Risks to Human Health from the Use of Antibiotics in Animal Feeds

9

Risks

to

Human

Health

from

the

Use

of

Antibiotics

in Animal Feeds

Philip J. Frappaolo

Downloaded by TUFTS UNIV on July 15, 2016 | http://pubs.acs.org Publication Date: September 18, 1986 | doi: 10.1021/bk-1986-0320.ch009

Center for Veterinary Medicine, U.S. Food and Drug Administration, Rockville, MD 20857

Since 1969, the Food and Drug Administration's Center for Veterinary Medicine (formerly the Bureau of Veterinary Medicine) has had cause for concern that the subtherapeutic use of a n t i b i o t i c s i n animal feeds may cause bacteria i n animals to become resistant to a n t i b i o t i c s . This resistance to a n t i b i o t i c s i s said by many knowledgeable s c i e n t i s t s to be transferred to bacteria i n humans, thus making these a n t i b i o t i c s i n e f f e c t i v e i n treating human b a c t e r i a l infections due to compromise of therapy. For this reason, FDA proposed i n 1977 to withdraw the use of p e n i c i l l i n i n animal feed and r e s t r i c t the use of the tetracyclines (chlortetracycline and oxytetracycline) to certain uses i n animal feed. This talk w i l l focus on FDA's e f f o r t s to f i n a l i z e i t s review of the issue and present an update on the current status of the 1977 proposals.

In a l e t t e r to Science i n 1980 (1), U.S. Representative John Dingell (D-MICH) stated with respect to the debate concerning the subtherapeutic use of a n t i b i o t i c s i n animal feeds: "The science of this issue i s well i n hand, but we cannot c a l l upon i t to do the impossible. Twenty years of s c i e n t i f i c investigation have i d e n t i f i e d but not quantified the r i s k to human health. We now face a fork i n the road where prudent policy decision and not further study w i l l be the pathfinder." There are several ways i n which the feeding of a n t i b i o t i c s of animals may pose a potential health hazard to humans and other animals. F i r s t , pathogenic organisms such as Salmonella, existing i n the GI tract of animals, can become resistant to the a n t i b i o t i c ( s ) fed to the host animal at subtherapeutic levels and over time be passed into the environment and/or food to humans. This chapter not subject to U.S. copyright. Published 1986, American Chemical Society

Moats; Agricultural Uses of Antibiotics ACS Symposium Series; American Chemical Society: Washington, DC, 1986.

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Risks to Human Health from Antibiotics in Animal Feeds

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Since the organisms are a n t i b i o t i c resistant, i f they produce c l i n i c a l i n f e c t i o n i n humans or other animals, then the same a n t i b i o t i c would be an i n e f f e c t i v e treatment. Secondly, resistance that develops i n non-pathogenic bacteria, for example, jE. c o l i may be transferred to pathogenic bacteria either i n animals or humans which may i n turn cause a drug resistant i n f e c t i o n . There i s also concern that a n t i b i o t i c s i n animal feeds may increase the prevalence or prolong the shedding of Salmonella organisms i n animals, thus increasing the r i s k of disease i n animals and humans.


