Food Safety: The Agricultural Use of Antibiotics and Its Implications for
Human Health (Letter Report, 04/28/99, GAO/RCED-99-74).

Pursuant to a congressional request, GAO provided information on
antibiotic resistance issues that may stem from the use of antibiotics
in agriculture, focusing on the: (1) use of antibiotics in agriculture
and the implications of that use for human health; (2) federal roles and
responsibilities for overseeing the use of antibiotics in agriculture;
and (3) issues surrounding the debate over whether to further regulate
or restrict the use of antibiotics in agriculture.

GAO noted that: (1) antibiotics are used in agriculture to treat and
prevent diseases in animals and in food plants and as a feed additive to
improve the growth rate in animals; (2) data are not available on the
quantities of specific antibiotics used in agriculture and the purposes
for which they are used; (3) research has linked the use of antibiotics
in agriculture to the emergence of antibiotic-resistant strains of
disease-causing bacteria; (4) although the ill effects of these
foodborne pathogens are generally mild to moderate, each year several
thousand persons have severe illnesses resulting in hundreds of deaths;
(5) in addition to the direct transfer of antibiotic-resistant organisms
through animal products, some research suggests that the use of
antibiotics in food animals may reduce the effectiveness of related
antibiotics when used to treat humans; (6) approving antibiotics and
setting allowable levels for antibiotic residues in food products is
determined by the Food and Drug Administration (FDA) for animals and the
Environmental Protection Agency for food plants; (7) testing for
antibiotic levels in foods is performed by the Food Safety and
Inspection Service for meat and poultry and by FDA for eggs, milk, and
food plants; (8) monitoring the development of resistance to antibiotics
in humans is conducted under a program run jointly by the Department of
Agriculture (USDA), FDA and the Centers for Disease Control and
Prevention; (9) the debate over whether to further regulate or restrict
the use of antibiotics in animals and plants centers around the risk
their use may pose to human health relative to their benefits to
agriculture; (10) this concern has prompted several European countries
to ban the use in animal feed of four antibiotics that are considered
very important in treating humans; (11) beef, pork, and poultry
producers and pharmaceutical manufacturers believe agricultural use is
only one potential contributor to antibiotic resistance in humans; they
claim that research does not warrant restricting antibiotic use in
agriculture; (12) USDA believes that more research is needed before
decisions are made regarding the further regulation or restriction of
antibiotic use in food animals; (13) the Department of Health and Human
Services believes that based on the scientific evidence, steps are
needed now, not at some time in the future, to decrease such use; and
(14) FDA's recently proposed framework for evaluating the safety of
antibiotics for use in food-producing animals does not include specific
timeframes for reevaluating approved antibiotics.

--------------------------- Indexing Terms -----------------------------

 REPORTNUM:  RCED-99-74
     TITLE:  Food Safety: The Agricultural Use of Antibiotics and Its
	     Implications for Human Health
      DATE:  04/28/99
   SUBJECT:  Product safety
	     Public health research
	     Health hazards
	     Infectious diseases
	     Agricultural products
	     Agricultural chemicals
	     Contaminated foods
	     Drugs
	     Food additives
IDENTIFIER:  National Antimicrobial Resistance Monitoring System
	     National Animal Health Monitoring System
	     CDC FoodNet
	     Campylobacter jejuni/coli Bacteria
	     Salmonella Enteritidis Bacteria
	     E. coli Bacteria

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FOOD SAFETY: The Agricultural Use of Antibiotics and Its
Implications for Human Health GAO/RCED-99-74 United States General
Accounting Office

GAO Report to the Honorable Tom Harkin, Ranking Minority Member,
Committee

on Agriculture, Nutrition, and Forestry, U. S. Senate

April 1999 FOOD SAFETY The Agricultural Use of Antibiotics and Its
Implications for Human Health

GAO/RCED-99-74

  GAO/RCED-99-74

GAO United States General Accounting Office

Washington, D. C. 20548 Resources, Community, and Economic
Development Division

B-281942 April 28, 1999 The Honorable Tom Harkin Ranking Minority
Member, Committee on Agriculture, Nutrition, and Forestry United
States Senate

Infectious diseases are the third leading cause of death in the
United States, behind heart disease and cancer, and antibiotics
are often necessary in their treatment. Antibiotic resistance,
which occurs when antibiotics that had been used effectively to
treat infections are no longer able to kill bacteria growth, is a
serious human health problem. The factors that contribute to
antibiotic resistance include the nature of disease- producing
bacteria (pathogens), environmental pressures, and the use of
antibiotics in human medicine as well as in agriculture.

As you have requested, this report explores antibiotic- resistance
issues that may stem from the use of antibiotics in agriculture.
Specifically, this report examines (1) how antibiotics are used in
agriculture and the implications of that use for human health, (2)
the federal roles and responsibilities for overseeing the use of
antibiotics in agriculture, and (3) the issues surrounding the
debate over whether to further regulate or restrict the use of
antibiotics in agriculture.

To conduct this work, we reviewed scientific and medical studies,
reports, and other literature and spoke with experts in
government, academia, and private industry. We performed our
review from May 1998 through April 1999 in accordance with
generally accepted government auditing standards. Further details
of our scope and methodology are discussed in appendix I.

Results in Brief Antibiotics are used in agriculture to treat and
prevent diseases in animals and in food plants and as a feed
additive to improve the growth rate in

animals. Research has linked the use of antibiotics in agriculture
to the emergence of antibiotic- resistant strains of disease-
causing bacteria. These bacteria, which are known to cause illness
or disease in humans, include

Salmonella, Campylobacter, and Escherichia coli, commonly known as
E. coli. Although the ill effects of these foodborne pathogens are
generally mild to moderate, each year several thousand persons
have severe illness resulting in hundreds of deaths. However,
there are no current comprehensive estimates of the extent to
which antibiotic- resistant strains

GAO/RCED-99-74 Food Safety Page 1

B-281942

have resulted in illnesses and deaths. Researchers believe these
organisms acquire resistance to antibiotics while in an animal;
the resistant strain is then passed to humans through food or
through direct contact with animals or animal waste. In addition
to this direct transfer of antibiotic- resistant organisms, some
research indicates that the use of antibiotics in food animals may
reduce the effectiveness of related antibiotics when used to treat
humans. While research has linked the use of antibiotics in
agriculture to the emergence of antibiotic- resistant foodborne
pathogens, agricultural use is only one of several factors that
contributes to antibiotic resistance in humans for pathogens that
are not foodborne.

Several federal agencies have responsibilities regarding the use
of antibiotics in agriculture. Approving antibiotics and setting
allowable levels for antibiotic residues in food products is
determined by the Department of Health and Human Services' Food
and Drug Administration for animals and the Environmental
Protection Agency for food plants. Testing for antibiotic levels
in foods is performed by the Food Safety and Inspection Service
for meat and poultry and by the Food and Drug Administration for
eggs, milk, and food plants. Monitoring the development of
resistance to antibiotics in humans, including resistance stemming
from agricultural sources, is conducted under a program run
jointly by the U. S. Department of Agriculture, the Food and Drug
Administration, and the Department of Health and Human Services'
Centers for Disease Control and Prevention.

