drugs in livestock feed - princeton university
TRANSCRIPT
Drugs in Livestock Feed
June 1979
NTIS order #PB-298450
Library of Congress Catalog Card Number 79-600094
For sale by the Superintendent of Documents, U.S. Government Printing OfficeWashington, D.C. 20402
Foreword
This report addresses the question of the continued use of certaindrugs in livestock feed.
The assessment was undertaken at the request of Senator HermanE. Talmadge, Chairman of the Senate Committee on Agriculture, Nutri-tion, and Forestry.
The Office of Technology Assessment utilized a diverse range ofpersonnel and methodologies for this assessment. An overall assess-ment advisory panel was appointed and individual papers dealing withthe key issues were commissioned. This work was supplemented by areview of Food and Drug Administration documents, input from publicparticipation meetings, and critical review of draft reports by a widespectrum of individuals. These wide-ranging inputs from public interestand consumer representatives, agribusiness and producers, scientificexperts, and Government officials helped shape the study and the con-gressional options. To all of these people OTA acknowledges a deepdebt. Without their individual and institutional assistance and coopera-tion the report would not have been possible. This report is an OTA staffsynthesis and does not necessarily reflect the position or views of anyparticular individual.
/yzL#&-JOHN H. GIBBONSDirector
. . .111
OTA Food Program Staff
Joyce C. Lashof, Assistant DirectorHealth and Life Sciences Division
J. B. Cordaro, Group Manager
Phyllis Balan Elizabeth Galloway Yvonne Noel
Contractors
Lawrence MiikeSamuel Iker Walter Wilcox Marietta Whittlesey
Winrock International Livestock Research and Training CenterT. C. Byerly, Principal InvestigatorE. K. Byington H. A. Fitzhugh
OTA Publishing Staff
John C. Holmes, Publishing Officer
Kathie S. Boss Joanne Heming
v
OTA Food Advisory Committee
David CallDean, College of Agricultural
and Life SciencesCornell University
Cy CarpenterPresidentMimesota Farmers Union
Martin E. Abel, ChairmanSenior Vice President, Schnittker Associates
Johanna Dwyer, Vice ChairmmDirector, Frances Stern Nutrition Center
Eliot ColemanDirectorCoolidge Center for the
Study of Agriculture
Almeta Edwards FlemingSocial Program CoordinatorFlorence County, S.C.
Lorne GreeneChairman of the BoardAmerican Freedom From
Hunger Foundation
Richard L. HallVice President, Science and
TechnologyMcCormick & Company, Inc.
Laura HeuserMember, Board of DirectorsAgricultural Council of America
Arnold MayerLegislative RepresentativeAmalgamated Meat Cutters and
Butcher Workmen of NorthAmerica
Max MilnerExecutive DirectorAmerican Institute of Nutrition
Robert O. NesheimVice President, Science and
TechnologyThe Quaker Oats Company
Advisory Working Group
H. R. BirdProfessor of Poultry ScienceUniversity of Wisconsin
David B. ClaysonDeputy DirectorEppley Institute for Research on
Cancer and Allied Diseases
W. W. CochraneProfessor of Agricultural
EconomicsUniversity of Minnesota
Ruth DesmondPresidentAmerican Federation of
Homemakers
vi
Lauren Seth, ChairmanAgricultural Consultant
Charles M. DobbinsAssociate DeanCollege of Veterinary MedicineUniversity of Georgia
S. T. DontaDirector of Infectious DiseaseServicesDepartment of MedicineUniversity of Iowa Medical School
C. M. HardinDirector of ResearchRalston-Purina Feed Company
Kenneth MonfortChairman of the BoardMonfort of Colorado
Kathleen O’ReillyDirectorConsumer Federation of America
R. Demis RouseDean, School of AgricultureAuburn University
Lauren SethAgricultural Consultant
Thomas SporlederProfessor of Agricultural
EconomicsTexas A&M University
Sylvan WittwerDirector and Assistant DeanCollege of Agriculture and
Natural ResourcesMichigan State University
Sheldon MurphyProfessor and Director, Division
of ToxicologyDepartment of PharmacologyUniversity of Texas MedicalSchool
Pauline PaulActing Head, Foods and NutritionHuman Resources and Family
StudiesUniversity of Illinois
Virgil RosendalePresidentPork Producers Council
James S. TurnerCo-DirectorConsumer Action for Improved
Drugs
. . .