H i s t o r i c a l Perspective The health concerns over the practice of feeding animals a n t i b i o t i c s came to the forefront i n 1965 when i n England there was an epidemic of drug resistant Salmonella typhimurium i n dairy calves that subsequently spread to humans. Thousands of animals as well as seven humans died as a result of the epidemic which lasted for several years. The offending s t r a i n of Salmonella was believed to have originated on a c a l f dealer's premises from which infected calves were sold to many parts of England. The use of a n t i b a c t e r i a l s i n the calves was thought to have caused the development of the resistant s t r a i n of Salmonella. Spread of the organism and treatment of diseased animals with various a n t i b i o t i c s led to the s t r a i n acquiring resistance to eight different drugs by the time the epidemic had run i t s course. This incident and concerns that resistance to a n t i b i o t i c s was increasing led to the formation of the Swann Committee, which examined the use of a n t i b a c t e r i a l s i n feeds i n England. In 1969, the Committee issued i t s report (2) on the use of a n t i b i o t i c s i n veterinary medicine and animal husbandry. I t recommended that a n t i b i o t i c s and other a n t i b a c t e r i a l s be divided into a "feed" class and a "therapeutic" class which would be used only by issuance of a veterinary prescription. The B r i t i s h government accepted the Swann Commmttee recommendations i n 1971. FDA's concerns regarding a n t i b i o t i c resistance and the implications for human and animal health span some 30 years during which symposia, consultations with outside experts and task force reviews were held. Most notable among these actions was the establishment of the FDA Task Force on the Use of A n t i b i o t i c s i n Animal Feeds. Established i n 1970 at the recommendation of FDA's Science Advisory Committee, the Task Force was asked to undertake a comprehensive review of the use of a n t i b i o t i c s i n animal feeds. In i t s report (3) issued i n 1972, the Task Force acknowledged the potential human and animal health hazard of drug resistant bacteria and made a number of recommendations. In addition to basic research to better understand the nature of the problem, the Task Force recommended that r e s t r i c t i o n s be placed on the use of a n t i b a c t e r i a l agents i n feeds which f a i l to meet guidelines established by the Task Force i n regard to safety and/or e f f i c a c y . Agents that do not meet these standards would be prohibited from growth promotion and any subtherapeutic use i n animals but could continue to be used at therapeutic levels for short-term treatment on the order of licensed veterinarians.



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A G R I C U L T U R A L USES O F ANTIBIOTICS

Shortly a f t e r the Task Force made i t s recommendation, FDA i n 1973 established a regulation (4) that specified that a n t i b i o t i c s to be used i n animal feeds for more than two weeks must meet the Task Force's c r i t e r i a for safety i n order to gain approval or to remain on the market. A few years a f t e r the issuance of the Task Force Report, the Commissioner of the Food and Drug Administration (FDA) ordered additional review of the data and the issues involved by the Agency's National Advisory Food and Drug Committee. This review involved public meetings and comments from a l l interested p a r t i e s . After this review and taking into consideration the recommendations of the Advisory Committee, former Commissioner Donald Kennedy directed the Bureau of Veterinary Medicine [now the Center for Veterinary Medicine (CVM)] to publish a Notice of Opportunity for Hearing on a proposal to withdraw approval of New Animal Drug Applications for use of p e n i c i l l i n i n animal feeds. This Notice 05) published i n the FEDERAL REGISTER on August 30, 1977, and was followed on October 21, 1977, by a s i m i l a r Notice (6) which proposed withdrawal of certain subtherapeutic uses of the tetracyclines, s p e c i f i c a l l y chlortetracycline and oxytetracycline i n animal feeds. The manufacturers of the a n t i b i o t i c s requested a hearing. Because of disagreement among some s c i e n t i s t s as to whether the subtherapeutic use of these a n t i b i o t i c s results i n s i g n i f i c a n t health r i s k s , Congress intervened and i n 1979 directed FDA to contract with the National Academy of Sciences (NAS) to study the issues involved and earmarked $250,000 f o r that purpose. Congress also mandated that FDA hold i n abeyance any implementation of i t s proposed actions pending f i n a l results of these studies. Nevertheless, FDA announced i t s intention to hold a formal evidentiary hearing i n response to the drug sponsors' request, but the start of the hearing would be delayed u n t i l release of the NAS report. In addition to the NAS report, other Congressionally mandated studies included the Office of Technology Assessment report 07) on "Drugs i n Livestock Feed" i n June of 1979, and the USDA's report (8) on the "Economic Effects of a Prohibition on the Use of Selected Animal Drugs" i n December of 1978. These reports e s s e n t i a l l y supported the views held by FDA. For example, the OTA report concluded that the health r i s k s from the use of low-level a n t i b i o t i c s are of greater concern than the risks of cancer from DES and furazolidone as used i n l i v e s t o c k p r a c t i c e . They also concluded that the drugs FDA proposed r e s t r i c t i n g could be replaced with alternative drugs. The USDA economic study concluded that while farm and food prices would increase i n i t i a l l y , the economic system would generally "be quite resistant to a more r e s t r i c t i v e policy on animal drug use." This conclusion was reached even though the USDA study was based on the erroneous assumption that a l l feed additive a n t i b i o t i c s would be banned. In March of 1980, the NAS submitted i t s report (9) e n t i t l e d "The Effects on Human Health of Subtherapeutic Use of Antimicrobials i n Animal Feeds." The report stated "the postulations concerning the hazards to human health that might result from the addition of subtherapeutic antimicrobials to feeds


