Bovine somatotropin

Bovine somatotropin also known as bovine growth hormone or recombinant bovine somatotropin, is an animal drug approved by U.S. Food and Drug Administration (FDA) to increase milk production in dairy cows ¹, but it is prohibited in several countries, among others Canada, Australia, New Zealand, Japan, Israel and the Member States of the European Union, following animal welfare concerns connected to the use of the substance, in particular increased mastitis in dairy cows ². Bovine growth hormone drug is based on the somatotropin naturally produced in cattle. Growth hormone (GH) or somatotropin is a protein hormone produced in the pituitary gland of animals, including humans, and is essential for normal growth, development, and health maintenance. The Joint Expert Committee on Food Additives (JECFA) concluded that “there was no evidence to suggest that the use of recombinant bovine somatotropin would result in a higher risk to human health due to the possible increased use of antimicrobials to treat mastitis” ². JECFA interprets the absence of evidence for the association between the treatment with recombinant bovine growth hormone and the development of resistant mastitis pathogens as sufficient to support the previous JECFA-50  conclusions. In the absence of such evidence, the link between the use of recombinant bovine growth hormone and antimicrobial resistance in dairy cattle should be further investigated before being able to provide definite conclusions ².

Although the use of recombinant bovine growth hormone is still approved in the United States, demand for the product has decreased in recent years. Many large grocery store chains no longer carry milk from cows treated with recombinant bovine growth hormone. A United States Department of Agriculture survey conducted in 2007 found that less than 1 in 5 cows (17%) were being injected with recombinant bovine growth hormone.

Approximately 80 years ago in the 1930s in Russia ³ and 1940s in England ⁴, it was discovered that injecting cows with growth hormone extracted from cattle pituitary glands, specifically bovine somatotropin, increased milk production. English scientists attempted to increase milk production in cows during World War II with pituitary-derived bovine somatotropin to alleviate food shortages. However, it wasn’t until the 1980s that it became technically possible and economically feasible to produce large commercial quantities of bovine somatotropin by a process using biotechnology ⁵. The bovine somatotropin derived by this process is typically called “recombinant” bovine somatotropin or “rbovine somatotropin”. This process is also advantageous for producing a more consistent and purified source of bovine somatotropin.

The FDA approves an animal drug only after information and/or studies have shown that the food (in this case, milk and meat) from the treated animals is safe for people to eat, and that the drug does not harm treated animals, or the environment. The drug also must be effective, meaning that it works as intended. The labeling for animal drug products provides all instructions for safe and effective use and is approved by FDA.

FDA approved a recombinant bovine somatotropin product in 1993 with the brand name “Posilac™” (sometribove zinc suspension) after determining that its use would be safe and effective. Posilac™ is approved for over-the-counter use in dairy cows starting at around 2 months after the cow has a calf until the end of the lactation period. During this time, cows are injected with Posilac™ subcutaneously (under the skin) every 14 days. A cow’s typical lactation period is approximately 10 months long, starting right after she has a calf. Thus, treated dairy cows are typically given Posilac™ for about 8 months of the year. After the 10-month lactation period, the producer stops milking the cow to allow a 2-month period for her mammary gland to rest and regenerate before she has a calf and starts the next lactation period.

A key factor in FDA’s determination that milk and meat from cows treated with Posilac™ is safe for humans to eat is that bovine somatotropin is a large protein. Like most dietary proteins, bovine somatotropin is degraded by digestive enzymes in the gastrointestinal tract and not absorbed intact. The digested proteolytic fragments have no biological activity. Furthermore, even if it was injected, bovine somatotropin does not promote biological activity in the human body because somatotropins from lower mammalian species have no activity in humans. Posilac™ has a zero day withdrawal. This means that the milk and meat from cows is safe for humans to eat at any time after the animal is treated with Posilac™. Numerous international health and food safety organizations and many national regulatory agencies have confirmed the safety of milk and meat from bovine somatotropin-treated cows for human consumption. Additional information on the safety of milk and meat from treated cows is provided in the references below.

