MAD COW DISEASE | May 31, 2004 Issue - Vol. 82 Issue 22 | Chemical & Engineering News
Volume 82 Issue 22 | pp. 21-26
Issue Date: May 31, 2004

Cover Story

MAD COW DISEASE

Regulatory changes stemming from discovery of one diseased cow create new conflicts spawned in part by gaps in scientific understanding
Department: Science & Technology
OUT TO PASTURE
Black Angus on one of the farms that supplies cattle to the meatpacker Creekstone Farms in Arkansas City, Kan.
Credit: CREEKSTONE FARMS PHOTO
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OUT TO PASTURE
Black Angus on one of the farms that supplies cattle to the meatpacker Creekstone Farms in Arkansas City, Kan.
Credit: CREEKSTONE FARMS PHOTO

Conflicts over measures aimed at controlling bovine spongiform encephalopathy (BSE), commonly called mad cow disease, show it presents a very difficult regulatory challenge. So far, its threat appears relatively minimal--only two cases of BSE have been detected in North America. The human form of BSE, variant Creutzfeldt-Jakob disease (vCJD), which is caused by exposure to prions from eating BSE-infected beef, has killed only about 150 people worldwide. The more common sporadic CJD and its variant form, vCJD, are always-fatal brain disorders that usually kill in less than one year after symptoms appear.

Because so little is known about prion diseases, it is hard to determine a regulatory approach that is based on sound science. For example, the human incubation period for vCJD is unknown, the minimum dose of prions--the misfolded prion proteins--needed to cause vCJD is unknown, and the likelihood that new and more easily transmitted prion strains will arise is unknown. It is certain that the brain and other central nervous system tissue are the most infectious parts of a diseased cow, but it is not known whether muscle tissue or blood have high enough concentrations of prions to infect humans. There is even some question whether prions from BSE-infected cows may cause other, less lethal neurological diseases in humans.

But the issue is a charged one, and public interest and consumer groups have been vocal about the need for the government to ensure a safe food supply. Government agencies have scrambled to address the voiced concerns.

The discovery on Dec. 23, 2003, of a single cow in the U.S. with BSE has led to many changes at the Department of Agriculture, the Food & Drug Administration, and in the beef industry. It has also precipitated a new set of conflicts between consumer organizations and government, as well as among various industry factions. And it has led to charges from some members of Congress that USDA and FDA are not taking strong enough action to protect the beef supply, and from other congressmen that the agencies are overreacting to the issue. Each side in the debate frequently invokes the term "sound science" to justify their point of view. If more were known about the science of prion diseases in animals and in humans, finding a balanced regulatory approach would be less contentious.

Stewart
Credit: CREEKSTONE FARMS PHOTO
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Stewart
Credit: CREEKSTONE FARMS PHOTO

Since Dec. 23, the most dramatic change was USDA's decision in mid-March to test more than 200,000 cattle for mad cow disease over the next 12 to 18 months, in comparison with only 20,000 tested in 2003. But other policy changes were significant as well, including the certifying of rapid BSE tests and of university and state labs to perform them and ordering the removal of all downer cattle--animals that cannot walk--from the food supply. Each year, USDA estimates, about 446,000 cattle become too sick or injured to walk.

USDA made most of these changes to ensure the safety of beef as food and to try to convince about 50 countries that have stopped buying U.S. beef because of BSE fears to resume imports. Formerly, the U.S. exported about 10% of its beef, a market worth $3 billion that has mostly dried up.

Adding to the controversy is USDA's denial of Creekstone Farms' request to be allowed to voluntarily test all its slaughtered cattle for BSE. Creekstone, a Kansas-based meatpacker, wants to resume beef sales to Japan, which is demanding that all beef imports from the U.S. be tested. The decision regarding Creekstone has been denounced by stakeholders on nearly all sides of the debate.

Consumer and food safety groups say some steps USDA and FDA have taken do not go far enough and others are not being implemented quickly enough. Carol Tucker Foreman, director of the Food Policy Institute at the Consumer Federation of America (CFA), explains the situation this way: "I would suggest that USDA has chosen in every instance since the issue of BSE arose to look at the available science and then take the course of action that will impose the least possible cost on the industry and provide the least reassurance and protection to consumers."

