Growth Hormone Report

Betty Martini betty at noel.pd.org
Tue Jul 4 00:17:34 EST 1995


Since there appears to be interest in this news group on growth hormone 
here is the report submitted by Robert Cohen to the FDA in an effort to 
revoke its use.  The insulin growth factor is increased, the regulator of 
cancer, and spleen size was increased as much as 46% in lab animals, a pre-
leukemic condition.  An explosion in leukemia and cancer is expected.  
Anyone wanting more information can call Robert Cohen at 1 201-599-0325.

Betty Martini
Domain:  betty at pd.org
UUCP:  ...!emory!pd.org!betty
-------------- next part --------------
     Recombinant bovine somatotropin (rBST) increases levels
     of insulin-like growth factor (IGF) in milk; IGF in milk
     is orally active; IGF is a key factor in the growth and
     survival of cancer in animals and humans.

                       Robert Cohen


     This paper was presented to the FDA on April 21, 1995 at the 
     Invitation of Dr. Stephen Sundlof, Director of the Center for 
     Veterinary Medicine, as a Result of a Citizen Petition Filed by 
     Robert Cohen (94P-03431CP1) 9/16/94.

     Attending that Meeting for FDA were:

            1) Dr. Richard Teske
            2) Dr. Robert Condon
            3) Dr. John Leighton
            4) Dr. William Marnane
            5) Mr. Robert Sauer

Fourth Draft                                          Robert Cohen
April 20, 1995


                AS A RESULT OF THAT MEETING FDA:
                --------------------------------

1)  Believes that after cows are treated with BST there *is* an 
    increase in IGF levels in milk.
2)  Believes that some IGF bypasses digestion and is absorbed intact 
    by the intestinal lumen.
3)  Believes that although IGF levels in milk increase after BST 
    treatment and although some quantities of IGF survive digestion, IGF 
    is *not* orally active.  Neither are similar milk hormones.  
    Therefore, while nursing mothers have biological effects from 
    hormones and human breast feeding might have psychological benefits 
    for the infant, but it is not possible for there to be hormonal 
    benefits.
4)  Agrees to rigorously review all of the references and data in 
    this article and to re-examine the data cited in the unpublished 
    reports cited as references in the Juskevich and Guyer article.



     RECOMBINANT BOVINE SOMATOTROPIN (rBST) INCREASES LEVELS
     OF INSULIN-LIKE GROWTH FACTOR (IGF) IN MILK; IGF IN MILK
     IS ORALLY ACTIVE; IGF IS A KEY FACTOR IN THE GROWTH AND
     SURVIVAL OF CANCER IN ANIMALS AND HUMANS.


                           INTRODUCTION
                           ------------

The Food and Drug Administration (FDA) approved the use of a 
genetically engineered version of bovine somatotropin (rBST) after a 
process which represented the most researched and controversial food 
and drug application in history.  This paper will explore three major 
topics:

    1)  The data presented to FDA was not rigorously reviewed,
        was presented in a biased manner and the actual product
        which was approved by FDA was significantly different
        than the actual product in use today.

    2)  Numerous tests including toxicology studies were not
        performed because it was pre-determined that there
        could be no biological effects upon animals or humans
        from oral ingestion of rBST or IGF.  This conclusion
        was made because of a belief that strong digestive
        enzymes would destroy milk hormones.  This paper will
        demonstrate that milk is an enzyme inhibitor and that
        hormones survive digestion.

    3)  IGF is a key factor in the growth and survival of
        tumors in humans.  IGF is a proliferative growth
        hormone which increases after cows are treated with BST.

Milk and dairy products are staples in the American diet and 
represent the largest food industry in the United States.  To 
increase milk output of cows, scientists have genetically engineered 
bovine growth hormone through DNA technology and have developed a 
substance which was meant to be similar to a cow's normally occurring 
somatotropic hormone.

Through the use of genetic engineering technology the bacterium, E. 
coli, received the gene that enabled it to produce a synthetic 
version of the natural bovine growth hormone.


                     A GENE TRANSCRIPTION ERROR
                     --------------------------

Monsanto (1) has admitted that an unusual amino acid was created by 
their new technology.  Amino acid #144 which should have been lysine 
has been replaced on the normal chain with epsilon-N-acetyllysine.  
Monsanto's publication did not indicate how long (after rBST was 
introduced into milk in 1990) this unusual amino acid has been 
consumed by the American milk drinking public.


                   DATA WAS NEVER PROPER REVIEWED
                   ------------------------------

The FDA and Monsanto, manufacturer of rBST, collaborated on a paper 
(2) which was published in "Science."  This article was intended to 
end the controversy surrounding rBST.  As a result of this article, 
the Journal of The American Medical Association and the National 
Institutes of Health endorsed rBST use.  Evidence exists that the 
data in that article were not reviewed by the NIH or JAMA.  
Unpublished reports were cited but never made available for peer 
review.  By not making available actual data for tissue and organ 
weights of subjects treated with genetically engineered hormones, 
peer review was compromised.  References were requested through the 
Freedom of Information Act office but Monsanto cites "trade 
protection" and hides behind a protective veil.


               ACTUAL REFERENCES NEVER PEER REVIEWED
               -------------------------------------

>From the Juskevich and Guyer paper:

      REF. # 40 is an unpublished Upjohn report.
      REF. # 41 is an unpublished Hazleton Lab report.
      REF. # 42 is an unpublished Searle report.
      REF. # 43 is an unpublished American Cyanamid report.
      REF. # 44 is an unpublished Eli Lilly report.
      REF. # 70 is an unpublished Elanco report.

It is clear that these reports are shared by Monsanto competition.  
Trade protection should not be reason to deny a researcher access to 
reports cited as references.


          BST-TREATED MILK DIFFERS FROM UNTREATED MILK
          --------------------------------------------

The Juskevich and Guyer paper contradicts the conclusion reached by 
FDA, NIH and the World Health Organization.  All agree that milk from 
rBST-treated cows is indistringuishable from the milk of non-treated 
cows.  Their conclusion contradicts the actual data presented.  The 
authors state:

      "Recombinant bGH treatment produces an increase in the
       concentration of insulin-like growht factor-I (IGF-I)
       in cow's milk"


                     BIOLOGICAL EFFECTS
                     ------------------

Data in the Juskevich paper suggest that there are indeed biological 
effects from oral ingestion of rBGH on laboratory animals.  Animals 
reacting to subcutaneous injections demonstrated significantly large 
and abnormal spleen growth rates (as compared to the control group).  
>From table #2 on page 878 we note that the typical male spleen 
increased in size 39.6% while the female spleen grew 46%.  Those 
doing the research had to note these dramatic numbers and had to have 
observed the spleen effects from oral ingestion.

