Report of the Royal College of Physicians and Surgeons of Canada Expert Panel on Human safety of RBST

Prepared for Health Canada, January 1999

Table of Contents

Executive Summary

At Health Canada's request, the Royal College of Physicians and Surgeons of Canada established an expert panel in April of 1998 to examine the human safety issues pertinent to the use of RBST in dairy cattle in Canada.

The panel was asked to "review international scientific reports and conclusions that have been made about RBST "and "to make observations and recommendations regarding the adequacy of the scientific data submitted by the manufacturer of Nutrilac (RBST) or (to examine scientific information) existing elsewhere to make sound scientific assessments regarding the human health risks associated with the use of Nutrilac (RBST) in Canadian dairy cattle."

The panel members were chosen for their expertise in medicine, pediatrics, oncology, nutritional science, epidemiology, pharmacology and toxicology. All are active or emeritus members of Canadian Faculties of Medicine or Health Sciences. The panel operated independently with a reporting relationship to the Royal College of Physicians and Surgeons of Canada.

The panel reviewed an extraordinary volume of scientific data and literature relevant to its task. The quality of the scientific evidence available to the Bureau of Veterinary Drugs, Human Safety Division with respect to the Nutrilac file appears to be excellent and complete as far as is possible in a field of scientific study which has evolved rapidly during the course of a review lasting more than nine years. In particular, there is a quickly expanding literature on biologic effects of insulin-like growth factor-1 (IGF-1), which is indirectly relevant to the human safety of food products from rbST-treated cattle. The panel experienced no difficulty in finding up-to-date information required for its analysis. It was apparent to the panel that scientific awareness of relevant human safety issues within Health Canada has kept pace with growth of scientific perception concerning somatotropin (ST) and IGF-1 during the 1990s.

The panel has reached a number of conclusions concerning the human safety of food products from rbST-treated cattle.

1. Cow's milk contains bST whether or not the cow has been treated with rbST. No increase in total bST concentration is observed in milk from rbST-treated cows and therefore no human risk related to ST consumed by this route is likely to result.
2. rbST given to rats in a 90-day study conducted by the manufacturer caused an antibody response in some test animals, including one that received a relatively low dose of 0.1 mg/kg/day. The antibody response in question was detected at 14 weeks. This effect, if validated, would suggest the possibility of occasional hypersensitivity reactions in those consuming food products from rbST-treated cattle. The panel recommends further discussion of the antibody results by Health Canada scientists with the manufacturer and repetition of the studies in question to clarify the risk of hypersensitivity following exposure to oral rbST at low doses.
3. RbST increases the production of IGF-1 concentrations in recipient animals and IGF-1 concentrations are increased in food products from rbST-treated cattle. The increments of IGF-1 in milk and other food products represent a minor increase in exposure for human recipients when compared to endogenous (physiological) production of and exposure to IGF-1. The panel recognizes major difficulties in drawing inferences about the potential for indirect human toxicity related to the increased production of IGF-1 in recipient animals. However, there is no biologically plausible basis on which to conclude that rbST-associated changes in human exposure to IGF-1 will lead to any immune response, change in neonatal intestinal growth and development, or cancer risk in recipients of milk or food products from treated cattle.
4. Apart from concern, as noted above, about the antibody response observed in a single rat treated subchronically (90 days) with rbST at a dose of 0.1 mg/kg/day, the panel does not think that chronic toxicity or reproductive studies in laboratory animals are justified since there are no receptor-mediated rbST effects in human.
5. Biological study of IGF-1 will remain of exceptional interest; however, there is no evidence to suggest that oral intake of IGF-1 is carcinogenic. As an endogenous substance, IGF-1 may play a role in the pathophysiology of neoplasia; however, Health Canada would not be justified in requiring further studies of IGF-1 to be conducted by the manufacturer of Nutrilac with respect to the pathogenesis of human malignancy.
6. It appears that the incidence of mastitis increases in rbST-treated cows and that this condition is likely to be treated on many Canadian farms with antibiotics. The panel does not consider that these events pose a risk to human safety since Canada has an enforced testing program for all milk pooled in tank reservoirs. That program will assure that antibiotic residues are maintained within nationally accepted standards. Furthermore, the panel thinks that any increase in exposure of bacteria to antibiotics as a result of rbST-related mastitis would be of marginal importance compared to the effects of antibiotic exposure resulting from other agricultural and human antibiotic uses. It is highly unlikely that rbST use will have any impact on the important public health issue of increasing antibiotic resistance.

In summary, with one exception, the panel finds no biologically plausible reason for concern about human safety if rbST were to be approved for sale in Canada. The only exception to this statement is the occurrence of an antibody reaction (possible hypersensitivity) in a subchronic (90-day) study of rbST oral toxicity in rats that resulted in one test animal developing an antibody response at low dose (0.1 mg/kg/day) after 14 weeks. In the opinion of the panel, this anomalous result deserves further study, including discussion between the manufacturer of Nutrilac and Health Canada scientists. The panel recommends, on the basis of present knowledge, that the study in question be repeated.

Table of Contents

The report has been prepared as one HTML file (82K) for easier printing.

• Report of the rbST Human Safety Panel
  • Background
  • Conflict of interest screening
  • Panel membership
  • Operation of panel
  • Questions posed to the panel
  • The challenge of indirect risk assessment in human toxicology
  • Comments re: review process
  • Review of international scientific reports and literature
    
• Discussion of Human Safety Issues Related to rbST
  • Human exposure to bovine food products
  • Pharmacology/toxicology of somatotropin
  • IGF-1
  • Somatotropin effects on the composition and characteristics of bovine products
  • Controversies
    
• Conclusions
  
• References
  
• Glossary
  
• Appendix 1: Information distributed to human safety panel members
  
• Appendix 2: Monsanto 90-day study: determination of sometribove immunoglobulin in rat serum

Committee membership

1. Dr. Stuart M. MacLeod (Chair)
   Professor, Departments of Clinical Epidemiology and Biostatistics,
   Medicine and Pediatrics,
   McMaster University, Hamilton, Ontario
   
2. Dr. Réjeanne Gougeon
   Assistant Professor, Nutrition and Food Science Centre,
   Faculty of Medicine, McGill University,
   with cross-appointment in the School of Dietetics and Human Nutrition,
   Faculty of Agricultural and Environmental Sciences,
   McGill University, Montreal, Quebec
   
3. Dr. Gerald S. Marks
   Professor Emeritus, Department of Pharmacology and Toxicology,
   Queen's University, Kingston, Ontario
   
4. Dr. Michael Pollak
   Professor, Departments of Medicine and Oncology,
   McGill University, Montreal, Quebec
   
5. Dr. Milton Tenenbein
   Professor,
   Departments of Pediatrics and Pharmacology and Therapeutics,
   University of Manitoba, Faculty of Medicine, Winnipeg, Manitoba
   
6. Ms. Cindy Woodland (Research Assistant to the Committee)
   Doctoral Candidate, Department of Pharmacology,
   Division of Clinical Pharmacology and Toxicology,
   The Hospital for Sick Children,
   University of Toronto, Toronto, Ontario

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