However, the American Meat Institute (AMI) and the National Cattlemen's Beef Association (NCBA) contend that the measures the government has taken are more than adequate to protect the U.S. beef supply. "The risk of BSE in U.S. cattle is very low, and the risk to humans from BSE is even lower," AMI Foundation President James Hodges says. "Despite speculations to the contrary, the facts show that our risk levels are many orders of magnitude lower than Europe's," he says.

There is no fixed goal in USDA's expanded BSE testing program. Some observers say it is understandable that the department is not setting a fixed goal because it has had no experience with such a large program and cannot at this point anticipate all the difficulties that may lie ahead. "USDA will be testing as many animals as possible out of a target population of 400,000-plus animals, over a 12- to 18-month period," USDA spokesman Jim Rogers says. Most of the animals to be tested will be chosen from the estimated 446,000 downer cattle, but 20,000 randomly chosen, healthy looking, older animals will also be sampled. Downer cattle are considered at greatest risk of harboring BSE because one symptom of advanced BSE is the inability to walk. The surveillance program will begin in June.

"If we are able to collect 201,000 samples, this would allow us to detect BSE with a 95% degree of confidence if the prevalence of the disease is just one positive cow in 10 million adult cattle," says Ron DeHaven, administrator of USDA's Animal & Plant Health Inspection Service.

Instead of targeting mainly downer cattle, consumer advocates want every carcass intended for the food supply tested for BSE. They say animal inspectors are not trained to identify symptoms of the disease, and even trained inspectors may not be able to identify BSE-infected cattle because many exhibit no obvious signs.

CONSUMER GROUPS claim that USDA's statement that its sampling program will find one infected cow in 10 million adult cattle is based on false assumptions. USDA assumes that nearly all BSE occurs in downer cattle and in animals older than 30 months, says Michael K. Hansen, senior research associate at Consumers Union. However, most of Japan's known instances of BSE-infected cattle so far have been healthy looking animals, not downers, and two were younger than 30 months, he observes. So it is possible that most U.S. BSE cases would be hidden among healthy animals, he says.

Stanley B. Prusiner, who won a Nobel Prize for discovering that prions cause transmissible spongiform encephalopathies (diseases such as BSE and CJD), also argues that all cattle carcasses should be tested for BSE. The disease is generally thought to arise from eating infected meat and bone meal, he explains, but isolated cases could occur spontaneously, just as prion diseases arise spontaneously in many mammals--humans and sheep, for example. He also claims that 30 months is an arbitrary cutoff age for testing. Although BSE symptoms do not appear until after 30 months, the animal may be infective long before then, he explains.

The cost of testing all cattle would be very low, only a few cents per pound, compared with the danger of not testing, Prusiner says. At a May hearing before the California Senate agriculture committee, he used an analogy: If there were two ticket lines at an airport and one guaranteed you would get to your destination safely for $1.00 extra while the other line offered no guarantee, most consumers would pay the extra dollar. Similarly, he expects that most consumers would be willing to pay a few extra cents per pound for BSE-tested beef.

Prusiner notes that he has studied prion diseases for two decades, but there is still a great deal that isn't understood about them. At any time, a new strain of BSE prions could develop that is more infective for humans. "Only the Japanese solution of testing every slaughtered cow or bull will eliminate prions from the food supply and restore consumer confidence," he says.

But what Prusiner believes is that an acceptable expense is considered unacceptable by NCBA. NCBA argues that the cost of testing every slaughtered animal would be "huge"--about $30 per animal. Since about 35 million cattle are slaughtered each year in the U.S., the total cost of a universal testing program would be more than $1 billion and would increase beef prices by about 5 cents per lb, NCBA claims.

John Stewart, chief executive officer of the meatpacker Creekstone Farms, says the major meat processors--the four corporations that process more than 80% of U.S. beef--don't want to test all their beef because 4 or 5 cents per lb to a commodity packer is big money. "Commodity packers basically believe they can't move extra costs up the food chain to the consumer," he says. "So they end up doing one of two things: reducing their profits or moving those costs down the food chain to the cattle producer," he observes.

In March, USDA also said it would license rapid BSE tests, which produce results in a few hours, for the expanded program. Previously, the department was using an immunohistochemistry assay exclusively, which takes at least five days to yield results. And USDA has licensed 12 laboratories to do the rapid tests. Previously, only one lab--the National Veterinary Services Laboratory in Ames, Iowa--was certified to do the assays.

