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Bovine somatotropin Technology Assessment Conference Statement

National Institute of Health,
Office of Medical Applications of Research,
Technology Assessment Conference Statement
December 5-7, 1990

Introduction

Recombinant bovine somatotropins (rbST) are biosynthetic versions of the naturally occurring pituitary hormone in cows. They also are known as bovine growth hormones (bGH). Bovine somatotropin differs in structure from human pituitary growth hormone and is biologically inactive in the human being. rbST increases milk production in cows. rbST treatment in dairy cows has generated a great deal of controversy and public interest. Questions have been raised about possible adverse health effects of the consumption of milk and meat from rbST-supplemented animals and of the treatment on dairy cows.

To assess these issues, the National Institute of Child Health and Human Development, the National Institute of Diabetes and Digestive and Kidney Diseases, the Division of Nutrition Research Coordination, and the Office of Medical Applications of Research of the National Institutes of Health convened the Technology Assessment Conference on Bovine somatotropin on December 5-7, 1990. A panel was charged with reviewing scientific data and weighing the evidence on the safety of milk and meat from rbST- treated cows for human consumption and its effect on the health of cows. Issues of public policy, including economic, social, and environmental concerns, are important but are not within the charge of the panel.

The panel reviewed a large body of data in the published literature, presentations by scientific experts and other interested participants, and discussion by the audience before making its final assessment. The available information on animal safety, although extensive, only included a small subset of the data on the effects of rbST in more than 20,000 dairy cows on file with the Food and Drug Administration (FDA). The panel, drawn from specialists and generalists from the medical profession and related scientific disciplines, clinical investigators, and public representatives, considered the evidence and addressed the following questions:What is the role of milk in human nutrition, and how is its safety for human consumption monitored?

1. What is the comparative biology of human and bovine lactation and milk composition?
2. What is the effect of administration of rbST on milk production of cows and on the nutritional quality and hormonal content of their meat and milk?
3. What are the health effects on cows resulting from administration of rbST?
4. What are the health effects on humans resulting from consumption of meat or milk from cows given rbST?
5. What further animal and human research is needed on use of rbST?

What is the Role of Milk in Human Nutrition, and How is Its Safety for Human Consuption Monitored?

Role of Milk in Human Nutrition

Milk makes important contributions to the nutrition of people in many parts of the world. In the United States, cows produce nearly all of the commercial supply.

"Recommended Dietary Allowances," a publication of the National Research Council of the National Academy of Sciences, summarizes the scientific consensus on which nutrients are essential for man and in what quantities. There are approximately 37 essential nutrients, and recommended dietary allowances have been established for 17; allowances differ depending on age, sex, and body size, and during pregnancy and lactation. Many governmental and other health organizations publish guidelines for selection of healthful diets that would ensure the intake of essential nutrients in appropriate quantities.

Calcium is one of the nutrients most likely to be limited in Americans' diets. Milk is the primary dietary source of calcium, and is also an excellent source of phosphorus, protein, magnesium, riboflavin, vitamin B-12, and other nutrients; it is almost uniformly fortified with vitamin D. (Milk and milk products are the source of about 70 percent of the total calcium intake of Americans.) Calcium, phosphorus, and vitamin D are essential for development and maintenance of bones and teeth, and milk is the central dietary source of all three.

Milk is an important food throughout the life cycle, especially in the diets of infants, children, pregnant and lactating women, and the elderly. Recent research emphasizes the importance of milk products in providing calcium throughout life to promote bone density and to prevent or delay osteoporosis. Thus, milk plays important roles in the human diet throughout life.

Control of Milk Safety and Quality

Because milk is such an important food in the American diet and is susceptible to contamination by pathogenic and toxigenic bacteria and by hazardous residues such as animal drugs and pesticides, it receives critical attention of regulatory agencies to ensure its safety and wholesomeness. Milk is the most monitored food in the American food supply.

The control and regulation of the wholesomeness and safety of milk and milk products rest on the cooperative efforts of the Federal government; State governments; and producers, processors, and vendors of these products.

Safety, sanitary, and wholesomeness standards are the responsibility of the FDA, operating in cooperation with all 50 States under the "Grade A Pasteurized Milk Ordinance" (PMO).

