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The Effects on Human Health of Sub~herapeutic Use of Antimicrobials in Animal Feeds Committee to Study the Human Health Effects of Subtherapeutic Antibiotic Use in Animal Feeds Division of Medical Sciences Assembly of Life Sciences National Research Council NATIONAL ACADEMY OF SCIENCES WASHINGTON, D.C. 1980

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NOTICE The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the Councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This report has been reviewed by a group other than the authors according to procedures approved by a Report Review Committee consist- ing of members of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The work on which this report is based was performed pursuant to Contract No. 282-78-0163, T. O. 8, with the Food and Drug Admin- istration. Library of Congress Catalog Card Number 80-81486 International Standard Book-Number 0-309-03044-7 Available from Off ice of Publications National Academy of Sciences 2101 Constitution Avenue, N.W Washington, D. C. 20418 Printed in the United States of America

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COMMITTEE TO STUDY THE HUMAN HEALTH EFFECTS OF SUBTHERAPE;UTIC ANTIBIOTIC USE IN ANIMAL FEEDS Reuel A. Stallone s, Chairman University of Texas School of Public Health Houston, Texas E. Russell Alexander Un avers i ty of Ari zone Health Sciences Center Tucson, Ar i zone Charles E. Antle Pennsylvania State Un ive rsi ty University Park, Pennsylvania Pierce Gardner The Pritzker School of Medicine Chicago, Illinois Edward H. Kas s Channing Laboratory Harvard fledic`.al School and Peter Bent Brigham Hospital Bos ton, Flas sac~.huset ts Carl A. Keller National Institute for Chef Id Health and Human Devel opment National Institutes of Health Bethesda, Maryland Assembly of Life Sciences Staff: Enrique ta C. Bond Alvin G. Lazen Counc ilman Morgan Frances A. Peter Daniel L. Weiss Roy tJiddus . . . J. Michael Lane Center for Disease Control, Atlanta, Georgia Frank J. Massey, Jr. University of California School of Public Health Los Angeles, California Robert H. Rownd University of Wisconsin Madison, Wisconsin Paul R. Sheehe Upstate Medical Center State University of New York Syracuse, New York Vernon L. Tharp Ohio State University, Columbis, Ohio

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CONSULTANTS N. Franklin Adkinson, Jr. Good Samaritan Hospital Baltimore, Maryland Board on Agriculture and Renewable Resources (BARR/CNR) National Academy of Sciences National Research Council Washington, D.C. See page v. Robert N. Goodman University of Missouri Columbia, Missouri George A. Jacoby Massachusetts General Hospital Boston, Massachusetts Stanley E. Katz Rutgers University New Brunswick, New Jersey Jackson S. Kiser Consultant, Agricultural Division of American Cyanamid Co. Princeton, New Jersey TV K. Bro oks Low Yale University Medical School New Haven, Connecticut Thomas F. O'Brien Peter Bent Brigham Hospital Boston, Massachusetts William E. Pace Bolling Air Force Base Washington, D.C. Dwayne C. Savage University of Illinois Urbana, Illinois John F. Timoney Cornell University, Ithaca, New York John P. Utz Georgetown University Hospital Washington, D.C.

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ADVISORY PANEL ON ANTIBIOTICS IN ANIMAL FEEDS BOARD ON AGRICULTURE AND RENEWABLE RESOURCES COMMISSION ON NATURAL RESOURCES Joseph P. Fontenot, Cochairman Virginia Polytechnic Institute and State University Blacksburg, Virginia George C. Poppensiek, Cochairman New York State College of Veterinary Medicine Ithaca, New York David P. Anderson University of Georgia Athens, Georgia Ernest L. Biberstein University of California Davis, California James L. Bit tie Pitman-Moore, Inc. Washington Crossing, New Jersey BARR/CNR Staff: Philip Ross Selma P. Baron v William Hale University of Arizona Tucson, Arizona Leo S. Jensen University of Georgia Athens, Georgia Vaughn C. Speer Iowa State University Ames, Iowa Clarence M. Stowe University of Minnesota St. Paul, Minnesota Howard S. Teague, Liaison Member U.S. Department of Agriculture Washington, D.C.