So far, five rapid test kits have been licensed: one test made by Bio-Rad Laboratories in Hercules, Calif.; one by Idexx Laboratories in Westbrook, Maine; one by Abbott Laboratories in Abbott Park, Ill.; and two tests made by Prionics based in Zurich, Switzerland.

The Bio-Rad, the Idexx, the Abott, and one of the Prionics test kits employ the enzyme-linked immunosorbent assay (ELISA) technique to detect the protease-resistant form of prion protein in brain samples. These proteins, usually called prions, are the cause of BSE. The second Prionics kit is based on the Western blot assay. According to Prionics, its Western blot kit was used in18 million tests conducted worldwide from 2001 to 2003 and has never produced a false positive result.

Another rapid test kit developed by InPro Biotechnology in South San Francisco, Calif., has not yet been approved by USDA even though it has been certified for use in the European Union. Some observers consider the InPro method the most sensitive of all the tests.

DOWNWARD SPIRAL
Cattle with BSE experience progressive degeneration of the nervous system. Changes in temperament, abnormal posture, lack of coordination, difficulty in rising, decreased milk production, and weight loss are followed by death.
Credit: APHIS PHOTO BY ART DAVIS
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DOWNWARD SPIRAL
Cattle with BSE experience progressive degeneration of the nervous system. Changes in temperament, abnormal posture, lack of coordination, difficulty in rising, decreased milk production, and weight loss are followed by death.
Credit: APHIS PHOTO BY ART DAVIS

THE SENSITIVITY of tests can be compared with the sensitivities of bioassays in lab animals. The InPro test, called the conformation-dependent immunoassay (CDI), is as sensitive as the most sensitive known bioassay--the BSE bioassay in mice genetically engineered to express bovine prion protein, says Jiri Safar, associate professor of neurology at the University of California, San Francisco. In contrast, the BioRad test, for example, is only as sensitive as the bioassay in standard lab mice. This means that the InPro test is about 10,000 times more sensitive than the BioRad method. Soon, CDI will be used in the U.K. to test a large percentage of its cattle.

In January, shortly after the discovery of the diseased cow in the U.S., FDA, which has jurisdiction over animal feed, announced that poultry litter, freeze-dried cow's blood, and plate waste from restaurants would no longer be fed to cattle. These are potential ways to propagate and amplify BSE. Plate waste usually contains beef. Poultry litter often contains cattle-derived meat and bone meal, an ingredient in some poultry feed. And cow's blood, which is fed to calves as a milk replacer, is a potential source of prions if it comes from an infected cow.

However, it is still legal to give these items to cattle because FDA has not yet published regulations in the Federal Register concerning them. Recently, Acting FDA Commissioner Lester M. Crawford said it has been far more difficult to write regulations about these feed sources than the agency anticipated.

In January, in addition to banning downer cattle, USDA banned various cattle parts called "specified risk materials" from the food supply. These include the skull, brain, eyes, vertebral column, spinal cord, dorsal root ganglia (clusters of nerve cells connected to the spinal cord), and trigeminal ganglia of cattle 30 months of age and older and the small intestine of all cattle. Tonsils from all cattle had already been banned. In a BSE-infected animal, these tissues have a higher concentration of prions than other parts of the carcass.

USDA ALSO BANNED the use of air-injection stunning during slaughter. This practice sometimes dislocates portions of the brain into muscle tissues.

There is little disagreement that these specified risk materials should be banned. But consumer groups advocate banning specified risk materials from cattle of all ages because prion diseases develop slowly and tissues may be infective long before an animal reaches 30 months of age, Consumer Union's Hansen says.

A technology called advanced meat recovery--removing beef muscle tissue from bone under high pressure--is another source of conflict. In January, USDA ruled that the dorsal root ganglia must be removed from the bone before advanced meat recovery can be used. USDA also decided in January that processing plants must now test their advanced meat recovery product to make sure neither spinal cord no dorsal root ganglia are present.

"We would like to see a ban on advanced meat recovery," says Chris Waldrop, health and safety associate at CFA. "It cuts so close to the bone that there is definitely a chance that you could get nerve endings or other high-risk materials into the meat," he explains. "More and more [meat processing] plants are realizing the advanced recovery product is risky, and they don't want to deal with it," he says.

