Mad Cow Disease and Supplements
9 April 2001
by Wyn Snow, Managing Editor

In a letter to the editor of the New England Journal of Medicine, Dr. Scott Norton warns that dietary supplements with imported ingredients from cow tissues could expose Americans to mad cow disease. How real is this danger, and are any steps being taken to protect public health?

The danger is real

Mad cow disease, or bovine spongiform encephalopathy (BSE), is thought to be caused by prions -- which are unusually shaped proteins that cause other normal proteins to "flip" into this same unusual shape. Heat, ultraviolet light, and ionizing radiation do not affect prions. Thus, precautions used to prevent the spread of viral, bacterial, and fungal infections are not effective for BSE.

BSE is one of a group of neurological diseases called transmissible spongiform encephalopathies (TSEs). Specifically, it is:

• transmissible by ingesting diseased tissue
• spongiform because of the sponge-like appearance of infected brain tissue
• encephalopathy meaning brain disease

The epidemic of BSE in Great Britain may have begun either spontaneously or through scrapie-infected feed stocks. At the time, cow feed was enriched with a protein supplement consisting of meat-and-bone-meal (MBM) made from the remnants of slaughtered cows and/or sheep. Scrapie is a TSE that occurs in sheep.

However BSE began, it became epidemic when MBM from infected cows was fed to calves. BSE has now claimed the lives of 180,000 cows since it was first diagnosed in 1986. The epidemic peaked in 1992.

BSE can cross the species barrier to humans

Until recently, it was thought that TSE diseases like scrapie and BSE could not cross the species barrier to infect other kinds of animals or humans. In 1996, British scientists linked BSE to a new variant of a human TSE: Creutzfeldt-Jakob Disease (CJD). As of February 2001, 98 cases of this new variant CJD (nvCJD) have been suspected or confirmed in the European Union -- 3 in France, 1 in Ireland, and the remaining 94 in Britain. It takes about 10 years after ingesting BSE for symptoms of nvCJD to appear.

Several mammals other than humans and cows are known to have TSE diseases: sheep, goats, cats, mink, deer, elk, and mice. The prion-protein that is believed to cause scrapie, BSE, and CJD is an unusual variant form of a protein that all mammals make. In the normal form, the protein is spiral shaped. In the disease form, it is folded into sheets. When mixed together in the test tube (and presumably in the body), the disease form causes the normal form to "flip" from the spiral shape into folded sheets.

There are five varieties of human TSEs. Kuru, called the laughing death by the Fore people of New Guinea who suffered from the disease, is transmitted by ritualistic cannibalism. Gertsmann-Straussler-Scheinker syndrome is an inherited human prion disease. Fatal Familial Insomnia is caused by a mutation in the human prion protein gene. Creutzfeld-Jakob Disease (CJD) is predominantly a spontaneous mutation of the human prion protein, and the new variant CJD (nvCJD) appears to be caused by ingestion of BSE-contaminated materials.

CJD can be caused either by genetic mutation or transmission of prions from an infected source, but 85 percent of cases occur sporadically -- meaning spontaneously: that the normal spiral-shaped molecule "flips" for no apparent reason into the folded shape. CJD has also been transmitted by several other means, including contaminated corneal transplant tissue and hormone extracts such as human growth hormone and gonadotropin derived from cadavers. Incubation periods range from 3 to 20 years.

What kinds of supplements use ingredients from animals?

Fewer than one percent of supplements use mammalian ingredients. Both the National Nutritional Foods Association (NNFA) and the Council for Responsible Nutrition (CRN) have reported that only 0.4 percent of supplement sales contain glandular ingredients.

Most supplements are either made from plants or synthesized in a laboratory. A smaller number come from animal sources like shellfish. Supplements with zero risk of being contaminated with BSE include all vitamins, all minerals, and all amino acids.

Only supplements that contain glandular products (including some hormones) are at risk of contamination with BSE. How can we know if supplements are free of BSE? The usual method -- testing raw materials or final products for contamination -- won't work for BSE.

Tests for TSE diseases

As of April 2001, the only reliable tests for identifying TSE diseases are done postmortem by examining brain tissue during autopsies. These tests cannot determine if blood or a live person or animal is infected. Also, although special staining procedures can detect the presence of the abnormal prion protein in tissues such as brain, these methods do not accurately assess how likely it is that the material would cause infection.

Tests for TSE disease in living subjects are likely to appear soon. British expert Dr. Stephen Dealler says, "There is probably already enough data to produce a blood diagnostic test [for living subjects] plus a corroborating test that would be needed for human testing. If the various diagnostic companies and groups share some of their technology amongst themselves then things would move faster."