REPRINTED FROM "SCIENCE" - AUGUST, 1990, PAGE 878

Table 2 Absolute organ weights (in grams) in control rats and 
rbGH-treated rats (means +/- SD).  Charles River CD rats (n=30 rats 
per sex) were treated for 90 days with rbGH either by gavage or by 
subcutaneous administrations, and one group of animals served as 
untreated controls.  From (42) with permission. c 1989 Monsanto 
Agricultural Company.

Organ            Subcutaneous                  Oral

             0       1.0        0.1       0.5      5.0       50.0

                               Males

Kidneys    3.677     4.188     3.178     3.695     3.540     3.544
Liver     16.549    20.364    15.614    15.740    15.993    15.098
Heart      1.726     1.941     1.645     1.608     1.618     1.640
Spleen     0.912     1.274     0.910     1.051     0.987     1.002


                               Females

Kidneys    2.067     2.464     2.040     2.170     2.102     2.025
Liver      8.637    11.146     8.302     8.754     8.446     8.297
Heart      1.041     1.215     1.061     1.101     1.034     1.070
Spleen     0.585     0.855     0.601     0.663     0.630     0.608

Let use examine what occurs to the animals (mean averages):

    1)  subcutaneous males gained 39.69% spleen weight
    2)  subcutaneous females gained 46.15% spleen weight

    3)  oral males gained 8.33% spleen weight
    4)  oral females gained 6.92% spleen weight

The subject animals in this study were sacrificed after 90 days.  
Scientists at the Albert Einstein College of Medicine found that mice 
treated with IGF-II developed a diverse spectrum of tumors at a 
higher frequency than controls after 18 months of age.  This long 
latent period before tumors arise and the wide spectrum of tumor 
types suggest that IFG may function primarily as a tumor progression 
factor in mice via autocrine and endocrine mechanisms of action. (3)

There is evidence of such latent effects in Juskevich.  Data is 
presented in a remarkably biased manner:

TABLE #1 (PAGE 877) Body weight changes (in grames) of control rats 
and rbGH-treated rats (means +/- SD).  Charles River CD rats were 
treated for 90 days with rbGH either by gavage or by subcutaneous 
injection; and one group of animals served as untreated controls.  
>From (42) with permission c 1989 Monsanto Agricultural Company.

(AUTHOR'S NOTE:  I HAVE PRINTED ONLY THE CONTROL GROUP AND 
SUBCUTANEOUS GROUP WEIGHTS TO ILLUSTRATE THE POINT OF DATA 
MANIPULATION BY THE MONSANTO/FDA PUBLICATION)

STUDY DAY

              MALES (CONTROL)  (SUBCUTANEOUS)
              ---------------  --------------

8              58 +/-  8.5        72 +/- 20.4
29            170 +/- 20.3       207 +/- 34.5
50            239 +/- 29.8       294 +/- 44.8
85            324 +/- 39.2       432 +/- 60.3


            FEMALES (CONTROL)  (SUBCUTANEOUS)
            -----------------  --------------

8              24 +/-  8.7        33 +/-  6.5
29             81 +/- 12.0       101 +/- 13.6
50            110 +/- 16.6       150 +/- 18.9
85            148 +/- 24.4       217 +/- 32.3


The average weight gains for subcutaneous animals (per time period) 
are 20-30 percent greater than the control group.  Look closely at 
the parameters.  Is this a standard chart?  Day 8, day 29, day 50, 
and day 85?  Did the data simply fit neatly into these designated 
time slots?

Let's examine what occurs to the animals between days 50 and 85.  The 
average male gains 62% more weight than the control male during that 
period.  The average female gains 76% more than the average control 
female.

This is a very clever non-presentation of data.  There is indeed a 
dramatic latency growth spurt that occurs at some time two months 
after initial introduction of the hormone.

It would be interesting to do statistical analysis on all of the 
subject cited in the Juskevich article, but alas, FDA and MONSANTO 
will not release such data, citing the privilge of protection from 
exclusivity of "trade secrets."

No oral effects?  In addition to the average male (TABLE 2) gaining 
(from oral ingestion) 8.33% in his spleen weight, the average female 
gains 6.92%.  The average male also loses 5.10% kidney weight, loses 
5.6675% liver weight, and loses 5.6925% heart weight (when compared 
to the control group).  These are biological effects!  Are they 
statistically significant?  We may never know, because freedom of 
information act requests are not enough to induce FDA or Monsanto 
into releasing data necessary to perform such analyses.  (Requests by 
this author have been denied.)


               IGF - CELL PROLIFERATION AND CANCER
               -----------------------------------

Should IGF (insulin growth factor) be such a concern?  Hammond and 
Collier, writing for Monsanto Agricultural Company (4) state:

       "Based upon the no effect levels determined in rat
        gavage studies (oral ingestion of rBGH), it is possible
        to approximate safety factors for ingestion of these two
        proteins (sometribove and IGF-I).  However, estimation of
        safety factors for sometribove (BST,rbGH) consumption is
        not necessary, since it would not be hormonally active in
        humans even if it could be absorbed.  IGF-I is not orally
        active in laboratory animals supporting a large margin of
        safety for their consumption."

The most recent research would tend to support the dramatic role that 
IGF plays in cellular growth.  Keinman (5) report that IGF-I is found 
to be involved in the growth regulation of endometrial tumor cells 
and is 30-fold more potent than insulin, suggesting that the effects 
of these growth factors are mediated by the IGF-I receptor.  D'Errico 
(6) notes that results obtained using molecular biology techniques 
suggest a possible role for insulin-like growth factor II (IGF-II) in 
the pathogenesis of hepatocellular carcinoma (HCC).  Kowk (7) has 
found that the biological effects of IGF-I are initiated by its 
binding to the IGF-I receptor, which is able to transduce mitogenic 
and metabolic signals, supporting the hypothesis that the IGF-I 
receptor is involved in the development of diabetic vascular 
complications.  Wimalasena (8) found IGF-I to increase cell growth, 
and a maximal effect of 3-5 fold increase in cell number was 
observed.