The debate over whether to further regulate or restrict the use of
antibiotics in animals and plants centers around the risk their
use may pose to human health relative to their benefits to
agriculture. This concern has prompted several European countries
to ban the use in animal feed of four antibiotics that are
considered very important in treating humans. Representatives of
beef, pork, and poultry producers and pharmaceutical manufacturers
assert that antibiotics play an important role in providing an
abundant and affordable food supply. In their view, agricultural
use is only one potential contributor to antibiotic resistance in
humans and the research does not warrant restricting antibiotic
use in agriculture. This debate exists within the federal
government as well. The U. S. Department of Agriculture believes
that more research is needed before decisions are made regarding
the further regulation or restriction of antibiotic use in food
animals. The Department of Health and Human Services, on the other
hand, believes that based on the scientific evidence, steps are
needed now not at some time in the future to decrease such use.
However, the

GAO/RCED-99-74 Food Safety Page 2

B-281942

Food and Drug Administration's recently proposed framework for
evaluating the safety of antibiotics for use in food- producing
animals does not include specific time frames for reevaluating
currently approved antibiotics. The proposed framework targets new
antibiotics and new uses of currently approved antibiotics. The
framework will apply to the current uses of antibiotics only to
the extent resources allow. We are recommending that the
departments of Agriculture and Health and Human Services work
together to develop and implement a plan with specific goals, time
frames, and resources needed for determining the safe use of
antibiotics in agriculture.

Background Many infectious diseases including pneumonia,
tuberculosis, and common childhood ear infections are caused by
bacteria that have

developed resistance to one or more previously effective
antibiotics. Resistance may occur when the introduction of an
antibiotic imposes selective pressure on an organism that has
mutated by random genetic change. The antibiotic will not be able
to kill the resistant strain of the organism. If susceptible
bacteria are killed, remaining resistant bacteria may then become
the dominant strain. For example, for nearly 40 years after
penicillin was introduced, it was used successfully to treat
pneumonia; today, penicillin- resistant strains of pneumonia are
dominant in many countries. Also, disease- causing bacteria or
pathogens may develop resistance spontaneously. For further
information about the development of antibiotic resistance and the
public health burden associated with resistant bacteria, see
Antimicrobial Resistance: Data to Assess Public Health Threat From
Resistant Bacteria Are Limited (GAO/ HEHS/ NSIAD/ RCED- 99- 132,
Apr. 28, 1999). 1

Experts Believe the Use of Antibiotics in Agriculture Is Linked to
the Emergence of Antibiotic Resistance

Antibiotics are used in both food- producing animals and on food
plants to treat specific diseases afflicting specific animals and
plants and to prevent the spread of diseases that are known to
occur in particular herds, flocks, and crops under certain
conditions. Antibiotics are also used in food animals to enhance
their growth rate and feed efficiency that is, increasing the
amount of feed that is absorbed by the animal. Antibiotics used on
animals may be obtained over- the- counter in feed stores and are
included in commercially available animal feed. Antibiotics may
also be dispensed under a veterinarian's prescription. For larger
animals (such as cattle), antibiotics may be administered by
injection or mixed with water; for smaller animals (such as
poultry), they are generally mixed with feed

1 An antimicrobial is a substance used to treat a bacterial,
fungal, or viral infection.

GAO/RCED-99-74 Food Safety Page 3

B-281942

or water. As a pesticide for disease treatment and prevention,
antibiotics are generally sprayed onto plants. However, data are
not available on the quantities of specific antibiotics used in
agriculture and the purposes for which they are used. Appendix II
presents information on the major classes of antibiotics, provides
examples of specific antibiotics within each class, and indicates
the antibiotics within that class have been approved for use on
animals, plants, and/ or humans.

Research Has Linked Three Diseases With Antibiotic- Resistant
Strains Affecting Humans to the Use of Antibiotics in Animals

Experts, including those in the Department of Health and Human
Service's (HHS) Food and Drug Administration (FDA), and Centers
for Disease Control and Prevention (CDC), believe that resistant
strains of three specific organisms that cause illness or disease
in humans Salmonella, Campylobacter, and E. coli are linked to the
use of antibiotics in animals. Salmonella and Campylobacter
infections generally cause intestinal distress and do not require
medical treatment.

However, each year several thousand persons have severe illnesses
resulting in hundreds of deaths. Young children, the elderly, and
patients whose immune systems are compromised are especially at
risk. Severe cases of Salmonella have been associated with
infections in the blood and the lining of the brain and other deep
body tissue. According to CDC, each year an estimated 8,000 to
18,000 hospitalizations, 2,400 bloodstream infections, and 500
deaths are associated with Salmonella infections. One in 1,000
Campylobacter infections result in Guillain- Barr Syndrome, a
disease that can cause paralysis. Most E. coli strains are
relatively harmless in humans, but one strain causes a potentially
serious illness in children and individuals with weakened immune
systems. However, there are no current comprehensive estimates of
the extent to which antibiotic- resistant strains of Salmonella,
Campylobacter and E. coli have resulted in severe illnesses or
deaths in humans. According to scientists at CDC, resistant
strains of these organisms acquire resistance to antibiotics while
in the animal. The resistant strain of the disease is then
transferred to humans through food or through contact with animals
or animal waste. A more detailed discussion of these organisms and
their development of antibiotic resistance is presented in
appendix II.

In addition to the direct foodborne transfer of antibiotic
resistance from these three specific organisms, some research
suggests that the use of antibiotics in food animals may reduce
the effectiveness of related antibiotics used to treat humans.
This concern is often raised about antibiotics administered in low
doses over a continuous period, such as

GAO/RCED-99-74 Food Safety Page 4

B-281942

those used in agriculture to promote animal growth. The research
most often cited with this issue was conducted in Denmark during
the early 1990s and concerns the closely related antibiotics
avoparcin and vancomycin. Scientists there reported linking the
use of avoparcin in animals to the emergence of vancomycin-
resistant enterococci generally known as VRE in humans. VRE is an
organism generally contracted in a hospital setting that causes
serious, and in some cases untreatable, infections in humans.

In the United States, avoparcin has never been approved for use in
agriculture or human medicine, and vancomycin has never been
approved for use in agriculture. However, according to FDA
officials, FDA discovered an instance in which avoparcin was used
illegally in the United States in the production of veal and
possibly other meat products. FDA pursued regulatory enforcement,
and, according to officials, the individual responsible was
convicted of a crime.