However, such tests are not likely to be an effective method of inspecting cow tissues used as ingredients for dietary supplements to see if they are contaminated with BSE prions. To protect public health, different methods are needed.

Preventing the spread of TSE diseases

The BSE epidemic in Britain was brought under control by eliminating ruminant MBM from the feed of cud-chewing animals and by slaughtering animals that are thought to be infected. In the US, several government agencies have taken a variety of steps to prevent BSE and nvCJD from appearing in this country. These agencies include the Department of Agriculture (USDA), Food and Drug Administration (FDA), Centers for Disease Control (CDC), and National Institutes for Health (NIH). Actions and dates undertaken by various agencies include:

• prohibiting importation of live ruminants from all countries having BSE (USDA, 1989)
• expanding prohibition against importation of live ruminants and most ruminant products to include all countries in the European Union (USDA, 1997)
• examining the brains of US cattle with abnormal neurological behavior to test for BSE (USDA, ongoing)
• prohibiting the use of most mammal protein in the manufacture of animal feeds given to ruminant animals (FDA regulation, August 1997)
• recommending that animal tissues used in drug products, including vaccines, should not come from a country with BSE (FDA, several letters to manufacturers starting in 1992)
• asking blood centers to exclude potential donors who have spent six or more cumulative months in Britain between 1980 and 1996 from donating blood (FDA guideline, August 1999)
• conducting regular surveillance for any cases of nvCJD (CDC, ongoing review of death certificate data)
• conducting research on BSE, CJD, nvCJD and related neurological diseases (NIH, ongoing)

To date, these methods appear to have been successful. No cases of BSE or of nvCJD have been discovered in the US.

Specifically concerning supplements, the FDA has recommended that the industry "take whatever steps necessary to assure themselves and the public that ingredients do not come from cattle born, raised, or slaughtered in countries where BSE exists." The FDA sent five letters to dietary supplement manufacturers between 1992 and 2000 concerning importation of tissues from cows and sheep.

In 1995, the FDA also initiated a domestic compliance inspection program -- as part of their GMP inspection program. Supplement manufacturers are required to have a procedure for ensuring that animal products from BSE countries do not get into their products. GMP inspectors must determine if ingredients from cows are used, and if so, must discover the country of origin. Import restrictions from the USDA and FDA have been in place since 1989 and 1992 respectively.

A list of countries where BSE has been identified is maintained on the website of the Office International des Epizooties -- a world organization for animal health (www.oie.int).

Gelatin capsules can be either vegetable-based or derived from bones and hides of beef and pork. Gelatin from animals undergoes rigorous processing -- including prolonged exposure to highly acidic or alkaline solutions. Even though gelatin is thought to carry little or no risk of BSE contamination, in 1997 the FDA added gelatin to the list of products that should not be imported from countries with BSE.

Industry precautions for minimizing potential BSE contamination

The National Nutritional Foods Association (NNFA) represents approximately 1000 manufacturers and suppliers of dietary supplements. NNFA and other supplement trade organizations have cooperated with the FDA from the outset to prevent the spread of BSE to the US.

"Response from companies has been very good," according to Phil Harvey, PhD, Director of Science and Quality Assurance for NNFA. "Manufacturers want to be sure their products are safe, and are taking the appropriate safeguards. Many are switching from bovine [cows] to porcine [pigs] sources for glandular ingredients. Also, most manufacturers use domestic rather than imported sources of glandular ingredients."

Harvey emphasizes that there has been no evidence of a link between dietary supplements and human TSEs, even in Europe -- and says, "This is a perceived health concern, but not a crisis in any sense. Dietary supplements are far more processed than food, so the chances are they are safer than food. The FDA has put up rigorous and effective safeguards to protect us."

A primary goal of NNFA is to educate both the public and manufacturers. According to Harvey, "Our last issue of NNFA Today [their newsletter for members] was devoted primarily to BSE, and we have posted a BSE Guidance document on our website to assist manufacturers with documentation and record keeping. We also want to make sure that information for the public is factual and not sensationalized, and that consumers understand that glandulars are different from vitamins, minerals, and amino acids."

NNFA's good manufacturing practices (GMP) inspection process now includes explicit measures for minimizing any risk of BSE contamination. To pass this inspection, companies must have rigorous methods of identifying raw materials and documenting their source.

What parts of the cow are most dangerous?

Different tissues carry different risks of infectivity. Also, methods used in slaughtering and butchering animals can affect the amount of infectivity -- as can production methods such as heat sterilization and chemical treatment used to prepare bovine materials.

The following list of highest through smallest risk of infectivity was gathered from an FDA letter to dietary supplement manufacturers and other US government documents.

Highest risk
Especially brain tissue and spinal cord, possibly also retina of the eye.

