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Quality control and safety of animal products

M. A. Miller
Human Food Safety and Consultative Services, Office of New Animal Drug Evaluation, Center for Veterinary
Medicine, US Food and Drug Administration, Rockville, MD 20857, USA. Received 29 January 1999, accepted 8
September 1999.

Miller, M. A. 1999. Quality control and safety of animal products. Can. J. Anim. Sci. 79: 533538. This paper discusses the
new animal drug approval process regulated by the Center for Veterinary Medicine (CVM), Food and Drug Administration (FDA)
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of the United States. The Center for Veterinary Medicine of FDA considers two criteria in ensuring the human food safety of edible
animal products: i) safety of the chemical residues and ii) for antimicrobial products, microbiological safety including changes in
bacterial pathogen load and resistance pattern. The hazard associated with animal drug products of non-carcinogenic compounds
is assessed by conducting a standard battery of toxicology test, whereas the hazard from the carcinogenic potential of compounds
is evaluated based on structure, results of genetic toxicity tests, and toxicology studies. Post approval monitoring is carried out to
ensure that the animal drugs are being used properly after their approval. Particular concern is given to those eliciting an acute
toxic reaction at relatively low levels. The other aspect of food safety regulated by CVM of FDA is microbiological safety, espe-
cially to antimicrobial drugs used at subtherapeutic levels in feeds. The studies are designed by FDA to ensure that antibiotic treat-
ment of food-producing animals does not alter pathogen load or resistance pattern of pathogens. Two studies are generally
performed: i) the salmonella shedding study, which addresses the effect of drug treatment on the excretion of salmonella in the
feces of animals artificially infected with salmonella; and ii) the coliform resistance study, which monitors the effect of the drug
on the resistance pattern of E. coli present in the endogenous fecal flora. After a retrospective study of the microbiological safety
over past 20 yr, CVM of FDA is planning to revise some microbiological safety studies with focuses on: i) pathogen load, pathogen
excretion and microorganism resistance pattern at the time of slaughter; and ii) susceptibility studies on products that have utility
in human medicine.
For personal use only.

Key words: Animal drug, food safety, antibiotic

Miller, M. A. 1999. Contrle de qualit et scurit des produits animaux. Can. J. Anim. Sci. 79: 533538. Dans cette commu-
nication nous scrutons le nouveau protocole dapprobation des mdicaments pour animaux rgi par le Centre for Veterinary
Medicine (CVM), lequel relve de la Food and Drug Administration (FDA) des tats-Unis. Dans sa tche de veiller la scurit
pour les consommateurs des produits animaux comestibles, le CVM prend en considration deux critres 1) linnocuit des rsidus
chimiques et 2) en ce qui concerne les produits antimicrobiens, la scurit microbiologique, y compris les modifications de la
charge de bactries pathognes et les phnomnes de rsistance. Les risques rattachs aux substances mdicamenteuses non can-
crignes sont valus au moyen dune batterie de tests toxicologiques standards, tandis que lvaluation du pouvoir cancrogne
dun produit repose sur des tudes structurales ainsi que sur des preuves de toxicit gntique et sur des tests toxicologiques. La
surveillance post-approbation voit ce que les mdicaments pour animaux soient utiliss bon escient. Une attention particulire
est accorde aux mdicaments qui provoquent une raction toxique aigu des doses demploi relativement basses. Lautre sujet
de surveillance du CVM est la scurit microbiologique, en particulier celle lie lemploi des antimicrobiens des doses sub-
thrapeutiques dans les aliments des animaux. On veille ce que le traitement aux antibiotiques des animaux destins lalimen-
tation ne modifie pas les populations de pathognes ou leur comportement de rsistance. Deux tests sont couramment utiliss i) le
test dexcrtion de salmonelles, par lequel on observe leffet du traitement mdicamenteux sur le niveau dexcrtion de salmo-
nelles dans les fces des animaux artificiellement salmonelliss. Deuximement le test de la rsistance des coliformes, qui surveille
lvolution de comportement de rsistance de E. coli, prsent dans la flore fcale endogne sous leffet dun mdicament. Aprs
une rtrospective sur ltat de la scurit microbiologique au cours des 20 dernires annes, le CVM se propose de rexaminer les
mthodes de surveillance microbiologique, notamment en ce qui a trait i) la charge en organisme pathogne, lexcrtion des
pathognes et le comportement de rsistance microbiologique au stade de labattage des animaux viande et ii) aux tudes de sen-
sibilit sur les produits qui revtent une utilit en mdecine humaine.

