FDA report on Searle's submission for NutraSweet approval 1977 - Part 14

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An attempt was made to construct a Survival Table using data from the

"Tissue Masses and Deaths" book.


We were unable to determine the exact method used in constructing the

table in the FDA submission. There was some survival data in the "Tissue

Masses and Deaths" book (Exhibit 65), but this only extended through week

109 and consisted solely of running totals. According to Tony Martinez

deaths purportedly were initially recorded in any one of the following



(1) Body/Feeder Weight Sheets

(2) Autopsy/Pathology Sheets

(3) Observation Sheets

(4) Palpable Mass Sheet


He said that animals found dead at feeding/observation intervals were

usually recorded on the observation, or Body/Feeder Weight Sheets. At

other times, the death was recorded on a "scrap" of paper and then later

transcribed to one of the documents. The term "scrap of paper" was used

by Searle personnel both during the Task Force and current investigations.

No notebooks containing observations or deaths ever surfaced during either

investigation. Animals killed "in extremis" were recorded on Autopsy

sheets. The least likely source for original death recording would be the

Body/Feeder Weight Sheets.


Dates of death sometimes differed on the various records, making it

impossible to determine which one was correct. A survival table was

finally constructed for weeks 40-115, using the Body/Feeder weight

teletype (hard copy) sheets and dates on which animals no longer appeared

as a base (Exhibit 68). In this manner, the number of days on study was

calculated for each animal (Exhibit 66). Using starting dates for each

group, a calendar was made to encompass the entire duration of this study

(Exhibit 67). Toward the end of the study, some feedings/observations

were made at intervals such as 109 3/7, 110 6/7 and 111 6/7 weeks, so some

differences are anticipated between this table and the one in the FDA

submission. However, the final number of animals in each dosage group

and sex do coincide. The table constructed for this report was on a

weekly basis; that in the submission covering only weeks 40, 46, 52, 60,

68, 76, 84, 88, 92, 96, 100, 104, 108 and 115.




A Life Table Analysis was performed from the Survival Table by Dennis

Wilson, Department of Mathematics, Bureau of Foods (Exhibit #73). The

female control population differed from the high level population p < 0.05.

The male control population differed from both the medium and high dose

levels (p. 0.05 in both cases). In all cases, the differences are due to

the higher mortality level of controls.




A. Clinical laboratory procedures.


Hematologic, clinical, chemical and urinalysis examinations are described

on pages 5-7 of Volume I of the submission. The same rats were employed

for all clinical laboratory examinations throughout the study. In cases

where one of these rats died during the study, another rat chosen from a

corresponding group was substituted.


The following hematology parameters were measured at treatment days

42,92,189,364,547 and 734: hematocrit, hemoglobin, total RBC, total WBC,

differential WBC, and prothrombin time.


The following clinical chemistry (serum) measurements were made: pyruvic

transaminase (days 42,92,189,364,547,736), glutamic oxaloacetic

transaminase (days 41,92,189,364,547 and 734), alkaline phosphatase (days

42,92,189,364,547.734), total bilirubin (days 42,,92,189,364,547,734)

blood (serum) urea nitrogen (days 42,92,189,364), total cholesterol (days

42,92,189,364,734), L-phenylalanine (days 42,92,189,364,547,734) sodium

(day 734), potassium (day 734), calcium (day 734), protein electrophoresis

(day 734).


The following urinalysis (2 hour collection) measurements were made at

days 42,92,190,364,547, & 734: specific gravity, pH, occult blood,

protein, bilirubin, microscopic on sediment, and phenylketones; glucose

and ketones were determined at days 42,92,190,364, & 734; urobilinogen was

measured at day 42,190,364 and 547.


We noted that some of the data sheets for urinalysis had erroneously

labeled the phenylketones test values as "phenylalanine" (see exhibit



Some cholesterol and BUN determinations were carried out which were not

described in the submission to FDA. They were as follows:




1) Serum cholesterol determinations were done at days 796 & 798 (terminal

bleeding), but not included in the submission to FDA.


The protocol indicated that clinical chemistry determinations,

including serum cholesterol, were to have been performed at termina-

tion. The submission to FDA (Vol. 1 p. 286) reported a significant

decrease in serum cholesterol that was more perceptible towards the

end of the study, and may have been related to compound administra-

tion. Therefore, the omitted data may have been important. (Copies

of these data were obtained and are attached as exhibit #77,

Section V.


2. BUN determinations were done at day 546 but not reported in the

submission to FDA (see exhibit #77 Section V).


3) Serum cholesterols were also done on day 546 and not reported in the

submission (see exhibit #77). These determinations were only done

for females, and only for a few animals, reportedly due to insuffi-

cient quantity of sample.


4) BUN's were also done on day 735 and not reported in the submission.

This data was not complete for all animals at day 735.


5) Additional animals (other than those designated) were bled at the

regularly scheduled times and determinations were made. These

determinations were not reported and we could not determine why the

animals were bled. (See Exhibit #77)


B. A list of persons involved with lab analysis along with their

responsibilities and duties is as follows:


1) Judith R. Hehmal? - Nov l971 to present, Supv., Clinical Chemistry,

section of Bioanalytical laboratory.


2) Judith A. Beauchamp - Supervisor, Hematology Laboratory, April 1971

to present.


3) Denise Prikins? - Supervisor Hematology Laboratory until April l971

(no longer employed by Searle).


Continue to Part 15


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