There is evidence that IGF functions on a nanomolecular level.  MCF-7 
cancer cells proliferate in response to nanomolar concentrations of 
IGF-I and IGF-II.  De-Leon (9) reported that the actions of both 
peptides are mediated through the IGF-I receptor concluding that 
IGF-I and IGF-II are potent mitogens in MCF-7 cells and can stimulate 
cell proliferation through all three receptors.  Martin (10) reports 
that IGF-II stimulates cell proliferation via the type I IGF 
receptor.  The type I IGF receptor mediates IGF-II induced autocrine 
neuroblastoma cell growth.

Ambrose (11) observed that the interaction of insulin-like growth 
factors with the IGF-I receptor is an important step in the control 
of cell proliferation and development.  In particular, IGF-I and 
IGF-II are key regulators of central nervous system development and 
may modulate the growth of glial tumors.  Nielsen (12) noted that the 
transcription of IGF-II genes lead to the production of significant 
amounts of IGF-II which stimulate the proliferation of MSRCT 
(cancerous growths) by interaction with IGF-I receptors on the cells.

FDA, based upon Monsanto's research, continues to proclaim that IGF 
in milk has no effect on human metabolism.  IGF-I is a mitogenic 
growth factor.  Prager (13) found rat cells responding to in vitro 
IGF-I treatment by increased proliferation and DNA synthesis.  Tumor 
cell assays confirmed continued expression of IGF-I receptors.  Raile 
(14) observed similar effects.  Insulin-like growth factor I and II 
were implicated in the growth promotion of in vivo tumors and tumor 
cells in vitro.  Tumor cells responded to an addition of exogenous 
insulin growht factor with an increase of DNA synthesis.

Langford (15) found that IGF-I has multiple metabolic actions and 
effects on the differentiation and proliferation of a wide variety of 
cell types.


                    IGF IN MILK SURVIVES DIGESTION
                    ------------------------------

FDA continues to accept the premise made by Monsanto that IGF-I is 
degraded by digestive enzymes and is not active in the upper 
gastrointestinal tract.  FDA's conclusion is echoed by most respected 
observers.

Yet, according to Olanrewaju, recently published in the "American 
Journal of Physiology," infusion of IGF in rats (in levels similar to 
those in bovine milk) increases the cellularity of the intestinal 
mucosa. (16)  Data indirectly supports the hypothesis that dietary 
IGF-I may be absorbed.  This was supported by Baumrucker at the 
Department of Dairy and Animal Science at Pennsylvania State 
University (17) who wrote that dietary IGF-I may be absorbed and 
causes transient systemic effects in the newborn calf.

Taylor (18) reports that insulin-like growth factors have a potent 
mitogenic action on the bowel.

Playford (19) reports that milk proteins prevent digestion of luminal 
growth factors, allowing them to stimulate intestinal growth.  Casein 
acts as an enzyme inhibitor.  Unlike IGF-I in serum, IGF-I secreted 
into the gastrointestinal lumen is not bound to insulin-like growth  
factor I binding proteins.  Since the growth factor is not protein 
bound, its concentration in the gut lumen may be high enough to exert 
biological activity.  IGF is actually abserbed in a similar manner to 
EGF and passes through the digestive system undigested.

Rat milk soluble fraction (RMSF) protects milk borne peptides in the 
gastrointestinal lumen by inhibiting in vitro the luminal 
peptidolysis, according to Rao. (20)

Oster (21) presented evidence that bovine xanthine oxidase is 
entrapped in liposomal form by the milk homogenization process.  In 
this form, milk resists gastric digestion and becomes biologically 
available.  As a result of unnatural micronization (homegenization) 
the number of fat globules are increased and the size of those 
globules reduced.  This enhances hormonal carrier potential and the 
permeability of intestinal mucosa increases as does hormonal 
absorption.

FDA is incorrect in assuming that IGFs are broken down in the gut, 
and therefore cannot affect animal or human metabolic functions.  The 
evidence overwhelmingly contradicts this conclusion.


             NATURALLY OCCURRING IGF IN THE HUMAN BODY
             -----------------------------------------

Human blood and saliva does contain IGF-I.  That IGF-I is bound to 
proteins and receptors, and are building components of cellular 
material.  An analogy must be made to the levels of IGF-I present in 
the human body.  If one were able to analyze the average home, on 
could make the statement that the home contained a 55 gallon drum of 
glue.  One could not walk through the house and find that glue; it 
would be present in the carpet, sheetrock, tiles, furniture, etc.  If 
an individual walked into that house with a bucket of free flowing 
un-bound glue, splashing that bucket as he walked through the house, 
he would be creating great damage.

Free IGF-I works the same way.  The actual levels of free IGF-I are 
relatively quite small.  They have been measured most recently by 
Frystyk (22) who found that IGF-I levels in humans were inversely 
proportional to age ranging from 950 ng/L (20-30 yrs. of age) to 410 
ng/L (60+ yrs. of age).  Levels of IGF-II were independent of age, 
being 1480 ng/L.


                SYNERGISM OF IGF WITH OTHER HORMONES
                ------------------------------------

The mediating effects of IGFs appear to be greatly enhanced and are 
synergistic when combined with other factors.  Kachra (23) found that 
when glucagon and GH are combined with rBGH (50 mg/ml), they 
augmented increased levels of IGF-I up to 12-fold.

Frodin (24) demonstrated that the combined effect of IGFs and bFGF is 
synergistic.  The degree of synergism was 2-4 fold in neonatal 
chromaffin cells and 10-20-fold in adult chromaffin cells compared 
with the effect of each growth factor alone.  IGF-I and IGF-II acted 
in synergy with bFGF to stimulate proliferation and survival of 
chromaffin cells.  Romagnolo (25) found that the induction of IGF-I 
cells with dexamethasone (DEX) triggered a 29.5-fold increase in the 
secretion of IGF-I.