Mots cls: Mdicaments pour les animaux, scurit des aliments, antibiotique

The United States Food and Drug Administration is the States Department of Agriculture, Food Safety Inspection
primary federal agency responsible for the regulation of Service is primarily responsible for testing the meat supply
food and drug products intended for use in humans and for microbiological contamination and animal drug residues.
animals. While the Center for Food Safety and Applied In fact, both FDA and USDA have extensive programs to
Nutrition regulates the vast majority of human food, the
Center for Veterinary Medicine ensures the human food Abbreviations: ADI, acceptable daily intake; CVM,
safety of animals drug products that enter the human food Center for Veterinary Medicine; FDA, Food and Drug
supply as residues in milk, meat and eggs produced from Administration; INAD, Investigational New Animal Drug;
treated animals. While CVM is responsible for performing MRL, maximum residue limits; NADA, New Animal Drug
the safety assessments for animal drug residues, the United Application; NOEL, no observed effect level
533
534 CANADIAN JOURNAL OF ANIMAL SCIENCE

ensure that meat, milk and other animal products are safe, Table 1. Standard battery of toxicology tests
wholesome and of high quality. I. 90-day feeding study in rodent and non-rodent species
II. Multigeneration reproduction study with teratology component
New Animal Drug Approval Process III. Battery of genetic toxicology tests
Before any animal drug is legally marketed for use in food-
producing animals, the drugs sponsor must have a New
Animal Drug Application (NADA) approved by the FDA. Table 2. Consumption values for edible tissues
To obtain a NADA approval, the drug sponsor must demon- Muscle 300 g
strate to the FDA that the drug is effective and safe in the Liver 100 g
Kidney, Fat 50 g
target animals, safe for humans consuming edible products Milk 1.5 L
from treated animals, safe for the environment and can be Eggs 100 g
manufactured to uniform standards of purity, strength and
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identity. Under the federal Food Drug and Cosmetic Act


(the Act), animal drugs mean articles intended for use in the tissues. As analytical methods improved, the zero toler-
diagnosis, cure, mitigation, treatment or prevention of dis- ance was continually needing to be lowered.
ease in animals and articles (other than food) intended to To correct this problem, the agency adopted a negligi-
affect the structure or any function of the body of animals ble tolerance policy. Under this policy, the amount of tox-
(Anonymous a). To conduct investigational studies with icology data required for approval was limited to subchronic
new animal drugs before approval, the drug sponsor must studies in dogs and rats; and the tolerance was generally
request an Investigational New Animal Drug (INAD) assigned as 0.1 ppm in all edible tissues. As with the zero
exemption from the FDA. Under the INAD exemption, the tolerance procedure, the negligible tolerance was not
drug sponsor can conduct safety and efficacy studies related to the potential hazard of the compound. Thus, there
required for approval of their product. Relatively early in the was a disconnect between the permitted residue level or tol-
investigational process for a drug used in food animals, erance and public health concerns for the drug.
CVM scientists review studies relating to human food safety To remedy this situation, the Center adopted its current
and establish an appropriate period for drug withdrawal risk assessment procedure whereby the tolerance is based on
For personal use only.