Vancomycin is an extremely important drug in the treatment of
antibiotic- resistant bacterial infections in humans, many of
which are serious and life- threatening and cannot be treated by
any other currently approved antibiotic. According to CDC, the
excessive use of vancomycin in human medicine is a primary cause
for the rapid rise of VRE in the United States. Studies estimate
that doctors inappropriately prescribe vancomycin in treating
illnesses in humans 30 to 80 percent of the time.

While research is available on the emergence of antibiotic-
resistant strains of foodborne pathogens, such as Salmonella,
Campylobacter, and E. coli,

for nonfoodborne human pathogens (such as VRE), agricultural use
is only one factor that contributes to the problem of antibiotic
resistance in humans. Only a few studies, primarily in Europe,
have examined agriculture's contribution relative to the
contributions of other factors, such as the inappropriate
prescribing of antibiotics in human medicine to the development of
resistance in nonfoodborne human pathogens. Appendix I identifies
several studies, reports, and scientific articles by, among
others, the National Research Council, World Health Organization,
Institutes of Medicine, Office of Technology Assessment, and
British House of Lords, that discuss and assess the research on
these issues.

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Several Agencies Have Responsibilities Regarding the Use of
Antibiotics in Agriculture

Several federal agencies have roles involving the use of
antibiotics in agriculture and a multiagency program the National
Antimicrobial Resistance Monitoring System- Enteric Bacteria
tracks the development of antibiotic- resistant strains of
Salmonella and Campylobacter (see table 1).

Table 1: Federal Agencies' Roles Related to the Use of Antibiotics
in Agriculture Federal agencies Approval for

agriculture use Testing for residual levels Monitoring resistance

development Related monitoring programs U. S. Department of
Agriculture

Agricultural Research Service X

Animal and Plant Health Inspection Service X X

Food Safety and Inspection Service X X

Department of Health and Human Services

Centers for Disease Control and Prevention X X

Food and Drug Administration X X

Environmental Protection Agency

Office of Pesticide Programs X

Two agencies are responsible for approving the use of antibiotics
by the agriculture industry. FDA approves all antibiotics used for
food- producing animals; the Environmental Protection Agency (EPA)
approves antibiotics used as pesticides on produce and plants. FDA
has approved many antibiotics for use on food- producing animals;
EPA has approved two antibiotics for use on plants. FDA and EPA
each establish maximum allowable residue levels (tolerances) for
the antibiotics they approve and have regulatory authority to
withdraw approvals, although withdrawing approval can be a lengthy
and difficult process.

The U. S. Department of Agriculture's (USDA) Food Safety and
Inspection Service (FSIS) operates a program to ensure that
antibiotic residues in food products are within established
limits. FSIS' National Residue Program tests meat and poultry
products for antibiotic residues. These tests are

GAO/RCED-99-74 Food Safety Page 6

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performed on the carcasses of slaughtered animals and on samples
collected at ports of entry throughout the United States. 2

The National Antimicrobial Resistance Monitoring System's- Enteric
Bacteria program is the only federal program specifically focused
on testing for antimicrobial resistance related to agriculture.
The program was created in 1996 as a joint effort by FDA, CDC, and
USDA. Initially,

Salmonella was selected as the sentinel organism for tracking
antibiotic resistance. Samples for this program are collected from
humans in clinical settings and from animals in clinical and
nonclinical settings. The samples are tested for susceptibility to
17 antibiotics. These antibiotics were selected because they are
either commonly used in animal and/ or human medicine or because
they are very important to human medicine. CDC tests the samples
collected from humans, and USDA tests the samples collected from
animals. In 1997, the program was expanded to include testing of

Campylobacter samples. The head of veterinary testing for this
program told us that its scope has been relatively limited,
however, because the resources devoted to it have been limited.

Two other federal programs collect information related to disease-
causing organisms and antibiotic use, but neither is focused on
antibiotic resistance. USDA's Animal and Plant Health Inspection
Service operates the National Animal Health Monitoring System.
Through this program, the agency conducts studies on animal health
that include information about antibiotic use the reasons
producers use antibiotics, the way antibiotics are administered to
the animals, and the size of producers' operations. The studies do
not collect information about the quantities of antibiotics used.
However, the program has contributed samples for the National
Antimicrobial Resistance Monitoring System- Enteric Bacteria
program. CDC operates the Foodborne Disease Active Surveillance
Network also known as FoodNet. This is a surveillance system
designed to allow more accurate and precise estimates and
interpretation of the prevalence of foodborne diseases over time.

2 FSIS is planning to eventually include the testing of egg
products in the National Residue Program.

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Debate Is Ongoing Over the Potential Risk to Human Health From the
Agricultural Use of Antibiotics

The debate over whether to further regulate or restrict the use of
antibiotics in agriculture centers around the risk their use may
pose to human health relative to their benefits to agriculture.
Much of this debate concerns the uncertainty about whether and to
what extent antibiotic resistance in humans may be acquired from
the continued application of low doses of certain antibiotics in
animal feeds. We first questioned the health implications of using
antibiotics in animal feeds in 1977. 3 We noted that the safety
and effectiveness of the practice had not been established and
that the possibility existed that antibiotic- resistant bacteria
may develop and be transferred from animals to humans. Among other
things, we recommended that FDA determine the safety of
antibiotics used in animal feeds on the basis of available data
and withdraw approval of any not shown to be safe.

According to the Director of FDA's Center for Veterinary Medicine,
in 1978, FDA proposed withdrawing approval of penicillin and
tetracycline for other than disease treatment in animals. In
response to concerns over the absence of definitive data to
confirm that those antibiotics presented a hazard to human health,
FDA contracted with the National Academy of Sciences to review the
available data. According to a June 1980 report by a House
appropriations subcommittee, the Academy's review found that the
postulated hazards to human health... were neither proven nor
disproven. The Academy recommended that additional research be
conducted to fill data gaps. The subcommittee report asked FDA to
delay implementing its proposal pending the final results of the
additional research and evidentiary hearings.

The World Health Organization, the United Nations' group
responsible for monitoring global health, sponsored two recent
conferences to examine the research on antibiotic resistance and
agriculture. The first conference, in October 1997, addressed the
medical impacts of the use of antimicrobials in food- producing
animals. At the conclusion of this conference, scientists
advocated (1) a more thorough assessment of the risks, (2)
increased monitoring to detect the emergence of resistance, and
(3) terminating the use of antibiotics for growth promotion in
animals if they are also used in human medicine or are known to
potentially become cross- resistant to antibiotics used in human
medicine. Scientists attending the second conference in June 1998
recommended more research on the emergence of resistance to, and
prudent practices for using, the class of antibiotics known as
quinolones in animals.

