adrenal           - Left, slightly enlarged.  Right, unremarkable.
 Ovary             - Right, small cyst measuring 4.0 x 4.0 mm and
                     distended with a clear yellow fluid.

   All other organs examined were grossly normal and unremarkable.

 G10LM

 Submission:

   Testis  - Marked atrophy, unilaterally.
   Kidney  - Moderate enlargement, mottled appearance, bilaterally.
   Small and large intestine exhibited moderate autolysis, no sections
   submitted.

   All other organs examined were grossly normal and unremarkable.

 Original:

   Mass which was initially palpated on 2/9/72 (86 days Rx)
   in the left inguinal area was actually the left testis which
   ascended and went thru weakened left inguinal ring into the
   subcutaneous area.

   Testis  - Left (ascended) appears atrophied (submitted in toto).
   Kidney  - Moderate, diffuse and uniform enlargement, mottled,
             bilaterally (submitted in toto).
 Small and large intestines are moderately autolyzed (no sections
 submitted).
 Thyroid   - Moderately enlarged, bilaterally.  A 2 mm in dia., dis-
             crete, sl raised, moderately firm yellowish-grey lesion
             is located in the posterior tip, bilaterally. (Thyroid
             submitted in toto wrapped in a lens paper).

   All other organs examined were grossly normal and unremarkable.

                            (59)

 L11LM

 Submission:

   Kidney     - Mottled appearance
   Testes     - Marked atrophy, bilaterally
   Prostate   - Marked atrophy

   All other organs examined grossly exhibited marked autolysis.

 Original:

   Adrenal    - Pale yellow, bilaterally
   Kidney     - Pale yellow, bilaterally, rough-surfaced, bilaterally,
                moderately autolyzed, bilaterally, tiny spaces in the
                cortex region measuring about 1 mm in diameter,
                bilaterally.
   Testes     - Marked atrophy, bilaterally, marked autolysis,
                bilaterally.
   Prostate   - Marked atrophy, all lobes
   Seminal Vesicles - Marked atrophy, bilaterally
   Spleen     - Marked autolysis
   Pancreas   - Marked autolysis
   Stomach    - Marked autolysis.  A glandular portion - numerous, tiny,
                pitted ulcerations measuring 1 -4 mm in diameter.
   Lymph Nodes, Mesenteric - Marked autolysis
   Heart      - Wall of left ventricle thin
   Brain      - Marked autolysis
   Pituitary  - Marked autolysis
   Liver      - Marked autolysis

   All other organs examined were grossly normal and unremarkable.

 M17LF

 Submission:

   Pituitary        - Marked enlargement.
   Adrenal          - Markedly enlarged and hyperemic, bilaterally.
   Mammary Gland    - Mass 1, located subcutaneously in left axillary
                      region, measuring 3 X 3 X 2.5 cm; mass 2, located
                      subcutaneously adjacent to mass 1, measuring 3 X 2
                      X 1 cm; mass 3, located subcutaneously in the right
                      axillary region, measuring 2.5 X 2 X 1 cm; mass 4,

                            (60)

                      located subcutaneously in the left inguinal region,
                      measuring 3 X 1 X 1 cm; mass 5, located subcutane-
                      ously in the right inguinal region, measuring 2 X
                      1.5 X 1 cm.

   All other organs examined grossly were unremarkable.

 Original

    Pit         - appears markedly hyperemic
    Adrenal     - Exhibits numerous minute greyish spots on the serosal
                  surface bilaterally.  It appears markedly enlarged.

    Mass (1)    - A 3 X 3 X 2.5 cm. spheroidal, multinodular, yellowish
                  white, slightly firm mass located subcutaneously in
                  the left axillary area.  Mass non-adherent to the
                  surrounding muscles or tissue (submitted in toto).

    Mass (2)    - A 2.5 X 2 X 1 cm spheroidal, smooth, yellowish white
                  firm mass located subcutaneously and adjacent to the
                  above described mass (submitted in toto) mass non-
                  adherent to the surrounding muscles or tissues.

    Mass (3)    - A 2.3 X 2 X 1 cm. irregularly shaped, multinodular,
                  yellowish white, firm mass located subcutaneously on
                  the rt. axillary area.  Mass non-adherent to the
                  surrounding muscles or tissues (submitted in toto).

    Mass (4)    - A 3 X 1 X 1 cm. elongated, multinodular, yellowish
                  white, firm mass located subcutaneously on the left
                  inguinal area.  Mass non-adherent to the surrounding
                  muscles or tissues (submitted in toto).

    Mass (5)    - A 2 X 1.5 X 1 cm. flat, multinodular, yellowish white,
                  firm mass located subcutaneously on the rt. inguinal
                  area.  Mass non-adherent to the surrounding muscles
                  or tissues (submitted in toto).

    All other organs examined were grossly normal and unremarkable.

 C1MM

 Submission

    Kidney        Marked enlargement with yellowish discoloration.
    Testis        Marked atrophy, bilaterally.