FDA evaluated the results of numerous studies before approval to determine if Posilac™ was safe for treated dairy cows. Many of the studies were conducted under typical farm conditions in multiple regions of the U.S. The effects of treatment were evaluated on all aspects of cows’ health, feed intake, ability to have a calf, and the health of their offspring. FDA concluded that Posilac™ was safe to use in healthy dairy cows. Some increased side effects were observed in Posilac™-treated cows, but FDA determined that these effects were manageable under normal U.S. farming conditions. The labeling for the product identifies the potential side effects to treated cows so that dairy farmers can make an informed decision on whether to use Posilac™ in their herd. A post-approval monitoring study in 28 herds around the U.S. and including more than 1000 dairy cows confirmed the safety of the product to treated cows. Additional information on the safety of Posilac™ for dairy cows is provided in the references below.

As with all drugs approved by FDA, the Agency continues to monitor the safety and effectiveness of Posilac™ through post-approval surveillance and review of all reported adverse drug experiences.

Bovine growth hormone effects on humans

Concerns about possible health effects on humans from milk produced using recombinant bovine growth hormone have focused on 2 main issues.

1. First, does drinking milk from recombinant bovine growth hormone-treated cows increase blood levels of growth hormone or insulin-like growth factor 1 (IGF-1) in consumers? If it does, would this be expected to have any health effects in people, including increasing the risk of cancer? Several scientific reviews have looked at these issues and are the main focus of this document.
2. Second, cows treated with recombinant bovine growth hormone tend to develop more udder infections (mastitis). These cows are given more antibiotics than cows not given recombinant bovine growth hormone. Does this increased use of antibiotics lead to more antibiotic-resistant bacteria, and is this a health concern for people? This remains a concern, but it has not been fully examined in humans.

The evidence for potential harm of bovine growth hormone or recombinant bovine somatotropin to humans is inconclusive. It is not clear that drinking milk produced using recombinant bovine growth hormone significantly increases insulin-like growth factor 1 (IGF-1) levels in humans or adds to the risk of developing cancer. More research is needed to help better address these concerns.

The increased use of antibiotics to treat recombinant bovine growth hormone-induced mastitis does promote the development of antibiotic-resistant bacteria, but the extent to which these are transmitted to humans is unclear.

IGF-1 in milk from recombinant bovine growth hormone-treated cows

Although possible recombinant bovine somatotropin (bovine growth hormone) residues contained in milk from treated animals should be destroyed in the human digestive system, there are some non-clarified concerns about its safety for consumers ⁶. It has been reported that recombinant bovine somatotropin treatment may cause an increase on insulin-like growth factor 1 (IGF-1) in milk, in comparison to milk from non-treated dairy cattle and presents human health safety concerns ⁷. As IGF-1 levels are not altered by pasteurization of milk ⁸, the hypothesis of IGF-1 reaching the consumer seems plausible and biologically feasible ⁹. Insulin-like growth factor 1 (IGF-1) is a protein normally found in all humans, and is not intrinsically harmful. IGF-1 is necessary for normal growth, development, and health maintenance. Circulating plasma levels of the hormone increase from birth to late puberty and subsequently decline in adults to approximately 100 ng (10-9 grams)/ml (range = 42 – 308 ng/ml for men and women >23 years). IGF-1 is structurally similar to insulin and, like insulin, is not biological effective following oral administration.

Bovine growth hormone levels are not significantly higher in milk from recombinant bovine growth hormone-treated cows. On top of this, bovine growth hormone is not active in humans, so even if it were absorbed from drinking milk, it wouldn’t be expected to cause health effects.

Of greater concern is the fact that milk from recombinant bovine growth hormone-treated cows has higher levels of IGF-1, a hormone that normally helps some types of cells to grow. Several studies have found that IGF-1 levels at the high end of the normal range may influence the development of certain tumors. Some early studies found a relationship between blood levels of IGF-1 and the development of prostate, breast, colorectal, and other cancers, but later studies have failed to confirm these reports or have found weaker relationships. While there may be a link between IGF-1 blood levels and cancer, the exact nature of this link remains unclear.