Under agreements with the States, primary control of milk and milk products is carried out by State officials. The PMO sets minimum standards, but some States set more stringent requirements. For example, although there is a mandatory requirement that the States evaluate and take action on antibiotic test results from a minimum of 1,200,000 raw milk and 70,000 finished-product samples each year, the actual number is far greater. Additional analyses are carried out by milk processors and manufacturers of milk products. Results of such analysis may result in the rejection of the complete output of a farm, or if already in tank, the rejection of the complete tank. Depending on conditions and ordinances involved, this could place the cost of the discarded milk upon the farm source of the illegal residues.

In addition to sanitary and microbiological standards, the FDA regulates the use of animal drugs and feed additives and establishes regulations for safe residues in milk. The agency also controls the use of food additives used in the processing, packaging, and transport of milk and milk products.

Although the Environmental Protection Agency sets the tolerances for the pesticides that might enter milk through forage crops and cattle feeds, the regulatory control and residue analyses are a responsibility of FDA and State governments.

The control of mammary gland development and lactation is similar in the cow and human. It requires the action of prolactin secreted by the pituitary gland in concert with the actions of estrogen and progesterone and those supportive actions of other hormones. Milk is synthesized and secreted by the alveolar cells of the mammary gland, which do not fully develop until pregnancy. Full lactation (lactogenesis) is initiated at parturition when progesterone levels fall; progesterone inhibits milk secretion. In the cow, maintenance of lactation (galactopoiesis) does not require the continued production of prolactin, and it is believed that this function is carried out by the secretion of growth hormone from the pituitary gland. In contrast, prolactin is required throughout the period of lactation in the human. In both species, however, growth hormone is a potent galactopoietic agent, but its mechanism of action in this gland is unknown.

Bovine and human milk are similar in energy content and overall nutritional value. Bovine milk, however, is higher in protein and lower in carbohydrate content than human milk; the fat content is approximately the same in both. In cows' milk, casein is the predominant protein, while whey proteins predominate in human milk.

The content of hormones, growth factors, and hormone-like peptides, where they are known, appears to be similar in both milks. Concentrations of bovine growth hormone in cows' milk and human growth hormone in human milk are both approximately 1 ng/ml (one part per billion). The concentration of insulin-like growth factor-I (IGF-1), a mediator of growth hormone action, is in the range of 1.5 to 8 ng/ml in pooled bovine milk and 1 to 3 ng/ml in human milk. Because these hormones are digested in the gastrointestinal tract and are not absorbed intact into the bloodstream, they are not believed to have biological significance when ingested, at least after the newborn period.

What is the Effect of Administration of rbST on Milk Production of Cows and on the Nutritional Quality and Hormonal Content of Their Meat and Milk?

There is compelling evidence in the scientific literature that rbST injection increases average milk production by 10 percent or more under a variety of environmental and farm management conditions. There is large variation in the average increase for any particular dairy herd, with the larger increases occurring with better management and larger doses. Like many hormones, there is a dosage beyond which there is no additional response.

The evidence indicates that the nutritional quality of milk and meat from rbST-treated cows is equivalent to that of milk and meat from untreated cows. Protein, fat, and mineral content, including calcium, of the milk are all within the range found in untreated cows. The concentration of casein, a major milk protein, is slightly lower, and the concentration of oleic acid, the 18-carbon, mono-unsaturated fatty acid, is slightly higher, but both are within the usual range of variation. Meat derived from treated cows is lower in fat content but otherwise is nutritionally equivalent to that from untreated animals.

Extensive information is available regarding the somatotropin and IGF-1 content of milk and meat from untreated and rbST-treated cows. The concentration of bST in the milk of cows treated with usual doses of rbST is no higher than the concentration in untreated cows. The concentration of IGF-1, a hormone mediating many of the effects of growth hormone, is higher in cows' milk (3 to 10 ng/ml) than in human milk (1 to 3 ng/ml), and the concentration increases by 2 to 5 ng/ml in cows treated with rbST. (The concentration of IGF-1I does not increase with rbST treatment.) There are few data available on the effects of rbST treatment on the concentration of other hormones and growth factors normally present in cows' milk.