                            (61)

 Tissue mass located subcutaneously in the right inguinal area measuring
 2.5 X 1 cm.

 All other organs examined grossly were unremarkable.

 Original:

   Mass       - Previously described on 12/9/72 and located subcutaneously
                in the right inguinal area now measures 2.5 X 2.0 X 1.0
                cm and may be described as smooth-surfaced, purplish-
                yellowish in color, non-glistening, firm, multi-nodular,
                non-adherent to the underlying muscles and containing a
                firm yellowish-whitish tissue.  (Submitted in toto
                together with a portion of the skin and underlying muscle
                with remainder of tissue).
   Heart      - Left ventricle has undergone a moderate amount of dili-
                tation.  Wall, left ventricle is thin.
   Liver      - Prominent lobular architecture.
   Lung       - Right, post-caval lobe-consolidation.
   Kidney     - Markedly enlarged, yellow and rough-surfaced, bilaterally.
                Dilitation of the pelvis.
   Adrenal    - Covered with tiny yellow spots measuring 1 mm in diameter,
                bilaterally.

   Testes     - Marked atrophy, bilaterally.

   All other organs examined were grossly normal and unremarkable.

 Tiss. Trimming -  Nodules discovered immediately posterior (2.0 cm) to
                   the pyloric portion of the stomach within the adipose
                   tissue.  Nodules may be described as firm, yellowish
                   brownish in color.  Non-glistening measuring 1.2 X
                   1.0 mm to 4.0 X 4.0 mm.

 E27MM

 Submission:

   Lung         - Moderate diffuse hyperemia.
   Eye          - Opaque cornea, bilaterally.

   All other organs examined grossly were unremarkable

 Original:

    Lungs - All lobes exhibit moderate diffuse and uniform hyperemia.

                            (62)

    Kidney      - Moderate autolysis.
    Eye         - The entire cornea is opaque, bilaterally.
    Spleen      - Moderately autolyzed.
    Stomach     - Numerous 1-2 mm. hemorrhagic ulcerations are located on
                  the glandular mucosa.  Entire small and large intestines
                  are moderately autolyzed.
    Brain & Pituitary - Moderately autolyzed.

    All other organs examined were grossly normal and unremarkable.

 A1HM

 Submission:

    All organs examined were grossly unremarkable.

 Original:

    Testes       - Markedly atrophy, bilaterally
    Lung, Rt     - Middle lobe exhibits a 1 X 1 cm consolidation on the
                   posterior portion.
    Liver        - All lobes appear olive green otherwise unremarkable.

    All other organs examined were grossly normal and unremarkable.

 L27HM:

 Submission:

     Testes      - Right, slightly enlarged; left, mild atrophy.

     All other organs examined grossly were unremarkable.

 Original:

     Testes      - lt./appears markedly atrophy
                   rt./appears to be distended with yellowish white
                   substance

     Seminal V-  Appears markedly atrophy bilaterally.
     Intestinal  - Large, markedly distended with "gas".

 All other organs examined were grossly normal and unremarkable.

     P.M. Testes - Also, small black areas are noted within along with
                   the yellowish areas.  Black areas measuring 1.0 X 1.0 to
                   4.0 X 4.0 mm in diameter.

                            (63)

 J30HM

 Submission:

    Lung    - Moderate consolidation of all right lobes.
    Testis  - Moderate atrophy

    All other organs examined grossly were unremarkable.

 Original:

    Pituitary  - Markedly enlarged; slightly hyperemic.
    Heart      - Left Ventricle has undergone dilitation walls thin.
    Lung       - Right, anterior, medial and post-caval lobe have
                 undergone consolidation.
    Testes     - Marked atrophy, bilaterally.

    Seminal Vesicle - Marked atrophy, bilaterally.

    All other organs examined were grossly normal and unremarkable.

 Dr. Stejskal told us that the other pathologist (Dr. Joseph Smith) who
 made microscopic evaluations of the slides, came from a hospital
 background (human pathology) and therefore his descriptions and
 terminology were a little bit different than one would expect from a
 veterinary pathologist.

 MICROSCOPIC PATHOLOGY

 We have assisted in our review of the Microscopic Pathology of Study
 E-77/78 by Charles H. Frith, D.V.M., Ph.D, Director, Pathology Services,
 NCTR.  Dr. Frith arrived on 6/22/77 and spent 3 days with the FDA team.
 He examined slides for a representative number of animals, the selection
 of which was made jointly by Dr. Frith and the other members of the FDA
 team.  A Searle Pathologist was not present during Dr. Frith's review of
 the slides.  However, Dr. Frith did meet with Dr. Rudolf Stejskal, SEarle
 Pathologist, at the conclusion of this review and discussed some of his
 findings with him.

 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:

                            (64)

 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.

                            (65)

        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.

                            (66)

       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 auto-
           lysis.

      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).

                            (67)

 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.


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