3 Need to Establish Safety and Effectiveness of Antibiotics Used
in Animal Feeds (GAO/HRD-77-81, June 27, 1977).

GAO/RCED-99-74 Food Safety Page 8

B-281942

Other Countries Believe Potential Human Health Risks Warrant
Limiting Antibiotic Use in Agriculture

On the basis of their assessment of the potential risks, several
countries have acted to reduce the agricultural use of
antibiotics. The United Kingdom banned the use of penicillin and
tetracycline for growth promotion in the early 1970s; other
European countries followed suit shortly thereafter. Sweden banned
the use of all antibiotics for growth promotion in 1986, and
Denmark banned the use of one antibiotic in animal feed in 1998. 4
Canada's health department has called for a voluntary reduction in
the amount of antibiotics used in agriculture. In December 1998,
health ministers for the European Union voted to ban four
antibiotics that were widely used to promote animal growth. They
announced that they were taking this action as a precaution to
minimize the risk of the development of resistant bacteria and to
preserve the efficacy of certain antibiotics used in human
medicine. 5 The ban is scheduled to become effective for the 15
members of the European Union on July 1, 1999.

Associations Representing Agriculture and Pharmaceutical
Industries and Veterinarians Believe Restricting Antibiotics Is
Not Warranted

In the United States, associations representing beef, pork, and
poultry producers and pharmaceutical manufacturers have stated
that restricting the use of antibiotics in agriculture is not
warranted and is not supported by science. In their view, the use
of antibiotics in agriculture is only one potential contributor to
antibiotic resistance in humans and the extent of agriculture's
contribution has not been determined. They also believe that the
research does not warrant restricting the use of antibiotics in
agriculture. These associations believe that antibiotics are vital
to agricultural industries and contend that most producers are
already using antibiotics prudently.

The Animal Health Institute, a trade association representing
manufacturers of animal health products, including
pharmaceuticals, has announced a plan that calls for (1) assessing
the benefits and risks to humans from treating animals with
antibiotics, (2) developing guidelines for prudently using
antibiotics in farm animals, and (3) supporting improved
surveillance and monitoring of the use of antibiotics.

Associations representing beef, pork, and dairy producers are also
advising their members on antibiotic use. The National Cattlemen's
Beef Association has advised its members to strive to limit the
need for

4 Denmark's ban on virginiamycin went into effect in January 1998.
5 The European Union, which is comprised of Austria, Belgium,
Denmark, Finland, France, Germany, Greece, Ireland, Italy,
Luxembourg, the Netherlands, Portugal, Spain, Sweden, and the
United Kingdom, has proposed a ban on bacitracin zinc, spiramycin,
virginiamycin, and tylosin phosphate.

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[antibiotic] use through sound husbandry and preventative
practices. Both the National Milk Producers Federation and the
National Pork Producers Council have developed 10- point Quality
Assurance programs that advise members how to properly use
antibiotics during production.

The National Broiler Council told us that poultry producers use
antibiotics prudently. Officials from Tyson, the nation's largest
poultry producer, told us that the company stopped using
antibiotics to promote animal growth more than 2 years ago and has
been experimenting with alternative poultry production practices.

The American Veterinary Medical Association has been working with
its members to develop a set of principles aimed at safeguarding
public health and educating veterinarians on the potential risks
posed by antibiotic use in agriculture. The proposed principles
include (1) emphasizing appropriate animal husbandry and hygiene,
routine health examinations, and vaccinations in preference to
antibiotics; (2) considering therapeutic alternatives prior to
using antibiotics; (3) avoiding, in initial therapy, those
antibiotics that are considered important in treating infections
in humans, and (4) avoiding the inappropriate use of antibiotics,
such as for viral infections without bacterial complications.

Federal Efforts to Identify and Address Potential Risks

USDA, CDC, and FDA agree that antibiotics are critical in treating
diseases in animals as well as humans. As we noted earlier, under
the National Antimicrobial Resistance Monitoring System- Enteric
Bacteria program, these agencies have been active in monitoring
the emergence of antibiotic- resistant Salmonella since 1996 and
resistant Campylobacter

since 1997. They shared their concerns with us about the potential
impact on human health from using antibiotics in agriculture. CDC
and FDA agree that the agricultural use of antibiotics is a
significant source of antibiotic resistance among foodborne
pathogens. They also agree that the extent to which the
agricultural use of antibiotics contributes to resistance in other
nonfoodborne pathogens that cause diseases in humans is not
precisely known, although evidence is increasing that these uses
can be an important contributing factor.

USDA's activities have been limited to the testing and monitoring
that the Food Safety and Inspection Service, the Animal and Plant
Health Inspection Service, and the Agricultural Research Service
do under the National Antimicrobial Resistance Monitoring System-
Enteric Bacteria program. With regard to the debate over whether
to further regulate or

GAO/RCED-99-74 Food Safety Page 10

B-281942

restrict the use of antibiotics in agriculture, USDA believes
that, before any decisions are made, more research is needed to
determine how animals acquire resistant strains of Salmonella,
Campylobacter, and E. coli. USDA also believes that research is
needed to determine the extent to which environmental sources
contribute to the development of resistance in these pathogens. In
addition, according to USDA officials, the potential health risks
to humans from using antibiotics to promote animal growth need to
be weighed against the economic benefits to the consumers of this
use.

CDC's experts have advocated several measures to reduce the use of
antibiotics in agriculture. CDC researchers believe that some
antibiotics should not be used in animal feed to promote growth.
These researchers told us that, in treating diseases,
veterinarians need to ensure that they are prescribing the
appropriate doses of antibiotics. To prevent the spread of
disease, alternatives to antibiotics such as improved hygiene and
sanitation, feed safety, and direct- fed microbials good or
harmless bacteria that can be used to outcompete harmful or bad
bacteria should be used when appropriate. With regard to promoting
growth in animals, CDC supports restricting the use of antibiotics
because CDC believes such use results in antibiotic resistance
that is transmitted to humans through the food supply and may
limit treatment options in ill persons. CDC has specifically
suggested that FDA reconsider its approval of penicillin and
tetracycline for promoting growth in animals, as well as its
approval of fluoroquinolones for disease treatment and prevention
in poultry. According to CDC, fluoroquinolones are vital
antibiotics for the treatment of serious Salmonella and
Campylobacter infections in humans.

According to FDA officials, the development of fluoroquinolone-
resistant strains of Salmonella and Campylobacter highlights the
need to better address the potential development of bacterial
resistance as part of the safety determination prior to approving
new antibiotics for use in food- producing animals. FDA has
publicly stated that the current regulatory structure is
inadequate to properly evaluate the human health impact of
antibiotic resistance from the use of antibiotics in food-
producing animals. To address these concerns, in November 1998
FDA's Center for Veterinary Medicine published Proposed Framework
for Evaluating and Assuring the Human Safety of the Microbial
Effects of Antimicrobial New Animal Drugs Intended for Use in
Food- Producing Animals. This framework is intended to provide a
mechanism for evaluating and ensuring the human safety of
antibiotics and other antimicrobials used in food animals,
including those used for growth promotion.