Attendance at Public Participation MeetingSeptember 12, 1977
Lauren Seth, Chairman
OTA: J.B. CordaroWalter Wilcox
John B. AdamsNational Milk Producers Federation
George AllenEconomic Research ServiceU.S. Department of Agriculture
Selma P. BaronCommittee on Animal NutritionNational Research CouncilNational Academy of Sciences
James R. BeanOffice of Toxic SubstancesEnvironmental Protection Agency
John J. BirdsallAmerican Meat Institute
Ann BornsteinNational Farmers Organization
Jerry BruntonAnimal Health Institute
Grace ClarkFood Safety and Quality ServiceU.S. Department of Agriculture
Mitchell L. CohenBacterial Disease DivisionCenter for Disease ControlU.S. Department of Health,
Education. and Welfare
Stephanie C. CroccoDepartment of Foods and NutritionAmerican Medical Association
Robert ElderOffice of ScienceFood and Drug AdministrationU.S. Department of Health,
Education, and Welfare
Burton EllerNational Cattlemen’s Association
W. G. FlammNational Cancer InstituteNational Institutes of HealthU.S. Department of Health,
Education, and Welfare
Frank FrazierAmerican Agribusiness Associates
J. Marvin GarnerNational Pork Producers Council
Roger J. GerritsLivestock and Veterinary ScienceAgriculture Research ServiceU.S. Department of Agriculture
Mary T. GoodwinMontgomery Count y Health
DepartmentState of Maryland
Richard H. GustafsonAmerican Cyanamid Company
Donald L. HoustonMeat and Poultry Inspection ProgramFood Safety and Quality ServiceU.S. Department of Agriculture
C. D. Van HouwelingBureau of Veterinary MedicineFood and Drug AdministrationU.S. Department of Health,
Education, and Welfare
Robert W. KeirsPoultry & Egg Institute of America
Terry B. KinneyAgricultural Research ServiceU.S. Department of Agriculture
Catherine A. KoobKoob Associates
Robert LenahanU.S. Department of Agriculture
Fred H. McDiarmidBiochemical DepartmentDuPont Company
Ian McNettFree-lance Writer
Kirk MillerAmerican Farm Bureau Federation
Natalie PargasFood Chemical News
Maryln K. PerezBureau of FoodsFood and Drug AdministrationU.S. Department of Health,
Education, and Welfare
Bill RoenigkNational Broiler Council
Phillip RossBoard on Agriculture and Renewable
ResourcesNational Academy of Sciences
John W. ThomasAmerican Veterinary Medical
Association
G. L. WaitsNational Turkey Federation
Winrock International LivestockResearch and Training Center:
T. C. Byerly, Principal InvestigatorE, K. ByingtonH. A. Fitzhugh
Charles E. Wismer, Jr,
vii
Attendance at Public Participation MeetingApril 21, 1978
Lauren Seth, ChairmanAgricultural Consultant
OTA: J, B. CordaroNancy IkedaWalter WilcoxCathie Woteki
L. E. BarnesDiamond Shamrock Company
Jerry BruntonAnimal Health Institute
Clark R. BurbeeEconomics, Statistics, and
Cooperatives Service,U.S. Department of Agriculture
Nancj’ J. ColeNational Cotton Council
Stephanie C. CroccoDepartment of Foods and NutritionAmerican Medical Association
Ruth G. DesmondFederation of Homemakers
Burton EllerNational Cattlemen’s Association
John FarnhamAmerican Cyanamid Company
Ann Cottrell FreeRachel Carson Trust
Roger J. GerritsLivestock and Veterinary ScienceAgriculture Research ServiceU.S. Department of Agriculture
Rosa GryderBureau of Veterinary MedicineFood and Drug AdministrationU.S. Department of Health,
Education, and Welfare
Richard H. GustafsonAmerican Cyanamid Company
Frederick S. Hird, Jr.Vineland Laboratories, Inc.
Harry W, Jamison, Jr.American Cyanamid Company
Cornell JohnsonDiamond Shamrock Company
Fritz KessingerAnimal Health Institute
Irene KieferAmerican Chemical Society
Robert L. KoobKoob Associates
Robert LenahanU.S. Department of Agriculture
Kirk MillerAmerican Farm Bureau Federation
Patty MitchellFood Chemical News
Neil RobinConsumer AffairsThe White House
Thomas B. SmithCommunity Nut rition Institute
I.A. SolomonsPfizer Company
John W. ThomasAmerican Veterinary Medical
Association
Ann W. TurnerRachelle Labs
C, D. Van HouwelingBureau of Veterinary MedicineFood and Drug AdministrationU.S. Department of Health,
Education, and Welfare
G. L. WaitsNational Turkey Federation
Winrock International LivestockResearch and Training Center:
T. C. Byerly, Principal InvestigatorE. K, Byington
. . .Vlll
Contents
(;h a]} fc r P(lge
I.
II.
III.
I v .