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have been neither proven nor disproven. The lack of data l i n k i n g human i l l n e s s with subtherapeutic levels of antimicrobials must not be equated with proof that the proposed hazards do not e x i s t . The research necessary to establish and measure a d e f i n i t e r i s k has not been conducted and, indeed, may not be possible." The NAS committee further concluded that i t i s not technically feasible to conduct a single comprehensive epidemiological study that w i l l s e t t l e the issues. They offered suggestions for several less comprehensive, but more f e a s i b l e , studies with the caveat that these studies had potential for c l a r i f y i n g certain points, but would not s e t t l e the issues. They would, i n essence, better define the links i n the chain of events that i s believed to exist from the feeding of subtherapeutic levels of a n t i b i o t i c s i n animals to the development of drug resistant disease i n humans. Recent

Events

In view of the NAS report, Congress, through the appropriations process for f i s c a l 1981, instructed FDA to conduct additional studies to generate new epidemiologic information consistent with the NAS suggestions and hold i n abeyance any proposed actions u n t i l the studies are concluded. In response to the 1981 mandate of Congress to generate additional data, FDA awarded a contract (10) to the Seattle-King County Department of Public Health to conduct an epidemiologic study of Salmonella and Campylobacter i n commercial meat products i n the community and their association with human disease. In August of 1984, CVM received the f i n a l study report and although i t has been accepted as having met contractual obligations, the study i s currently undergoing s c i e n t i f i c review. The study used a dual surveillance approach, one monitoring cases of human i l l n e s s and the other involving the sampling of food for contamination. For human case surveillance, a l l cases of Salmonella and Campylobacter jejuni e n t e r i t i s diagnosed i n enrollees at Group Health Cooperative of Puget Sound, a 320,000 member health maintenance organization (HMO), were investigated over an 18-20 month period. A case/control study was also conducted. In addition, household environmental samples were taken from family members of index cases, household pets, and i n some cases, foods were sampled i n an e f f o r t to i d e n t i f y reservoirs of Campylobacter. Food surveillance was integrated into the health departments meat inspection program and thus provided access to a l l r e t a i l purveyors of meat products i n King County, Washington. Added to the r e t a i l meat surveillance system was a s p e c i f i c a t i o n for culturing poultry products at a large independent poultry processor i n Seattle. The food surveillance system was designed to provide for the culture of 2,000 specimens of food products of animal o r i g i n for Salmonella and Campylobacter during a 20 month-period. In order to evaluate relationships among individual Campylobacter and Salmonella i s o l a t e s , a n t i b i o t i c s u s c e p t i b i l i t y testing was conducted along with serotyping and several types of plasmid analyses. The predominant finding reported by the contractor i n the food surveillance system was s i g n i f i c a n t contamination of r e t a i l poultry