before slaughter to ensure that no unsafe residues are pre- toxicology, residue and metabolism data. The current risk
sent in the food products. Once the human food safety is assessment model is: the risks from animal drug residue
confirmed, the FDA may authorize the use in human food of equals the hazard of the drug product times the exposure to
products from animals treated in investigational studies the drug residues. The agency regulates the public health
(Anonymous 1997a). risks associated with animal drug residues by assessing hazard
and controlling exposure to meet a risk standard of reason-
Human Food Safety Requirements able certainty of no harm.
Whenever an animal is treated with an animal drug, some
amount of the drug (i.e., residue) remains in edible tissue of Hazard Assessment: Standard Battery of
the treated animal. Drug residue is defined as any com- Toxicological Tests
pound present in edible tissue of the treated animals that The hazard associated with an animal drug product is
results from the use of the drug including the drug itself, its assessed by having the sponsor conduct a standard battery of
metabolites and any substances formed in or on the food as toxicology tests (Table 1). Each one of these toxicology
a result of drug use. Substance can be broadly defined to tests is designed to examine a different endpoint and deter-
include everything from drug metabolites to resistant bacte- mine a dose at which the drug causes an effect and a dose at
ria (Anonymous a). However, generally, CVM considers which the drug produces no observed effect. In determining
two criteria in ensuring the human food safety of edible ani- the toxicological endpoints to be examined, the battery of
mal products: 1) safety of the chemical residues including tests focuses on the adverse effect of chronic, low-level
the parent drug and all metabolites; and 2) for antimicrobial exposure to drug residue (FDA 1994).
products, microbiological safety including changes in bacte- For compounds that are not carcinogenic, the no observed
rial pathogen load and resistance pattern that occur as a effect level (NOEL) of the most sensitive effect from the
result of drug use in food producing animals. most appropriate toxicology studies is divided by a safety
Although food safety has always been a major concern of factor to determine an acceptable daily intake (ADI). The
the FDA, the human food safety requirements for animal ADI represents the total drug residues, parent and all
drug residues have changed over the years. Originally, ani- metabolites, that can be safety consumed daily throughout
mals drugs were approved based on a No residue or ones lifetime. The amount of drug residue permitted in each
Zero tolerance policy. While the No residue concept of the edible tissues, i.e., the safe concentration, depends
was generally acceptable to consumers and politicians, the upon the quantity of tissue that is consumed by the 90th per-
zero tolerance actually represented the sensitivity of the centile consumer on a daily basis (FDA 1994) (Table 2).
analytical method used to monitor drug residues not a true
zero value. In fact, because most drugs are eliminated from Controlling Exposure I: Residue and Metabolism
the body by first order kinetics, pharmacokinetic theory pre- Once the safe concentration is determined, the risk to con-
dicts that some drug residue would always remain in animal sumers is minimized by controlling exposure. Generally, the
MILLER QUALITY CONTROL AND SAFETY OF ANIMAL PRODUCTS 535

tissue concentrations of drug are highest immediately after above the tolerance at the end of the withdrawal period.
treatment. Also, edible organ tissues, i.e., liver and kidney, Most animals are slaughtered at market weight not at the
contain more drug residues than muscle. With time, the ani- end of the withdrawal period, virtually no violative residues
mals normal metabolic and excretory processes remove the will occur when drugs are used according to the label.
drug from the animal. Thus, the first step in controlling Information about the withdrawal time is included on the
exposure is to determine when the level of drug in the ani- drug label (FDA 1994).
mals reaches the calculated safe concentration for each of
the different edible tissues. Regulation of Carcinogens
The first residue chemistry study conducted is the total The Delaney Clause of the FD&C Act prohibits the use of
residue and metabolism study. This study utilizes radio- compounds found to induce cancer when ingested by man
labeled drug and is therefore capable of monitoring all drug- or animal, or if it is found, after tests which are appropriate
derived residues resulting from the administration of the test for the evaluation of the safety of the food additive, to
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compound. In this study, the radiolabeled drug is administered induce cancer in man or animal (Anonymous b). An excep-
to a group of animals for which the product is intended. tion to the Delaney Clause, known as the DES Proviso,
Animals are killed and the tissues analyzed at various times exists for animal drugs, when it is determined by methods of
after drug administration to determine where the drug examination prescribed or approved by the Secretary (...)
deposits, how it is metabolized and how it depletes from the that no residue of that compound will be found in the food
animal. Usually, the total radioactivity in the edible tissues produced from those animals under conditions of use rea-
is measured by combustion of the tissue samples to liberate sonably certain to be followed in practice (Anonymous
the radiolabel followed by liquid scintillation counting. 1997b).
Since the only source of radioactivity is the administered To implement the DES Proviso of the Delaney Clause,
drug, any detected radioactivity is drug-related (FDA 1994). FDA relies upon quantitative risk assessment procedures to
Metabolism of the drug is evaluated by extracting the determine when the amount of residue of the carcinogenic
radioactive material from the tissue followed by chromato- concern present in edible tissue produces an incremental
graphic analysis. By measuring the concentration of the estimated cancer risk for a lifetime of 1 in 1 million. This
major radiolabeled metabolites isolated from the tissues col- level is functionally defined as no residue (FDA 1987).
For personal use only.