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Glossary . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .,Introduction . . . . . . . . . . . . . . . . . . . . . ., . . . , ., . ., , , ..., . . . . . . . . . .HowthcD rugs Are[Jsed . . . , ..., , , . . . . . . . . . ..., ., . . . . . . . . . . . . .Benefits. ., . . . ., . . . . . . ., . . . , ., ., , . . . . . . . . . . . . . . . . . . . . . . . . . . .Risks From Continued UseoftheDrugs , ., . . . . . . . . . ., ..., , . . . . . . . .f;arcinogenic I)rugResidues . . . , . . . , , . . . . . . . . , ..., ., . , . . . . . . . . .,4.ssessing and Quantifyin~Risks and Benefits . . . . . . . . . . . . . . . . . . . . .Current ~egulatOryPOlicy . . . , , . . . , . . . . . , . . , . . . . . . , . . . , . . . , , . . .Findings axld(;onclusions. , . . . . . . . . . ., . . . , ..., . . . . . . . . . . . . . . . . ,~~~~ressi~n~loptions ., . . . . . . . . . , ..., , . . . , . . . . . . . . . . . . . . ., . . .
Federal Regulation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .RegulaloryBasis, , , . . . , ..., , ..., . . . . . . . . , , ., ..., ..., . . . . . , , . .Current Activities. . . . . . . . . . . . , . . . , . . . , , ..., . . . . . . . . . . . . . . . . , .Approved Uses . . . . . . . . . . . . . . . . . . . . ..., . . . . . . . . . . . . . . . . . . . . , .
Benefits . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Antibacterial . . . . . . . . . . . . . . . . . . . . . ..., . . . . . . . , ..., ..., . . . . .
MocleofAction . . ., ..., . . . . . . . . . . . . . , . . . . . . ., . . . . . . . . . . . . . .Effectiveness, ., . . . . . . ..., ..., . . . . . . . . . . . . . . . , , . . . . . , . . . . . .Effect on Production. . , , , . . . ., ., ., . . . . . . . . . . . . . . . . . . . . . . . . . .
Die{hylstilbestrtfl (DES) . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .hfodeofAction . . . . . . ., ..., ..., . . . . . . . . . . . . . . . . . , . . . . . . . . . .Effectiveness. . . . . . . . . . . . . . . . . . , , . . . . . . . . . . . . . . . . . . . . . . . , .Effect onProduction. , , . . . , . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Risks, . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Infectious Diseases. . . . . . . , . . . . . . , . . . . . . . . , . . . . . . . , . . . . . . . , . . .
Antibiotic-Related Risks , ., . . . , ..., ..., ..., ., . . . . . . . . . . . . ...,Risks From Infectious Diseases . . . . , . . . . . . , . . . . . , . . . . . , . . . . . . .Magnitude of theRisk. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Drug Residues. . . . . . . . . . . . . . . . . . . . . , ..., . . . . . . ., . . . . . . . . . . . . .TypesofRisk, , . . . . . . . . . . . . . . . . ..., ..., . . . . . . . . . . . . . . . . . . . .Noncarcinogenic Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Carcinogenic Risks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
General Consideration . . . . . . . . . . . . . . . t . . . . . . . . . . . . . . . . . . . .Quantificiition ofRisk. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Diethylstilbestrol (DES). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .~~[r~furans. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . , ..., , . . . . . . .
AppendixCommissioned Papers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1234557899
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Fig[frt:J\’f). P(lpc
1. Comparisonsof S;] feDoses[~ompllte(l FronltheL lantel-Brvan Procedure andFroma Proce(lure13:ised on the hlultistagc klo(iel, , . . . . . . . . . . . . . . . . . . . . . . . . . 53
ix
LIST OF TABLES
Table No, Pagel, Approved Uses for Penicillin in Chicken Feeds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232. ApprovedUses forPenicillin inTurkeyFeeds ..,... . . . . . . . . . . . . . . . . . . . . . . . . 233. ApprovedUses forPenicillin inSwineFeeds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234. ApprovedUses forTetracycline inChickenFeeds. . . . . . . . . . . . . . . . . . . . . . . . . ., 245. ApprovedUses forTetracycline inTurkeyFeeds . . . . . . . . . . . . . . . . . . . . . . . . . . . 246. ApprovedUses forTetracycline inSwineFeeds . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247. ApprovedUses forTetracycline inCattleand SheepFeeds . . . . . . . . . . . . . . . . . . . 248. ApprovedUses for Sulfa inAnimalFeeds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259. ApprovedUses forNitrofurans inAnimalFeeds . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
10. ApprovedUses forDiethylstilbestrol inFoodAnimals . . . . . . . . . . . . . . . . . . . . . . . 2511. Effect ofChlortetracycline onWeightGainsofPigsin Different Environments. . . . 3012. ResponseofChicks to Chlortetracycline (CTC) and Penicillin inNewand
PreviouslyUsed Environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3013. Relationship Between Growth Rate ofControl Animals and Animals Fed
Antibiotics(Pigs) ....,. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3114. Relationship Between Growth Rate ofControl Pigs and Pigs Fed a Combination