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The proposed framework includes components for assessing
antibiotics on the basis of (1) the importance of the antibiotic
to human medicine, (2) preapproval data showing a safe level of
resistance transfer, (3) the establishment of thresholds for
monitoring safe resistance levels, (4) the effect of proposed uses
on human pathogen load, and (5) post approval studies and
monitoring. The Animal Health Institute objects to the post-
approval monitoring requirements of FDA's proposed framework,
saying that it would be cost- prohibitive and that it is not
justified from a public health standpoint.

HHS noted that the framework sets out a conceptual risk- based
process, the goal of which is to ensure that the antibiotics that
are significant in human treatment are not lost because of the use
of antimicrobials in animals while also providing for the safe use
of antimicrobials in animals. The proposed framework includes a
footnote indicating that the agency anticipates that the framework
will be used, as resources allow, to review existing approved uses
of antibiotics on food- producing animals. Although FDA officials
told us that they intend to use the framework for evaluating the
safety of all antibiotics currently approved, the framework does
not specify a specific strategy and time frame for this
reevaluation. In January 1999, FDA convened a public meeting to
discuss and obtain comments on the proposed framework. FDA is in
the process of revising the framework in response to the meeting
and the written comments it has received.

Finally, although FDA officials told us in July 1998 that they
shared CDC's concerns about fluoroquinolone resistance, FDA has
not initiated an action to withdraw its earlier approval for the
use of fluoroquinolones on poultry. In addition, FDA approved
fluoroquinolones for use on beef cattle in August 1998.

Conclusions Although research has linked the use of antibiotics in
agriculture to antibiotic- resistant strains of specific foodborne
pathogens that affect

humans, agricultural use is only one factor in the emergence of
antibiotic resistance in nonfoodborne pathogens. Debate exists
over whether the role of agricultural use in the overall burden of
antibiotic- resistant infections of humans warrants further
regulation or restriction. CDC believes the potential human health
risks call for action to restrict antibiotics for growth promotion
in animals. We first raised concerns in 1977 about the potential
human health risks of this practice. Today, more than two decades
later, federal agencies have not reached agreement on

GAO/RCED-99-74 Food Safety Page 12

B-281942

the safe use of antibiotics in agriculture. In developing a
federal response, both human health concerns and the impact on the
agriculture industry are factors to consider.

Recommendation to the Secretaries of Agriculture and Health and
Human Services

In light of the emergence of antibiotic resistance in humans,
questions about the extent that the agricultural use of
antibiotics contributes to the human health burden, and the debate
over whether further regulation or restriction of use in
agriculture is needed, we recommend that the Secretaries of
Agriculture and of Health and Human Services develop and implement
a plan that contains specific goals, time frames, and resources
needed to evaluate the risks and benefits of the existing and
future use of antibiotics in agriculture, including identifying
and filling critical data gaps and research needs.

Agency Comments We provided copies of a draft of this report to
USDA, HHS, and EPA for their review and comment. To obtain USDA's
comments, we met with officials in

the Food Safety and Inspection Service; the Animal and Plant
Health Inspection Service; and the Agricultural Research Service,
including the Associate Deputy Administrator for Animal
Production, Product Value and Safety. HHS provided written
comments, which appear with our response in appendix IV. EPA had
no formal comments on the draft report. The agencies also provided
technical comments that we incorporated throughout the report as
appropriate.

USDA generally found the draft report to be an accurate
presentation of the facts and agreed with the recommendation but
believed the draft overstated the extent to which antibiotic use
in agriculture may be linked to the emergence of antibiotic
resistance in humans. USDA acknowledged that the use of
antimicrobials can lead to the development of resistance but does
not believe that there is consensus among experts that research
has linked the use of antibiotics in agriculture to the emergence
of resistant strains of Salmonella, Campylobacter, and E. coli in
humans. USDA also commented that more research is needed before
decisions are made to further regulate or restrict the use of
antibiotics in agriculture. We have incorporated USDA's positions
into the report.

HHS, on the other hand, believed the draft report did not fully
recognize what HHS believes is the current state of knowledge the
increasing body of evidence pointing to the connection between the
agricultural use of antibiotics and resistant foodborne illnesses,
and the potential adverse

GAO/RCED-99-74 Food Safety Page 13

B-281942

human health consequences of antibiotic use in agriculture. Noting
that preventive action is needed now, the Department stated, steps
need to be taken to decrease the use in agriculture of antibiotics
that contribute to the development of resistant strains of human
pathogens. It also pointed out that the public health community is
concerned not only with the growth promotion uses of antibiotics
in agriculture but also with uses to treat and prevent disease,
which can be significant contributors to the pool of resistant
microorganisms that enter the food chain and often involve
critical drugs of last resort in treating a variety of human
infections. While the Department believes no further research is
needed to prove the link for foodborne pathogens, it does believes
more research would be beneficial in assessing agricultural
practices that can reduce antimicrobial use, identifying the types
of use that are high or low risk, and better understanding the
potential risks of resistance transfer from animal organisms other
than typical foodborne pathogens.

With regard to our recommendation, HHS pointed out that under the
Food and Drug Administration's proposed framework, applicants
would have to conduct tests to determine the potential for
inducing resistance for new animal drugs. It also stated that the
framework would allow the Food and Drug Administration to withdraw
already marketed antibiotics. While we agree that the framework is
an important step, especially for developing data on antibiotic
use, it does not include specific goals and time frames. Moreover,
the proposal states that currently approved antibiotics and their
uses will be assessed only to the extent resources allow. Without
a specific plan, goals, time frames, and the identification of
needed resources for such assessments, human health concerns that
were raised more than two decades ago may remain unanswered.
Finally, the disparity between USDA's and the HHS' views further
highlights the need for the departments to work together to ensure
that both human health concerns and the impact on the agriculture
industry are considered. We have incorporated HHS' comments into
the report as appropriate.

As arranged with your office, unless you publicly announce its
contents earlier, we plan no further distribution of this report
until 14 days from the date of this letter. At that time, we will
send copies of this report to the Honorable Richard Lugar,
Chairman, Senate Committee on Agriculture, Nutrition, and
Forestry; the Honorable Larry Combest, Chairman, and the Honorable
Charles Stenholm, Ranking Minority Member, House Committee on
Agriculture; the Honorable James Jefford, Chairman, and the
Honorable Edward M. Kennedy, Ranking Minority Member, Senate

GAO/RCED-99-74 Food Safety Page 14

B-281942

Committee on Health, Education, Labor, and Pensions; and the
Honorable Tom Bliley, Chairman, and the Honorable John Dingell,
Ranking Minority Member, House Committee on Commerce. We will also
send copies to the Honorable Dan Glickman, Secretary of
Agriculture; the Honorable Donna Shalala, Secretary of Health and
Human Services; the Honorable Carol Browner, Administrator,
Environmental Protection Agency; the Honorable Jane Henney, M. D.,
Commissioner, Food and Drug Administration; the Honorable Jeffrey
P. Koplan, M. D., Director, Centers for Disease Control and
Prevention; the Honorable Jacob J. Lew, Director, Office of
Management and Budget; and other interested parties. We will also
make copies available to other on request.