lected at difference times following treatment, it is possible The carcinogenic potential of a compound is evaluated
to determine the drug residue that persists the longest and based on structure, results of genetic toxicity tests, and toxi-
the edible tissue that eliminates the drug most slowly. cology studies. If the compound or its metabolites are struc-
Because the radiolabeled residues represent all the drug turally related to a demonstrated carcinogen, it is assigned to
present in edible tissue, these values can be compared with a category with the highest concern for carcinogenic risk. If
the safe concentration directly. When the total residue in further testing in short-term genetic toxicity tests and sub-
edible tissue is less than half the respective safe concentra- chronic feeding studies do not indicate carcinogenicity, use
tion, no preslaughter withdrawal period is assigned. In all and exposure levels of the compound are considered to
other cases, the drug depletion profile is used to determine determine if chronic rodent carcinogenicity studies are
the withdrawal period, i.e., the amount of time needed to required (Guyer et al. 1994).
allow the total residue to deplete below the safe concentra- When the results of chronic bioassays demonstrate that a
tion in the tissue that depletes the slowest. compound induces cancer by the oral route, a nonthreshold,
The total residue consists of parent compound, free conservative, linear-at-low-dose extrapolation procedure is
metabolites, and metabolites that are covalently bound to used to estimate an upper limit of low-dose-risk (Lorentzen
endogenous molecules, and is very difficult to measure on a et al. 1997). This no residue value is adjusted for con-
routine basis. Rather than measuring the total residues in all sumption and is used to determine how sensitive the analyt-
the edible tissues, FDA establishes one value, a tolerance, in ical procedure must be to ensure the safety of the food.
one tissue, the target tissue, for monitoring drug residues. Following a determination of no residue, residue and
The tolerance is based upon the marker residue rather than metabolism studies are conducted as described above.
the total residue. The marker residue may be parent, any
metabolite or a combination of residues that is in known International Food Safety Standards
relationship to the total residue and is measured by the reg- Most industrialized countries have regulatory bodies, like
ulatory assay. The tolerance is established so that when the the FDA, that perform similar risk assessments and set tol-
marker residue is below the tolerance in the target tissue the erances or maximum residue limits (MRL) for animal drug
whole carcass is safe. If an animal drug product requires residues in edible tissues. While risk assessment procedures
time after the last treatment to deplete to the calculated safe are similar, countries differ in the toxicology tests required,
concentration, the FDA establishes a withdrawal time for the safety factors applied to toxicology tests, their assump-
the product. To establish a withdrawal time, the drug spon- tions on food commodities consumed per day, and the
sor conducts a residue depletion study using the commercial amount of the ADI allocated into the MRL.
product in field use conditions. The withdrawal time is cal-
culated by determining the 99th percentile tolerance limit Codex Alimentarius Commission (CODEX)
with 95% confidence. Using this procedure there is only a In 1962, the CODEX was established as a subsidiary of the
5% probability that 1 animal in 100 could have residues Food and Agricultural Organization and the World Health
536 CANADIAN JOURNAL OF ANIMAL SCIENCE

