WILL TRANSGENIC FISH BE THE FIRST AG-BIOTECH FOOD-PRODUCING ANIMALS?
FDA STOPS IMPORTATION AND DISTRIBUTION OF CONTAMINATED ANIMALS DRUGS
FDA ANALYSIS OF DGXXIV REPORT ON PUBLIC HEALTH ASPECTS OF BST
CLARIFICATION -- CONSENT DECREE ENTERED IN ANIMAL DRUG CGMP CASE
PET OWNERSHIP - A MUTUAL RELATIONSHIP
National Pet Week will be celebrated May 2 - 8, 1999, and provides a time to reflect on the positive impact that pets have on our society. "Taking Care of Each Other" is the theme for this year’s campaign as we pay tribute to the joy and love pets bring to our lives.
Numerous studies now document the health benefits of the human-animal bond. In addition to the traditional role of animals as helpers and guardians of disabled individuals, pets have helped millions of people who suffer from a variety of afflictions, from high blood pressure to AIDS. Senior citizens receive enormous comfort from the companionship of pets, and the health benefits are becoming more evident. Pet therapy is now utilized increasingly as physicians are recognizing the positive effects in treating human patients with the therapeutic use of animals. A study of heart attack victims demonstrated that patients with pets in the family have a significantly greater chance of surviving. Another study showed that people’s blood pressure is lower when they are talking to pets than to other people.
Reasons for a pet’s positive impact on human health include: social support, reduction of stress, anxiety and anger, and the provision of something to nurture. Animals are also becoming an integral part of rehabilitation for children undergoing psychiatric treatment, or experiencing learning difficulties. Pets can teach children responsibility, and social interaction at a young age.
It is now widely recognized that pet ownership can have a very positive effect on the quality of human life. By the same token, pet owners must ensure the quality of their pet's lives by providing proper health care for their beloved friends. Due to the high social value on animals, veterinary care is gaining recognition in our society. Many pet owners think of medical care for their pets in much the same way they would for any other family member.
Many high-tech advances in veterinary medicine can extend the life of pets. Radiation therapy, bone replacements, allergy testing, dental work, and behavior modifications are now available options used regularly to ensure pets' comfort. Adjunct veterinary facilities, such as animal blood banks, are emerging, as well.
Together pet owners and their veterinarians can have a positive influence on their pet’s health and happiness for many years to come. The rewards of pet ownership will be mutually beneficial and will last a lifetime.
by Ann Stohlman, V.M.D.
The following article provides information on feline elimination behavior and provides suggestions dealing with this problem. Veterinarians may wish to duplicate this article and provide copies to their interested clients. As always, material which appears in the FDA Veterinarian is free of copyright and may be reproduced without permission.
Inappropriate elimination behavior is the most common behavioral problem for which cat owners seek advice from a veterinarian. Several million pets are euthanized each year in animal shelters across the country for behavioral problems. A 1996 study determined the most common behavior-related cause for surrendering a cat to a shelter was inappropriate elimination.
Cat elimination problems can be difficult to diagnose and treat, so a good relationship with your veterinarian and a lot of patience throughout the investigative process is essential. Elimination problems can involve either inappropriate urination, defecation, or both. Urinary problems are often more difficult to detect initially because urine can be difficult to see or smell when it is absorbed into or dries onto a surface. Once you are aware of your cat's urinating or defecating outside of the litter box, the real investigation can begin.
If your household includes several cats, you and your veterinarian must first determine which cat is eliminating outside the litter box. In some cases, more than one cat may be eliminating outside the box. Occasionally, a few simple questions and some detective work can find the culprit. If the identity is still uncertain, your veterinarian can give each cat a product that will stain its urine marks with a color that can be detected by an ultraviolet light.
Your veterinarian must then determine if the inappropriate elimination is due to a medical or behavioral problem. The veterinarian will ask many questions about your cat's background, medical history, normal activities and habits, and any unusual activities and habits that may have developed. You will also be asked details about your home environment, the outside environment, other pets, family members, and any recent changes in your household or in the cat's life. Many details about the litter box location and the type of litter will be gathered. This thorough history is time-consuming, but is critical in making a correct diagnosis. It may take a one to two-hour appointment to get all the necessary information. Some veterinarians have prepared questionnaires for their clients to complete before the visit.
After the history is taken, a thorough physical examination is performed to rule out any medical condition your cat may have. For example, older cats that develop constipation may experience pain while defecating, associate this pain with the litter box, and stop using the box. In order to further determine if the problem is due to a medical condition, some laboratory tests should be run. A urinalysis is routinely performed to look for evidence of urinary tract infection or cystitis. Your veterinarian may recommend additional tests such as a urine culture to look for bacteria in the urine, and radiographs to look for bladder stones or changes in the bones associated with arthritis. Depending on the findings, your veterinarian may also recommend specialized radiographs, or even an ultrasound examination of the abdomen. If a medical problem is detected, you and your veterinarian can initiate appropriate treatment for the specific problem.
After medical causes for the inappropriate elimination have been ruled out, your veterinarian will use the history obtained to make a list of potential diagnoses for the problem. Once the specific cause is determined, a therapy best suited to the problem can be planned and started.
There are two reasons why a cat eliminates. Cats urinate or defecate to rid the body of waste products. Cats will also urinate as a means of communication, called "marking". It is uncertain if domestic cats mark with feces. The cat will take on a different posture for each of these types of elimination. A cat that is urinating to eliminate waste will squat with its tail held parallel to the ground. A cat that is urinating to mark will hold its tail straight up, back towards an object to be marked, and quiver the tail while spraying urine on the object.
Doors or entranceways frequented by you or other cats may be marked. Placing urine on stoves or vertical surfaces is usually a type of marking behavior. Often, objects that smell like you such as bedding or laundry may be marked. Marking behavior can be triggered by stress or anxiety. One example of this is the cat that picks up cues that the owner is preparing for a trip and urinates in the suitcase. Another example is the cat that marks a piece of furniture after a new cat is introduced into the household.
Treatments for this type of behavior needs to be individualized to the cat and its particular circumstances. Usually, the treatment revolves around modifying the stresses in the environment or trying to modify the cat's response to them. In some cases, anxiolytic drugs may be prescribed to help the process. As with all therapies for behavior problems, the treatment plan may evolve as the therapy progresses.