If you any questions about this report, please contact me at (202)
512- 5138. Major contributors to the report are listed appendix V.

Lawrence J. Dyckman Director, Food and Agriculture Issues

GAO/RCED-99-74 Food Safety Page 15

Contents Letter 1 Appendix I Objectives, Scope, and Methodology

18 Appendix II Approved Uses of Selected Classes of Antibiotics in
the United States

20 Appendix III Antibiotic- Resistant Strains Have Emerged in
Three Food- Related Organisms That Cause Diseases in Humans

23 Appendix IV Comments From the Department of Health and Human
Services

25 GAO's Comments 30

Appendix V Major Contributors to This Report

33 Tables Table 1: Federal Agencies' Roles Related to the Use of

Antibiotics in Agriculture 6

Table II. 1: Major Classes of Antibiotics, Examples in Each Class,
and Approval for Use on Animals, Plants, and/ or Humans

20

GAO/RCED-99-74 Food Safety Page 16

Contents Abbreviations

APHIS Animal and Plant Health Inspection Service ARS Agricultural
Research Service CDC Centers for Disease Control and Prevention
EPA Environmental Protection Agency FDA Food and Drug
Administration FSIS Food Safety and Inspection Service HHS
Department of Health and Human Services VRE vancomycin- resistant
enterococci USDA Department of Agriculture

GAO/RCED-99-74 Food Safety Page 17

Appendix I Objectives, Scope, and Methodology

This report examines (1) how antibiotics are used in agriculture
and the implications of that use for human health; (2) federal
roles and responsibilities for overseeing the use of antibiotics
in agriculture; and (3) issues surrounding the debate over whether
to further regulate or restrict the use of antibiotics in
agriculture.

To determine how antibiotics are used in agriculture, we spoke
with officials from the Center for Veterinary Medicine in the Food
and Drug Administration (FDA); the Office of Pesticide Programs in
the Environmental Protection Agency (EPA); and the Agricultural
Research Service (ARS), Animal and Plant Health Inspection Service
(APHIS) and Food Safety and Inspection Service (FSIS) in the U. S.
Department of Agriculture (USDA). We also met with officials
representing specific agricultural industries, including the
National Pork Producers Council, the National Milk Producers
Federation, the National Broiler Council, and the National
Cattlemen's Beef Association. In addition, we spoke with officials
from the American Feed Industry Association, the American
Veterinary Medical Association, and the Animal Health Institute.
From these meetings, we also identified the classes of antibiotics
with examples of specific antibiotics approved for agriculture and
the agricultural use for which they are approved. For comparison,
we used the Physicians' Desk Reference to identify classes of
antibiotics and examples of antibiotics used on humans.

To determine the implications for human health of the agricultural
use of antibiotics, we reviewed the relevant research findings of
studies, reports, and other scientific and medical literature,
including, among others, The Use of Drugs in Food Animals:
Benefits and Risk; National Research Council, July 9, 1998; The
Medical Impact of the Use of Antimicrobials in Food Animals, World
Health Organization, October 1997; Workshop Report, Orphans and
Incentives: Developing Technologies to Address Emerging
Infections, Institute of Medicine, 1997; Workshop Report,
Antimicrobial Resistance: Issues and Options, Institute of
Medicine, 1998; Impacts of Antibiotic- Resistant Bacteria, U. S.
Congress, Office of Technology Assessment (OTA- H- 629;
Washington, D. C., U.. S. Government Printing Office, September
1995); Joint Committee on the Use of Antibiotics in Animal
Husbandry and Veterinary Medicine, November 1969 (Swann Report);
the British House of Lords, Select Committee on Science and
Technology Seventh Report; Emergence of Multidrug- Resistant
Salmonella Enterica Serotype Typhimurium DT- 104 Infections in the
United States, The New England Journal of Medicine (May 1998);
Technology Crisis and the Future of Agribusiness: Antibiotic

GAO/RCED-99-74 Food Safety Page 18

Appendix I Objectives, Scope, and Methodology

Resistance in Humans and Animals, Harvard Business School, July
1997; Can We Use Less Antibiotics? Swedish Ministry of
Agriculture, Food, and Fisheries, 1997; Protecting the Crown
Jewels of Medicine, A strategic plan to preserve the effectiveness
of antibiotics. Center for Science in the Public Interest, 1998.
We met with officials and scientists from the Centers for Disease
Control and Prevention (CDC), FDA and USDA and other experts, both
in and out of government, to obtain their expert opinions of the
studies and research that has been done on the subject.

To determine federal roles and responsibilities for overseeing the
use of antibiotics in agriculture, we spoke with officials and
collected data from FDA, EPA, CDC, and USDA's Agricultural
Research Service, Animal and Plant Health Inspection Service, and
Food Safety and Inspection Service. We also reviewed applicable
laws and regulations for these agencies.

To determine the issues surrounding the debate over whether to
further regulate or restrict the use of antibiotics in
agriculture, we reviewed and analyzed reports and documents
published by, among others, the Institute of Medicine, the
National Research Council, the Office of Technology Assessment,
CDC, FDA, USDA, EPA, agricultural industry associations, the New
England Journal of Medicine, and the World Health Organization. We
discussed the issues with officials from the National Institutes
of Health, CDC, FDA, USDA, EPA, and the World Health Organization,
and from associations representing agricultural associations,
veterinarians, and pharmaceutical manufacturers.

We performed our review from May 1998 through April 1999 in
accordance with generally accepted government auditing standards.

GAO/RCED-99-74 Food Safety Page 19

Appendix II Approved Uses of Selected Classes of Antibiotics in
the United States

Table II. 1 lists major classes of antibiotics, provides examples
of specific antibiotics within each class, and indicates whether
any antibiotics within the class have been approved for use on
animals, plants, and/ or humans. Based on information in the
Physicians' Desk Reference, this classification of antibiotics is
grouped according to specific characteristics, such as
similarities in chemical composition or in the way they kill or
inhibit bacterial organisms. (The Physicians' Desk Reference
provides the latest available information on more than 2,500
specific pharmaceutical products. Each entry provides an exact
copy of the product's FDA- approved labeling.) While the table
shows that many classes of antibiotics approved for use in
agriculture are also approved for use in human medicine, it is
important to note that the antibiotics cited as examples may or
may not be the antibiotic approved for a particular use. For
example, only two antibiotics have been approved for use on food
plants: streptomycin, which is an antibiotic in the class of
aminoglycosides, and oxytetracycline, an antibiotic in the class
of tetracyclines.