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by Campylobacter j e j u n i ; 22.3% of specimens cultured jejuni while only 3.5% cultured Salmonella. The research contractor concluded that e n t e r i t i s due to Campylobacter jejuni i s more common than that due to Salmonella and that £. jejuni appears to flow from chickens to man v i a consumption of poultry products. Considerable public attention has been focused on the a n t i b i o t i c s i n animal feed issue as of late as a r e s u l t of two recent reports from investigators at the Centers for Disease Control. One report (11) i n the August 24, 1984, issue of Science was a retrospective analysis of a l l CDC investigated Salmonella outbreaks during the 13 year period between 1971 and 1983. They discovered that i n over two-thirds of U.S. outbreaks of miltiple-drug-resistant Salmonella infections that had a defined source, such bacteria came from food animal populations. Animal origins were discovered more commonly i n outbreaks involving antimicrobial-resistant Salmonella than i n outbreaks involving antimicrobial-sensitive s t r a i n s . In addition, the case f a t a l i t y rate for patients with multiple resistant Salmonella infections was found to be 21 times higher than the case f a t a l i t y rate associated with antimicrobial-sensitive Salmonella i n f e c t i o n s . Their assessment was that antimicrobial-resistant bacteria frequently a r i s e from food animals and can cause serious infections i n humans. One of the major c r i t i c i s m s of FDA's s c i e n t i f i c basis for wanting to r e s t r i c t the use of a n t i b i o t i c s i n animal feeds has been that i t has not provided any s p e c i f i c instances of human i l l n e s s due to drug-resistant pathogens that resulted from the subtherapeutic feeding of a n t i b i o t i c s to animals. However, individual events i n the complicated sequence have been documented. Another report (12) by Dr. Scott Holmberg and others at CDC which appeared i n the September 6, 1984, issue of the New England Journal of Medicine purportedly linked, for the f i r s t time, the use of subtherapeutic a n t i b i o t i c s i n livestock feed to the development of serious drug resistant infections i n humans. The a r t i c l e described the investigation of an outbreak of Salmonella newport involving 18 persons i n the Midwest. The epidemic s t r a i n was resistant to a m p i c i l l i n , c a r b e n i c i l l i n , and t e t r a c y c l i n e . Twelve of the patients had been taking p e n i c i l l i n derivatives for other medical problems. Eleven required h o s p i t a l i z a t i o n and there was one death. Through epidemiologic techniques ground beef was implicated as the common food source of the i n f e c t i o n and the meat was traced to c a t t l e presumably from a farm i n South Dakota. The c a t t l e had presumably been fed subtherapeutic levels of c h l o r t e t r a c y c l i n e for growth promotion and disease prevention. A major finding i n this investigation was the i d e n t i f i c a t i o n of a segment of the population, i . e , those receiving a n t i b i o t i c s , that may be at higher r i s k of contracting a severe i l l n e s s due to a resistant Salmonella i n f e c t i o n . Presumably, the use of antimicrobials to which a pathogen i s resistant would constitute s e l e c t i v e pressure permitting the organism to f l o u r i s h . There have also been a number of other studies contracted for by FDA since the 1977 notices on the p e n i c i l l i n s and the t e t r a c y c l i n e s . These studies were designed to provide more information on s p e c i f i c segments i n the postulated chain of events


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linking the subtherapeutic use of a n t i b i o t i c s i n animals to the development of serious disease i n humans. Notable among them was the work by Thomas O'Brien and collegues the results of which were published i n the New England Journal of Medicine i n 1982 (13). This study provided for methodology developments that allowed one to determine whether or not plasmids from d i f f e r e n t sources (man and animal) were i d e n t i c a l or s i m i l a r . The Center's b e l i e f that the continued unrestricted subtherapeutic use of these a n t i b i o t i c s presents risks to human and animal health i s based upon consideration of a number of factors:


—

—

—

—

Long-term, low-level feeding of p e n i c i l l i n and the tetracyclines promotes, by natural selection from the pool of normal i n t e s t i n a l f l o r a , those enteric (gut) bacteria that contain R-plasmids. R-plasmids, also known as R-factors, are extrachromosomal genetic material which confer a n t i b i o t i c resistance to host bacteria. These plamids can be transferred between various kinds of bacteria through c e l l - t o - c e l l contact (conjugation). Simultaneous resistance to several unrelated a n t i b i o t i c s i s commonly carried on a single plasmid and therefore i s simultaneously transferred from one bacterium to another. IS. C o l i strains bearing R-plasmids can be transferred from animal to man. Under the proper circumstances, organisms of animal o r i g i n can colonize i n the human gut. However, colonization i s not considered necessary for transfer of drug resistance to strains that inhabit the human gut. Use of p e n i c i l l i n and the tetracyclines also causes selection for pathogenicity factors, that i s , disease-causing factors. These factors and drug resistance have been shown to be linked on the same plasmid. Pathogenicity and a n t i b i o t i c resistance can therefore be transferred simultaneously to other organisms. R-plasmids can be transferred from normally nonpathogenic .E. c o l i to certain pathogenic strains of bacteria with which they may come i n contact i n man or animals. Since R-plasmids carry drug resistance, this transfer can result in the creation of pathogenic strains of bacteria which are resistant to a n t i b i o t i c therapy.