Organization of the United Nations. CODEX was created to Violative levels of certain animal drugs can induce phar-
facilitate international trade by developing international macological effects in consumers. For example, the beta-
food standards. The Codex Commission on Residues of agonist, clenbuterol, was approved for therapeutic use as a
Veterinary Drugs in Foods provides expert advise on tech- bronchial dilator in some food-producing animals in
nical barriers to trade for veterinary products and is respon- Europe. There have been several reports of people becom-
sible for establishing international MRLs for veterinary ing ill after consuming beef products containing clenbuterol
drugs. CODEX MRLs are not mandatory but are established residues. Clinical symptoms include muscle tremors, heart
as the standard for trade negotiations. In establishing the palpitations, nervousness, chills and vomiting, i.e., symp-
MRLs, the Codex Commission on Residues of Veterinary toms characteristic of the pharmacological activity of beta-
Drugs in Foods receives advice from the FAO/WHO Joint agonists (Paige et al. 1997).
Expert Committee on Food Additives. This committee of Also, violative levels of antimicrobial animal drugs may
international experts on toxicology, pharmacology and perturb the human gut microflora. The indigenous bacteria
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metabolism reviews data similar to that reviewed by the that populate the GI tract of humans provide resistance to
FDA and establishes international ADIs and MRLs for drug infections, metabolize toxins and carcinogens, produce vita-
residues. Countries that do not have regulatory bodies over- mins and aid in food digestion. Therapeutic levels of some
seeing animal drug use can adopt the CODEX standard and antibiotics perturb the gut ecosystem causing adverse health
be assured that their animal-derived food products are safe effects. To date, there have been few studies to determine
and permitted in international trade. the lowest dose of antibiotic required perturbing the normal
human flora. While it is generally agreed that the very low
Controlling Exposure II: Post Approval Monitoring tolerance levels of antibiotic residues in food are not suffi-
In addition to establishing a tolerance or MRL for drug cient to affect the flora, violative levels of antibiotics may
residues, countries must have a monitoring program to perturb this ecosystem (Paige et al. 1997).
ensure that the animal drugs are being used properly. There FDA takes regulatory action, including criminal prosecution,
is no international program for assuring that animal drugs against individuals that misuse animal drug products when
are being used properly; this function is performed by these acute toxic effects represent a public health concern.
national regulatory authorities. In the US, the proper use of
For personal use only.

the animal drug product is ensured by providing appropriate Microbiological Safety