Despite all the regulatory changes and publicity resulting from the discovery of one BSE-infected cow, USDA was until recently showing signs that it may not be taking the concerns seriously enough.

According to USDA press briefings, a dispute or a misunderstanding at a Texas slaughterhouse recently resulted in failure to test a cow that was showing possible signs of BSE. After passing a safety inspection at the Lone Star Beef slaughterhouse in San Angelo, Texas, the cow in question staggered and collapsed. The veterinarian on duty with USDA's Food Safety & Inspection Service (FSIS) decided the cow was unfit for human consumption and should be tested for BSE. Staggering could indicate BSE or another type of brain damage.

However, the regional director of USDA's Animal & Plant Health Inspection Service (APHIS) in Austin apparently overruled the on-site vet and ordered that the animal not be held for testing. The cow was then taken to a rendering plant and made into meat and bone meal for swine.

Federal regulations require that cows showing signs of neurological disease be tested. USDA's Inspector General is investigating the Lone Star case.

"I am deeply disappointed that the Department of Agriculture failed to follow its own procedures to test this cow for mad cow [disease] after the animal was observed staggering and falling," said Rep. Rosa L. DeLauro (D-Conn.) in a statement. "I have joined many experts in pushing the Administration to institute faster, more stringent, surveillance. ... Each step of the way, the Administration has moved slowly and inadequately," she said.

"THE REAL IMPORTANCE of that cow," CFA's Foreman says, "is that testing might have shown that there is BSE in an animal born and raised in the U.S."

To make sure that cattle showing signs of neurological disease are tested in the future, APHIS is currently training 75 to 90 of the FSIS on-site veterinarians in sample collection so they can submit samples from condemned animals to the certified laboratories. "We believe this is a significant step to ensure that there's no question that if an FSIS veterinarian feels a sample needs to be taken based on condemnation, the sample will be taken without question," says Barbara Masters, acting administrator of FSIS.

CROSS SECTION
Vacuoles--microscopic holes in the gray matter--give the brain of BSE-affected cows a spongelike appearance when tissue sections are examined in the lab.
Credit: APHIS PHOTO BY AL JENNY
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CROSS SECTION
Vacuoles--microscopic holes in the gray matter--give the brain of BSE-affected cows a spongelike appearance when tissue sections are examined in the lab.
Credit: APHIS PHOTO BY AL JENNY

In early January, USDA announced it would implement a National Animal Identification System for all cattle and other livestock. Eventually, most cattle will be identified with radio-frequency or another sort of ear tag, or retinal scanning, or DNA testing. Records will be kept of movement of individual cattle from farm to feedlot and finally to a slaughterhouse. Radio-frequency identification tags allow an animal's location to be pinpointed by picking up radio-frequency signals with a small antenna. Tracking is considered important for controlling BSE. When the diseased cow was found in December, many of its herd mates could not be located because they had no identifying marks, and no records of their movements had been kept.

USDA's Rogers says all farm animals will eventually be tracked from birth until slaughter. Poultry will be identified as flocks rather than individual animals.

During the initial stages of the program, USDA will evaluate animal ID systems used in other countries and determine which systems should be used. Later this year, USDA hopes to identify farms, feedlots, auction blocks, and slaughterhouses where animals are sold.

The ID system will be voluntary, at least in the early years, and the entire system will probably not be in place before July 2006.

CFA's Waldrop claims the animal ID system is aimed primarily at tracking BSE and foot-and-mouth disease. It is not designed to track the pathogens E. coli and Listeria, causes of much human illness, back to the farm or slaughterhouse where they originated, he explains. "None of the proposed systems has even mentioned pathogens. We'd like to see the animal ID system track pathogens, as well as BSE and foot-and-mouth disease," he says.

However, Rogers says the animal ID system is not aimed at any particular disease.

After the BSE-infected cow was discovered in the U.S., Kansas-based Creekstone Farms wanted to maintain its beef exports to Japan. Japan was demanding that all its imports from the U.S. be tested for BSE, just as it tests 100% of its domestically raised cattle.

Creekstone CEO Stewart decided there is no way Japan would accept U.S. beef unless all carcasses are tested. Stewart then spent about $500,000 to set up a testing laboratory at his firm's plant and hired seven chemists and biologists to operate the lab. He planned to charge his customers for the cost of testing all cattle slaughtered at Creekstone, which he estimated would be $20 per animal.