Problems relating to elimination of urine and feces as waste products are very common. Cats eliminate outside the litter box because there is something about the box they don't like or they just prefer another place. There are many types of litter available ranging from clay to recycled newspaper. Some have fragrances added to help control the natural odor of the urine or feces. Litter boxes come in several styles. Some have domed lids to keep the odor confined to the box area. Most litters and boxes are designed to be convenient to the owner. Cats have individual preferences and some may not like the texture of a particular litter, or the smell of a fragrance added to the litter. Many cats don't like the domed lids because they make the box too cramped and may cause the box to have an unpleasant smell.
Location of the box is important. Many cats don't like to eat near the litter box. An owner may hide a litter box behind the noisy washer or dryer in the laundry room, which may frighten the cat. If a cat spends most of its time upstairs with you, it may find a box in the basement inconvenient. There should be a litter box for each cat in the household. The box should be kept free of solid waste and cleaned every few days to once a week, depending on the litter type and amount of use.
The solution to these problems may be as simple as cleaning the box more often, removing the lid, providing more litter boxes or testing new locations. Sometimes the veterinarian will recommend a "litter box smorgasbord." Many boxes are provided with a different litter type in each. The cat can then choose its preferred litter and the others can be discarded.
Not all elimination behavior problems can be predicted or prevented. However, you can take certain steps to avoid some of these problems. Cats should be spayed or neutered, preferably between 4 and 8 months old, before they reach sexual maturity. When teaching a new kitten to use the litter box, look at its location from the kitten's perspective. When the urge to eliminate hits in the kitchen after a meal, a tiny kitten may not be able to climb two flights of stairs to get to the box. Likewise, a geriatric cat may not be able to easily negotiate stairs or a litter box with tall sides. Any new cat should be placed in a large room with a litter pan for a few days so he can get used to the new box in a new environment before exploring the rest of the home. If possible, you should find out what kind of litter the cat used previously and use the same kind in your home.
Inappropriate elimination can be a very frustrating problem to diagnose and treat. At the first sign of a problem, you should notify your veterinarian about your concerns. These problems are usually easier to treat early before they have become habits. There are veterinarians who have received formal, specialized training in diagnosis and management of behavior problems in pets. The veterinarian who is a general practitioner can refer cases to these specialists or consult with them over the phone regarding difficult cases. Your veterinarian is your best resource for information on these behavior problems. With patience and your veterinarian's help, many elimination problems can be resolved to ensure a long and happy relationship between you and your cat.
by David A. Dzanis, D.V.M., Ph.D., DACVN
Many Americans enjoy the vegetarian lifestyle today, either for health or ethical reasons. Some people choose to extend this dietary philosophy to their pets as well, which has prompted the marketing of commercial vegetarian dog and cat foods. There is a spectrum of foods and ingredients that may be included or excluded from a "vegetarian" diet, depending on one’s definition. At minimum, it usually means that most meat sources are excluded from the diet (such as beef, pork, lamb, poultry, and sometimes fish). More restricted diets exclude other foods of animal origin, such as egg and dairy products. Perhaps the most extreme example would be a "vegan" diet, where all foods and ingredients of foods, including vitamin and mineral sources, are excluded if they are derived from animals. Provided foods are carefully combined in appropriate proportions, vegetarian or vegan diets for people can be very nutritious and tasty. However, is the same true for dogs and cats?
To help answer that question, one must consider the normal anatomy and physiology of the dog and cat. Both species are in the scientific order Carnivora ("meat- eaters"), although today the domestic dog is considered more as an "omnivore" (animals that eat both animals and plants). Still, just by comparing the dentition of dogs and cats with that of humans and herbivores (plant-eaters, such as cattle and horses), it is readily apparent that their teeth are designed by nature for eating a diet largely comprised of animal tissue. Their short intestinal tracts compared to humans and especially to animals like sheep or horses also indicate that they are not designed to accommodate diets containing large amounts of plant materials. Their nutritional requirements, such as the need for relatively high amounts of protein and calcium, reflect these dietary limitations.
Cats are even more specific in their nutritional needs, emphasizing their status as "true carnivores." For example, cats cannot convert the beta-carotene in plants such as carrots and dark green vegetables into vitamin A. Rather, they require "pre-formed" vitamin A, such as found in liver and fish oils. Cats also need dietary sources of taurine (an amino acid-like nutrient) and arachidonic acid (an essential fatty acid), both of which are found in appreciable levels only in animal tissues. Thus, while both species can eat and utilize some plant-source ingredients (dogs more than cats), they simply are not intended to eat only plants as are other animals such as cattle and sheep.
FIRST EQUINE DRUG APPROVED FOR ULCERS
Help is now available for horses diagnosed with gastric ulcers. The Center for Veterinary Medicine recently approved GastroGard™ (omeprazole) for the treatment and prevention of recurrence of gastric ulcers in horses and foals 4 weeks of age and older. GastroGard™ is produced and marketed by Merial Limited, and is available only by prescription.
Gastric ulcers are a common problem in horses, especially in foals and horses in stressful environments, e.g., race horses. Today’s horses are expected to adapt to lifestyles far different from their natural habitats, specifically confinement, intensive competition, changes in diet, etc. As with people, individual animals handle stress in different ways, but ulcers may be extremely debilitating, and can affect a horse’s performance and attitude. Most horses do not manifest symptoms of ulcers, but if neglected, ulcers can cause constant discomfort or even colic, a potentially fatal condition. Stress is considered the major cause of ulcers, but certain anti-inflammatory drugs may also contribute to the onset of this condition.
Veterinarians can diagnose ulcers using gastric endoscopy. The recommended treatment regimen for GastroGard™ is once-a-day for 28 days. The drug is administered as an oral paste in a calibrated syringe. Safety of the drug in pregnant or lactating mares has not been determined.
Omeprazole is marketed for humans under the tradename Prilosec® and is indicated for short-term treatment of duodenal and gastric ulcers. In addition, it is approved for the short-term (4 - 8 weeks) treatment of erosive esophagitis and of symptomatic gastro-esophageal reflux disease.
FDA FUNDS RESEARCH FOR FOOD SAFETY
In FY 98, FDA funded seven (7) cooperative agreements under the President’s Food Safety Initiative. The primary objective of these projects is to study the microbiological hazards associated with the food animal production environment which includes animal feeds. FDA/CVM has appointed project officers to monitor and work with principal investigators in conducting the research studies, which are described below.