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PREFACE In 1978, the Congress of the United States provided to the Food and Drug Administration (FDA) an appropriation designated for the National Academy of Sciences to evaluate epidemiolo~i2cal approaches to the effects on human health of subtherapeutic 3 use of antimicrobials in animal feeds as defined by the FDA. The task accepted by the committee was: "1. "3. To study the human health effects of subtherapeutic use of penicillin and tetracycline (chlortetracycline and oxytetracycline) in animal feeds. "2. To review and analyze published and unpublished epidemiological data and other data as necessary in order to assess the human health consequences of subtherapeutic use of penicillin and tetracycline in animal feeds. To assess the scientific feasibility of additional epidemiological studies, and, if needed, to make recommendations about what kinds of research should be carried out, the estimated cost and time required to complete such research and the possible mechanism to be used to conduct such studies." To complete this task, the committee decided that it should 1. define and evaluate the effects on human health that are associated with bacterial resistance to antimicrobials, 2. measure changes in numbers of pathogens and define changes in their virulence and in the prevalence of antimicrobial resistance resulting from the use of antimicrobials in animals, and 200 g or less/ton for 2 weeks or longer. Throughout this report, use of the word ton denotes the "short" ton (2,000 lb), which is most commonly used in the United States. Exceptions to this are noted in the text. Including milk replacers, medicated blocks, and liquid feeds, but not as used in water alone. FDA does not have jurisdiction over drinking water. V11

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3. differentiate the effects attributable to subtherapeu- tic levels of antimicrobials from those due to other uses in animal husbandry and in medical applications to animals and human beings. Because of insufficient data in certain areas, the committee was not able to accomplish all of the above. The significance of possible effects on human health due to the use of antimicrobials in animal feeds has been the subject of exhaustive reviews by several groups of distinguished scientists in the United States and Europe. Controversy surrounding the re- striction of subtherapeutic uses of antimicrobials in animals can be expected to continue until more definitive epidemiological evidence confirms or refutes the potential hazards to human health postulated by these review groups. The formulation of policy concerning such restriction requires that both benefits and adverse effects be weighed. This committee, however, was not asked to determine policy. Rather, it was charged with and undertook a more limited responsibility: evaluation of existing evidence and development of recommendations pertaining to the kinds of research needed to provide a clearer view of the effects on human health. COMMITTEE PROCEDURE An extensive bibliography of the research reports relating to the subtherapeutic use of antimicrobials in animal feeds has been preparede Plans are being made to publish the bibliography in the near future. Selected consultants and a special advisory panel from the National Academy of Sciences Board on Agriculture and Renewable Resources were asked to write papers on certain aspects of the problem for use by the committee. These papers are attached to this report as appendixes. 1. The Clinical Use of Antimicrobials and the Development of Resistance--John P. Utz (Appendix A) 2. Possible Human Health Effects of Subtherapeutic Anti- microbial Use as Pesticides--Robert N. Goodman (Appendix B) . . . vain

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Genetics of Antimicrobial Resistance--George A. Jacoby and K. Brooks Low (Appendix C) 4. Impact of Antimicrobials on the Microbial Ecology of the Gut--Dwayne C. Savage (Appendix D) Antimicrobial Residues and Resistant Organisms: Their Occurrence, Significance, and Stability--Stanley E. Katz (Appendix E) 6. Zoonotic Aspects of Subtherapeutic Antimicrobials in Feed--John F. Timoney (Appendix F) Transmission of Food-Borne Diseases--Implications of the Subtherapeutic Use of Antimicrobials --Jackson S. Kiser (Appendix G) 8. Food Contamination--William E. Pace (Appendix H) 9. Infectious Disease: Effect of Antimicrobials on Bacterial Populations--Thomas F. O'Brien (Appendix I) 10. Immunological Consequences of Antimicrobials in Animal Feeds--N. Franklin Adkinson, Jr. (Appendix J) 11. Antibiotics in Animal Feed. A report prepared by the Committee on Animal Health and the Committee on Animal Nutrition, Board on Agriculture and Renewable Resources, Commission on Natural Resources, National Research Council, National Academy of Sciences (Appendix K). On August 22, 1979, the committee met in Washington, D.C. to hear presentations by its consultants and to exchange information and opinions. On the following day, August 23, 1979, a public meet- ing was held to receive information from persons and organizations. The members of the committee reviewed and evaluated pertinent epidemiological research and, during the week of September 16-21, 1979, convened to develop proposals for further epidemiological studies. ACKNOWLEDGMENTS It is a pleasure to express, on behalf of the entire committee, a special note of thanks to the staff: Dr. Enriqueta C. Bond, Dr. Roy Widdus, Mrs. Frances Peter, and Mrs. Susan Barron, whose informed and tireless efforts ably supported the committee. We are grateful 1X