Continued unrestricted subtherapeutic use of a n t i b i o t i c s i n animal feed increases the pool of drug-resistant bacteria i n our environment. Moreover, the prospect of pathogens becoming drug resistant i s , as FDA believes, a r e a l threat to human health. In a speech before the Congress i n 1978, former Commissioner Donald Kennedy stated: "the evidence indicates that enteric microorganisms i n animals and man, t h e i r R-plasmids, and human pathogens form a linked ecosystem of their own i n which action at any one point can a f f e c t every other." If the v u l n e r a b i l i t y of microorganisms to a n t i b i o t i c s i s reduced by the use of a n t i b i o t i c s for nonmedical purposes i n animals, the effectiveness of medical treatment w i l l be diminished i n man. Potential risks to animal health also e x i s t , and while the linkage to human health i s i n d i r e c t , animal agriculture faces the r i s k d i r e c t l y . The


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development of resistant s t r a i n s , which i s enhanced by subtherapeutic drug use, reduces the e f f i c a c y of those same drugs for the treatment of animal diseases. The o v e r a l l implications are addressed by Marc Lappe i n his book (14), "Germs That Won't Die." He states: "Organisms almost t o t a l l y resistant to the major a n t i b i o t i c s now run rampant i n h o s p i t a l quarters, nurseries, and animal stockyards a l i k e , creating unprecedented problems for infectious disease control s p e c i a l i s t s and public health o f f i c i a l s . In spite of the awesome nature and speed of this spread of resistant organisms, many American agencies l i k e the Center for Disease Control i n Atlanta, Georgia, have only recently recognized the f u l l implications of this problem. Hospitals and physicians (and veterinarians I might add) s t i l l only grudgingly admit a problem e x i s t s , even as new a n t i b i o t i c s appear to p r o l i f e r a t e as fast as the old ones are outstripped by resistant organisms." NRDC Analysis of Risks to Human Health On November 20, 1984, Secretary Heckler received from the Natural Resources Defense Council (NRDC) a p e t i t i o n to declare the subtherapeutic uses of p e n i c i l l i n and the tetracyclines i n animal feeds an imminent hazard to the public health. NRDC argues that, on the basis of three recently published s c i e n t i f i c s t u d i e s — t h e O'Brien and the two Holmberg studies discussed e a r l i e r — F D A i s l i k e l y to eventually withdraw approval of the subtherapeutic uses of p e n i c i l l i n and the t e t r a c y c l i n e s i n animal feeds. NRDC argues, based on these studies, that these uses meet the c r i t e r i a for imminent hazard under the law. The p e t i t i o n and i t s impact were discussed before Congress, i n hearings before the Committee on Science and Technology i n December of 1984 (15). Before making any recommendation to FDA Commissioner Young and then to Secretary Heckler, the Center for Veterinary Medicine had to evaluate a l l available information, not just the three studies c i t e d , before deciding on the p e t i t i o n . To assist i n i d e n t i f y i n g pertinent available data and information, FDA decided to hold a l e g i s l a t i v e - t y p e hearing on January 25, 1985, on the NIH Campus i n which interested persons were invited to present their views. Some 35 individuals representing industry, academia, government, consumers, a g r i c u l t u r e , pharmaceutical manufacturers, producers of red meat and poultry, and even a member of Congress spoke either for or against the NRDC imminent hazard proposal. F i n a l comments were due i n by February 11, 1985, and an o f f i c i a l transcript was prepared. The c r i t e r i a used to evaluate the p e t i t i o n were the following: — — — — —

The l i k e l i h o o d that FDA w i l l eventually withdraw approval; The severity of harm pending withdrawal of approval; The l i k e l i h o o d of harm pending withdrawal of approval; The r i s k to treated animals from suspended marketing; and Other approaches to protect the public health.