                         IGF AND CANCER
                         --------------

IGF-I and II have been identified as autocrine and endocrine growth 
regulators which accelerate various types of carcinomas.  IGF-I is 
considered to play an important role in the proliferation of 
pancreatic cancer cells, according to Gillespie (26).

Glick (27) noted that IGFs play an important role in the regulation 
of glucose metabolism in CNS tumors.

It was reported by Atiq that insulin-like growth factor II is 
associated with human primary colorectal tumors and colin-carcinoma 
cell lines. (28)

Yashiro (29) found IGF-bp activity was significantly higher in cancer 
extracts, suggesting that higher IGF-bp activity in cancer tissue is 
involved in regulating growth of thyroid papillary carcinoma cells.

Robbins (Genentech, Inc.) found that IGF-I increased lymphocyte 
numbers in all of the peripheral lymphoid organs examined.  This 
increase had functional significance, and Robbins concluded that 
IGF-I produced locally by thymic and bone marrow cells may be a 
natural component of B and T cell lymphopoiesis. (30)

Yun demonstrated that IGF transcripts were 32-64-fold more abundant 
in Wilms tumors than in the adjacent uninvolved kidneys.  IGF-II is 
suggested as playing a role in transforming growth factor in Wilms 
tumorigenesis. (31)

Minniti concluded that insulin-like growth factor II (IGF-II) acts as 
an autocrine growth and motility factor in human rhabdomyosarcoma 
cell lines.  Analyses of tumor biopsy  specimens demonstrate high 
levels of IGF-II mRNA expression.  All tumor specimens examined 
expressed the gene for IGF-II, to surrounding stroma.  These data 
suggest that the IGF-II autocrine loop may be operating not only in 
vitro but also in vivo. (32)

Developing osteogenic sarcoma were researched by Kappel who wrote 
that this type of cancer is the most common bone tumor of childhood 
and typically occurs during adolescent growth spurts when growth 
hormone and insulin-like growth factor-I (IGF-I) may be at their 
highest lifetime levels.  He noted that human osteogenic sarcoma cell 
lines are dependent on signaling through IGF-I receptors for in vitro 
survival and proliferation.  Furthermore, they suggest modulation of 
the growth hormone IGF-I axis may affect the growth of these tumors 
in vivo. (33)

Lippman, as early as 1991, had implicated IGF-I as being critically 
involved in the aberrant growth of human breast cancer cells. (34)

Lee (35) observed the processing of insulin-like growth factor by 
human breast tissue and commented:

      "This indicates, for the first times, that oestrogen
       regulation of IGF-I peptide in breast cancer cells
       would support the hypothesis that IGF-II has and
       autocrine regulatory function in breast cancer."

Chen (36) noted that IGFs are potent mitogens for malignant cell 
proliferation in the human breast carcinoma cell line.

Figueroa confirmed that insulin-like growth factors (IGFs) are potent 
mitogens for breast cancer cells and their activity is modulated by 
high affinity binding proteins. (37)

Li (38) treated breast cancer cells (MCF-7) with IGF-I and observed a 
10-fold increase in mRNA levels of cancer cells and concluded that 
IGF-I modulation of gene expression appears to be an important step 
in cellular proliferation.  Krasnick (39) furnishes another clue to 
this puzzle by revealing that IGF-I may have a role in the regulation 
of human ovarian cancer.  His data support a role for IGF-I in 
proliferation of ovarian cancer and suggests that IGF-I and estradiol 
interact in a synergistic manner and regulate this malignancy.

Musgrove (40) states that growth factors play a major role in the 
control of human breast cancer cell proliferation.



                          THE MISSING LINK
                          ----------------

On November 8, 1994, the New York Times published a store (written by 
Gina Kolata) (41) which revealed:

    1)  There is good reason to believe that many very early cancers 
        never become clinically significant.

    2)  Although 1% of women between the ages of 40 and 50 are 
        diagnosed with breast cancer, autopsy studies reveal that
        39% of women in that age group have tumors in their breasts.

    3)  Forty-six percent of men between the age of 60 and seventy 
        have prostate cancer although only 1% are clinically
        diagnosed.

    4)  Virtually all people over 50 have thyroid tumors.

    5)  Cancerous tumors are the ones that have somehow thrown off 
        the usually tight genetic controls on unwanted division and
        growth.



                      COMMENTS AND CONCLUSIONS
                      ------------------------

Milk?  What have we done to it?  We've taken a substance that was 
intended for the infant of a species, already loaded with fat, 
cholesterol and hormones.  We've changed its constitution by 
genetically engineering it.  We've simmered away its goodness through 
pasteurization.  We've re-created its components through 
homogenization, a treatment in which fat droplets are shattered into 
droplets one-tenth their original size and suspended in solution.

FDA now has information indicating that data was manipulated and 
withheld from peer review.  In addition, new information has surfaced 
indicating that the product which was approved for use after many 
years of testing is not the same product that is now being used.  
Most critically important are the facts presented in the previous two 
years of research which indicate that IGF in milk is absorbed intact 
and exerts proliferative growth effects.

Armed with the knowledge that virtually all humans have tumors 
waiting to proliferate, and milk hormones (IGFs) cause  proliferation 
of cancer, and that treatment of cows with recombinant bovine growth 
hormones causes an increase in IGF levels in milk, it is now time for 
science, industry and FDA to re-investigate and re-evaluate this 
controversy.

It is also appropriate that FDA immediately place a moratorium on the 
use of rBST until appropriate testing can be completed.