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for the assistance of those consultants who supplied information and critical reviews of a vast literature and for the help of many members of the staff of the Food and Drug Administration, the De- partment of Agriculture, the Center for Disease Control, and the Office of Technology Assessment, especially Mr. Philip Frappaolo, Dr. Norman Tufts, Dr. Lester Crawford, Dr. Howard Teague, Dr. John Spaulding, Dr. Robert Brown, Dr. John Bennett, and Dr. Roger Feldman. The committee appreciates the cooperation and information provided by American Cyanamid Company, Pfizer Inc., National Pork Producers Council, representatives of the poultry industry, the Animal Health Institute, and other organizations and individuals too numerous to list. Last, but not least, we thank the members of the public and the international community of scientists who submitted suggestions and information for our consideration. {~;~ *A Reuel A. Stallones Chairman Committee to Study the Human Health Effects of Subthera- peutic Antibiotic Use in Animal Feeds x D

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TABLE OF CONTENTS SUGARY Chapter 1 Chapter 3 Chapter 4 Chapter 5 REFERENCES CONSULTANTS' PAPERS: The Use of Antimicrobial Agents Measuring Effects on Human Health from the Subtherapeutic Use of Anti- microbials in Animal Feeds Critical Review of the Epidemiological Literature Study Possibilities Conclusions and Recommendations Appendix A - The Clinical Use of Antimicrobials and the Development of Resistance--John P. Utz Appendix B - Possible Human Health Effects of Sub- theratherapeutic Antimicrobial Use as Pesticides--Robert N. Goodman Appendix ~ Appendix D Appendix E - - Genetics of Antimicrobial Resistance --George A. Jacoby and K. Brooks Low Impact of Antimicrobials on the Microbial Ecology of the Gut--Dwayne C. Savage Antimicrobial Residues and Resistant Organisms: Their Occurrence, Signifi- cance, and Stability--Stanley E. Katz X1 Page No. xiii 1 12 22 35 52 56 65 67 79 92 130 158

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TABLE OF CONTENTS (Continued) Appendix F Appendix G Appendix H Appendix I Appendix J ADVISORY PANEL REPORT: Appendix K - Antibiotics in Animal Feeds. A report pre- pared by the Committee on Animal Health and Committee on Animal Nutrition, Board on Agri- culture and Renewable Resources, Commission on Natural Resources, National Research Council, National Academy of Sciences. e e X11 Zoonotic Aspects of Subtherapeutic Antimi- 182 crobials in Feed--John F. Timoney Transmission of Food-Borne Diseases- Implications of the Subtherapeutic Use of Antimicrobials--Jackson S. Riser Food Contamination--William E. Pace Infectious Disease: Effect of Antimicro bials on Bacterial Populations--Thomas F. O'Brien 203 262 275 Immunological Consequences of Antimicrobials 301 in Animal Feeds--N. Franklin Adkinson, Jr. 317

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SUMMARY Soon after antimicrobials were introduced into medical prac- tice, the selection pressure exerted by their use caused an increase in the prevalence of microorganisms with resistance to antimicrobials, thereby reducing the effectiveness of therapy. The expanding array of antimicrobial drugs has provided alternative agents in most cases but control of infections is sometimes delayed because resistance may not be recognized initially. Moreover, the alternative drugs may be more toxic, more expensive, or less effective than those that would be used if the infecting organisms were not resistant. Most clinically significant antimicrobial-resistant bacterial strains are selected during the administration of antimicrobials to humans, but concern has been expressed that the continuous use of antimicrobials in the feed or drinking water of animals is also responsible for the emergence of resistant strains that may endanger human health. Penicillin and the tetracYclines are effective as ~ ~ . . ~ additives to animal teed, but since they are also particularly effective and widely used in the therapy of human disease, the Food and Drug Administration has proposed to restrict their use in animal feeds at subtherapeutic doses. Bacterial resistance to antimicrobials is a genetically deter- mined characteristic. - and genes for resistance may be carried either on chromosomes or on extrachromosomal elements called resistance (R) plasmids or R factors. Microorganisms possessing plasmid-mediated resistance to antimicrobials are designated R+. R factors may be transferred from some bacterial species to certain other species, and resistance to several different antimicrobials is often linked on the same plasmid. Consequently, administration of one antimicrobial may result in the appearance of bacteria with resistance not only to the administered drug but also to one or more others. The use of antimicrobials in animal husbandry for the improve- ment of growth and efficiency of feed conversion, for prophylaxis, and for the treatment of diseases has steadily increased since 1950, as has animal production. In 1978, approximately 48% of the antibio- tics produced were designated for addition to animal feeds or for acne a- ~ aunor' urea. Antimicrobials are perceived as especially beneficial when animals are stressed either by intensive husbandry or shipment (BARR, Appendix K). ~ ~ _ ~ ~ _ Data demonstrate that the use of antimicrobials in animal hus- bandry increases the prevalence of R+ enteric organisms in animals. Some of these organisms may be pathogenic for humans. A number of . . - x~ I~