Dr. Dale Hancock is the principal investigator for a project at Washington State University titled "On-farm Risk Factors for Zoonotic Enteropathogens Associated with Cattle Feed and Water." The goal of this study is to reduce the prevalence of cattle infected on-farm with those zoonotic bacterial enteropathogens that are important causes of human foodborne infections. This approach complements efforts to ameliorate the contamination of bovine-origin foods through improved slaughter, processing, and retail procedures and, in turn, to reduce the risk of cross-contamination of other foods during preparation. Reduction of bovine infections with these agents will also reduce environmental contamination and will decrease their transmission to humans by direct contact and by vehicles other than foods of bovine origin. The project will focus on two specific agents: Escherichia coli serotype 0157:H7(0157) and Salmonella enterica serotype Typhimurium phage type DT104 R-type ACSSuT. For the purposes of this study, all Salmonella enterica serovars (SAL) will be included and the on-farm aspect will be limited to dairy farms only.
Dr. Charles Kaspar, University of Wisconsin, is directing a project titled "Waterborne Dissemination of Escherichia coli 0157:H7." Despite advances in detection methodologies and our understanding of virulence, comparatively little is known about the dissemination of E. coli 0157:H7 between farms and cattle. Each year E.coli 0157:H7 is estimated to cause between 7,000 to 20,000 cases, with 150 to 300 deaths. Therefore, an understanding of the dissemination and persistence of E. coli 0157:H7 among cattle is particularly important since ground beef is the primary food associated with outbreaks involving this human pathogen. The long-term goals of this study are to further define the farm ecology of E. coli 0157:H7 in order to understand and ultimately control the dissemination of this important foodborne pathogen in cattle. Dr. Kaspar hopes this project will provide valuable information on waterborne transmission in cattle of this important human pathogen and provide a potential point for on-farm control.
Dr. David Acheson, New England Medical Center, Boston, MA, is the principal investigator for the study titled "STEC, Salmonella Virulence and Antibiotic Resistance in Cattle and Feed." Since new varieties of foodborne illnesses emerge almost daily, it has never been more important to ensure the microbiological safety of our food supply. The focus of this work is on two groups of important foodborne pathogens: Shiga toxin producing E. coli (STEC), e.g., E. coli 0157:H7, and Salmonella. They will collaborate with investigators at Kansas State University who will provide samples and isolates. They will isolate and characterize STEC of multiple serotypes from cattle and animal feed for known human virulence factors (Shiga toxin 1 or 2 expression, hemolysin, attachment to epithelial cells, etc.) In addition, they will investigate the fate and transmission dynamics of antibiotic resistance in human foodborne pathogens. The long-term goal of this study is to establish baseline data on the longitudinal epidemiology and clonality of two important foodborne pathogens, STEC and Salmonella, and to provide a better idea of the prevalence of pathogenic STEC in cattle and feed, and how these move from feed to animals and change in animals with time.
Dr. James Russell, Agricultural Research Service, USDA, Ithaca, NY, is the principal investigator for a study titled "Factors Affecting Numbers of Acid-Resistance Escherichia coli in Cattle." Preliminary findings indicate that grain feeding, a practice common in the American cattle industry, seems to increase the numbers of E. coli as well as its acid-resistance. Most U.S. beef cattle are also fed the ionophore, monensin, and preliminary experiments indicated that E. coli is very resistant to this antibiotic. The long-term objectives of this study are to define the role of grain-feeding and feed additives in the dissemination of acid-resistant Escherichia coli from cattle, and to find dietary strategies that could reduce the numbers of acid-resistance E. coli in cattle feces. Dr. Russell expects to define relatively simple dietary changes that could reduce carcass contamination and foodborne illness by the withdrawal of monensin and the feeding of forage rather than grain in the period just before slaughter.
Dr. Marcus Zervos, William Beaumont Hospital, Royal Oak, MI, is conducting a study titled "Survey of Antimicrobial Resistance Enterococci in Animals." One of the most formidable treatment problems that has emerged recently has been vancomycin-resistant Enterococus faecium (VREF). Data from the Michigan Department of Public Health Sentinel Surveillance Hospital System indicated resistance rates of 45 percent to vancomycin in E. faecium in the fourth quarter of 1997. Since little is known about reservoirs for resistant strains and risk factors outside of the hospital setting, the incidence of resistant enterococci in food animals and the role of these animals as a source of resistance strains or "new" resistance genes that can be acquired by humans is not defined. The overall purpose of this three-year project is to gain a better understanding of the prevalence and spread of antibiotic resistant enterococci in food animals which are essential in the design of control and prevention strategies for human acquisition.
Michael Doyle, University of Georgia, is monitoring a study titled "Control of EHEC in Cattle by Probiotic Bacteria." Shiga toxin-producing enterohemorrhagic E. coli (EHEC), including 0157:H7, 026:H11, and 0111:NM, are a group of important human pathogens causing hemorrhagic colitis and hemolytic uremic syndrome (HUS). Increased incidences of these outbreaks have occurred in the past decade. Cattle, especially young animals, have been implicated as a principal reservoir, with undercooked ground beef being the major vehicle of foodborne outbreaks. However, apple juice, lettuce, and water-associated outbreaks have increased recently. Methods to reduce or eliminate carriage of E. coli 0157:H7, 026:H11, and 0111:NM in cattle are needed to decrease the risk of transmitting these pathogens through food and the environment. The goal of this study is to reduce the carriage of EHEC in cattle by administration of three probiotic bacteria. Results from this research will provide a practical critical control point for cattle producers to use at the farm to reduce meat and environmental contamination (via manure) by EHEC, as well as insights into the colonization mechanisms of E. coli in the gastrointestinal tract of calves.
Ann Draughton, University of Tennessee, is the principal investigator for the study titled "Evaluation and Use of BAM/FDA and Rapid Methods for On-farm Survey." This project will evaluate performance of existing Bacteriological Analytical Manual (BAM) methods and rapid microbiological methods for their ability to detect/isolate Escherichia coli 0157:H7, Yersinia enterocolitica, Salmonella spp., and Campylobacter jejuni in farm environmental samples associated with dairy cattle, swine, and poultry. This will be done by inoculating feeds and other farm environmental samples with known populations of these four human pathogens and determining recovery using BAM methods and several commercially available microbiological tests. In addition, they will conduct surveys of dairy cattle, swine, and poultry production environments to establish baseline data relative to occurrence of the above pathogens. The survey will include multiple sites on the bodies of cows, pigs, and chickens, animal feeds, feces, bedding, and other environmental sites that could serve as reservoirs for these bacteria. Hopefully, this information will be helpful in developing management strategies to reduce colonization of farm animals with human foodborne pathogens.