                               Robert Cohen


                        (1)
"Isolation of Escherichia coli synthesized recombinant eukaryotic 
proteins that contain epsilon-N-acetyllysine."
Violand-BN; Schlittler-MR; Lawson-CQ; Kane-JF; Siegel-NR;
Smith-CE; Kolodziej-EW; Duffin-KL
Animal Sciences Division, Monsanto Corporation, St. Louis,
Missouri 63198
Protein-Sci. 1994 Jul: 3(7): 1089-97


                        (2)
"Bovine Growth hormone: Human Food Safety Evaluation"
Juskevich-JC; Guyer-CG
Science, 24 August, 1990, Volume 249, pp. 875-884


                        (3)
"Altered body composition and increased frequency of diverse 
malignancies in insulin-like Growth factor-II transgenic mice."
Rogler-CE; Yang-D; Rossetti-L; Donohoe-J; Alt-E; Chang-CJ; 
Rosenfeld-R; Neely-R; Hintz-R
Marion Bessin Liver Research Center, Albert Einstein College of 
Medicine, Bronx, New York 10461
J-Biol-Chem. 1994 May 13; 269 (19)


                        (4)
"Food safety and Pharmacokinetic studies which support a zero 
(0) meat and milk withdrawel time for use of sometribove in 
dairy cows."
Hammond-BG; Collier-RJ; Miller-MA; McGrath-M; Hartzell-DL; 
Kotts-C; Vandaele-W
Monsanto Agricultural Company, Animal Sciences Division, 800 N. 
Lindbergh Boulevard, St. Louis, MO 63167
Pharmacokinetics of Veterinary Drugs, 11-12 October 1989


                        (5)
"Regulation of endometrial cancer cell growth by insulin-like growth 
factors and the luteinizing hormone-releasing hormone antagonist 
SB-75.
Keinman-D; Roberts-CT Jr.; LeRoith-D; Schally-AV; Levy-J; Sharoni-Y
Clinical Biochemistry Department, Faculty of Health Sciences, 
Ben-Gurion University of the Negev, Soroka Medical Center of Kupat 
Holim, Beer-Sheva, Israel.
Regul-Pept. 1993 Oct 20; 48(1-2) 91-8


                        (6)
"Expression of insulin-like Growth factor II (IGF-II) in human 
hepatocellular carcinomas: an immunohistochemical study."
D'Errico-A; Grigoni-WF; Fiorentino-M; Baccarini-P; Lamas-E; 
De-Mitri-S; Gozzetti-G; Mancini-AM; Brechot-C Institute of 
Pathological Anatomy, University of Bologna, Italy.
Pathol-Int. 1994 Feb; 44(2): 131-7


                        (7)
"Insulin-like Growth factor-I receptor increases in aortic 
endothelial cells from diabetic rats."
Kwok-CF: Ho-LT; Jap-TS
Department of Medicine, Veterans General Hospital-Taipei, 
Republic of China.
Metabolism. 1993 Nov; 42(11): 1381-5


                        (8)
"Growth factors interact with estradiol and gonadotropins in the 
regulation of ovarian cancer cell growth and growth
factor receptors."
Wimalasena-J; Meehan-D; Dostal-R; Foster-JS; Cameron-M; Smith-M
Department of Obstetrics/Gynecology, Graduate School of 
Medicine, University of Tennessee Medical Center, Knoxville, 
TN. 37920
Oncol-Res. 1993; 5(8): 325-37


                        (9)
"Effects Of insulin-like arowth factors (IGFs) and IGF receptor 
antibodies on the proliferation of human breast cancer cells."
De-Leon-DD; Wilson-DM; Powers-M; Rosenfeld-RG
Department of Pediatric Endocrinology, Stanford University
Medical School, California 94305
Growth Factors. 1992; 6(4): 327-36


                        (10)
"IGF receptor function and regulation in autocrine human 
neuroblastoma cell Growth."
Martin-DM; Singleton-JR; Meghani-MA; Feldman-EL
Department of Neurology, University of Michigan, Ann Arbor
Regul. Pept. 1993 Oct 20; 48(1-2): 225-32


                        (11)
"Growth regulation of human alioblastoma T98G cells by 
insulin-like Growth factor-I and its receptor."
Ambrose-D; Resnicoff-M; Coppola-D; Sell-C; Miura-M; Rubin-R;
Jameson-S; Baserga-R
Department of Pathology, Jefferson Medical College,
Philadelphia, Pennsylvania 19107
J-Cell-Physiol. 1994 Apr; 159(1): 92-100


                        (12)
"Insulin-like growth factor II mRNA, peptides, and receptors in a 
thoracopulmonary malignant small round cell tumor."
Neilsen-FC; Orskow-C; Haselbacher-G; Ramlau-J; Rehfield-JF;
Christiansen-J; Schmiegelow-K
Kepartment of Clinical Biochemistry, Rigshospitalet,
Copenhagen, Denmark
Cancer. 1994 Feb  15; 73(4): 1312-9


                        (13)
"Dominant negative inhibition of tumorigenesis in vivo by human
insulin-like Growth factor I receptor mutant."
Prager-D; Li-HL; Asa-S; Melmed-S
Department of Medicine, Cedars-Sinai Medical Center
University of California, Los Angeles School of Medicine, 
Los Angeles, CA 90048
Proc-Natl-Acad-Sci-U-S-A. 1994 Mar 15; 91(6): 2181-5


                        (14)
"Human osteosarcoma (U-2 OS) cells express both insulin-like
growth factor-I (IGF-I) receptors and insulin-like Growth
factor-II/mannose-6-phosphate (IGF-II/M6P) receptors synthesize
IGF-II: autocrine Growth stimulation by IGF-II via the IGF-I
receptor."
Raile-K; Hoflich-A; Kessler-U; Yang-Y; Pfuender-M; Blum-WJ
Kolb-H; Schwarz-HP; Kiess-W
Department of Pediatric Endocrinology, Children's Hospital, 
University of Munich, Germany.
J-Cell Physiol. 1994 June; 159(3): 531-41


                        (15)
"The insulin-like arowth factor-I/ bindina Protein axis:
physiology, Pathophysiology and therapeutic manipulation."
Langford-RS; Miell-JP
Academic Department of Medicine, King's College School of
Medicine and Dentistry, London, UK
Eur-J-Clin-Invest. 1993 Sep; 23(9): 503-16


                        (16)
"Trophic action of local intraileal infusion of insulin-like
growth factor-I: polyamine dependence."
Olanrewaju-H; Patel-L; Sledel-ER
Am-J-Physiol. 263:E282-286 (1992)


                        (17)
"Effects of dietary recombinant human insulin-like arowth 
factor-I on concentrations of hormones and Growth factors in 
the blood of newborn calves."
Baumrucker-CR; Blum JW Department of Dairy and Animal Science,
Pennsylvania State University, University Park, PA 16802
J-Endocrinol. 1994 Jan; 140(1): 15-21


                        (18)
"Hormonal regulation of intestinal adaptation."
Taylor-RG; Fuller-PJ
Department of Surgery, Royal Children's Hospital, Parkville, 
Victoria, Australia.
Baillieres-Clin-Endocrinol-Metab. 1994 Jan; 8(1): 165-83


                        (19)
"Effect of Luminal Growth factor Dreservation on intestinal Growth."
Playford-RJ; Woodman-AC; Clark-P; Watanapa-P; Williamson-RC;
Vesey-D; Deprez-PH; Calam-J
The Lancet, 2:843-848, 1993.


