5/10/95 Hi! About four months ago I posted an article by Robert Cohen about the BST/bGH issue where he showed that the use of the genetically- engineered hormone on cows causes significant health problems with the cows *and* significantly increases cancer risk for humans. He sent me an updated copy of the article which he recently presented to the FDA. I will enclose the article with his permission after this short introduction. I have to admit, I was a little disappointed with this article in the sense that it did not go into as much detail as the last revision. He cut out more detailed discussions of ideas that the FDA had already agreed to (such as the increase of IGF-I in milk from rBST-treated cows). I believe Mr. Cohen used this paper as a *basis* for discussion with the FDA and not as a detailed dicussion of the BST/bGH issue. I spoke with Mr. Cohen a couple of days ago and asked him a few questions that may begin to clear up some ideas in the article that might be confusing. I will enclose some of the answers to those questions following the article. Feel free to forward any questions to me which I will pass along to Mr. Cohen, as I am not an expert in this matter. By the way, the article is about 10 pages long. Best regards, - Mark mgold@holisticmed.com ************************************************************************* 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." 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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.