Some studies have shown that adults who drink milk have about 10% higher levels of IGF-1 in their blood than those who drink little or no milk. But this same finding has also been reported in people who drink soy milk. This suggests that the increase in IGF-1 may not be specific to cow’s milk, and may be caused by protein, minerals, or some other factors in milk unrelated to recombinant bovine growth hormone. There have been no direct comparisons of IGF-1 levels in people who drink ordinary cow’s milk vs. milk stimulated by recombinant bovine growth hormone.

At this time, it is not clear that drinking milk, produced with or without recombinant bovine growth hormone treatment, increases blood IGF-1 levels into a range that might be of concern regarding cancer risk or other health effects.

The safety of IGF-1 in milk was thoroughly considered by FDA in its review of the Posilac™ application ¹⁰. Some early studies suggested that treatment of dairy cows with recombinant bovine growth hormone produced a slight, but statistically significant, increase in the average milk IGF-1 concentration. FDA determined that this modest increase in milk IGF-1 concentration was not a human food safety concern because it was less than the natural variation in milk IGF-1 levels observed during lactation and was less than the fluctuation observed in milk from treated and control cows prior to recombinant bovine growth hormone administration.

Since making that analysis, however, FDA has received and reviewed several more comprehensive studies designed to ascertain the effect of recombinant bovine growth hormone treatment on milk IGF-1 levels. These studies have demonstrated that the levels of IGF-1 found in milk from treated cows are within the range of those normally found in milk from untreated cows. In 1993, the JECFA Committee concluded, “the most definitive and comprehensive studies demonstrate that IGF-1 concentrations [in milk] are not altered after recombinant bovine growth hormone treatment”. The 1998 JECFA Committee report summarized a study showing no significant difference in commercially available milk labeled as coming from non-recombinant bovine growth hormone treated cows and milk from cows presumed to be treated with recombinant bovine growth hormone but not labeled as to treatment.

A recent study ¹¹ has been published on the association between prostate cancer and IGF-1. This study showed a positive correlation between the level of IGF-1 in plasma and the increased risk of prostate cancer. Although the mechanism responsible for induction of cancer has not been characterized fully, it is clear that IGF-1 is not the causative agent.

FDA has examined the literature and finds no definitive evidence of any direct link between IGF-1 and breast cancer. Some authors have hypothesized a link, whereas others have expressed that while IGF-1 is one of several growth factors and hormones that can contribute to an increase in cell numbers of many cell types in vitro, no one factor is responsible for changing normal cells into cancerous cells. Furthermore, FDA has been advised that there is no substantive evidence that IGF-1 causes normal breast cells to become cancerous ¹².

In evaluating the potential for human health risk from a natural component of the body, one can examine the effect of an increased exposure to IGF-1 by employing several assumptions (i.e., IGF-1 levels in milk from recombinant bovine growth hormone-treated cows are increased from 4 ng/ml to 6 ng/ml, all of the IGF-1 in milk is absorbed into the body, and absorbed IGF-1 is confined to the vascular compartment). Assuming 5000 ml blood plasma volume in a 60 kg person and assuming this person consumes 1.5 liters of milk containing 9000 ng IGF-1 from recombinant bovine growth hormone-treated cows (as opposed to 6000 ng IGF-1 in milk from untreated cows), the maximum increase in blood IGF-1 would be less than 2 ng/ml of which only one-third could be attributed to the use of recombinant bovine growth hormone. This minute increase would dilute into the endogenous pool of circulating IGF-1. IGF-1 entering the circulation is rapidly bound to serum binding proteins which attenuate the biological activity ¹³.

It bears repeating that the assumptions that milk levels of IGF-1 are increased following treatment with recombinant bovine growth hormone and that biologically active IGF-1 is absorbed into the body are not supported by the main body of science. Careful analysis of the published literature fails to provide compelling evidence that milk from recombinant bovine growth hormone-treated cows contains increased levels of IGF-1 compared to milk from untreated cows. Despite recent studies that demonstrate that milk proteins protect IGF-1 from digestion, the vast majority of the published work indicates that very little IGF-1 is absorbed following ingestion. The most recent 1998 review by the JECFA concluded that, “the concentration of IGF-1 in milk from recombinant bovine growth hormone-treated cows is orders of magnitude lower than the physiological amounts produced in the gastrointestinal tract and other parts of the body. Thus, the concentration of IGF-1 would not increase either locally in the gastrointestinal tract or systemically, and the potential for IGF-1 to promote tumor growth would not increase when milk from recombinant bovine growth hormone-treated cows was consumed; there is thus no appreciable risk for consumers.”