All of the above research is now ongoing, and is expected to take up to three years to complete. Funding amounts range from $72,530 to $198,192 per study per year. For further information about any of these agreements, please contact Dr. David B. Batson, Center for Veterinary Medicine (HFV-502), Food and Drug Administration, 8401 Muirkirk Rd., Laurel, MD 20708, 301-827-8021.
WILL TRANSGENIC FISH BE THE FIRST AG-BIOTECH FOOD-PRODUCING ANIMALS?
by John Matheson
The FDA Center for Veterinary Medicine (CVM) regulates, in whole or in part, diverse animal biotechnology products. Two general areas that involve genetic modification are germ line transgenic modifications and non-heritable modifications (a.k.a.: somatic cell therapy and gene therapy).
Non-heritable modifications are still in early stages of development for animals, although this is a very active area in human medicine. These products are anticipated to be individual animal injections that would modify only some of the cells of the body to express a protein, protein hormone or enzyme. For example, individual steers could be modified to produce more muscle mass without having to modify the breeding herd, where additional muscle mass could cause calving difficulties.
Germ line transgenic modifications of animals, including fish and shellfish, have already begun to receive public attention in the U.S. and abroad. Most of the modifications currently relate to improving animal productivity. The biology of fish and shellfish facilitates more early work in the area of agronomic traits, compared to other farm animals.
One example is the inclusion of a gene cassette for increased expression of growth hormone in fish for increased growth rate and improved feed efficiency. This is a gene-based version for fish of CVM’s first recombinant DNA product - recombinant bovine somatotropin (BST) for dairy cows.
Most, but probably not all, gene-based modifications of animals for production or therapeutic claims fall under CVM regulation as new animal drugs. As strange as it may seem at first, many of the modifications being investigated involve the addition of new animal drug substances. For example, adding growth hormone to a cow can be accomplished through use of BST injections, through gene therapies to create BST-producing regions in the body of the cow, or through germ-line modification, making a transgenic variety that contains extra BST-coding genes in every cell of the body, including reproductive cells. It all amounts to adding an animal drug, but the conditions are different – dose, areas of the body where the drug is released, opportunity for a withdrawal time, etc. The substances being added are for the purpose of improving animal health or productivity.
Absent a new, special law for regulating transgenic animals, the Federal government is directed to apply the existing laws. The animal drug provisions of the Federal Food, Drug, and Cosmetic Act best fit transgenic animals that have agronomic traits now being investigated and developed. Other transgenics will no doubt come along that could be viewed as containing food additives, color additives, vaccines, and nutritional supplements. Development of site-specific gene insertion techniques and animal genome projects could change the scope of potential genetic modifications to yield a wider variety of products than are currently being investigated.
As there is active investigation of transgenic fish abroad, as well as in the U.S., the public and the research community are occasionally exposed to predictions of the imminent commercial release of transgenic fish into the food supply. This should not occur without the pre-market approval from CVM, for those fish that have an added gene-based animal drug. No transgenic fish have been approved for producing food in the U.S., although a variety of transgenic fish species can be found in laboratories around the world.
It might be useful to describe how transgenic fish varieties are currently being produced. In addition to the genes being added, the techniques used are the source of some of the safety questions being raised at FDA.
Steps for Making a Transgenic Fish
Step 1
Decide on which gene to add, e.g., tilapia growth hormone gene. Step 2. Decode the growth hormone protein and translate it into the corresponding DNA code, i.e., make an artificial gene to express growth hormone. Step 3. Add the DNA code for a promoter gene and/or other regulatory genes and prepare a gene construct. Step 4. Insert the gene construct into a bacterial plasmid (plasmids are small, self-replicating, circular pieces of DNA that carry a number of genes, often including drug resistance genes). Step 5. Insert the plasmid into a bacterial cell line, such as an E. coli K-12, and grow up billions of copies of the plasmid. Step 6. Isolate the plasmid from the bacteria and cleave it into linear cassettes. Step 7. Inject a million or so cassettes into each newly fertilized, undivided egg of the fish to be modified; repeat hundreds of times. Step 8. Incubate eggs and grow up surviving fry. Step 9. Survivors will include many transgenic individuals, each one unique in the site of integration of the cassette, the number of cassettes integrated in the genome, and the degree to which the added genes are expressed, i.e., the amount of extra growth hormone produced. Find the transgenics and pick out the individuals that have the growth characteristics that are potentially marketable. Step 10. Embark on breeding program to stabilize the genetic construct in the new fish variety and to obtain enough individual fish to assess for commercial value, food safety, etc. Step 11. Now that there is a reasonable example of the final product, seek regulatory approval for it. Develop safety and other data and convince a number of governments and the citizens of those countries that your transgenic fish strain is commercially desirable, safe to eat and safe when lost into the environment. Design biological or physical containment for the new variety of transgenic fish to protect wild populations from gene introgression and competition.
Current Technology for Producing Transgenic Fish Has Limitations
The current technology has limitations that affect what types of transgenics can be developed.
The "transgenes" are limited to short gene constructs and are inserted randomly and in variable numbers of copies in each individual. This creates difficulty in stabilizing genetic modifications in a breeding population. There may be uncontrolled expression of the transgene. It may be expressed all the time; it cannot be turned off. Insertion sites for the transgenes may inadvertently affect the expression of other genes by disabling them or turning them on at an inappropriate time. The incidental insertion of drug resistance genes from bacterial plasmids introduces further uncertainties as to food safety.
Breeding programs are needed to stabilize the transgenes in a patentable variety and to produce numbers necessary for regulatory approvals and for marketing. Biocontainment strategies, both from an engineering and biological point of view, are necessary to prevent escape of the transgene into wild fish populations and to provide a means of control over the unlicensed breeding of the patented variety. These features add to the costs of development and affect competitiveness of the approach versus other, more traditional, breeding approaches.
