Senator Howard M. Metzenbaum,                    (Dated 3 November, 1987)
United States Senate,
140 Russell Senate Office Building,
Washington, DC, 20510

Dear Senator Metzenbaum,

   The following is in response to a request for comments addressed to
me by Mr. James C. Wagoner of your Office in reference to the safety of
the artificial sweetener aspartame, known commercially as Nutrasweet.

   As you may know, during my service with the FDA from 1964 to 1979 I
participated along with others in the extensive investigation of the
quality of experimental studies carried out by or for the G.D. Searle &
Co. of Skokie, Ill.  Inasmuch as I had participated both in the "on-site"
investigations as G.D. Searle & Co., as well as in the evaluation of the
findings that emerged, my signature along with those of others appears on
the final report of that FDA investigations (known also as the Searle Task
Force Report) which was dated March the 24th, 1976.

   In early 1979 I was transferred for duty from the FDA to the EPA to
assume a position involving a promotion for me.  My comments here ought
not to be taken to imply in any way that they represent the views of the
EPA since this agency has no regulatory concerns whatsoever in the area of
food additives;  rather, such comments of mine represent strictly my own
views.

   During that 1975 FDA investigation at G.D. Searle & Co. and at a
number of their contractors, a total of 25 distinct experimental studies
were intensively audited.  Almost half of those 25 studies (11, to be
exact) were carried out for aspartame with the remaining 14 studies having
been distributed amongst 6 drug products manufactured by G.D. Searle &
Co.  It is worthy of note that the conduct of all experimental studies by
that firm, regardless whether they entailed food additives or drug
products, was the responsibility of a single group in the G.D. Searle &
Co.'s organization:-  the Pathology-Toxicology or Path-Tox Department.
Practices that were noted in connection with any given such study were
quite likely to have been noted also for other studies that were audited,
and this was a situation which was in no way unexpected:-  after all, the
set of all such studies executed by that firm from about 1968 to the mid
1970's were conducted in essentially the same facilities, by virtually the
same technicians, professional workers and supervisors, and the nature of
such studies does not differ much whether a food additive or a drug
product is being tested for safety in laboratory animals.  It is in this
sense, therefore, that the overall conclusions summarized at the beginning
of the Searle Task Force Report have relevance to a all the studies audited
in 1975 (whether they had reference to aspartame or to any of the six drug
products of Searle's) and, by extension, to the totality of experimental
studies carried out by that firm around that time - 1968 to 1975.

    The FDA's Task Force Report starts at the top of its page 1 with:-


    "At the heart of the FDA's regulatory process is its
ability to rely upon the integrity of the basic safety
data submitted by sponsors of regulated products.  Our
investigation clearly demonstrates that, in the (case of
the) GD Searle Company, we have no basis for such
reliance now.

   "Reliance on a sponsor is justified when FDA has
reasonable assurance that the sponsor will:  (1) inform
the agency of all material results, observations, and
conclusions of an experiment, (2) report fully and
completely all of the conditions and circumstances un-
der which an experiment was conducted, and (3) submit
its reports to the FDA in a timely fashion so that
measures to protect the public health and safety can be
taken promptly when warranted.  Through our efforts, we
have uncovered serious deficiencies in Searle's
operations and practices which undermine the basis for
reliance on Searle's integrity in conducting high quality
animal research to accurately determine or characterize
the toxic potential of its products."

   "Searle has not met the above criteria on a number
of occasions and in a number of ways.  We have noted that
Searle has not submitted all of the facts of experiments to
FDA, retaining unto itself the unpermitted option of
filtering, interpreting, and not submitting information
which we would consider material to the safety evaluation
of the product.  Some of our findings suggest an attitude
of disregard for FDA's mission of protection of the
public health by selectively reporting the results of
studies in a manner which allays the concerns of ques-
tions of an FDA reviewer.  Finally, we have found instan-
ces of irrelevant or unproductive animal research where
experiments have been poorly conceived, carelessly execu-
ted, or inaccurately analyzed or reported."