Most milk consumed in the United States is pasteurized (heat treated). Pasteurization inactivates or destroys most of the bST in milk but has little or no effect on IGF-1. The more intense heat treatment used in the manufacture of infant formulas inactivates approximately 90 percent of the IGF-1. The bST content of the uncooked meat from rbST-treated cows is within the range found in untreated cows, but there is approximately twice as much IGF-1 in the meat of cows treated with rbST. Cooking the meat destroys both bovine somatotropin and IGF-1.

What Are the Health Effects on Cows Resulting From Administeration of rbST?

Available evidence indicates that the use of rbST can be an important management tool for the American dairy farmer. Well-managed, rbST- treated cows appear to produce milk in the same manner as cows that are high producers for any reason and probably experience no greater health problems than untreated cows producing the same amounts of milk.

Mastitis is the most costly disease of the dairy industry and affects both the quantity and quality of the milk produced, and the effect of rbST on mastitis is an important and controversial issue. The published data do not allow definitive conclusions on its effect. Two important types of mastitis in dairy cattle are subclinical mastitis (indicated by increased somatic cell counts in milk) and clinical mastitis. An increased incidence of clinical mastitis has been observed in treated cows in some rbST trials, possibly because higher producing dairy cows have a greater incidence of clinical mastitis. If there is an increase in mastitis in rbST-treated cows, there might be a concomitant increase in antibiotic therapy. Somatic cell counts from cows free of mastitis appear to be unaffected by rbST, but cell counts appear to increase slightly in cows with subclinical mastitis.

The use of rbST may increase the optimal calving interval. Thus, annual herd turnover may decrease because of extended lactation. Reproductive effects appear to be similar to those seen with higher milk production. Use of rbST will have more of an impact on reproductive management than on the biology of reproduction in dairy cows.

On the basis of data reviewed by the panel, additional effects of rbST on health of the dairy cow appear to be minimal. Injection of rbST may cause a mild local reaction. There is no compelling evidence of increased incidence of foot and leg problems or metabolic disease. Body temperature and respiration rate are unaffected, but heart rate is slightly raised at high doses. Calves from dams administered rbST have normal birth weights, growth, and development. The rbST-treated cows appear to react to stress, such as high humidity and metabolic or environmental heat, in the same manner as untreated high-producing cows.

The panel was apprised of the fact that a large body of data has been submitted to the FDA that is not yet available either to the public or to the committee. The panel was informed that an evaluation and analysis of these data will be forthcoming.

What Are the Health Effects on Humans Resulting From Consumption of Meat or Milk From Cows Given rbST?

Human and bovine milk normally contain small amounts of growth hormone. After ingestion, growth hormone is handled by the gut as any other protein in milk: it is digested into its constituent amino acids and di- and tripeptides. There are no data to suggest that bST present in milk will survive digestion or produce unique peptide fragments that might have biological effects. Even if bST is absorbed intact, the growth hormone receptors in the human do not recognize bST and, therefore, bST cannot produce effects in humans. This conclusion is affirmed by earlier studies that showed that bST administered by injection to growth hormone-deficient children was ineffective in augmenting growth or promoting nitrogen retention, nor are there convincing data that fragments of bST are biologically active in humans. Further, from available animal studies, there is no evidence that rbST administered orally in very high doses to species capable of responding to injected rbST is absorbed or has a biologic effect. IGF-1 concentrations in human milk are 1 to 3 ng/ml (parts per billion) while pooled cows' milk contains somewhat higher amounts. This protein will also be digested into its amino acid, di- and tripeptide constituents by gut enzymes. Similarly, there is no evidence that proteolytic fragments of IGF-1 are biologically active in man, nor is there evidence of systemic biological effects in man from any IGF-1 absorbed intact, because the amounts of IGF-1 that might potentially be ingested are orders of magnitude less than those required to produce such effects. A single, unconfirmed, short-term study in rats given high doses of IGF-1 orally revealed a significantly greater rate of body growth in male but not female rats.