Table II. 1: Major Classes of Antibiotics, Examples in Each Class,
and Approval for Use on Animals, Plants, and/ or Humans Animals

Plants Agriculture

Humans Antibiotic classes (selected examples) Species Disease

treatment Disease prevention Growth

promotion Aminoglycosides

(gentamicin, neomycin, streptomycin)

beef cattle, goats, poultry, a sheep, swine, certain plants

Beta- Lactams

 penicillins (amoxocillin, ampicillin)

beef cattle, dairy cows, fowl, b poultry, sheep, swine

    Cephalosporins 1st generation (cefadroxil)

 Cephalosporins 2nd generation (cefuroxime)

 Cephalosporins 3rd generation (ceftiofur)

beef cattle, dairy cows, poultry, sheep, swine

Chloramphenicol  Florfenicol beef cattle

(continued)

GAO/RCED-99-74 Food Safety Page 20

Appendix II Approved Uses of Selected Classes of Antibiotics in
the United States

Animals Plants Agriculture

Humans Antibiotic classes (selected examples) Species Disease

treatment Disease prevention Growth

promotion Cycloserines

(cycloserine)

Glycopeptides

(vancomycin)

Ionophores

(monensin, salinomycin, semduramicin, lasalocid)

beef cattle, fowl, goats, poultry, rabbits, sheep

Lincosamides (lincomycin) poultry, swine

Macrolides

(erythromycin, tilmicosin, tylosin)

beef cattle, poultry, swine

Monobactams

(aztreonam)

Polypeptides (bacitracin) fowl, poultry, swine

Quinolones

Fluoroquinolones (sarafloxacin, enrofloxacin) beef cattle,

poultry

Streptogramins

(virginiamycin) beef cattle, poultry, swine

Sulfonamides

(sulfadimethoxine, sulfamethazine, sulfisoxazole)

beef cattle, dairy cows, fowl, poultry, swine, catfish, trout,
salmon

Tetracyclines

(chlortetracycline, oxytetracycline, tetracycline)

Beef cattle, dairy cows, fowl, honey bees, poultry, sheep, swine,
catfish, trout, salmon, lobster, certain plants

Other antibiotics

Bambermycin beef cattle, poultry, swine

Carbadox swine    Novobiocin fowl, poultry    Spectinomycin
poultry, swine

(Table notes on next page)

GAO/RCED-99-74 Food Safety Page 21

Appendix II Approved Uses of Selected Classes of Antibiotics in
the United States

a Poultry includes at least one of the following birds: broiler
chickens, laying hens, and turkeys. b Fowl includes at least one
of the following birds: ducks, pheasants, and quail. Source: GAO

GAO/RCED-99-74 Food Safety Page 22

Appendix III Antibiotic- Resistant Strains Have Emerged in Three
Food- Related Organisms That Cause Diseases in Humans

Federal experts believe that research has linked the use of
antibiotics in agriculture to the emergence of antibiotic-
resistant strains of three disease- causing organisms. These
organisms, which are known to cause illness or disease in humans,
are Salmonella, Campylobacter, and

Escherichia coli, commonly known as E. coli.

Salmonella Salmonella is an organism commonly found in poultry,
eggs, beef, and other foods of animal origin. According to public
health officials, an estimated 800,000 to 4 million cases of
Salmonella infections occur each year in the United States.
Salmonella typically causes intestinal distress and does not
require medical treatment. However, severe cases of

Salmonella have been associated with reactive arthritis, as well
as with infections in the blood, in the meningeal linings of the
brain, and in other deep body tissues. Persons experiencing severe
symptoms often seek medical treatment. According to CDC, each year
an estimated 8,000 to 18,000 hospitalizations, 2,400 bloodstream
infections, and 500 deaths are associated with Salmonella
infections. Also, according to CDC, 40 percent of people with a
Salmonella infection who seek medical attention are treated with
antibiotics.

One particularly serious strain of Salmonella Salmonella DT- 104
is known to be resistant to several antibiotics. CDC estimates
that between 68,000 and 340,000 cases of Salmonella DT- 104 occur
annually in the United States. About 95 percent of Salmonella DT-
104 strains are resistant to five antimicrobials ampicillin,
chloramphenicol, streptomycin, sulfonamides, and tetracycline.
Human illness from Salmonella DT- 104 was first recognized in the
United Kingdom in the mid- 1980s. In 1993, veterinarians in
England began to treat poultry with fluoroquinolones, an important
class of antibiotics for treating diseases in humans. By 1996,
United Kingdom scientists reported that 14 percent of the
Salmonella DT- 104 strains had a decreased susceptibility to
fluoroquinolones. Scientists are very concerned about the
development of fluoroquinolone- resistant Salmonella, because
fluoroquinolones are the drugs of choice to treat Salmonella
infections in adults. Although fluoroquinolone- resistant
Salmonella infections are currently rare in the United States,
there has been a trend of decreasing susceptibility to
fluoroquinolones since they were first approved for agricultural
use in 1995.

GAO/RCED-99-74 Food Safety Page 23

Appendix III Antibiotic- Resistant Strains Have Emerged in Three
Food- Related Organisms That Cause Diseases in Humans

Campylobacter Campylobacter is also an organism commonly found in
poultry and other food of animal origin, including pork and beef.
According to public health officials, 2 million to 4 million
people suffer Campylobacter infections annually. Campylobacter
infections generally cause intestinal distress and do not require
medical treatment. However, one in every 1,000 reported cases of
Campylobacter results in Guillain- Barr Syndrome, a disease
associated with paralysis. The first case of domestically acquired
fluoroquinolone- resistant Campylobacter in humans in the United
States were identified in 1996, shortly after FDA approved
fluoroquinolones for use in poultry. World Health Organization
scientists concluded that prior to the use of fluoroquinolones in
animals, there had been no reports of fluoroquinolone- resistant
Campylobacter infections in humans who had no previous exposure to
this class of antibiotics. CDC scientists believe this provides
evidence that antibiotic- resistant strains of Campylobacter are
transmitted directly from animals to humans.

E. Coli Although many strains of E. coli are carried normally in
the intestines of humans and animals, some strains cause foodborne
illnesses. One strain E. coli O157: H7 causes potentially serious
illness, particularly for children and individuals with weakened
immune systems. Each year in the United States, an estimated 50 to
100 people die from E. coli 0157: H7 infections. Although
antibiotics are not the recommended treatment for E. coli O157: H7
infections, antibiotics are often given because of the symptoms
displayed in the patient and because some doctors believe
antibiotics will help. Antibiotic- resistant strains of E. coli
O157: H7 have been identified in animals, food, and humans, and
the emergence of antibiotic resistance in E. coli O157: H7 is of
concern to scientists because laboratory studies have demonstrated
that organisms may exchange genes, including the gene that allows
an organism to resist an antibiotic.