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investigators have asserted that the administration of antimi- crobials in subtherapeutic doses to animals raised for human consumption increases the total numbers of R+ bacteria above that resulting from therapeutic uses of antimicrobials in animals and both therapeutic and prophylactic uses in humans. If this is true and if resistant bacteria are carried through the food processing system to the retail store, animal handlers, meat processors, and consumers would be at increased risk of infection by antimicrobial- resistant pathogens or have an increased likelihood of acquiring a nonpathogenic resistant organism capable of transferring such resistance to pathogens. The committee concluded that not enough information is available on these issues to determine the effects on human health. Several generalizations can be made: Little is known about the composition of the gas- trointestinal flora of humans or animals, especially their anaerobic components (Savage, Appendix D). In those studies of R factors that have been conducted on the enteric flora of animals or humans, investigators have observed changes in the populations of Escherichia cold or those of its close relative Salmonella because these organisms are easy to culture and manipulate and because they are pervasive pathogens of both animals and humans. The subtherapeutic use of antimicrobials does increase the prevalence of resistance among the E. cold and Salmonella of treated animals. 3. Persons in close contact with animals receiving antimi- crobials are more likely to harbor antimicrobial-resistant E. cold than are persons not so exposed. However, studies do not usually indicate the type, duration, and dose levels of the antimicrobials received by the animals. Subthera- peutic use is generally not distinguished from therapeutic use. Abattoir workers carry some of the same phase types1 that occur in the slaughterhouse environment and in slaughtered animals. Because this information was generated by a study of a small number of people, the comparisons are not conclu Phage typing is a procedure used by diagnostic laboratories to characterize and identify strains of bacteria according to their pattern of lysis by bacterial viruses (phase). x~v

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7 sive. Furthermore, these workers were exposed to animals that had probably received therapeutic as well as subtherapeutic doses of antimicrobials. There are no data from which to assess the relationship between consumption of meat from animals that received subtherapeutic amounts of antimicrobials and the preva- lence of antimicrobial-resistant E. cold in the general human population. Limited observations suggest that vegetarians do not harbor fewer resistant E. cold than do meat eaters. No data exist to establish a relationship between illness caused by antimicrobial-resistant, pathogenic bacteria, and contact with animals or meat from animals given only subtherapeutic amounts of antimicrobials. No data exist to quantitate the frequency of transfer of antimicrobial-resistance factors from the bacterial flora of animals to the flora of humans or of the transfer within the flora of humans. 8. The therapeutic or prophylactic use of anti~icrobials in humans results in a greater prevalence of R strains in the bacterial flora of treated people and their immediate contacts. 9. The disadvantages of using an alternative drug where anti- microbial resistance is present depend on the drugs chosen and each clinical situation. Thus, precise quantitation of the threat of potential "compromise of therapy" posed by an increased prevalence of antimicrobial resistance is exceedingly difficult. However, information on nosocomial infections (which are often resistant) does illustrate the magnitude of the problem. 10. Restrictions on the use of antimicrobials in other countries may well have altered the pattern of their use without sig- nificant reduction in the total amount used or in the apparent consequences for humans. After reviewing the evidence, the committee concluded that the postulated hazards to human health from the subtherapeutic use of antimicrobials in animal feeds were neither proven nor disproven. The lack of data linking human illness with this subtherapeutic use must not be equated with proof that the proposed hazards do not xv

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exist. The research necessary to establish and measure a definite risk has not been conducted. The committee also concluded that it is not possible to con- duct a feasible, comprehensive epidemiological study of the effects on human health arising from the subtherapeutic use of antimicrobials in animal feeds, partly because it is impossible to determine the antimicrobial history of the animal from which a particular piece of meat came. However, the committee does present several study possi- bilities to investigate certain aspects of the problem. These include (1) a study to determine the contribution of subtherapeutic and therapeutic antimicrobial dosing regimens to the prevalence of R+ enteric organisms in meat animals; (2) a study to measure the extent to which carriage of bacteria having R factors is associated with meat consumption by comparing the enteric flora of vegetarians and meat eaters; (3) a study to measure the extent to which occupa- tional exposure of humans to bacteria from animals in abattoirs is associated with carriage of bacteria having R factors and secondarily to gauge the spread of R factors among close contacts of abattoir workers; (4) a comparison of controls with subjects having urinary tract infections to determine if carriage of antimicrobial-resistant fecal flora is associated with increased morbidity or mortality from the infection. The committee recommends further research on the mechanisms by which subtherapeutic levels of antimicrobials promote growth of animals. Understanding of this mechanism may lead to the development of other substances or procedures (e.g., immunizations) that provide the same effect, thereby rendering moot the question of possible effects on human health. However, the committee also recommends continued monitoring and occasional review of the possible effects on humans resulting from the subtherapeutic use of antimicrobials in animal feeds. xvi