Milk from rbST-treated cows contains higher concentrations of IGF-1. The importance of the increased amounts of IGF-1 in milk from rbST-treated cows is uncertain. The amount of IGF-1 ingested in 1 liter of milk approximates the amount of IGF-1 in saliva swallowed daily by adults. Young children and infants already ingest IGF-1 in commercially available cows' milk or in mother's milk. Whether the small additional amount of IGF-1 in milk from rbST-treated cows has a significant local effect on the esophagus, stomach, or intestine is unknown. The gut of the very young infant is an immature organ that can absorb intact proteins, although in relatively small amounts. However, most infants are either breast fed or fed commercially prepared infant formulas that contain no more than trace amounts of IGF-1 or growth hormone.

What Further Animal and Human Research is Needed on the Effects and Use of rbST?

The panel identified several areas of research that would be useful in providing information on the use of rbST. However, it did not consider that decisions on the commercial use of rbST should be delayed until these studies are completed.

• Continue the study of long-term effects of rbST on cows, including reproduction.
• Evaluate more thoroughly both clinical and subclinical mastitis in rbST-treated cows and their relationship to milk production.
• Define and characterize "stress" in dairy cows.
• Determine the mechanisms underlying the galactopoietic effects of growth hormone.
• Determine the concentrations of IGF-1 in human saliva as a function of age.
• Determine the acute and chronic local actions of IGF-1, if any, in the upper gastrointestinal tract.

Conclusions and Recommendations

In the unanimous judgment of the panel:

• rbST treatment increases milk production of cows.
• Based on the data reviewed by the committee, rbST administration does not appear to affect appreciably the general health of dairy cows; the evidence does not permit a conclusion regarding its effect on the incidence of mastitis.
• The composition and nutritional value of milk from rbST-treated cows is essentially the same as milk from untreated cows.
• As currently used in the United States, meat and milk from rbST- treated cows are as safe as those from untreated cows.

Technology Assessment Panel

Melvin M. Grumbach, M.D.
Conference and Panel Chairperson
Edward B. Shaw Professor of Pediatrics
Emeritus Chair
Department of Pediatrics University of California at San Francisco
San Francisco, California

Dennis M. Bier, M.D.
Professor of Pediatrics and Medicine
Washington University School of Medicine
St. Louis, Missouri

Herbert Blumenthal, Ph.D.
Toxicologist
Silver Spring, Maryland

James Clark, Jr.
Dairy Farmer
Ellicott City, Maryland

Walter L. Dunkley, Ph.D.
Professor Emeritus
Department of Food Science and Technology
University of California at Davis
Davis, California

Gary M. Gray, M.D.
Professor of Medicine
Stanford University School of Medicine
Stanford, California

Raymond L. Hintz, M.D.
Professor of Pediatrics and Head
Division of Endocrinology
Stanford University Medical Center
Stanford, California

Norman E. Hutton, D.V.M.
Associate Dean
College of Veterinary Medicine
Oregon State University
Corvallis, Oregon

Ernst Knobil, Ph.D.
H. Wayne Hightower Professor in the Medical Sciences
Director
Laboratory for Neuroendocrinology
University of Texas Medical School at Houston
Houston, Texas

Barbara Lippe, M.D.
Professor of Pediatrics and Chief
Division of Endocrinology
UCLA School of Medicine
Los Angeles, California

James H. Matis, Ph.D.
Professor of Statistics
Department of Statistics
Texas A and M University
College Station, Texas

David Rush, M.D.
Professor of Nutrition and Community Health
Human Nutrition Research Center on Aging
School of Nutrition, and Department of Community Health
School of Medicine
Tufts University
Boston, Massachusetts

K. Larry Smith, Ph.D.
Professor
Department of Dairy Science
Ohio Agricultural Research and Development Center
Ohio State University
Wooster, Ohio

Speakers

Clifton A. Baile, Ph.D.
"Quality of Meat from bST-Treated Cows"
Distinguished Fellow
Director of Research and Development
Animal Sciences Division
Monsanto Agricultural Company
St. Louis, Missouri

R. Lee Baldwin, Ph.D.
"Overview of rbST Development and Use"
Professor
Department of Animal Science
University of California at Davis
Davis, California

