(43)
SURVIVAL
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
documents:
(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.
(44)
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.
CLINICAL LABORATORY
ANALYSIS
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
#84).
Some cholesterol
and BUN determinations were carried out
which were not
described in the
submission to FDA. They were as follows:
(45)
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).