   "While a single discrepancy, error, or inconsisten-
cy in any given study may not be significant in and of
itself, the cumulative findings of problems within and
across the studies we investigated reveal a pattern of
conduct which compromises the scientific integrity of the
studies.  We have attempted to analyze and characterize
the problems and to determine why they are so pervasive
in the studies we investigated."

   "Unreliability in Searle's animal research does not
imply, however, that its animal studies have provided no
useful information on the safety of its products.  Poorly
controlled experiments containing random error blur the
differences between treated and control animals and in-
crease the difficulty of discriminating between the two
populations to detect a product-induced effect.  A posi-
tive finding of toxicity in the test animals in a poorly
controlled study provides a reasonable lower bound on the
true toxicity of the substance.  The agency must be free
to conclude that the results from such a study, while
admittedly imprecise as to incidence or severity of the
untoward effect, cannot be overlooked in arriving at a
decision concerning the toxic potential of the product."

   In addition to those general comments and references to no basis for
reliance on reports generated by the GD Searle Company, serious
deficiencies in Searle's operations and practices, Searle's integrity,
Searle's selectively reporting the results, poorly conceived, carelessly
executed and inaccurately analyzed or reported experiments at Searle's, a
pattern of conduct which compromises the scientific integrity of the
studies, pervasive problems in the Searle studies, their unreliability,
etc., which apply across the board to all studies investigated, there are a
number of additional problems that attach specifically to the aspartame
studies. These are discussed in the FDA's Searle Task Force Report in its

page 25 - paragraph 1	- on the identity of the material tested;
page 26 - last paragraph	- on the excision of tumor masses ante-mortem and writing the protocol after the start of a study;
page 31 - paragraph 2	- on Searle tactics designed to obtain FDA approval for aspartame;
page 32 - last paragraph	- on continuity of personnel at Searle and on the adequacy of their training and supervi- sion of such personnel;
page 33 - paragraph 2	- on practices which could compromise the study;
- paragraph 3	- on improper departure from protocol specifica- tions on age of the animals used;
page 34 - paragraph 2	- on deviations from protocol at Hazleton Labo- ratories;
page 36 - paragraph 3	- on the lack of concern both at Searle and at Hazleton Laboratories over the homoqeniety, or stability of the ingredient-diet mixture; subsequent paragraphs deal with the same sort of problems at Hazleton Laboratories and it is concluded that "there is no way in which it can be assured that animals received the intended dosage.";
page 39 - paragraph 1	- on the improper use of pesticides in the areas where the studies were carried out; on the condition of the blenders used to mix the test agent in the diet; on the lack of records on mixing operations; on the conditions of the labels of the mixtures; on the lack of inventories of the test substance;
page 42 - paragraph 1	- on the records kept of the observations made and on the numerous errors and inconsistencies amongst observations and findings;
page 47 - near bottom	- on the impact of the errors in the records of observations;
page 51 - paragraph 1	- on the excision of tumor masses; see also page 52, paragraph 1 there for the impropriety of this practice;
page 52 - last paragraph	- on the "substantial" loss in pathology infor- mation due to autolysis, fixation "in toto", etc.
page 55 - top	- on the impropriety of changing a prosector's observations by others who did not participate in examining the carcasses of the animals;
page 57 - paragraph 2	- on the poor quality of material prepared for microscopic examination of the tissues;
page 60 - paragraph 3	- on observations being reported for material that never existed; this problem was noted at both Searle and Hazleton Laboratories;
page 62 - paragraph 2	- on the lack of training by the "professional" scientists making observations in teratogincity studies;
page 64 - paragraph 3	- on the abysmal quality of the aspartame tera- tology and reproduction studies and on an evaluation of these by a leading international British expert in this area;
page 66 - paragraph 3	- on the serious problems with the Waisman study of Aspartame in monkeys;
page 80 - top	- on the false values presented by Searle on observations collected during the aspartame studies in hamsters, with reference to blood, clinical chemistry, etc., and the improper filtering of results from the 115 week rat study with aspartame.