Biocontainment needs are specific for each species and the location where it would be reared. The primary environmental concerns about releases of transgenic fish, for example, include competition with wild populations, movement of the transgene into the wild gene pool, and ecological disruptions due to changes in prey and other niche requirements in the transgenic variety versus the wild populations. For example, transgenic tilapia (with cold tolerance similar to the unmodified species) might require little containment in the northern tier of the U.S., but might be excluded from the Gulf States altogether, where tilapia may be a serious exotic invader of freshwater streams and ponds. These site-specific concerns may make it necessary to control the sites where transgenic fish are reared and the level of biocontainment required might differ from site to site. Any biocontainment other than absolute containment will have to be assessed for specific proposed sites.
Public acceptance of foods derived from transgenic animals will be important to the success of any transgenic variety introduction. Approval by FDA or a food regulatory group in another country does not guarantee public acceptance. Labeling of food from transgenic animals will likely be even more important to consumers desiring a choice than has been observed for milk derived from BST-treated dairy cows or for transgenic plant varieties. Ethical concerns among the public over the appropriate use of animals are issues, not evident with transgenic plants, that may affect public acceptance of transgenic animals as food sources. There is also expected to be variation among the citizens of different countries as to their acceptance of transgenic animals.
Competition from Alternative Approaches
Finally, alternative approaches to breed improvement are in competition with transgenic approaches. This is especially true in fish and shellfish species, where there has been only a short history of attempts at breed improvement through selective breeding. The use of new genetic screening techniques in combination with selective breeding could produce even faster results. The strains of animals produced through these means face less regulatory or public scrutiny than transgenic varieties.
Improved nutrition and management techniques may also yield increased productivity, disease control and profitability of aquacultured species. Orally active growth promoters that can be withdrawn pre-harvest are currently not available for aquaculture. Such classical animal drug approaches, while regulated by the same process as transgenic fish, could be applied to any individual of the species, a potentially larger market than a transgenic variety could penetrate.
Does this mean that transgenic fish are not likely to be commercialized in the U.S.? Not at all! It means only that the improvements offered by transgenic fish, and any other transgenic animals, must be dramatic when compared to what is possible by other, better-accepted, approaches. Benefits to producers and consumers must be tangible and outweigh the costs in royalties, license fees, biocontainment, and regulatory and public acceptance. The technology for creating transgenic animals is constantly improving and will soon begin to reduce the limitations of the current approaches and improve the competitive balance with other approaches to breed improvement.
John Matheson works in the Office of Surveillance and Compliance where, among other duties, he follows biotechnology developments for CVM.
FDA STOPS IMPORTATION AND DISTRIBUTION OF CONTAMINATED ANIMALS DRUGS
Two California firms have agreed to stop manufacturing and importing injectable animal drugs after the Food and Drug Administration had found their products to be contaminated and to pose a health hazard to treated animals and to consumers of foods from animals.
The ban on distribution and importation is part of a consent decree entered by the United States District Court for the Eastern District of California by Sierra Pharmaceutical Inc., whose plant in Mexicali, B.C., Mexico, manufactured the drugs, and Veterinary Pharmaceuticals, Inc., a sister company that imported and distributed Sierra's products in the U.S. Both firms are based in Hanford, California.
The FDA identified the potential public health hazard in the fall of 1997, after the agency's investigators in California and Kansas collected samples of 45 lots of Sierra's injectable drugs and submitted them for analyses to FDA laboratories in San Francisco and Seattle.
Nine of the lots, which were labeled "sterile," were found to be contaminated with various types of bacteria, including Bacillus cereus, B. licheniformis, B. sphaericus and B. subtilis, and most of the samples contained alcohol as preservative, although they were represented as "preservative free". The detected bacteria can cause such diseases as blood poisoning, respiratory infections and mastitis in dairy cows, and produce toxins that remain in the animal tissue. As a contaminant on food, these pathogens can cause nausea, vomiting and diarrhea in people.
According to a report received by FDA from a California veterinarian, animals in several dairy herds had suffered illnesses attributable to the Sierra products. After remedial actions repeatedly promised by the firm were not carried out, FDA placed an import alert on Sierra's drugs in order to prevent any Sierra products from entering the U.S.
Since then, Sierra has informed FDA that it has sold all of its assets and that it is in the process of dissolution and winding up all corporate affairs. Under the permanent injunction, the firm may only resume distribution of its drugs in the U.S. following an FDA inspection of Sierra's manufacturing facilities in Mexico and a finding that they are in compliance with U.S. laws.
SCHEDULE III CLASSIFICATION PROPOSED FOR KETAMINE
As a follow-up to the article titled "Regulation of Controlled Substances" featured in the March/April 1999 issue of the FDA VETERINARIAN, this new information is now available.
In the April 9, 1999, Federal Register (64 FR 17299), the Drug Enforcement Administration (DEA) proposed the placement of the substance ketamine, including its salts, isomers, and salts of isomers, into Schedule III of the Controlled Substances Act (CSA).
The effect of this proposed action will be to discourage the diversion and abuse of ketamine, and subject ketamine to the regulatory, civil and criminal controls of a Schedule III controlled substance.
Ketamine hydrochloride has been marketed in the United States since 1971 as a rapid-acting general anesthetic, for both human and veterinary medicine. It can produce a unique anesthetic state characterized by sedation, immobility, marked analgesia, and amnesia. Chemically, ketamine is related to PCP, a Schedule II controlled substance. The effects produced with use of ketamine are similar, although less intense and shorter in duration, to those produced by PCP.
The pharmacological and behavioral effects of ketamine are similar, but somewhat less intense and shorter in duration, to those of PCP. Low dose intoxication with ketamine results in impaired attention, learning, and memory functions. Higher doses may result in ataxia, dizziness, elevated blood pressure, mental confusion, hyperexcitability, catalepsy (the inability to move), convulsions, a delusional dream-like, hallucinations, and psychosis. Long-term use of ketamine is associated with hallucinatory flashbacks and as inability to concentrate. Several case reports suggest that psychological dependence and tolerance develop in humans after long-term use of ketamine. Behavioral and physical dependence have been demonstrated in animals.
In 1981, The Department of Health and Human Services (DHHS) first recommended to the DEA that ketamine and products containing it be placed into Schedule III of the CSA, however, the DEA determined that the incidence of actual abuse was not sufficient to sustain the scheduling action. The DEA continued to monitor the situation, and incidents increased significantly until 1992, when 775 reports of ketamine diversion or abuse had been received by the DEA. The incidence of law enforcement encounters of individuals selling the drug, under its influence, or who had it in their possession, along with the wide geographic distribution of the encounters, the involvement of teenagers and young adults, the occurrence of veterinary clinic burglaries directed at ketamine, the spreading notoriety of ketamine as a party drug, "Special K'' or "K'', and the number of ketamine abuse-related hospital emergency department visits have caused the DEA to reconsider the noncontrolled status of the drug.