                        (20)
"Presence of multiple forms of peptidase inhibitors in rat milk."
Rao-RR; Lam-R; Philipps-AF; Williams-C; Lake-M: Roldovsky-O
Department of Pharmacology, Steele Memorial Children's Research
Center, University of Arizona, Tucson 85724
J-Pediatr-Gastroenterol-Nutr. 1993 Nov; 17(4): 414-20


                        (21)
"Liposomes as a proposed vehicle for the persorption of bovine 
xanthine oxidase."
Oster-KA; Ross-DJ; Sharnick, S.V.
Proc. Soc. Exper. Bio. & Med., Vol. 163, No. 1 Jan. 1980


                        (22)
"Free Insulin-like Growth factors (IGF-I and IGF-II) in human 
serum."
Frystyk-J; Skjaerbaek-C; Dinesen-B; Orskov-H
Institute of Experimental Clinical Research, Aarhus University 
Hospital, Denmark.
FEBS-Lett. 1994 July 11; 348(2): 185-91


                        (23)
"The augmentation of insulin-like growth factor-I messenger
ribonucleic acid in cultured rat hepatocytes: activation of 
Protein kinease-A and -C is necessary, but not sufficient."
Kachra-Z; Yang-CR; Posner-BI
Polypeptide Hormone Laboratory, Royal Victoria Hospital, 
Montreal, Quebec, Canada.
Endocrinology. 1994 Feb; 134(2): 702-8


                        (24)
"Insulin-like Growth factors act synergistically with basic
chromaffin cell proliferation."
Frodin-M; Gammeltoft-S
Department of Clinical Chemistry, Bispebjerg Hospital,
Copenhagen, Denmark.
Proc-Natl-Acad-Sci-U-S-A.     1994 Mar 1; 91(5): 1771-5


                        (25)
"Lactogenic hormones and extracellular matrix regulate
expression of IGF-I linked to MMTV-LTR in mammary erithelial 
cells."
Romagnolo-D; Akers-RM; Wong-EA; Boyle-PL; McFadden-TB, ByattJC; 
Turner-JD
Department of Dairy Science, Virginia Ploytechnic Institute and 
State University, Blacksburg, VA 24061-0315.
Mol-Cell-Endocrinol. 1993 Oct; 96(1-2):147-57


                        (26)
"Inhibition of Pancreatic cancer cell Growth in vitro by the 
tyrphostin Group of tysrosine kinase inhibitors."
Gillespie-J; Dye-JF; Schachter-M; Guillou-PJ
Academic Surgical Unit, St. Mary's Hospital Medical School, 
Imperial College of Science, Technology and Medicine, London, 
UK.
Br.-J-Cancer. 1993 Dec; 68(6): 1122-6


                        (27)
"Identification of insulin-like Growth factor (IGF) and Glucose 
transporters and -3 mRNA in CNS tumors."
Glick-RP; Unterman-TG; Lacson-R
Department of Neurosurgery, University of Illinois at Chicago, 
Cook County Hospital, 60612
Regul-Pept. 1993 Oct 20: 48(1-2): 251-6


                        (28)
"Alterations in serum levels of insulin-like Growth factors and 
insulin-like growth-factor-binding proteins in patients with 
colorectal cancer."
Atiq-F; Garrouste-F; Remacle-Bonnet-M; Sastre-B; Pommier-G
Laboratoire d'Immunologie, Faculte de Medecine, Marseille, France.
Int-J-Cancer. 1994 May 15; 57(4): 491-7


                        (29)
"Increased activity of insulin-like Growth factor-binding 
protein in human thyroid papillary cancer tissue."
Yashiro-T; Arai-M; Shizume-R; Obara-T; Murakami-H; Hizuka-N; 
Emoto-N; Miyakawa-M; Ito-R; Tsushima-T
Department of Surgery, Tsukuba University, Ibaraki, Japan. 
Jpn-J-Cancer-Res. 1994 Jan; 85(1): 46-52


                        (30)
"Immunological effects of insulin-like arowth factor-I(IGF-I) 
enhancement of immunoglobulin synthesis."
Robbins-K; McCabe-S; Scheiner-T; Strasser-J; Clark-R; Jardie-P
Department of Immunology, Genentech, Inc., South San Francisco, 
CA 94080
Clin-Exp-Immunol. 1994 Feb; 95(2): 337-42


                        (31)
Insulin-like growth factor II messenger ribonucleic acid 
expression in Wilms tumor, nephrogenic rest, and kidney.
Yun-K; Molenaar-AJ; Fielder-AM; Mark-AJ; Eccles-MR; Becroft-DM; 
Reeve-AE
Department of Pathology, University of Otago Medical School, 
Dunedin, New Zealand.
Lab-Invest. 1993 Nov; 69(5): 603-15


                        (32)
"Specific expression of insulin-like Growth factor-II in
rhabdomyosarcoma tumor cells."
Minniti-CP; Tsokos-M; Newton-WA; Helman-LJ
Pediatic Branch, National Cancer Institute, National Institutes
of Health, Bethesda, Maryland 20892.
Am-J-Clin-Pathol. 1994 Feb; 101(2): 198-203


                        (33)
"Human osteosarcoma cell lines are dependent on insulin-like 
Growth factor I for in vitro Growth."
Kappel-CC; Velez-Yanguas-MC; Hirschfield-S; Helman-LJ
Molecular Oncology Section, National Cancer Institute, 
Bethesda, Maryland 20892.
Cancer-Res. 1994 May 15; 54(10): 2803-7


                        (34)
"Growth factors, receptors and breast cancers."
Lippman-M J. 
J. Natl. Inst. Health, Res. 3:59-62 (1991)
IGF-I and related growth factors are critically involved in
aberrant growth of human breast cancer cells.