   It should be pointed out that the Task Force Report detailing those
general conclusions as well as those that relate specifically to the
aspartame studies are not merely the views of the members of the Task Force
itself.  That Task Force operated under the direction of a Steering Commit-
tee composed of a number of FDA Bureau Directors as well as others and the
Chairman of that Committee was none other then the FDA Commissioner
himself.  In fact the Task Force Report was addressed to the Commissioner
in his capacity as Chairman of the Steering Committee, and, it seems clear
that both the Committee and the Commissioner accepted that report and
transmitted it to the United States Senate as an institutional FDA report
without changing in it as much as a semicolon.  The following are quotes
from pages 3 and 4 of the record of hearings of April 8-9 and July 10,
1976, held by Sen. Edward Kennedy, Chairman, Subcommittee on Administrative
Practice and Procedure, Committee on the Judiciary, and Chairman, Subcom-
mittee on Health, Committee on Labor and Public Health:-

page 3 of the record

- Commissioner Schmidt of the FDA :- "Today I would like to report to you the final results of the Food and Drug Administration's (FDA) detailed investigation of animal studies performed by Searle..." (emphasis added);

page 4 of the record

- Senator Kennedy (addressing Commissioner Schmidt):- "Let me ask you this. These are the conclusions of the (Task Force appointed to that ) study. Do you agree with those conclu- sions?" Dr. Schmidt:- "Yes I do." Senator Kennedy:- "Yes, you do. Is this the first time, to your knowledge, that such a problem has been uncovered of this magnitude by the Food and Drug Administration?" Dr. Schmidt:- "It is certainly the first time that such an extensive and detailed examinations' of this kind has taken place. We have never before conducted such an examination as we did at Searle." "From time to time, we have been aware of iso- lated problems, but we were not aware of the extent of the problem in one pharmaceutical house..."

   Given those conclusions reached on the quality of Searle experimental
studies in general and of the aspartame studies in particular, as we have
seen above, by both the FDA as an institution and its Commissioner in 1976,
how is it possible for another Commissioner in July, 1981, to reapprove
the use of aspartame being marketed in dry foods?  How is it possible for
yet another Commissioner two years later, in July, 1983, to have extended
such approval for marketing aspartame also in carbonated beverages?  Such
approvals were based on largely the very same studies that were examined by
the Task Force in 1975-76.

   It seems to me that no amount of additional examinations of pathology
material such as undertaken by the UAREP and others, now additional statis-
tical analyses carried out on the data, and no judgmental evaluations or
interpretations of any data arising from those studies can in any way
rectify the basic problem expressed by the Task Force, i.e., the FDA
itself:  in the absence of reasonable expectation that the experimental
animals were administered the correct dosages of the test agent, any obser-
vational data carried out on those animals must be regarded as questionable
or flawed.  This is to say nothing of all the myriad of other problems
involving the competence of those conducting such studies, and the care
they exercised in their execution.  Once a study is carried out and the
test animals are disposed of, all that remains are the number of tiny bits of
fissure preserved from their organs for microscopic examination and the
written records of observations made by those who actually carried out that
study.  While the tissues themselves can be examined by others long after
the remains of those animals no longer exist, the reliability of the
written records has already been found to be unacceptable in a great
variety of ways.  Clearly, there is no way that even the most competent
scientists can make any new observations on those animals at a time subse-
quent to the conduct of the study.  Once a study is compromised in its
executions, it is beyond salvation by anyone.

   Even with respect to those small portions of tissue preserved for
microscopic examination for an indefinite period of time after any study is
completed there are serious problems as presented in the 1976 FDA report
with respect to Searle studies in general and for the aspartame studies in
particular:-  there is little if any assurance that such samples of tissues
as were preserved actually originate from the specific animals said by
Searle or Hazleton to have been their source (see the discussion on page 57
paragraph 2 et seq.)  Furthermore, due to the unacceptably high rate of
post-mortem autolysis, a great many such  tissues were not collected at all
from the experimental animals.  In any such study of even a few hundred
test animals, it takes no more than a dozen or so of them to exhibit a
particular lesion (such as brain tumors, for instance) where missing no
more than one or two animals manifesting such tumors in any given exposure
group may well make the difference whether that particular lesion is or is
not significantly associated with the test agent, i.e., aspartame or any of
its related chemicals.