use information on the label, educating animal producers The other aspect of food safety regulated by CVM is micro-
and veterinarians about proper drug use and monitoring the
biological safety. Although the microbial foodborne disease
food supply for violative drug residues. The Food Safety
burden of the US is not known with accuracy, it is estimated
Inspection Service of USDA oversees the residue monitor-
that from 6.5 to 33 million cases occur annually and that
ing program in the US and their monitoring data from random
deaths from foodborne disease may be as high as 9000 per
samples indicate that violative drug residues occur very
year. Foods of animal origin are often identified as the vehi-
infrequently, i.e. less than 1% of the nations food supply.
FDA is responsible for taking regulatory action when a cles of food borne disease; and therefore some portion of
violative residue is identified. FDA prioritizes its regulatory these foodborne diseases may be attributed to pathogens
action based on public health concerns. While the health risk present in the animals colon at the time of slaughter when
assessment for animal drug residues focuses on the chronic feces containing pathogens may contaminate the carcass.
low-level exposure effects of drug residues, regulatory com- Approximately 1% of the beef carcasses are contaminated
pliance actions on violative samples focus on the acute with Salmonella, while contamination of chicken carcasses
effects of drugs. Thus, FDA is particularly concerned about is 20-fold higher (US Department of Agriculture 1996).
drug residues that elicit an acute toxic reaction at relatively FDA/CVM began requiring specific antimicrobial studies
low doses. in the mid-1970s based on the concerns identified by FDAs
Task Force on Antibiotics and Animal Feed. This Task
Acute Toxicities Associated with Animal Drugs Force identified six safety criteria which must be met by
Allergic reactions are manifested in many ways, from life- antimicrobial drugs used at subtherapeutic levels in feeds
threatening anaphylactic reactions to lesser reactions such as prior to their approval. According to these criteria, the
rashes. Although animal drug residues probably do not antimicrobial drug shall not result in 1) a significant
cause primary sensitization of individuals because expo- increase in the frequency of antimicrobial resistant coliform
sures are too low and for short duration, violative levels of bacteria in the gut, 2) increased shedding of resistant
animal drug residues in food have caused allergic reactions Salmonella in animals, 3) increased virulence/pathogenicity
in sensitized individuals (Paige et al. 1997). of bacteria, 4) animal disease that is more difficult to treat,
Violative levels of penicillin are the most frequently cited 5) residues in edible tissues that are high enough to select for
cause of allergic reactions in persons consuming residues resistant bacteria when consumed by humans and 6)
probably because a large number of individuals are allergic increased frequency of hypersensitivity reactions in
to penicillin, allergic reactions occur at low doses and peni- humans. The last two criteria were applied to both therapeu-
cillin is extensively used in food producing animals. Many tic and subtherapeutic products because these concerns are
other animal drugs, including tetracyclines, sulfonamides the same for both classes of products (FDA 1977a, b).
and aminoglycosides, can cause allergic reactions in sensi- The first four criteria were applied to subtherapeutic
tized individuals (Paige et al. 1997). products because data indicated these products presented a
MILLER QUALITY CONTROL AND SAFETY OF ANIMAL PRODUCTS 537

greater risk. Subtherapeutic uses involved administering inoculated or given test drug. Since the test drug was deter-
low levels of antimicrobials to large numbers of animals for mined to have no effect when the results from the drug-
prolonged periods of time in some cases for a lifetime. treated and control group were the same, the environmental
Several studies showed that duration of treatment was as control was used as a sentinel to detect if bacterial cross-
important as dose in the selection of resistant organisms. contamination between the study groups contributed to the
Therefore, preapproval testing requirements to support lack of difference (FDA 1977a).
antimicrobial products were only required for those antibi- The drug-treated and control groups in the Salmonella
otics which were administered in animal feed for subthera- shedding studies were inoculated with a laboratory strain of
peutic purposes including growth promotion and feed S. typhimurium. The strain used was known to colonize the
efficiency claims. Subtherapeutic treatment was defined as test species, was easily recovered because it carried chro-
treatment for more than 14 d. It was assumed that any mosomal nalidixic acid resistance, was susceptible to 8 to 10
responses seen during the study would be maintained until medically-relevant antimicrobial drugs, and was a capable
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slaughter and negatively impact consumers if edible tissues recipient of resistance-carrying plasmids. Because it is diffi-
become contaminated with pathogens and/or resistant bacteria cult to detect changes in bacterial susceptibility following
(Cooper 1997). drug treatment, it was preferred that animals in the shedding
study carry high levels of resistance in their coliform popu-
Testing Design for Microbiological Studies lation. It was presumed that with more donor bacteria pre-
The studies designed by FDA scientists to ensure that anti- sent in the coliform population, it would be more likely that
biotic treatment of food-producing animals does not alter Salmonella would receive resistance factors. The intent of
pathogen load or resistance pattern of pathogens have been using a Salmonella strain free of plasmid resistance was to
summarized in detail (FDA 1977a,b). Two studies were determine the rate of transfer of resistance factors due to
generally performed; one study addressed the effect of drug drug effects (FDA 1977a).
treatment on the excretion of Salmonella in the feces of ani- Feces were collected at approximately weekly intervals.
mals artificially infected with Salmonella , i.e., Salmonella Tissues, e.g. mesenteric lymph node and spleen, and cecal
shedding studies. The other study, a coliform resistance contents were collected at the end of the study. Shedding
study, monitored the effect of the drug on the resistance pat- quantity, duration, and prevalence in animals as well as tis-
For personal use only.

