Recombinant Bovine Growth Hormone, Public Servants and Trust

Health Protection Branch, Health Canada
April 21, 1998

This volume consists of the submission by Consumers International, a 230- member organization in 100 countries: supplementary information dated Sept 25/97

Identified potential public health impacts were as follows:

1. Levels of IGF-I are significantly elevated in milk from rBST treated cows and will continue to rise with increased use of BST.It is the IGF-I, not the BST per se. that is the main cause for concern regarding possible adverse effects on human health. It is indicated that IGF levels are substantially increased in the latest Monsanto study and in 5/7 studies previously reviewed by JECFA. US FDA concurs that BST treatment leads to statistically significant increases in IGF-I levels in milk. Another study (Prosser et al, 1989) was cited which was reviewed neither by JECFA nor FDA, which reported very high levels (3.6x normal) – much higher than what had been presented in the submitted data. Table I is a good summary of the data.
3. IGF-I, in the presence of casein and other protective factors, is not destroyed by digestion in the stomach and can pass into the intestine, where it may produce local harmful effects. Epithelial cells in the colon grow more rapidly in response to IGF-I at the levels typically found in milk. Acromegaly, a disease involving high endogenous IGF-I levels, is associated with increased risk of colon cancer and pre-cancerous colon polyps.
5. It is suggested that toxicity studies with free IGF and the fact that endogenous levels of IGF levels are higher than what is found in the milk of BST treated cows is irrelevant because the IGF is not associated with any protective factors that would ensure bioactivity. IGF binds to receptors lining the GI tract and will stimulate the synthesis of its own receptors. It is also suggested that IGF -1 can be absorbed in the systemic circulation where it may affect the levels of other hormones.
7. Increased mastitis leads to higher antibiotic residues exacerbating antibiotic resistance. The FDA’s “safe” limits of up to 150 ppb can select for disease resistance in S. aureus.
9. It is speculated that IGF-I plays a role in the expression of genes that encode for prion synthesis and that increased IGF-I shortens the incubation period for Bovine Spongiform Encephalopathy (BSE). Thus, the use of BST might increase the risk of exposure to BSE infection.

• local effects on GI tract: both paracrine and autocrine in nature – growth factor for colon cancers -conclude that the colon is at special risk
• strong role in breast cancer
• may play a role in osteosarcoma, the most common bone tumor in children, usually occurring during the adolescent growth spurt
• implicated in lung cancer
• possess angiogenic properties – important to tumors some of which secrete their own growth factors to promote angiogenesis,
• e.g., retinal neovascularization in mice

In November of 1993, the FDA approved rBST zinc suspension to enhance milk production in lactating dairy cows, declaring that the milk from treated cows is safe for human consumption. The United States is the only developed country permitting the use of BST, of which there are four manufacturers. There are reports on file that Monsanto pursued aggressive marketing tactics, compensated farmers whose veterinary bills escalated due to increased side effects associated with the use of rBST, and covered up negative trial results. All the four US manufacturers refused to disclose the lists of their research grants to US universities.

 

• WHAT WAS DONE

  For the purpose of approving ESCs, HSD concluded that the milk and meat from BST treated cows was safe for human consumption as early as 1986, without providing any rationale as why this conclusion was reached. Studies submitted in support of this conclusion were not described until 1990.

  1990: 4-page review by D.R. Casorso completed within two weeks of the filing of the submission.

  1995: more detailed review by M.S. Yong which presented, for the first time, the rationale for concluding that meat and milk from BST -treated cows is safe for human consumption; first mention of the potential adverse health effects of IGF-I.

  1998 reviews by M.S. Yong: rationale for waiving the need for chronic toxicity testing; discussion of potential allergenicity.

  ---

  
  WHAT WAS NOT DONE

  Studies indicated by manufacturer as being available upon request were never requested by HSD reviewers.

  Importance of the 3-month rat toxicology study as an indicator of potential oral absorption of rBST, i.e., the demonstration of immunoglobins in rat serum, was not mentioned. This is an important omission in that the lack of oral bioactivity formed the basis for waiving chronic toxicity study requirements. The human health implications of the immunological findings in rats should have been thoroughly evaluated and dismissed only if adequately justified by the evidence available at the time (e.g., binding of rBST to HG receptor is negligible; antibodies raised to rBST will not cross react with HG, primary response was induced in only 30% of animals at high doses, etc.). IGF-I production in liver of rats was not examined. Species specificity issues and possible threshold effects (dose -response) should have been discussed. Secondary challenge bioassays should have been requested to further characterize the immunological response.

  The fact the rBST can be absorbed, albeit at high doses, calls into question the decision not to request additional chronic toxicity studies. The evaluator should have explored the physiological effects of such high oral doses (and effects on hypophysectomized rats further (e.g., effects on peripheral growth and metabolism).

  The 1990 evaluation was largely a theoretical review taking the manufacturer’s conclusions at face value. No details of the studies nor a critical analysis of the quality of the data was provided.

  The requirement for a 3-month study in a nonrodent species (e.g,, dog) was not requested. No long-term toxicology, teratology or reproductive/fertility studies were requested. Definitive studies demonstrating the lack of absorption of rBST or IGF-I upon oral administration were neither conducted nor requested.

  Potential adverse effects of IGF-I on human health were not discussed until 1995. When discussed, rationales were based purely on speculative reasoning and not on substantive data or studies. The rationale for not requiring chronic toxicity or teratology/reproductive studies was described in more detail in the 1998 reports but again is based on the assumption that there are no physiological consequences of oral absorption of rBST. This ignores the fact that the 3-month rat study did show a physiological response.

  Evidence from the animal safety reviews were not taken into consideration. These studies indicated numerous adverse effects in cows, including birth defects, reproductive disorders, higher incidence of mastitis, which may have had an impact on human health. This observation should be qualified by the poor quality of the data package. Similar observations were recorded in the FDA FOI summary and the company label. These findings should have stimulated the need for requesting additional teratology and reproduction studies in laboratory animals. This should have prompted HSD evaluators to re-examine the accuracy of their data and the assumptions based thereon.

  The mastitis issue should have raised concerns regarding increased use of antibiotics with consequent exacerbation of resistance to antibiotics.

  The nature of the product (being a hormone) and its chemistry should have prompted more exhaustive and longer toxicological studies in laboratory animals.