                        (35)
"Processing of insulin-like Growth factor-II (IGF-II) by human 
breast cancer cells."
Lee-AV: Darbre-P; Ring-RJ Imperial Cancer Research Fund,
Breast Biology Group, School of Biological Sciences,
University of Surry, Guildford, UK.
Mol-Cell-Endocrinol. Mar; 99(2): 211-20


                        (36)
"Insulin-like Growth factor-binding Protein enhancement of 
insulin-like Growth factor-I (IGF-I)-mediated DNA synthesis and 
IGF-I binding in a human breast carcinoma cell line."
Chen-JC; Shao-ZM; Sheikh-MS; Hussain-A; LeRoth-D; Roberts-C
Department of Medicine, University of Maryland School of Medicine, 
Baltimore, MD 21201
J-Cell-Physiol. 1994 Jan; 158(1): 69-78


                        (37)
"Recombinant insulin-like Growth factor binding protein-1
inhibits IGF-I serum, and estrogen-dependent Growth of MCF-7 
human breast cancer cells."
Figueroa-JA; Sharma-J; Jackson-JG; McDermott-MJ; Yee-D;
Hilsenbeck-SG Department of Medicine, University of Texas
Health Science Center, San Antonio, TX 78284-7884
J-Cell-Physiol. 1993 NOV; 157(2): 229-36


                        (38)
"Retinoic acid inhibition of insulin-like growth factor I 
stimulation of c-fos mRNA levels in a breast carcinoma cell 
line."
Li-XS; Chen-JC; Sheikh-MS; Shao-ZM; Fontana-JA Department 
of Medicine, University of Maryland School of Medicine, 
Baltimore, Maryland 21201
Exp-Cell-Res. 1994. Mar; 211(1):68-73


                        (39)
"Insulin-like Growth factor-I (IGF-I) and IGF-binding Protein-2 are 
increased in cost fluids of eDithelial ovarian cancer."
Krasnick-A; Menczer-J; Pariente-C; Ranety-H
Institute of Endocrinology, Chaim Sheba Medical Center, Tel-
Hashomer, Israel.
J-Clin-Endocrinol-Metab. 1994 Feb; 78(2)


                        (40)
"Acute effects of Growth factors on T-47D breast cancer cell
cycle progression."
Musgrove-EA; Sutherland-RL
Cancer Biology Division, Garvan Institute for Medical Research,
St. Vincent's Hospital, Darlinghurst, NSW, Australia.
Eur-J-Cancer. 1993; 29A (16) 2273-9


                        (41)
"New Ability to Find Earliest Cancers: A Mixed Blessing?"
Kolata-G
New York Times, Science Section. Nov. 8, 1994, Page 1.


*************************************************************************

1.  Epsilon-N-acetyllysine?

The rBST product Monsanto originally tested contained 
epsilon-N-acetyllysine instead of lysine as described in the article. 
According to the reference cited, Monsanto now filters out this amino 
acid (which is normally found in bacteria).

2.  Why cut out section on increases in IGF-I in milk from cows 
    treated with rBST?

Since this paper was being presented to the FDA and the FDA had 
already agreed that milk from cows treated with rBST increases the 
IGF-I content, Mr. Cohen did not want to get into a debate about what 
was already agreed to.

The amount of the increase in IGF-I is very difficult to determine 
from the studies available.  Apparently, there is no standard assay 
being used, but 5 different assays have been used with differing 
results.  The Juskevich & Guyer paper cites studies which show 
varying changes in IGF-I levels from 0 increase to 70% increase up to 
300% increase depending upon the assay.

In addition to problems with a lack of a standard assay, experiments 
on a small number of animals are not worth much because the IGF-I 
levels in milk can change from week to week.  What is really needed 
is to measure milk trucks using a standard assay.

Monsanto did this when they tested 100 truck-loads of milk from 
untreated cows and put the IGF-I level at 4,320 ng/l.  In a 
measurement of a small number of rBST-treated cows, the IGF-I level 
in milk was listed at 35,000 ng/l.  However, it is not fair to equate 
the two measurements as was pointed out to Mr. Cohen.  In Eli Lilly's 
application for approval of their rBST-like product, they state that 
the IGF-I level in rBST-treated cow milk should not increase above 
50,000 ng/l.

All parties agree that there will be a significant increase in IGF-I 
levels, but there have not been any large-scale testing done (using a 
standardized assay) on both treated and untreated cow milk.  The FDA 
admits that it does not have the facilities for such testing.  Mr. 
Cohen is try to push for this testing.

3.  How is rBST injected?

It is injected intramuscularly.  This bypasses the digestive system 
so that it is closer to the subcutaneous injections in lab animals 
than the oral administration in lab animals.

4.  Why was IGF-I assumed to by destroyed by the digestive system.

IGF-I was tested in "Tween-80" in animals and not in commercial milk 
products which protects IGF-I from the digestive system.

5.  What is EGF?

Epidermal Growth Factor.

6.  What is meant by the discussion on glucagon and GH?

Glucagan and GH are present in cows.  This gives us clues as to how 
rBGH interacts with glucagan and GH to increase IGF-I levels.

7.  What is bFGF?

Bovine Folicle Growth Hormone.  I think he said that it is found in 
milk.

***********************************************************************
                          BEGIN ENCLOSURE #2
***********************************************************************



C Greg Guyer                                 4/27/94
Director
Division of Chemistry
Center for Drug Evaluation
DHHS
Food and Drug Administration
Rockville, MD 20857

Dear Dr. Guyer:

On May 3rd, we will invalidate the SCIENCE article which you 
co-authored with Dr. Juskevich.  This will be done before legal 
counsel of the City of New York.

I invite you and the Monsanto people, please also bring Mr. Mike 
Taylor (the former Monsanto attorney, now Deputy Director FDA) to 
come and explain the following:

1.  The reasons for the errors between your Ann. Rich. Vet. article 
    and the SCIENCE article.  Please bring a copy of the original 
    notebook. There are four differences.

2.  Why in the summary of your paper statistically significant oral 
    effects were not mentioned but noted as significant in the Table 5 
    data.