tern of E. coli present in the endogenous fecal flora. sue invasion and Salmonella susceptibility results from the
The studies were designed to last 8 wk with animals drug- treated and control groups were compared.
receiving drug for the length of the study. Study duration Susceptibility test quality control results were evaluated to
was based on earlier studies, which suggested that at least determine if methodology was appropriate (FDA 1977a).
22 d were needed to detect changes in susceptibility pat- The design for the coliform resistance study was essen-
terns. In each study, the drug-treated animals had to ingest tially the same as that described for the Salmonella shedding
or receive by bolus at least 75% of the highest intended studies except that animals were not artificially inoculated
antimicrobial treatment dose each day of the study including with bacteria. Rather, the effect of drug on the endogenous
days when the animals would not eat. The number of ani- fecal flora was evaluated. Because it is difficult to detect a
mals in each group ranged from 7 to 12 across all species. change in resistant E. coli if the majority of the population
Animal numbers were considered acceptable if the differ- is resistant before drug exposure, for the coliform resistance
ence among the animals within a group did not exceed the study, it was necessary to use animals with a low level of
difference among the animals between the groups. The ani- resistance (less than 20%) in their endogenous E. coli.
mals were usually housed individually to avoid biasing the Changes in coliform susceptibility (against the same med-
study through bacterial cross-contamination and to increase ically relevant drugs used in the Salmonella shedding studies)
the statistical power of the study (FDA 1977a). While these between the drug-treated and control groups indicated drug
studies were originally intended to apply to all drugs intend- effects on either resistance transfer or new emergence. Thus,
ed for subtherapeutic use in any animal species; cattle, the results of this study were coupled with the results of the
swine, and poultry were the only species tested (Cooper Salmonella shedding study to determine if the drug effects
1997). were on the selection of resistant genes or on the transfer of
In the shedding study, treated and control animals were resistance factors (FDA 1977a,b).
inoculated a couple of days before the start of drug treat-
ment with Salmonella at a sufficient concentration and Retrospective Analysis of the Microbiological
under conditions to induce initial shedding at about 105 Safety Studies
CFU mL1 (i.e., up to two inoculations at approximately 109 The Center for Veterinary Medicine has recently completed
CFU mL1 concurrent with starvation). The purpose of this a retrospective analysis of all the data that have been sub-
artificially high inoculation dose was to create an initial mitted over the past 20 yr and is planning to revise these
infection sufficient to detect a 2 log difference in Salmonella microbiological safety studies to better suit todays needs.
excretion due to the drug. In cases where shedding was too Because of changes in antimicrobial product usage and
heavy to determine duration at the end of 8 wk; a second spectrum of activity, the current studies have some weak-
shedding study was performed at a lower inoculum density, nesses. For example, the microbiological safety studies, as
i.e., approximately 108 CFU mL1. All shedding studies designed, focus more on environmental or occupational
included an environmental control group, which was not safety concerns, i.e., the bacteria that are shed on the farm,
538 CANADIAN JOURNAL OF ANIMAL SCIENCE