Medium risk
Adrenal gland, cerebrospinal fluid, dura mater, ileum, lymph nodes, pineal gland, pituitary gland, placenta, proximal colon, spleen, tonsil.

Low risk
Bone marrow, distal colon, liver, lung, nasal mucosa, pancreas, sciatic nerve, thymus gland.

Smallest risk
Skeletal muscles and milk have never shown any infectivity.

If people are concerned about whether a specific supplement might contain glandular ingredients from cows, NNFA's Harvey recommends that store personnel and manufacturers be queried directly.

While the danger is real that dietary supplements with imported glandular ingredients can be contaminated with mad cow disease, the risk is also very small. Import barriers placed by US government agencies have prevented BSE from spreading to US cattle, and most bovine ingredients for dietary supplements are of domestic origin. Imported ingredients come from countries that do not have BSE.

Quality standards provide solution to concerns about contamination

Contamination with mad cow disease is one of many quality issues that can be addressed with comprehensive quality standards. Standards for good manufacturing practices (GMPs) deal with all aspects of manufacturing procedures: from raw materials to shipping and storage of final products.

NNFA's GMP inspection and certification program can assure consumers that products with NNFA's GMP seal are free of contamination with mad cow disease. However, NNFA membership does not include all dietary supplement manufacturers -- so if a company that is not a member of NNFA follows BSE-preventive practices, the only way consumers can be confident of this is to ask manufacturer personnel.

Consumers deserve better

The Dietary Supplement Health and Education Act passed in 1994 requires the FDA to establish GMP standards for dietary supplements. The FDA presented a proposed GMP regulation in 2000, but publication of a final rule is currently on hold pending appointment of a new FDA commissioner by President Bush. Until the final rule is published, dietary supplements continue to be held to food GMP standards.

While government regulation can solve many problems, it also has drawbacks: It is slow to change in response to new scientific information. A better solution might be to convene a Quality Congress with representatives from industry, government, health practitioners, supplement researchers, the insurance industry and consumers. This Congress would be empowered to establish and maintain ongoing quality standards, including such issues as contamination with mad cow disease.

Public safety could be assured either by requiring all supplement manufacturers to adhere to these standards (the current plan for FDA GMP standards under DSHEA) -- or by allowing companies to use a seal on their labels if they have passed third-party inspection of such GMP standards.

Sources

About.com. "Mad Cow and Human Prion Disease." About.com website, 18 May 1998. [Article no longer available on about.com website.]

Stephen Dealler. "Who is doing what in diagnostics?" Mad-Cow.org website, 15 February 2001. www.mad-cow.org/00/feb01_last.html.

Phillip W. Harvey, PhD, Director of Science and Quality Assurance, National Nutritional Foods Association. Personal communication, 30 March 2001.

National Nutritional Foods Association (NNFA), Committee for Product and Label Integrity. "NNFA BSE Guidance Manual." NNFA website, Adobe Acrobat document (PDF format), March 2001. www.nnfa.org/services/science/bse.htm.

Scott A. Norton, MD, MPH. "Raw Animal Tissues and Dietary Supplements." Letter to the editor of the New England Journal of Medicine, Vol. 343, No. 4, 27 July 2000. www.nejm.org [available for subscribers only].

Office International des Epizooties. List of countries with BSE, in English: www.oie.int/eng/info/en_esb.htm. Spanish and French versions are also available.

Stanley B. Prusiner, MD. (Prusiner is the Nobel Laureate who discovered prions and postulated them as the cause of CJD, BSE and scrapie.) "The Prion Diseases." Scientific American, Vol. 272, No. 1, Pages 48-57, January 1995.

US Food and Drug Administration. "BSE: Background, Current Concerns, and U.S. Response." FDA website, 1 March 2001. www.fda.gov/opacom/backgrounders/bse.html.

US Food and Drug Administration. "Letter to Reiterate Certain Public Health and Safety Concerns to Firms Manufacturing or Importing Dietary Supplements that Contain Specific Bovine Tissues." FDA website, 14 November 2000. vm.cfsan.fda.gov/~dms/dspltr05.html.

US Food and Drug Administration. "Questions and Answers on Bovine Spongiform Encephalopathy." FDA website, 2 January 2001. www.fda.gov/cber/bse/bseqa.htm.

US Food and Drug Administration. "Safety of Gelatin and Gelatin By-Products Reviewed." Letter on FDA website, 24 April 1997. www.fda.gov/bbs/topics/ANSWERS/ANS00793.html.

US Food and Drug Administration. "Search result for BSE." FDA website, 2 April 2001. vm.cfsan.fda.gov/cgi-bin/ws.cgi?QUERY=bse&STYPE=OR.