The NRDC p e t i t i o n was unique i n that i t involved an indirect e f f e c t , that i s , the effect from the use of subtherapeutic levels of p e n i c i l l i n and the tetracyclines i n animal feeds on the health


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of man. Previously submitted "imminent hazard" petitions dealt with direct effects as i n the effect of a drug on a treated i n d i v i d u a l . Because of the i n d i r e c t e f f e c t , demonstration of the harm to man i s decidedly more d i f f i c u l t to measure. Quantitation indeed has been one of the major issues since the subtherapeutic use of a n t i b i o t i c s i n feeds question arose i n the 1950 s. NRDC estimated that between 100 and 300 deaths each year (depending on which of the provided estimates were used) may be attributable to the subtherapeutic use of p e n i c i l l i n and the tetracyclines i n animal feeds. In addition, some 270,000 non-fatal cases of salmonellosis may also be due to the subtherapeutic use of a n t i b i o t i c s ( p e n i c i l l i n and the tetracyclines) i n animal feeds. NRDC u t i l i z e d two key rate estimates from the Holmberg paper published i n Science during 1984. Downloaded by TUFTS UNIV on July 15, 2016 | http://pubs.acs.org Publication Date: September 18, 1986 | doi: 10.1021/bk-1986-0320.ch009

f

A summary of these estimates i s as follows: 1.

2.

SUMMARY OF THE FIRST ESTIMATE OF MORTALITY RATE: a. Approximately 40,000 cases of salmonellosis are reported each year (CDC data base). b. 20% to 30% of Salmonella isolated from humans are resistant to one or more a n t i b i o t i c s (CDC data base). 40,000 cases times 20% due to resistant Salmonella equals 8,000 cases each year caused by resistant Salmonella. c. 4.2% death rate associated with resistant Salmonella (from Holmberg, et a l . ) . 8,000 cases from resistant Salmonella times a 4.2% death rate from resistant Salmonella equals 336 deaths each year from resistant Salmonella. d. 69% of reported Salmonella outbreaks due to resistant Salmonella are traceable to animal sources (from Holmberg, et a l . ) . 336 deaths from resistant Salmonella times 69% traceable to animal sources equals 232 deaths each year from resistant Salmonella associated with animal sources. e. 50% of the resistant strains of Salmonella from animal sources result from subtherapeutic use of p e n i c i l l i n and the tetracyclines i n animal feeds (NRDC estimate). 232 deaths from resistant Salmonella from animal sources times 50% of resistant Salmonella from animals due to subtherapeutic use of p e n i c i l l i n and the tetracyclines equals 116 deaths each year attributed to subtherapeutic use of p e n i c i l l i n and the tetracyclines i n animal feeds. SUMMARY OF THE SECOND ESTIMATE OF MORTALITY RATE: a. 1,000 to 1,500 deaths each year are associated with Salmonella outbreaks (from private communication with CDC). b. 76.5% of f a t a l cases of Salmonella infections are associated with resistant Salmonella (calculated by NRDC from information contained i n Holmberg, et a l . ) . 1,000 deaths from Salmonella times 76.5% of f a t a l Salmonella infections associated with resistant Salmonella equals 765 deaths each year from resistant Salmonella.


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c.

69% of resistant Salmonella outbreaks are traceable to animal sources (from Holmberg, et a l . ) . 765 deaths from resistant Salmonella times 69% traceable to animal sources equals 528 deaths each year from resistant Salmonella from animal sources. d. 50% of resistant Salmonella from animals result from subtherapeutic use of p e n i c i l l i n and the tetracyclines i n animal feeds (NRDC estimate). 528 deaths from resistant Salmonella from animal sources times 50% of the resistance i n Salmonella from animal sources resulting from subtherapeutic use of p e n i c i l l i n and the tetracyclines i n animal feeds equals 264 deaths each year attributed to subtherapeutic use of p e n i c i l l i n and the tetracyclines i n animal feeds. 3. SUMMARY OF THE MORBIDITY ESTIMATE: a. 40,000 cases of Salmonella infections reported each year (CDC data base). b. 20% of these cases are caused by resistant Salmonella (CDC data base). 40,000 cases times 20% equals 8,000 cases reported each year caused by resistant Salmonella. c. 69% of resistant Salmonella outbreaks traceable to animal sources (from Holmberg, et a l . ) . 8,000 cases from resistant Salmonella times 69% from animal sources equals 5,520 cases reported each year caused by resistant Salmonella attributable to animal sources• d. 50% of resistant Salmonella from animal sources result from subtherapeutic use of p e n i c i l l i n and the tetracyclines i n animal feeds (NRDC estimate). 5,520 cases times 50% equals 2,760 cases reported each year attributed to use of p e n i c i l l i n and the tetracyclines in animal feeds. e. 1% of a l l cases of Salmonella infections are reported (from private communication with CDC). 2,760 cases times 100 equals 276,000 cases of non-fatal salmonellosis each year that are associated with the subtherapeutic use of p e n i c i l l i n and the tetracyclines i n animal feeds. NRDC used Salmonella infections as the model to make their estimates of mortality and morbidity rates. They pointed out that these are conservative estimates (underestimates) because resistance also occurs i n other pathogenic bacteria that cause human diseases. Some of the resistance i n these other pathogens results from the pool of resistant bacteria i n animals, which i s ultimately due i n large part to subtherapeutic use of p e n i c i l l i n and the tetracyclines i n animal feeds. NRDC concluded that there w i l l be no s i g n i f i c a n t negative e f f e c t on animal health from banning subtherapeutic uses of p e n i c i l l i n and the tetracyclines i n animal feeds. They indicated that the use of these drugs for purposes of improving feed e f f i c i e n c y and weight gain i s for economic reasons only and no