Effect of recombinant bovine somatotropin on infants and children

Strong concerns over the potential risk to infants and children of milk containing recombinant bovine growth hormone were expressed by Vermont Public Interest Group and Rural Vermont but no specific issues were raised to substantiate this concern. The FDA considers the impact on high-risk populations in assessing the safety of new animal drugs. For recombinant bovine growth hormone in particular, issues related to levels of IGF-1 in infant formula were carefully examined by FDA. Other concerns, including the hypothetical development of insulin-dependent diabetes mellitus following the consumption of milk from recombinant bovine growth hormone-treated cows, have been reviewed by the FDA as well as other national and international scientists. To date, all of these reviews have concluded that consumption by infants and children of milk and edible products from recombinant bovine growth hormone-treated cows is safe ¹⁰.

References

1. Bovine Somatotropin (bST). https://www.fda.gov/animal-veterinary/product-safety-information/bovine-somatotropin-bst
2. EFSA (European Food Safety Authority), 2015. EFSA’s assistance for the 2015 Codex Committee on Residues of Veterinary Drugs in Food (CCRVDF) in relation to rBST. EFSA supporting publication 2015:EN-828. 89 pp. https://doi.org/10.2903/sp.efsa.2015.EN-828
3. Asimov, G. & Krouze, N. The lactogenic preparations from the anterior pituitary and the increase of milk yield in cows. J. Dairy Sci. 20, 289–306 (1937).
4. Young, F. Experiemental stimulation (galactopoiesis) of lactation. Br. Med. Bull. 5, 155–160 (1947).
5. Burton, J. L., McBride, B. W., Block, E., Glimm, D. R. & Kennelly, J. J. A review of bovine growth hormone. Can. J. Anim. Sci. 74, 167–201 (1994).
6. Lamas, A., Regal, P., Vázquez, B. et al. Tracing recombinant bovine somatotropin ab(use) through transcriptomics: the potential of bovine somatic cells in a multi-dose longitudinal study. Sci Rep 9, 4788 (2019). https://doi.org/10.1038/s41598-019-41343-6
7. Ludwig, S. K. et al. Calling biomarkers in milk using a protein microarray on your smartphone. PLoS One 10, e0134360 (2015).
8. Collier, R. J. et al. Factors affecting insulin-like growth factor-I concentration in bovine milk. J. Dairy Sci. 74, 2905–2911 (1991).
9. Shen, W. & Xu, R. Stability of insulin-like growth factor I in the gastrointestinal lumen in neonatal pigs. J. Pediatr. Gastroenterol. Nutr. 30, 299–304 (2000).
10. Report on the Food and Drug Administration’s Review of the Safety of Recombinant Bovine Somatotropin. https://www.fda.gov/animal-veterinary/product-safety-information/report-food-and-drug-administrations-review-safety-recombinant-bovine-somatotropin
11. June M. Chan, Meir J. Stampfer, Edward Giovannucci, Peter H. Gann, Jing Ma, Peter Wilkinson, Charles H. Hennekens, Michael Pollack, (1998) Plasma Insulin-like Growth Factor-I and Prostrate Cancer Risk: A Prospective Study. Science, 279:536-566.
12. Taken from a letter from Dennis M. Bier, M.D., Professor of Pediatrics and Director, Children’s Nutrition Research Center, College of Medicine, Baylor University, to David A. Kessler, M.D., Commissioner, Food and Drug Administration, February 25, 1994.
13. Louis E. Underwood and Judson J. Van Wyk, (1992) Normal and Aberrant Growth. In Williams Textbook of Endocrinology, Jean D. Wilson and Daniel W. Foster, eds. WB Saunders Co., Philadelphia, 1079-1138.