3.  Why no teratogenic [fetal development hazards] data were reported
    or done

4.  Why no long term exposure data and two year feeding studies were 
    done on zinc rBGH and rBGH milk, and why the liver effects cited by 
    Groenewegen brom rBGH milk fed 90 days were ignored (J. Nutrition 
    120, 514)

5.  Why IGF-I was tested only about two weeks when it showed a 
    statistically significant oral effect during this period of exposure 
    in some tests.

6.  As a policy I invite the Policy Director, Mr. Taylor, to explain 
    to the public how short term tests are being used to clear chemicals 
    for long term exposure.  Please explain how epidemiology can be 
    replaced by short term tests.  Also explain how we can go from 30 
    rats to 240 million people using a 90 days test.

7.  Please ask Commissioner Kessler to give you a note saying to the 
    people of New York why no quality assurance test is in the public 
    domain as for antibiotics imported and so forth.

We look forward to hearing your explanations and also to see the 
actual data which were used in the Ann. Rech. Vet. article.

                              [signed Dr. William C. von Meyer]
                              Fairview Industries

-----------------------------------------------------------------------

    Invalidation of Scientific Publication(s) Ann. Rech. Vet. 21, 
    Suppl. 1, 107s, 1990 and SCIENCE 249, 875, 1990 by Hammond and 
    Juskevich et. al, respectively, as Documentation for Determination of 
    Safety of Bovine Growth Hormone Derived Milk and Components of the 
    Milk Process.

Whereas, documents in health research concerning the safety of 
materials to large number of consumers must be accurate and precise; 
and,

Whereas, large numbers of people are contacted by milk and milk 
process products over a life span, and

Whereas, Monsanto Corporation of St. Louis and others propose to 
change the process for the manufacture of milk using new h ormone 
chemicals, signified as rBGH and rBST from recombinant genetic 
processes involving fermentation; and

Whereas, data have been submitted to the F.D.A. on the safety of the 
milk and the process and its components, and

Whereas, the data as published show errors and clever deviations from 
standard and well established safety practice which would be detected 
only by an experienced scientist as given in Attachment 1, and

Whereas, the editor of the publication SCIENCE has shown a bias which 
is not permitted in strict science data reviews (Attachment 2) such 
that this bias may permit the propagation of errors and 
misinterpretation; and,

Whereas, data concerning the residual action and occurrence of forms 
of IGF-I (insulin-like growth factor -I, a material not well 
understood as to its actions) may involved the biochemistry and 
development of or enhancement of cancer cell growth, and

Whereas, several experiments show an increase in IGF-I in raw rBGH 
milk such that long term feeding tests are mandatory, and

Whereas, a report of off-grad rBGH has leaked to the public as 
reported in letters to Dr. Kessler and Ms. Browner (E.P.A.) and the 
City Council of New York, and we lack a public quality control 
methodology for rBGH, a subject omitted in the SCIENCE paper;

Now, therefore, the SCIENCE and Ann. Rech. Veg. 21, suppl 1 107s 
documents defined in the title above are declared invalid as careful 
reviews of the health and safety data concerning rBGH milk as 
provided in Attachment 1.

[signed]
Dr. William C. von Meyer    5/1/94
C.E.O., Member N.Y. Academy of Science and
Am. Association of Adv. of Science

                                              [signed]
                                              Notary
----------------------------------------------------------------------

                        Attachment 1.

The figures in Table 4. of SCIENCE 249, 875, 1990, derived from the 
same animals as reported in an article in Ann. Rec. Vet. 21, suppl. 
1, 107s lack numerical agreement.

All publications of the health review of rBGH milk lack any long term 
or chronic toxicological data in standard animal models; no test 
longer than 90 days.

The summary of the SCIENCE article indicates no oral effects were 
noted while the tables of data reported indicate, by symbols 
indicating statistical significance at P.05 or P.01, oral activity 
was observed.

Reproduction and teratogenicity data have not been published in 
SCIENCE and critical tests were not conducted, however, reports of 
reproductive disturbances in cow have come to the public's attention 
and concern (Montpelier Chronicle Nov. 20, 1991 and comments from Mr. 
Kurtz, Lewiston, MN.)  In the former report animals receiving a 
growth hormone preparation showed retained placenta and skipped 
generation teratogenic effects.  In the Minnesota report, 19% of the 
cows died from stress including hip breakdown after two lactations on 
rBGH.  These kinds of data have been omitted from the reviews and 
freedom of information documents issued to date.

A short term oral feeding test in rat of rBGH milk showed effects on 
liver in J. Nutrition 120, 514.  The SCIENCE article failed to alert 
the public that a 90 day test on 30 rats at a given dose is the 
longest test which has been conducted on rBGH milk.  Normal tests and 
publications regarding chronic safety involve a minimum of two years 
exposure and careful observation.  In this case the American public 
would be asked to accept a product, without a label in many states, 
which lacks long term tests, quality control in public labs, and with 
only short term test on potenial orally active by-product hormones 
like IGF-I.

The data review of rBGH milk fails to relate for its value in quality 
control concerns that other proteins are very toxic at low dosage 
and/or orally active such as botulinin, cholera toxin, and even such 
vaccines as polio vaccine.

The SCIENCE article assumes digestion of all putative rBGH milk 
toxins because they are proteins but fails to cite any well known 
stable and orally active proteins.

Long term, or slow diseases, like diabetes and arthritis were not 
examined.

The Report in SCIENCE fails to related to the public the role of zinc 
in the product and process.  Of concern is the formation of stable 
zinc derivatives which may have unique toxicology and chemistry.  A 
well known form of zinc protein is the zinc loop protein which can 
bind to DNA.  Also there is lacking a discussion involving the 
problem of women and children contacting raw milk on the farm which 
is higher in IGF-I.
-----------------------------------------------------------------------


Question by Walter McCaffrey, City of New York, to Robert Collier of 
Monsanto, "Is Dr. von Meyer's testimony that the longest test on rBGH 
milk is 90 days true?"

Reply by Robert Collier, Director Animal Health Research, Monsanto.

"Yes."

            (Hearing 194, City of New York, May 3, 1994)

Just prior to this testimony the FDA's publication of the safety data 
on rBGH and IGF-I was invalidated by Fairview Industries, Inc. of 
Middleton, Wisconsin.


More information about the Neur-sci mailing list