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health risks to animals w i l l result i f these uses are discontinued. The only potential animal health r i s k involves the use of these drugs for prevention of animal diseases. Since the p e t i t i o n i s for suspending uses of p e n i c i l l i n and the tetracyclines, there are other a n t i b i o t i c s that can be used to prevent these diseases. Also, there are e f f e c t i v e alternatives to a n t i b i o t i c s , such as vaccines, to prevent diseases. NRDC also advocated changing certain farm management practices, such as reducing the crowding of animals i n feedlots, which should reduce stress and transmission of diseases. Both of those actions i t was said should reduce the need for disease prevention. NRDC pointed out that i t i s not advocating a ban of p e n c i l l i n and the tetracyclines used at therapeutic levels to treat diseases. NRDC also noted that the frequency of a n t i b i o t i c resistance i n bacteria that cause disease increases when animals are fed subtherapeutic levels of these drugs. Thus, when animals become i l l with one of these resistant organisms, treatment with therapeutic levels of the a n t i b i o t i c of choice may not be effective• NRDC contended that the suspension of these subtherapeutic uses of p e n i c i l l i n and the tetracyclines i n animal feeds poses no human health problem. No potential human health problem has been i d e n t i f i e d i n the l i t e r a t u r e . Any r i s k of eating meat from an animal that becomes i l l , because p e n i c i l l i n and the tetracyclines were not available, could be a l l e v i a t e d by using substitute a n t i b i o t i c s and better farming practices to prevent or reduce the incidence of disease. Moreover, there would be an increased probability of e f f e c t i v e l y treating the diseases with therapeutic levels of a n t i b i o t i c s i f they were not used at subtherapeutic levels. According to NRDC, the only possible impact of a ban on humans would be economic. A higher price for meat would be temporary. I t was proposed that the average c i t i z e n consumes almost three times more meat per year than the U.S. Department of Agriculture considers necessary to meet n u t r i t i o n a l needs. Thus, the consumption of a few pounds less meat per person per year because of economic reasons would not have any human health e f f e c t according to NRDC. If the Agency decides to proceed with withdrawal, a formal evidentiary public hearing before an administrative law judge (ALJ) would be required. Under our law, such a hearing would be needed in this case even i f the drug uses i n question were to be found to be an imminent hazard. Granting an imminent hazard p e t i t i o n does not avoid formal proceedings. Rather, granting a p e t i t i o n suspends the marketing of a drug immediately—before the completion of the formal evidentiary public hearing, the ALJ's i n i t i a l decision, and the Commissioner's f i n a l decision. Under the ordinary withdrawal procedures, i n which a drug does not meet statutory requirements but does not present an imminent hazard, the drug may be marketed u n t i l the completion of a l l of these steps. CONCLUSION In an a r t i c l e (16) written for the American Journal of Epidemiology, Reuel Stallones, Chairman of the NAS Committee to