David M. Barbano, Ph.D.
"Effect of bST on Milk Production and Nutrient Composition"
Associate Professor
Department of Food Science
Cornell University
Ithaca, New York

Richard J. Burroughs, D.V.M.
"Comment on the Methodology of Data Collection"
Mt. Airy, Maryland

Robert J. Collier, Ph.D.
"Qualitative and Quantitative Changes in Hormones and Growth Factors in Milk as Affected by the Administration of rbST to Cattle"
Dairy Research Director and Senior Fellow
Monsanto Agricultural Company
St. Louis, Missouri

William H. Daughaday, M.D.
"Historical Perspectives of the Primate GH and GH Receptor Specificity"
Professor of Medicine Emeritus
Metabolism Division
Washington University School of Medicine
St. Louis, Missouri

Theodore H. Elsasser, Ph.D.
"Effects of Heat Treatment, Enzymatic, and Microbial Processing on Quantification of Peptide Hormones in Milk and Dairy Products"
Research Animal Scientist
Ruminant Nutrition Laboratory
United States Department of Agriculture
Animal Research Service
Beltsville, Maryland

Samuel S. Epstein, M.D.
"Summary Public Health Perspectives on rbGH"
Professor of Occupational and Environmental Medicine
School of Public Health
University of Illinois Medical Center
Chicago, Illinois

Anne Ferguson, F.R.C.P., F.R.C.Path.
"Human Digestion and Absorption of Milk and Its Components at Different Stages of Development. Immune Effects"
Professor
Department of Medicine
Western General Hospital
University of Edinburgh
Edinburgh, Scotland

James D. Ferguson, V.M.D.
"Bovine somatotropin--Reproduction and Health"
Assistant Professor, Clinical Nutrition
School of Veterinary Medicine
University of Pennsylvania
Philadelphia, Pennsylvania

James E. Fitts
"Control of Milk Quality and Safety"
New York State Milk Laboratory Evaluation Officer
New York State Department of Agriculture and Markets
Albany, New York

Peter D. Gluckman, M.B.Ch.B., D.Sc.
"The Effects of Growth on Lactation and Performance in Ruminants and Humans: Mechanisms of Action and Effects on Milk Hormone Composition"
Chairman of Pediatrics
University of Auckland
Auckland, New Zealand

Otakar Koldovsky, M.D., Ph.D.
"Hormone and Hormone Like Substances in Human and Bovine Milk; Comparison of Levels"
Professor of Pediatrics and Physiology
Department of Pediatrics
University of Arizona
Tucson, Arizona

David S. Kronfeld, Ph.D., D.V.M.
"Bovine Growth Hormone's Impact on Cow Health, Hence, Public Health"
The Mellon Professor
Department of Animal Science
Virginia Polytechnic Institute and State University
Blacksburg, Virginia

James W. Lauderdale, Ph.D.
"Summary Perspectives for the Technology Assessment Conference on Bovine somatotropin"
Director, Animal Health Performance Enhancement Research
The Upjohn Company
Kalamazoo, Michigan

Douglas M. Morton, Ph.D.
"Bioavailability of rbST and Associated Growth Factors from Various Food Sources and Their Significance"
Vice President, Pharmacology and Toxicology Research
Lilly Research Laboratories
Greenfield, Indiana

Buford L. Nichols, Jr., M.D.
"Variability of Protein and Lipid Composition in Human and Bovine Milks"
Director
Children's Nutrition Research Center
Baylor College of Medicine
Houston, Texas

Mary Frances Picciano, Ph.D.
"Milk and Human Nutrition"
Professor of Nutrition
Pennsylvania State University
University Park, Pennsylvania

H. Allen Tucker, Ph.D.
"Regulation of Growth and Lactation in Cattle and Humans"
Professor
Department of Animal Sciences
Michigan State University
East Lansing, Michigan

Henry F. Tyrrell, Ph.D.
"Effects of rbST on Bovine Physiology and Bioenergetics"
Principal Ruminant Nutritionist
Cooperative State Research Service
United States Department of Agriculture
Washington, D.C.