But there was one hurdle. In late April, USDA decided that Creekstone Farms would not be allowed to do its own testing. The company has the equipment to test for BSE, but it lacks the specific chemical reagents required for the tests. USDA controls the sale of the reagents and has ruled that only certified labs in the USDA testing program will be allowed to buy reagents. USDA believes that permitting Creekstone to test would establish an expensive precedent and result in essentially all meatpackers having to test their cattle, whether they felt it necessary or not.

Creekstone, one of the largest firms in southeastern Kansas, used to employ 790 people, but it had to lay off 40 workers after exports to Japan stopped.

In the weeks following USDA's decision, many major newspapers published editorials supporting Creekstone's position, and the company received thousands of e-mails and phone calls praising its position, Stewart says. "We have not gotten any correspondence telling us we should not test," he adds.

"From the Creekstone perspective, we are not suggesting testing because of a safety issue," Stewart says. "We have to listen to consumers. What the government does not understand is that in free enterprise and marketing, consumers make the decision. They decide whether or not testing is worth it," he explains.

"The American people should be outraged that the government is going to spend $72 million to test 220,000 animals--about $300 per animal--when we are going to do it for $20 per animal" and pass the cost on to the consumer, Stewart says.

"I just don't buy the argument" that if Creekstone tests all its animals that "it is going to force all meatpackers to test everything," says Roger Johnson, North Dakota's agriculture commissioner. "Japan is not asking Creekstone to do anything it is not already doing domestically. That is the standard we set for every other country. If they want to export to us, we say you've got to meet our standards," he explains.

"I don't think every animal ought to be tested that is sold in the U.S. market," Johnson continues. "The question is how can we get back into the Japanese market and do it quickly before other countries have moved in and taken it over," he warns.

Kansas Agriculture Secretary Adrian J. Polansky says Creekstone's desire to do 100% testing is a marketing decision similar to some farmers' decisions to sell certified organic beef. Certain consumers will pay more to have an organic product, just as some consumers will pay for BSE testing, he says. Allowing a few meatpackers to test all their animals voluntarily would not mean that all processors would have to test their meat, he says.

Still, USDA is not convinced that it is useful or rational for a meatpacker to test 100% of its carcasses. "It is not scientific to test all cattle," USDA spokesman Rogers argues. "Most animals in this country are slaughtered between 18 and 20 months of age, and the disease doesn't start to present itself until 30 months of age," he contends. "For example, if you picked up some ground beef and it said, 'BSE-negative,' that really doesn't mean anything because the tests won't pick up anything until the animals are 30 months or older," he notes.

The California Senate agriculture committee recently approved legislation that would allow meatpackers to voluntarily test their cattle for BSE and to label their meat "BSE-tested." The legislation now goes to the Senate appropriations committee for consideration.

Research published over the past few years suggests that BSE could turn out to be more of a problem for human health than has been apparent thus far.

Some scientists speculate that a second wave of vCJD cases may follow the first wave in the U.K. These cases might occur in a set of people who are genetically less susceptible to the disease than the first set of cases that appeared starting in 1996, they say.

Research published in May 2001 in the Proceedings of the National Academy of Science suggests that the incubation period for vCJD may vary greatly depending on the genetic makeup of its victims [PNAS, 98, 6279 (2001]. This could mean that the first set of vCJD victims were the most susceptible genetically, and will be followed by another wave of victims. Polymorphisms in the prion protein gene are known to affect prion disease incubation periods in humans and mice. In this research, John Collinge, neurologist at Imperial College, London, and his colleagues studied mice and found that new genes, in addition to the prion protein gene, influence how quickly mice develop brain disease from specially adapted scrapie prions. Because the mouse and human genomes are very similar, this could mean that there are several genes in humans that influence incubation periods for vCJD, Collinge reports. This new research casts doubt on the genetic models used in the current estimates of the ultimate size of the CJD epidemic, he notes.

To test the "second-wave" hypothesis, researchers in the U.K. led by David Hilton, a pathologist at Derriford Hospital in Plymouth, tested 12,964 stored human samples of tonsils and appendices for prions and found prions in three samples [J. Pathol., published online May 21, http://dx.doi.org/10.1002/path.1580]. If the results are extrapolated to the entire population of the U.K., this could mean that as many as 3,800 apparently healthy individuals would test positive for the prions, he reports.