Ketamine is presently regulated as a controlled substance in 18 states; 15 states have placed it into Schedule III, two states have placed it into Schedule IV, and Massachusetts has designated it as a Class A substance.
Interested persons are invited to submit their comments, objections, or requests for a hearing, in writing, with regard to this proposal to the Deputy Administrator, Drug Enforcement Administration, Washington, D.C. 20537. Attention: DEA Federal Register Representative/CCR. Comments and objections must be received on or before June 8, 1999.
FDA ANALYSIS OF DGXXIV REPORT ON PUBLIC HEALTH ASPECTS OF BST
FDA approved Monsanto Company's recombinant bovine somatotropin (rbST) product, Posilac® , in November 1993 after a comprehensive review of the product's safety and efficacy, including human food safety. Recently, FDA reviewed the European Commission Directorate General XXIV "Report on Public Health Aspects of the Use of Bovine Somatotropin -- 15 -16 March 1999."
The conclusions of the DGXXIV report with respect to the safety of IGF-I do not appear to be consistent with the current state of scientific knowledge. Specifically, the report states that establishing an in vivo quantitative dose-effect relationship for IGF-I is virtually impossible because of the diverse biological effects attributable to the intrinsic activity of IGF-I. In fact, there are standard hazard assessment procedures for assessing the hazard associated with all types of compounds that exert a broad variety of metabolic effects. These procedures have been applied to determine the safety of vitamins, food additives, and drugs, including hormones, for over twenty-five years.
Numerous independent researchers and scientific committees have examined the data on the dietary exposure of IGF-I and related proteins present in milk. The data provide ample evidence that the amount of IGF-I and truncated forms excreted in milk following the administration of rbST to dairy cows is safe for all consumers, including infants. Additional exposure data are not necessary.
FDA's determination that food products from cows treated with rbST are safe for consumers has been supported by numerous scientific and regulatory bodies including the Joint Food and Agricultural Organization/World Health Organization Expert Committee on Food Additives (JECFA), an international panel of experts in the field of toxicology and chemistry of animal drug residues that meets to evaluate the safety of animal drugs. In 1992, the JECFA concluded that "the lack of oral activity of rbST and insulin-like growth factor I (IGF-1) and the low level and non-toxic nature of the residues of these compounds, even at exaggerated doses, results in an extremely large margin of safety for humans consuming dairy products from rbST-treated cows." In 1998, JECFA reaffirmed the safety of milk and meat from rbST-treated cows.
Recently, FDA reviewed the issues raised in Health Canada's report on the food safety of rbST, and concluded that there were no biologically significant effects. Based on the current body of science relative to the safety of rbST, FDA has reaffirmed that meat and milk from rbST-treated cows are safe for human consumption.
The full FDA report, "Report on the Food and Drug Administration's Review of the Safety of Recombinant Bovine Somatotropin," is available on CVM's Internet Home Page. A copy of this report may also be obtained by calling or writing the FDA Veterinarian.
COURT OF APPEALS UPHOLDS CONTEMPT ORDER IN ANIMAL DRUG CASE
On February 5, 1999, the U.S. Court of Appeals for the Third Circuit affirmed an order of civil contempt entered by the District Court requiring Frank Lampley to stop promoting and distributing unapproved new animal drugs. Lampley manufactures and sells unapproved new animal drugs. In 1992, FDA received information that Lampley was distributing unapproved animal drugs in violation of the Federal Food, Drug, and Cosmetic Act, and sought an injunction against him in the U.S. District Court for the Eastern District of Pennsylvania. Several months later, the District Court issued a permanent injunction prohibiting Lampley from distributing unapproved new animal drugs in interstate commerce.
In 1996, FDA learned that Lampley once again was distributing unapproved animal drugs as he made claims that his products could cure, treat, or prevent diseases in horses and cows. FDA filed a motion for an order to show cause, asking that Lampley be held in civil contempt. At a hearing held March 13, 1998, the District Court held Lampley in contempt of the 1992 order. The Court asked Lampley to cooperate with FDA, and agree to a plan to cure his past violations within 30 days. After the parties were unable to reach an agreement, Lampley sent a letter to his customers saying that the Court takes the position that his products are unapproved new animal drugs, and that "...the FDA, U.S. Attorney, and Judge ...are ignor[ing] the law and just do what they want to."
The District Court held a second hearing on June 3, 1998. At that hearing, FDA presented evidence that since the March 13 hearing, Lampley had continued to promote his products as drugs. The Court ordered the parties to propose a final contempt order. After the parties again failed to reach an agreement, the Court ordered Lampley to (1) mail a letter to his customers stating that his products have not been approved by FDA for any drug claims; (2) withdraw all advertising and promotional material for his product that directly or indirectly made drug claims for those products; and (3) destroy all existing labeling, advertising, and promotional materials for his products.
Lampley then appealed the District Court's order to the Third Circuit arguing that the District Court abused its discretion in ordering him to send letters to his customers informing them of the court's ruling, and that the contempt order violated his First Amendment rights under the commercial speech doctrine. The Court of Appeals found that the District Court had not abused its discretion in entering the order since Lampley repeatedly violated the District Court's 1992 injunction. The Court of Appeals also found that Lampley's First Amendment rights were not violated because his drug claims promote unlawful activity -- the sale and purchase of unapproved animal drugs. In addition, the Court of Appeals held that Lampley's products did not fit within the exemptions created by the Dietary Supplement Health Education Act of 1994 (DSHEA). The Court of Appeals found that the DSHEA does not apply to claims that a particular product will cure, prevent, treat, or mitigate disease. Furthermore, the Court stated that it appears that the DSHEA does not apply to dietary supplements intended for veterinary use. The Court of Appeals affirmed the contempt order entered by the District Court.
CLARIFICATION -- CONSENT DECREE ENTERED IN ANIMAL DRUG CGMP CASE
The following is a clarification of an article that appeared in the January/February FDA Veterinarian (pp. 8-9).