than on food safety aspects, i.e., the bacteria present at the required for antimicrobials administered in feed, studies
time of slaughter. Food is distributed throughout the coun- may be necessary for other routes of administration with
try and foodborne pathogens are more likely to affect large long-term or widespread exposure.
portions of the population compared with environmental or
occupational routes of exposure. CONCLUSION
Studies will be redesigned to focus on pathogen load, The Food and Drug Administrations Center for Veterinary
pathogen excretion and microorganism resistance pattern at Medicine approves the use of safe and effective animal drug
the time of slaughter, since it is organisms present in the ani- products for food producing animals. Before these products
mal at the time of slaughter that have the greatest potential are approved, CVM ensures the food products from these
to contaminate the food supply. animals will be safe and wholesome. After product
The Center for Veterinary Medicine will focus the sus- approval, FDA/CVM interacts with other federal and state
ceptibility studies on products that have utility in human agency to ensure that the consumer enjoys quality animal
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medicine. Drugs tested under the old criteria included food products.
ionophores, bambermycins, and other unclassified gram-
positive drugs that have no utility in human medicine. None Anonymous a. Federal Food Drug and Cosmetic Act, Chapter II,
of these drugs changed the susceptibility pattern of coliforms Section 201(g)(1).
or Salmonella in the traditional studies. Also, there was no Anonymous b. Federal Food Drug and Cosmetic Act, Chapter IV,
demonstration in the literature of transferable resistance to Section 409(c)(A)(2).
drugs in these pharmacological classes. In the future, sus- Anonymous. 1997a. United States Code of Federal Regulations 21
ceptibility studies may not be needed for drugs similar to Part 514, revised 1 April 1997.
these products and with no utility in human medicine. Anonymous. 1997b. United Stated Code of Federal regulations 21
In the traditional microbiological studies, Salmonella and (Part 500) revised 1 April 1997.
Cooper, J. N. 1997. Perspective on the therapeutic and growth
E. coli were the only pathogens investigated for changes in enhancing use of antibiotics by the livestock industry and the
susceptibility. These pathogens are gram-negative bacteria, antibiotic resistance monitoring program. J. Anim. Sci. (submitted).
and many antimicrobials given to animals have activity Food and Drug Administration 1977a. Penicillin in animal feed.
against gram-positive organisms only. In the future, pathogen Federal Register 42: 4376943793.
For personal use only.

testing will be matched to the spectrum of drug activity. Food and Drug Administration 1977b. Chlortetracycline and
That is, Salmonella and E. coli will continue to be evaluated oxytetracycline in animal feed. Federal Register 42: 5625356289.
for drugs possessing activity against a broad spectrum of Food and Drug Administration 1987. Sponsored compounds in
organisms and gram-negative organisms; but enterococci food-producing animals: Criteria and procedures for evaluating the
will be evaluated for products with a gram-positive spec- safety of carcinogenic residues: Animal drug safety policy. Federal
Register 4957249590.
trum of activity.
Food and Drug Administration 1994. Guideline for establishing
The effect of the antibiotic on pathogen load and resis- a safe concentration; Availability. Federal Register 52: FR
tance pattern will be evaluated under proposed conditions of 3749937500.
use for the product. Salmonella inoculation concentrations Gaylor, D. W., Axelrad, J. A., Brown, R. P., Cavagnaro, J. A.,
will be comparable to levels seen in natural infections, drug Cyr, W. H., Hulebak, K. L., Guyer, C. G. and Miller, M. A.
treatments will be similar to those proposed for approval, 1994. Human food safety evaluation of repartitioning agents.
and, when appropriate, the effects of a drug withdrawal period Pages 355417 in H. Hafs and R. G. Zimbelman, eds. Low-fat
will be assessed. Furthermore, since the retrospective analy- meat: Design strategies and human implications. Academic Press,
sis never showed that drug treatment affected tissue colo- Inc., New York, NY.
nization by Salmonella, tissue colonization tests will be Lorentzen, R. J., Miller, M. A., Mulligan, L. T. and Schwetz,
B. A. 1997. Health risk assessment practices in the U.S. Food and
required only when there is evidence to suggest a particular
Drug Administration. Regul. Toxic. Pharmacol. 26: 307321.
antimicrobial might affect this parameter. Paige, J. C., Tollefson, L. and Miller, M. 1997. Public health and
Finally, changes in the use pattern of therapeutic antimi- drug residues in animal tissues. Vet Human Toxicol. 30: 162169.
crobials may necessitate performing microbiological food US Department of Agriculture. 1996. Pathogen reduction; hazard
safety studies for some of these products as well as the sub- analysis and critical control point (HACCP) systems; Final Rule.
therapeutic products. While traditional studies were only Federal Register 61: 3880638989.