Hilton, however, cautions that the results are highly uncertain. It is not clear how accurate the prion test is in human tissue or that prions in tonsils or the appendix would eventually lead to clinical disease, he notes. To help resolve uncertainties, the U.K. government will be testing 100,000 additional tonsils and appendices removed over the next three years.

Finally, an article published online last week in Nature Medicine shows that prion proteins can be found in the muscles of sheep that are infected with scrapie--the prion disease of sheep [Nat. Med., published online May 23, http://dx.doi.org/10.1038/nm1055]. Olivier Andreoletti, a prion specialist at the National Veterinary School in Toulouse, France, says the prions are present in the muscle months before clinical signs of the disease appear, but at a level far lower than eventually develop in the brain. This is the first time prions have been found in muscle meat that humans normally eat. However, the risk of transmission of scrapie to humans is low, Andreoletti notes. This research indicates that prions may be present in the muscle meat of BSE-infected cattle, he reports.

IN JANUARY, the Institute of Medicine published a report that calls for a greatly expanded research program into prion diseases. Richard Johnson, professor of neurology, microbiology, and neuroscience at Johns Hopkins School of Medicine, chaired the committee that wrote the report. The report concludes that much more than the $25 million the National Institutes of Health now spends each year on prion research needs to be invested.

The report also recommends that the National Prion Research Program established by Congress in 2002 attract and train more investigators and provide grants of five to seven years for research in animals--because prion diseases incubate slowly.

In addition, it recommends "the expansion or upgrading of existing [prion research] laboratories, animal facilities, and containment laboratories, and construction of new ones."

U.S. researchers lack the scientific knowledge and the resources to gauge the extent of the danger people face from prion diseases that affect humans and animals, Johnson says.

"When there is no sound science, should we delay regulatory measures until the science is more sound? Or should we take heroic measures against a disease that has killed relatively few people?" asks Robert A. Hahn, an attorney at Olsson, Frank & Weeda, Washington, D.C., who specializes in USDA regulations. "If we wait and postpone," the consequences, both health and legal, may be severe, he warns.


 

ENVIRONMENTAL TRANSMISSION

Study Provides Strong Evidence Chronic Wasting Disease Is Spread Indirectly

Research published online this month in Emerging Infectious Diseases indicates that chronic wasting disease (CWD) can be transmitted indirectly from one infected mule deer to another, as well as by direct interaction. CWD-the prion disease that afflicts mule deer, white-tailed deer, and elk-has been observed in 12 states and Canada. CWD creates microscopic holes in the brains of deer and elk, making them lose weight and die.

In the study, healthy mule deer were confined in three sets of separate paddocks. In the first set, healthy deer were exposed to a CWD-infected deer. In the second set, deer were exposed to carcasses of deer that had died of CWD. In the third set, deer were confined in paddocks where infected deer had lived. Some of the healthy deer in each set of paddocks contracted CWD within one year.

"Our findings show that environmental sources of infection may contribute to CWD epidemics, and they illustrate how potentially complex these epidemics may be in natural populations," says Colorado Division of Wildlife veterinarian Michael Miller, a coauthor of the research article.

Although there has been strong anecdotal evidence that CWD is transferred through the environment, previous disease models have been based on animal-to-animal contact as the sole source of transmission, says Colorado State University researcher Thomas Hobbs, another coauthor.

But "our findings indicate that contaminated environments can cause transmission," Hobbs says. Therefore, the disease will be harder to eradicate than predicted by models based on animal-to-animal transmission, he adds.

This research shows CWD could be propagated by excrement in the environment even if all infected animals are eradicated, Miller says.

There is as yet no clear evidence CWD can be transmitted to humans, but people are advised not to eat venison from sick animals.

Stanley B. Prusiner, who received a Nobel Prize for discovering that prions cause transmissible spongiform encephalopathies (TSEs), worries that a new strain of CWD prions may arise that is capable of infecting humans. There are 14 known strains of prions for scrapie, the TSE that affects sheep, so it is possible new strains of CWD prions might develop, he says. Much more effort should be made to eradicate the disease, he warns.

 
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