John N. Udall, Jr., M.D., Ph.D.
"Human Digestion and Absorption of Milk and Its Components at Different Stages of Development: Protein, Hormones, and Growth Factors (Including rbST)"
Associate Professor of Pediatrics
Chief Pediatric Gastroenterology
University of Arizona College of Medicine
Tucson, Arizona

Planning Committee

Robert M. Blizzard, M.D.
Planning Committee Chairperson
Professor of Pediatrics
Chairman Emeritus
Department of Pediatrics
University of Virginia School of Medicine
Charlottesville, Virginia

Duane Alexander, M.D.
Director
National Institute of Child Health and Human Development
National Institutes of Health
Bethesda, Maryland

R. Lee Baldwin, Ph.D.
Professor
Department of Animal Science
University of California at Davis
Davis, California

Dale E. Bauman, Ph.D.
Liberty Hyde Bailey Professor
Department of Animal Science
Cornell University
Ithaca, New York

Darla E. Danford, M.P.H., D.Sc.
Director
Division of Nutrition Research Coordination
Office of the Director
National Institutes of Health
Bethesda, Maryland

Jerry Elliott
Program Analyst
Office of Medical Applications of Research
National Institutes of Health
Bethesda, Maryland

Theodore H. Elsasser, Ph.D.
Research Animal Scientist
Ruminant Nutrition Laboratory
Animal Research Service
Department of Agriculture
Beltsville, Maryland

John H. Ferguson, M.D.
Director
Office of Medical Applications of Research
National Institutes of Health
Bethesda, Maryland

Judith E. Fradkin, M.D.
Chief
Endocrinology and Metabolic Diseases Programs Branch
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health
Bethesda, Maryland

Clark E. Grosvenor, Ph.D.
Senior Research Professor
Department of Molecular and Cellular Biology
Pennsylvania State University
University Park, Pennsylvania

Melvin M. Grumbach, M.D.
Panel and Conference Chairperson
Edward B. Shaw Professor of Pediatrics
Emeritus Chair
Department of Pediatrics
University of California at San Francisco
San Francisco, California

C. Greg Guyer
Regulatory Chemist
Center for Veterinary Medicine
Food and Drug Administration
Beltsville, Maryland

William H. Hall
Director of Communications
Office of Medical Applications of Research
National Institutes of Health
Bethesda, Maryland

John A. Hoyt, D.D.
President
The Humane Society of the United States
Washington, D.C.

Otakar Koldovsky, M.D., Ph.D.
Professor of Pediatrics and Physiology
Department of Pediatrics
University of Arizona
Tucson, Arizona

Buford L. Nichols, Jr., M.D.
Director
Children's Nutrition Research Center
Baylor College of Medicine
Houston, Texas

Office of Medical Applications of Research
National Institutes of Health
John H. Ferguson, M.D.
Director

National Institute of Child Health and Human Development
Duane Alexander, M.D.
Director

National Institute of Diabetes and Digestive and Kidney Diseases
Philip Gorden, M.D.
Director

Division of Nutrition Research Coordination
National Institutes of Health
Darla Danford, M.P.H., D.Sc.
Director

About the NIH Technology Assessment Program

NIH Technology Assessment Conferences and Workshops are convened to evaluate available scientific information related to a biomedical technology when topic selection criteria for a Consensus Development Conference are not met. The resultant NIH Technology Assessment Statements are intended to advance understanding of the technology or issue in question and to be useful to health professionals and the public.

Some Technology Assessment Conferences and Workshops adhere to the Consensus Development Conference format because the process is altogether appropriate for evaluating highly controversial, publicized, or politicized issues. Other Conferences and Workshops are organized around unique formats. In this format, NIH Technology Assessment Statements are prepared by a nonadvocate, nonfederal panel of experts, based on: (1) presentations by investigators working in areas relevant to the consensus questions typically during a 1-1/2-day public session; (2) questions and statements from conference attendees during open discussion periods that are part of the public session; and (3) closed deliberations by the panel during the remainder of the second day and morning of the third. This statement is an independent report of the panel and is not a policy statement of the NIH or the Federal Government.

Preparation and distribution of these reports are the responsibility of the Office of Medical Applications of Research, National Institutes of Health, Federal Building, Room 618, Bethesda, MD 20892.

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