On November 30, 1998, a U.S. District Court Judge for the Northern District of Ohio, Eastern Division, incorporated into an order the entry of a Consent Decree for Permanent Injunction between the United States, and Berlin Industries, Inc., William J. Barnett (President) and Robert R. Roth (General Manager). Berlin Industries, Inc., is located in Berlin Center, Ohio. Only a limited portion of Berlin's business involved the manufacture of animal drugs.
The Complaint for Permanent Injunction filed by the government alleged that Berlin Industries violated current good manufacturing practice regulations (21 CFR 211) for finished pharmaceuticals and that the firm engaged in manufacturing and distributing unapproved new animal drugs intended for use in horses.
The U.S. Department of Justice, FDA, and Berlin negotiated a Consent Decree for Permanent Injunction in which the firm neither admitted nor denied the allegations, and opted to settle the case. In this Consent Decree the firm agreed to voluntarily discontinue manufacturing, processing, packing, or labeling of any drugs and/or distributing unapproved new animal drugs. It was also agreed that the firm will surrender its drug establishment registration. The firm may not re-enter the business of manufacturing, processing, packing, or labeling any drugs, unless it re-registers with FDA and implements any measures that FDA may deem necessary to prevent future violations of the Federal Food, Drug, and Cosmetic Act. Violation of this consent decree may carry civil or criminal penalties.
The FDA's Cincinnati District Office conducted all investigative work for this case. The CVM's Division of Compliance, the FDA's Office of the Chief Counsel, and the U.S. Department of Justice's Office of Consumer Litigation were in charge of the case processing and litigation.
The following firms/individuals received warning letters for offering animals for slaughter that contained illegal drug residues:
Steven H. Nash, Nash Farms, Inc., Selma, CA
Robert Wilbur, Wilbur Brothers, Tulare, CA
Frank R. Coelho, Coelho Dairy, Modesto, CA
Tony Martin Sr., Partner, Martin's Dairy, Chino, CA
Michael H. Frings, Mike Frings Cattle Company, Tulare, CA
John L. Borba, Borba Dairy Farms, Hilmar, CA
Joe B. Lopes, Owner, El Nido, CA
Douglas and Debra Hillegass, Mountain View Farm, Berlin, PA
Ron Calfe, C Bar D Cattle Company, Gravity, IA
Robert A. Brumbaugh Sr. and Jr., Brumbaugh Farms, Martinsburg, PA
Roy S. Remund, Remund Dairy, Inc., Midway, UT
Richard H. Byma, By-Acres Farm, Sussex, NJ
These violations involved illegal residues of sulfadimethoxine in dairy cows; oxytetracycline in a dairy cow; streptomycin in a calf; oxytetracycline and sulfamethazine in cows; gentamicin in a heifer calf; neomycin in a cow; tilmicosin in a heifer; penicillin in a cow; gentamicin and streptomycin in cows;
Warning letters were also sent to the following firms/individuals which had a history of offering animals for sale for human food use which were adulterated with drug residues. These warning letters stated that these individuals/firms had offered animals for slaughter that contained illegal drug residues:
Robert D. Kelly Jr., Flying H Dairy, Stevinson, CA
Leo Warmerdam, Warmerdam Dairy, Inc., Hanford, CA
Melvin Laughery, Fontanelle, IA
Ezequiel "Ike" Tapia, Tapia Brothers Dairy Inc., Miles, TX
Mark P. Mayo, Mayo Dairy, Le Grand, CA
These violations involved illegal residues of sufadimethoxine in cows; tilmicosin and gentamicin in a heifer; gentamicin in a dairy cow;
Warning letters were sent to the following firms/individuals for violations from Good Manufacturing Practices (GMPs):
Thomas T. Rucks, United Feed Co-op, Inc., Okeechobee, FL
James E. Cherwinka, Wausau Chemical Corporation, Wausau, WI
|
Company |
Generic and (Brand) Names |
Indications |
Routes/Remarks |
|
Alharma Inc. |
Decoquinate medicated powder |
Calves (ruminating and non-ruminating, including veal). For prevention of coccidiosis. |
ORAL: he powder is added to whole milk and fed to calves. The0.8 percent medicated powder in milk is to prevent coccidiosis caused by Eimeria bovis and E. zurni. In addition, an ADI for decoquinate is codified. Federal Register: 3/2/99 |
|
Elanco Animal Health, a Division of Eli Lilly and Co. (NADA 141-110) |
Monensin and Virginiamycin |
Turkeys. For the prevention of coccidiosis caused by Eimeria meleagrimitis, E. adenoeides, and E. gallopavonis, and for increased rate of weight gain, and improved feed efficiency. |
MEDICATED FEED: Combining approved monensin and virginiamycin Type A medicated articles to make a combination drug Type C medicated growing turkey feed containing 54 to 90 g/t monensin with 10 to 20 g/t of virginiamycin. For growing turkeys only. Do not allow horses, other equines, mature turkeys or guinea fowl access to feed containing monensin. Federal Register: 03/17/99 |
|
Merial Ltd. (NADA 141-097) |
Ivermectin |
Swine. For use as antiparasitics, antibacterials, and growth promotants. |
MEDICATED FEED: Combining approved ivermectin and BMD Type A medicated articles to make Type B and C medicated swine feeds. The Type C medicated feeds contain 1.8g of ivermectin and 10, 30, or 250g of BMD® per ton for feeding to growing and finishing swine and pregnant sows. Federal Register: 03/18/99 |
ABBREVIATED NEW ANIMAL DRUG APPROVALS
|
Company |
Generic and (Brand) Names |
Indications |
Routes/Remarks |
|
Phoenix Scientific, Inc. (ANADA 200-247) |
Oxytetracycline hydrochloride soluble powder |
Chickens, turkeys, cattle, swine, and sheep. In drinking water for the treatment and control of various bacterial diseases. |
ORAL: The ANADA is a generic copy of Pfizer Inc.'s NADA 8-622 (Terramycin-343). Federal Register: 03/18/99 |
|
Med-Pharmex, Inc. (ANADA 200-241) |
Lincomycin hydrochloride soluble powder |
Swine, broiler chickens. In drinking water for use in swine for treatment of dysentery and in broiler chickens for the control of necrotic enteritis. |