   Following the Senate hearing in the Spring and Summer of 1976, during
the winter beginning in that year the FDA began negotiating with GD Searle
& Co. on retaining the UAREP (Universities Associated with Research and
Education in Pathology), a private organization, on the feasibility of
investigating a number of other Searle studies with aspartame.  Whin I
heard of those negotiating being in effect, I wrote a memorandum to Mr.
Carl Sharp, the chairman of the FDA's Searle Task Force, on November the
4th, 1976. a copy of it is given here as Attachment 1, and my apprehen-
sions over such plans is clearly evident there.  Basically, they amounted
to the fact that the UAREP was totally unsuited for such task since it had
never before engaged in anything like it and I also objected to the idea
that Searle was to fund that particular activity by the UAREP.  As men-
tioned there, the FDA had just received a supplemental appropriation from
the US Congress for the express purpose of expanding its own activities in
that very area of investigating the conduct of such experimental studies by
the regulated industry. Under that appropriation (which came to some
$16,000.000) a great number of additional investigators were hired and
trained for this particular task by the FDA.

   A few months prior to the UAREP beginning its investigations in August
of 1977, in April of that same year, yet another FDA investigation of three
aspartame studies conducted at GD Searle & Co. was undertaken.  The 76-page
report of that investigation (also known as the Bressler report, after the
name of the leader of the investigative team, Mr. Jerome Bressler, a
compliance officer in the FDA's Chicago District) reveals the reference to
a single one of those studies (the 115-week experiment in rats exposed to
DKP or diketopiperazine, a breakdown product of aspartame) the following:-

- substitutions of some of the animals in that study;
- the presence of intercurrent disease amongst the test animals and
  the administration of drugs to combat this, neither of which were
  completely reported to the FDA;
- incomplete examinations of tissues from the experimental animals;
- excision of tissue masses likely to be tumors from live animals
  during the study;
- absence of batch records for the mixing of the test substance into
  the diet of the test animals;
- incomplete stability studies for the agent on test;
- absence of homoqeneity studies for the agent on test;
- deficiencies in the methods of chemical assay for the actual DKP
  that was mixed into the diet of the experimental rats;
- problems with the dosage of the DKP that was given to those rats;
- problems with the fixation-in-toto and autolysis;
- failure to report to the FDA all tissue masses (likely to be tumors)
   which were found in the experimental rats;
- failure to report to the FDA all internal tumors present in the
  experimental rats, e.g., polyps in the uterus (animal K9MF), ovary
  neoplasms (Animals H19CF, H19CF, and H7HF) as well as other lesions
  (Animal D29CF);
- inconsistencies between different parts of the report on this study
  submitted by GD Searle & Co. to the FDA on the precise nature of the
  lesions manifested by the test rats;
- numerous transcription errors in that report.

   Interestingly and most important, the Bressler investigating group
found not only that no homogeneity test were conducted by GD Searle & Co.
on the mixture of the test agent within the animals' diet, but they
actually obtained direct evidence that in fact the distribution of the test
agent in that diet was clearly not homogeneous due to failure to have the
test agent ground in a sufficiently fine manner.  Descriptive remarks on
this issue were found by the FDA investigators in a notebook kept by Searle
personnel on observations made during the study, as was a Polaroid photo-
graph taken by the same Searle technicians and which clearly shows the test
agent in the form of coarse particles with the animals' diet.  If follows
that the experimental rats could have consumed their feed without actually
touching the DKP and, consequently, no-one can state with any assurance
whatsoever just how much DKP (if any) those rats were actually exposed to
in the course of that study.  Evidence such as this obtained by the FDA
investigators seems to me to have been crucial to the interpretation of any
findings or observations by Searle.

