FDA report on Searle's submission for NutraSweet approval 1977 - Part 5

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A copy of the protocol for this study was obtained and is attached to this

report (See Exhibit #11). The protocol includes 4 amendments which are

dated Aug 20, l973, (amendments #1 and 2), Sept. 6, l973 and Jan 9, l974.


Amendment #1 dated Aug 20, l973 specified 4 additional clinical chemistry

laboratory measurements: 1.) serum insulin, 2.)serum ornithine carbamyl

transferase, 3.) serum protein electrophoresis, 4.) serum total protein.


Two of the above assays (serum insulin, and serum ornithine carbamyl

transferase) were apparently not done, because no data for these two

parameters was submitted to FDA, and we could find no raw data or other

evidence that they were done.


Amendment #2 dated Aug 20, l973, specified 8 coronal sections of brain to

be examined microscopically, and also described the procedure for

sectioning the urinary bladder. Four transverse sections from each

urinary bladder were to be examined microscopically.


Amendment #3 dated Sept. 6, l973 extended the study until it reached a

point where mortality reduced the control group to 20 animals per sex,

provided survival of treated groups was not less than 10 per sex per

group. (This represented a survival of approximately 30%).


Amendment #4 dated Jan 9, l974 added serum cholesterol to the clinical

chemistry measurements to be made at terminal sacrifice, and terminated

the study after 114 weeks of treatment. Terminal sacrifice was to begin

on 1-24-74 and continue through 2-1-74.


Our examination of the original data showed that serum cholesterol

determinations were done at day 796 and 798 (terminal bleeding) as

specified in the above amendment, but the data was not included in the

submission to FDA. 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

administration. Therefore, the omitted data may have been important.


Serum cholesterol determinations were also done at day 546 (78 weeks) and

not reported in the submission to FDA.




The protocol for Clinical Chemistry procedures specified that BUN

determinations were to be done at 78 weeks (546 days). The submission to

FDA contained no BUN data for day 546, but our review of the raw data

indicated that BUN's had been done at day 546. Some BUN's were also done

at day 735 (105 weeks) and not reported in the submission to FDA, but this

data was not complete for all animals.


Attached to the protocol is a memo dated Oct. 31, l972 which describes an

acute infection spreading in the rat colony, and the administration of

penicillin to combat the infection, and a memo dated May 8, l973 listing

scheduled dates to be added to Body and Feeder Weights of housing groups A

& B.


The final Histology Lab Protocol, dated 1-21-74, specifies 24 organs to be

embedded for control and high dose animals, and 19 organs to be embedded

for low and mid dose groups. The organs which were to be embedded for the

control and high dose groups but to be omitted in the low and mid dose

groups include: lymph node, nerve, bone, eye, and salivary glands.


Pathology sheets (blank forms) to be used at terminal sacrifice were

reproduced (xeroxed) with check marks, time (death to tissue fix),

fixative, study, and project number already entered. Twenty-seven (27)

organs were checked off, to be embedded. However, as stated above, the

control and high dose animals were to have 24 organs embedded, according

to the protocol, and the mid and low dose 19. Therefore, all pathology

sheets for animals killed by design have incorrectly identified the

specific organs and tissues to be embedded.


In addition to the above error, in many cases the actual number of tissues

embedded was less than the 24 (control and high dose) or 19 (low and mid

dose) specified in the final Histology Lab Protocol dated 1-21-74.

Specific figures for numbers of tissues embedded at terminal sacrifice are

as follows:






CONTROLS 10-24 20 24 129 of 144

LOW DOSE 12-23 19 19 19 of 72

MID DOSE 4-24 18 19 28 of 72

HIGH DOSE 9-25 22 24 51 of 72






The names of Dr. K.S. Rao, Dr. R. Stejskal, and Dr. R.G. McConnell

appear on the final study report, indicating that they are the

authors of this report, and were responsible for the study.


Following are the principal person involved with study E-77/78 and

their specific areas of responsibility:


1.) Dr. Robert G. McConnell - Director, Pathology-Toxicology

Laboratory 1970 through 1974. Dr. McConnell functioned as the Path-

Tox advisor on study E-77/78. He is no longer employed by Searle.


2.) Dr. Suryanarayana K. Rao - Manager, General Toxicology

Laboratory, June 1971 until he left Searle in May of 1977.

Dr. Rao was the Path-Tox monitor for study E-77/78. In

1971 Dr. Rao monitored 30 studies, in 1972 forty-seven

(47) studies, in 1973 twenty-nine (29) studies and in

1974twenty-five (25) studies.


3.) Dr. Rudolf Stejskal - Senior Research Investigator,

Pathologist. Dr. Stejskal was responsible for the micro-

scopic findings and accuracy of these findings in the study

report of E-77/78. Because Dr. Stejskal joined Searle in

July, 1973, he had no input into the pathology protocol.

Also, he did not examine all of the slides for this study,

but was assisted in that task by Dr. Joseph H. Smith M. D..


4.) Dr. Joseph H. Smith, M.D. - Group Leader and Senior Patholo-

gist at Michael Reese Hospital, Chicago, IL., before joining

Searle in June of 1973. Dr. Smith examined some of the

slides for study E-77/78, and supervised the necropsy labora-



5.) Tony Martinez - Toxicology Laboratory Supervisor, 1970

through 1973. Mr. Martinez participated in twelve (12)

studies in 1971, Seventeen (17) studies in 1972, and

thirteen (13) studies in 1973. Mr. Martinez supervised

the technicians who worked on the study. He also

performed some necropsies.




6.) David K.T. Kie, B.S., Research Assistant in Pathology

Laboratory. He performed some of the necropsies on E-77/78.


7.) Robert Spaet - Research Assistant. He also performed



8.) Bartolome R. Tangonan - Research Technician II - He was

involved with preparation of diet mixtures, daily observa-

tions, weighing and feeding animals, etc.


9.) Donna K. Helms - Manager, Safety Evaluation, Project Sche-

duling, Reporting, and Data Storage, Path-Tox Dept. and

Administrative Assistant to Dr. McConnell.


10.) Patrica Erdenberger - Research Assistant, and Histology

lab Supervisor.


11.) Dr. Eugene Joseph Youkilis - Senior Research Investigator.

He performed the opthalmoscopic examinations in study



12.) Judy A Henderson - August 1972 to present, Research Tech-

nician III, Histopathology Dept. She was involved with

tissue processing on study E-77/78.


13.) Judith R. Schmal - Nov. 1971 to present, Supervisor, Clini-

cal Chemistry Section of Bioanalytical Laboratory.


14.) Judith A. Beauchamp - Employed Aug, 1970 to present;

Supervisor Hematology laboratory since April 1973.


15.) Barbara (Ross) Bickford - Research Technician, Quality Control

Department. She performed analyses of DKP diet mixtures for

study E-77/78.


16.) Clifford J. Seul - Supervisor, Method Development, Stability

Evaluation Laboratory. He was Barbara Bickford's supervisor

at the time the DKP stability study was performed.


17.) Jack Drogt - 1967 to present, Senior Research Assistant,

Chemical Development. Mr. Drogt manufactured the 7

lots of DKP used in the study E-77/78.


18.) Dr. John E. Dutt - Math-Stat. Dept.


19.) John Mellman, Math-Stat Dept.


Continue to Part 6


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