ORAL: The ANADA is a generic copy of Pharmacia & Upjohn's NADA 111-636 (Lincomix ® soluble powder). Federal Register: 03/19/99 |
|
Phoenix Scientific, Inc. (ANADA 200-253) |
Dinoprost tromethamine sterile solution |
Cattle, swine, mares. For estrus synchronization, treatment of silent estrus and chronic endometritis in cattle; for abortion of feedlot and other nonlactating cattle; for paturition induction in swine; and for controlling the timing of estrus in estrous cycling mares that have a corpus luteum. |
INTRAMUSCULAR: The ANADA is a generic copy of Pharmacia & Upjohn's NADA 108-901(Lutalyse® ). Federal Register: 04/01 |
SUPPLEMENTAL ABBREVIATED NEW ANIMAL DRUG APPROVAL
|
Company |
Generic and (Brand) Names |
Indications |
Routes/Remarks |
|
Merial, Ltd. (ANADA 200-144) |
Oxytetracycline hydrochloride soluble powder |
Chickens, turkeys, swine, cattle and sheep. In the drinking water for the treatment and control of various bacterial diseases. |
ORAL: The supplement provides for a larger package size. The ANADA reflects the sponsor change from Rhone Merieux Canada, Inc. Federal Register: 03/04/99 |
|
PennField Oil Co. (ANADA 200-026) |
Oxytetracycline hydrochloride soluble powder (OTC HCl-343) |
Turkeys. For the treatment and control of bacterial infections caused by oxytetracycline susceptible organisms. |
ORAL: The ANADA provides for a zero-day withdrawal period for use of OTC HCl soluble powder in the drinking water of turkeys. Federal Register: 03/22/99 |
|
PennField Oil Co. (ANADA 200-026) |
Oxytretracycline hydrochloride soluble powder. (OTC HCl-343) |
Turkeys, chickens, cattle, sheep, swine. For the treatment and control of bacterial infections caused by oxytetracycline susceptible organisms. |
ORAL: The ANADA provides for an additional package size (512 grams of OTC HCl-343 per 23.9 ounces of soluble powder) for making medicated drinking water. Federal Register: 03/22/99 |
SUPPLEMENTAL NEW ANIMAL DRUG APPROVALS
|
Company |
Generic and (Brand) Names |
Indications |
Routes/Remarks |
|
Schering-Plough Animal Health Corp. (NADA 141-063) |
Florfenicol |
Cattle. For treatment of foot rot. |
SUBCUTANEOUS: For treatment of cattle for bovine interdigital phlegmon (foot rot, acute interdigital necrobacillosis, infectious pododermatitis) associated with Fusobacterium necrophorum and Bacteroides melaninogenicus. Federal Register: 02/26/99 |
|
Alpharma, Inc. (NADA 65-470) |
Bacitracin Methylene Disalicylate soluble (BMD® soluble) |
Replacement chickens. An aid in the prevention and control of necrotic enteritis. |
ORAL: For making a medicated drinking water containing the equivalent of 100 mg of bacitracin per gallon to be used in the prevention of necrotic enteritis caused by Clostridium perfringens susceptible to BMD®. Medicated drinking water containing the equivalent of 200 to 400 mg of bacitracin per gallon is used in the control of necrotic enteritis caused by C. perfringens susceptible to BMD®. Federal Register: 03/17/99 |
|
Roche Vitamins, Inc. (NADA 96-298) |
Lasalocid (Bovatec® ) |
Rabbits. For the prevention of coccidiosis. |
MEDICATED FEED: Use of a lower concentration of lasalocid Type A medicated article (15 percent and 20 percent) to make a Type C rabbit feed. Also provided is a tolerance for drug residues in rabbits. Federal Register: 03/17/99 |
|
Pharmacia & Upjohn Co. (NADA 34-025) |
Lincomycin (Lincocin®) |
Dogs, cats, swine. |
SUBCUTANEOUS: Injectable use in dogs, cats, and swine. A swine residue tolerance and an ADI added. Federal Register: 03/18/99 |
|
Pharmacia & Upjohn Co. (NADA 97-505) |
Lincomycin (Lincomix®) |
Swine and Broiler Chickens |
MEDICATED FEED: Use of Lincomix® 20/50 Type A medicated article and Lincomix® 10 Type B medicated feed. Also add a zero withdrawal period, a swine residue tolerance, and an ADI. Federal Register: 03/18/99 |
|
Pharmacia & Upjohn Co. (NADA 111-636) |
Lincomycin (Lincomix®) soluble powder |
Swine and Broiler Chickens |
ORAL: Use of Lincomix soluble powder in the drinking water of swine and broiler chickens. Also for a zero withdrawal period, establishing residue tolerances of 0.6 parts per million in swine liver and 0.1 ppm in swine muscle, and establishing an ADI of 25 micrograms per kilo of body weight per day. Federal Register: 03/18/99 |
|
Schering-Plough Animal Health Corp. (NADA 141-070) |
Propofol (Rapinovet Anesthetic Injection) Rx |
Cats. For general anesthesia. |
INTRAVENOUS: Expands the use to include cats; it is approved for dogs. Federal Register: 03/19/99 |
|
Pfizer, Inc. (NADA 141-061) |
Doramectin (Dectomax®) |
Cattle. Treat and control of infections and to protect from reinfections with nematodes including Haemonchus placei for 14 days after treatment. |
SUBCUTANEOUS AND INTRAMUSCULAR: To provide for persistent use and protect from reinfection with H. placei for 14 days after treatment. The approved use in cattle is for treatment and control of various gastrointestinal roundworms, lungworms, eyeworms, grubs, sucking lice, and mange mites, and persistent use for certain worms. Federal Register: 03/19/99 |
|
Elanco Animal Health, A Division of Eli Lilly & Co. (NADA 141-064) |
Tilmicosin (Pulmotil®) Rx VFD |
Swine. For control of swine respiratory disease. |
MEDICATED FEED: For veterinary prescription use of tilmicosin Type C medicated swine feeds under a veterinary feed directive(VFD) provides a revised limitation to prevent accidental access by horses. Also provides a swine muscle tolerance and an acceptable daily intake(ADI). The limitation states "Do not allow horses or other equine access to feeds containing tilmicosin." Federal Register: 03/22/99 |
|
Pfizer, Inc. (NADA 15-102) |
Sulfadimethoxine tablets and boluses (SDM) Rx |
Dogs and cats. To treat bacterial infections. |
ORAL: The supplement supports prior approval, several sponsor changes, and requests codification. Federal Register: 04/01/99 |
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