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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