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Study the Human Health Effects of Subtherapeutic A n t i b i o t i c Use i n Animal Feeds stated: "Public policy and the actions stemming from i t cannot always await the accumulation of s c i e n t i f i c evidence and the development of prevailing views among s c i e n t i s t s . " At the time of our o r i g i n a l proposal to ban the subtherapeutic uses of p e n i c i l l i n and the tetracyclines i n animal feeds, the contention was advanced that there were gaps i n the s c i e n t i f i c position to supporting the chain of events l i n k i n g low l e v e l a n t i b i o t i c feedings to disease i n humans. Since then, newly generated data have been useful i n f i l l i n g these gaps i n our knowledge. After FDA reviews and evaluates these new data, the Agency w i l l know whether to proceed with the proposed ban. In sum, two decisions must be made i n the near future. F i r s t , whether the hazards to human health are of such significance as to c a l l for an immediate ban of low l e v e l uses of p e n i c i l l i n and the tetracyclines i n animal feeds, and (2) whether to move forward with the withdrawal proceedings. CVM i s currently engaged i n an active review of a l l available research and other information, p a r t i c u l a r l y that generated since 1977, to assess the impact of this complex s c i e n t i f i c issue on the subtherapeutic feeding of a n t i b i o t i c s to animals. Thank you for allowing me to share these views with you and I am available for any questions that you may have. Literature Cited 1.

Dingell, J . , 1980. "Animal Feeds: Effect of A n t i b i o t i c s " ( l e t t e r ) , Science. 208: 1069. 2. Report of the Joint Committee on the Use of A n t i b i o t i c s i n Animal Husbandry and Veterinary Medicine, 1969. Her Majesty's Stationary Office, London. 3. FDA Task Force, 1972. Report to the Commissioner of the Food and Drug Administration on the Use of A n t i b i o t i c s i n Animal Feeds. FDA #72-6008, 23 pp. 4. Code of Federal Regulations, 1985. A n t i b i o t i c , Nitrofuran, and Sulfonamide Drugs i n the Feed of Animals. Section 558.15: 484-497. 5. FEDERAL REGISTER, 1977. P e n i c i l l i n : Use i n Animal Feed. V o l . 42, No. 168: 43770-43793. 6. FEDERAL REGISTER, 1977. Tetracycline i n Animal Feeds and Tetracycline Containing Premixes. V o l . 42, No. 204: 56254-56289. 7. Office of Technology Assessment, 1979. Drugs i n Livestock Feed. OTA-F-91, 67 pp. 8. U.S. Department of Agriculture Economics, S t a t i s t i c s , and Cooperatives Service, 1978. Economic Effects of a Prohibition on the Use of Selected Animal Drugs. A g r i c u l t u r a l Economic Report #414. IV + 68 pp. 9. Committee to Study the Human Health Effects of Subtherapeutic A n t i b i o t i c Use i n Animal Feeds, 1980. The Effects on Human Health of Subtherapeutic Use of Antimicrobials i n Animal Feeds. ISBN 0-309-03044-7, XVI + 376 pp. 10. FDA Contract #223-81-7041, 1981. Surveillance of the Flow of Salmonella and Campylobacter i n a Community.



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11. Holmberg, S. D., J . G. Wells, M. L. Cohen, 1984. Animal-to-Man Transmission of Antimicrobial-Resistant Salmonella: Investigations of U.S. Outbreaks 1971-1983. Science 225-833-835. 12. Holmberg, S. D., M. T. Osterholm, K. A. Senger, ET AL., 1984, Drug-Resistant Salmonella From Animals Fed Antimicrobials. New England Journal of Medicine, 311: 617-622. 13. O'Brien, T. F., J . D. Hopkins, E. S. Gilleece, ET AL., 1982. Molecular Epidemiology of A n t i b i o t i c Resistance i n Salmonella from Animals and Human Beings i n the United States. New England Journal of Medicine. 307:1-6. 14. Lappe, M., 1982. Germs That Won't Die: Medical Consequences of the Misuse of A n t i b i o t i c s . Anchor Press, Garden City, NY, 246 pp. 15. Committee on Science and Technology: U.S. House of Representatives, 1984. A n t i b i o t i c Resistance. 98th Congress, Second Session. Report No. 150, 139-188. 16. Stallones, R. A., Epidemiology and Public Policy: Pro-And-Anti-Biotic, 1982. American Journal of Epidemiology. Vol. 115, No. 4: 485-491. R E C E I V E D April 1, 1986


Risks to Human Health from the Use of Antibiotics in Animal Feeds

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