   On page 32 of the GAO report one can read the view of the FDA's
Center for Food Safety and Applied Nutrition (CFSAN) on the findings of the
investigators.  To me these read like a script written for Abbott and
Costello in the sense of their  having their perceptions inside-out or
upside-down - "the diets may have been homogeneous because of a
dose-related increase in the incidence of uterine polyps and decrease in
blood cholesterol levels" (a clear non-sequitur, such as one almost never
encounters in real life); on the problem with autolysis of the tissues the
CFSAN felt "they could not determine whether the results would have been
altered if these tissues had been obtained before autolysis (an obvious
instance of placing the burden of proof that a study is unsound on the
Government rather then requiring the petitioner for approval of a food
additive to demonstrate, as the Law requires, that any study is of sound
quality);  the observation by the investigators that 329 fetuses were
examined in two days by a single person (a clear impossibility) was laid
aside by the CFSAN with another non-sequitur:- that "the Searle scientist
who performed these examinations estimated that he examined about 30
fetuses a day...";  on the fact that an insufficient number of sections
were made out of the heart, the CFSAN observed:- "...while there was no
evidence that the study was compromised by this issue, the practice of not
making enough sections through the organs, as specified in the protocol,
did not preclude a possible failure to observe abnormalities which may have
occurred."

   Despite all these problems, at least some of which undermined or
compromised the study in an unredeeming manner, apparently the CFSAN and
the FDA Commissioner found the quality of those three studies reported on
by the Bressler investigating group as being in fact of an acceptable
nature and GD Searle & Co. were notified to this effect in September, 1977.

   The investigation undertaken by the UAREP began in August, 1977.
After reading the report of that group, it became painfully clear to me
that the misgivings which I foresaw in November 1976 (see Attachment 1
here) were indeed justified and my worst fears were eventually realized.
If one compares the kind of detailed and painstaking findings made by the
professional investigators from the FDA both in 1975 and in 1977 with the
rather amateurish activities by the UAREP outlined in their report, the
contrast between these could hardly have been greater.  Of course, inasmuch
as GD Searle had paid for the UAREP investigation, the cost of it for the
FDA was nil;  what the FDA got in return for its money, was not worth much
more than this.

   Perhaps the most disappointing aspect of this entire fiasco with the
quality or reliability of the experimental studies with aspartame was the
failure of the Public Board of Inquiry (PBOI) to consider these aspects in
their deliberations. The PBOI expressly declined to do so even after the
principal objectors to the approval of aspartame for marketing, Mr. James
Turner and Dr. John Olney, asked for such consideration.  To me it seems
almost beyond belief that a collection of scientists can sit on judgement
over the interpretations to be made on a set of results arising from
certain studies, not only failing to consider the adequacy of the conduct
of those studies but actually refusing to do so.

   Given this sort of circumstance, it should not come as a surprise to
anyone that eventually the Commissioner of the FDA finally reapproved
aspartame for marketing even though his own panel of experts were divided
over the issue whether this particular food additive had been shown in a
reasonable manner to be safe.

   As mentioned in the GAO report (page 12 there) "The Federal Food,
Drug, and Cosmetic Act does not specifically define 'safety'.  However, the
legislative history of the Food Additives Amendment indicates that safety
means ''proof of a reasonable certainty that no harm will result from the

proposed use of an additive'."  It is intuitively clear to anyone that no
"reasonable certainty" can attach to any results emanating from studies as
profoundly flawed as the Commissioner of the FDA had determined in 1976 and
as amply reconfirmed since then.

   This concludes my remarks on the quality or reliability of the
experimental studies with aspartame carried out by the GD Searle & Co. or
by the contractors working under the direction of that firm.

   Since Mr. Wagoner of your Office has requested my comments in a very
short period of time, I am expediting this letter to you now; however, I
plan to send you in the very near future an additional communications where
two other issues are discussed in some detail:- the problem with the brain
tumors induced by aspartame and that the FDA's having set a very high
(and, to my view, clearly dangerous) level of Acceptable Daily Intake,
or ADI, for this particular food additive in the diet of humans.

   Finally, I wish to state here that, quite aside from my professional
background as a scientist and speaking merely as an individual citizen, I
am grateful for the concern you have had over the safety of aspartame for
many years now;  as such, I wish to thank you for having given me this
opportunity of being of some service to you.  With best wishes for the
future, I remain, Senator Metzenbaum,

Sincerely yours,

M. Adrian Gross,
Senior Science Advisor,
Benefits and Use Division,
Office of Pesticide Programs
Sworn to be a true copy on 30 Oct, 1987.