GAO/RCED-99-74 Food Safety Page 24

Appendix IV Comments From the Department of Health and Human
Services

Note: GAO comments supplementing those in the report text appear
at the end of this appendix.

GAO/RCED-99-74 Food Safety Page 25

Appendix IV Comments From the Department of Health and Human
Services

See comment 1. See comment 2. See comment 3.

See comment 4.

GAO/RCED-99-74 Food Safety Page 26

Appendix IV Comments From the Department of Health and Human
Services

See comment 5. See comment 6.

See comment 7. See comment 8. See comment 9. See comment 10.

GAO/RCED-99-74 Food Safety Page 27

Appendix IV Comments From the Department of Health and Human
Services

See comment 11.

GAO/RCED-99-74 Food Safety Page 28

Appendix IV Comments From the Department of Health and Human
Services

GAO/RCED-99-74 Food Safety Page 29

Appendix IV Comments From the Department of Health and Human
Services

GAO's Comments 1. We recognize the complexity of antimicrobial
resistance and have reviewed the considerable body of research on
the human health

implications of the agricultural use of antibiotics. However, this
report is not intended to be a complete technical assessment of
the public health issues surrounding the agricultural use of
antibiotics. Rather, it provides information on agricultural use
and the implications of that use for human health, federal roles
and responsibilities regarding the use of antibiotics in
agriculture, and the issues surrounding the debate over whether to
further regulate or restrict agricultural use. With regard to this
debate, we present the many divergent, sometimes conflicting,
viewpoints. For a more technical discussion of this complex public
health issue, with citations to several specific research papers,
see Antimicrobial Resistance: Data to Assess Public Health Threat
From Resistant Bacteria Are Limited (GAO/ HEHS/ NSIAD/ RCED- 99-
132, Apr. 28, 1999).

2. The report acknowledges that the factors that contribute to
antibiotic resistance include the nature of pathogens,
environmental pressures, and the use of antibiotics in human
medicine and in agriculture. The report also discusses three
antibiotic- resistant foodborne infections linked to the use of
antibiotics in food- producing animals.

3. It was not our intent to suggest that a major scientific study
should be undertaken to quantify agriculture's contribution to the
resistance problem relative to other factors. However, the report
does recognize that there is not consensus on agriculture's role.
Indeed, the U. S. Department of Agriculture (USDA) does not
believe there is consensus among experts that research has linked
the use of antibiotics in agriculture to the emergence of
resistant strains of Salmonella, Campylobacter, and E. coli

in humans. We revised the report to clarify the Department of
Health and Human Services' (HHS) positions that research has
established that the use of antimicrobials in agriculture
contributes to resistant foodborne pathogens and that there is a
pressing need to promote the more prudent use of antibiotics in
each setting.

4. HHS notes that growth promotants deserve careful scrutiny but
that a simple ban on growth promotants would not address all uses
of antibiotics in agriculture. HHS states that the Food and Drug
Administration's (FDA) proposal: Proposed Framework for Evaluating
and Assuring the Human Safety of the Microbial Effects of
Antimicrobial New Animal Drugs Intended for Use in Food- Producing
Animals will address all uses of antibiotics in agriculture. While
the framework is an important step forward, it does not include
specific goals and time frames for such

GAO/RCED-99-74 Food Safety Page 30

Appendix IV Comments From the Department of Health and Human
Services

assessments to help ensure that needed evaluations occur in a
timely manner. Moreover, the framework will be applied to
currently approved antibiotics including currently used growth
promotants only to the extent resources allow. We revised the
report to clarify HHS' position on the issue of antibiotic use in
food- producing animals and to more fully describe FDA's proposal.

5. The report text discusses the National Antimicrobial Resistance
Monitoring System- Enteric Bacteria program, and appendix II
discusses the emergence of multidrug- resistant strains of
foodborne diseases.

6. HHS notes that the draft report did not mention that the lack
of detailed animal drug use information is a barrier to advancing
scientific discussion on the adverse human health consequences of
antibiotic use in agriculture. HHS states that the implementation
of FDA's framework would obtain these data. We have revised the
report to acknowledge that data are not available on the
quantities of specific antibiotics used in agriculture and the
purposes for which they are used. Our recommendation directs HHS
and USDA to identify data gaps as part of a plan for evaluating
the risks and benefits of existing and future uses of antibiotics
in agriculture. As stated previously, however, we do not agree
that the implementation of FDA's framework would obtain these data
in a timely fashion for new antibiotic uses or, necessarily, at
any time for existing uses.

7. As our report states, only a few studies, primarily conducted
in Europe, have examined agriculture's contribution to the
development of resistance in nonfoodborne human pathogens. We
believe our report presents a balanced perspective with respect to
the positions of industry, researchers, and federal agencies.
However, in recognition of the different perspectives on the
issue, we modified the recommendation to focus on the debate over
the need to further regulate or restrict the agricultural use of
antibiotics.

8. While our report does not discuss in detail the transfer of
resistance from nonpathogenic organisms to human pathogens, which,
as HHS points out, is a difficult and unresolved issue, it does
discuss the development of resistance from other than direct
pathogen transfer and the fact that laboratory studies have
demonstrated that organisms can exchange genes, including the gene
that allows resistance.

9. We revised the report to include the data on the extent to
which

Salmonella and Campylobacter pose a threat to humans.

GAO/RCED-99-74 Food Safety Page 31

Appendix IV Comments From the Department of Health and Human
Services

10. HHS also pointed out that the public health community is
concerned not only with growth promotion uses of antibiotics in
agriculture but also with disease treatment and prevention uses,
which can be significant contributors to the pool of resistant
microorganisms that enter the food chain and often involve
critical drugs of last resort in treating a variety of human
infections. It was not our intent to suggest otherwise. Our report
discusses several antibiotics that are importance to human
medicine that have been approved for use on animals, including
fluoroquinolones, which FDA has recently approved for disease
treatment on poultry and cattle. We included this comment in the
Agency Comments section of the report.

11. Finally, with regard to our recommendation, HHS pointed out
that under FDA's proposed framework, applicants would have to
conduct tests to determine new animal drugs' potential for
inducing resistance. HHS also stated that the framework would
allow FDA to withdraw already marketed antibiotics. As we noted
earlier, the FDA framework is an important step, especially for
developing data on antibiotic use; however, the proposal states
that currently approved antibiotics and their uses will be
assessed only to the extent resources allow. Moreover, without a
specific plan, goals, time frames, and the identification of
needed resources for such assessments, human health concerns that
were raised more than two decades ago may remain unanswered.

GAO/RCED-99-74 Food Safety Page 32

Appendix V Major Contributors to This Report

Robert E. Robertson, Associate Director Erin Lansburgh, Assistant
Director Stuart Ryba, Evaluator- in- Charge Natalie Herzog Jerry
Seigler Shannon Bondi

(150090) GAO/RCED-99-74 Food Safety Page 33

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