ofPenicillinand Streptomycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3115. Effect ofa ’’Nonspecific Infection’’ onChickGrowth. . . . . . . . . . . . . . . . . . . . . . . . . 3116. ResponseofPigs toAntibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3317, Continued Effectiveness ofTetracyclinein Swine . . . . . . . . . . . . . . . . . . . . . . . . . . . 3318. ResponseofChickens toAntibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3319. ImprovementinChick Performance: AllYearsVersus Since 1970, . . . . . . . . . . . . . 3320, Effect of Selected Antibiotics onEggProduction, FeedPerDozenEggs, and
Matchability. ....,.... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3321. ReponseofTurkeysto Antibiotics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3422. Production ofMeatAnimals, 1976 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3423. Estimated Percentage Change in Livestock Production From Banning
Selected Antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3524. EstimatedDecreasein LivestockProductionFrom BanningSelectedAntibiotics . . 3525. PercentChangeinQuantity ofMeatFromaBanonthe UseofSelectedAntibiotics 3626. Percent ChangeinFarm Prices From aBanonthe Subtherapeutic Usesof
SelectedAntibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3627. Percent Change in Retail PriceFroma Ban on the Subtherapeutic Uses ofSelected
Antibiotics ....,..,. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3628. NoDrugVersusMGA VersusDESVersus Estrogen Implant. . . . . . . . . . . . . . . . . . . 3829. Percent Changeson the Supply, Farm Prices, and Retail PricesofBeefFrom
aDESBan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3830. HomologyBetweenPlasmids ofAnimal andHumanOrigin. . . . . . . . . . . . . . . . . . . . 4431. Antibiotic Resistance in Salmonella Isolated From Hospitalized Patients . . . . . . . . 4532. Incidence ofViolations Among Different Antibiotics inKidneys From
Food Animals.....,.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4833. Occurrence andLatent Periods of Mammary Carcinoma inMiceFedVarying
Concentrations ofDESinthe Diet. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5434. Extra RiskofMammary Tumors ataDoseofO.02ppb. . . . . . . . . . . . . . . . . . . . . . . . 5535. Estimates ofDosage(ppb) ofDESRequired ToEffect anAddedCarcinogen
Responseof l/lOb. .,.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5536. Summary ofTumorigenic and Carcinogenic Results From Four Experiments
WithFurazolidone, . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5637. Levels ofSignificance of Various Goodness-of-Fit Tests PerformedonDatain
Table 36.,....,.,,,.. , . .,, ., . .,, . .,, .,,,... . . . . . . . . . . . . . . . . . . . . . . . . . 5638. Estimates ofExtraRisk Froma DoseofTwoPartsPer Billion of FurazolidoneUsing
theDatainTable36 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5739. Estimates ofDoseinParts Per Billion ofFurazolidone Required ToProduceanExtra
Riskofl/lO’Using theData inTable 36 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ,. 58
Chapter I
SUMMARy
GLOSSARY
E. coli: A species of gram-negative bacteriaconstituting the greater part of the intesti-nal flora of man and other animals andoccasionally pathogenic for man.
Enteric: Of or relating to the intestines.Feed efficiency: The use of certain drugs
which results in animals gaining moreweight than animals not given such drugsfor the same amount of feed consumed.
Genotoxic: A toxic effect on the chromo-somes—for example, mutation. In the con-text of cancer-causing agents, the hypoth-esis is that the agent acts directly on thechromosomes to cause cancer.
Gram-negative or gram-positive: A method ofidentifying bacteria, related to the colorthey retain in the gram’s method of stain-ing for microscopic examination. Bacteriaare usually identified as being eithergram-negative or gram-positive.
H. influenza: A species of gram-negative bac-teria that may cause meningitis in infantsand young children related to a respira-tory tract infection.
N. gonorrhea: A species of gram-negativebacteria that is the specific causativeagent of gonorrhea.
Nongenotoxic: In the context of cancer-caus-ing agents, the hypothesis is that theagent acts indirectly to cause cancer. Forexample, the agent may enhance or pro-mote the ability of a genotoxic agent tocause cancer but cannot cause cancer byitself.
Nonpathogen: An agent not usually capableof causing disease.
1/106 extra lifetime risk of cancer: A methodof quantifying risk to humans from expo-sure (e.g., ingestion) to a specified amount
of a cancer-causing substance over a life-time for regulatory purposes. It is derivedfrom extrapolation of cancer rates in lab-oratory animals (e.g., rats) exposed to thesubstance over their lifetimes. For exam-ple, if a daily dose of x over the animals’lifetimes leads to a cancer rate of 1/100 inthe experimental animals, the extrapola-tion model might be used to predict whatdaily dose over the human lifetime wouldlead to a cancer rate of 1/10’. Alternative-ly, the model might be used to predictwhat the cancer rate would be in humansfor the average daily lifetime consump-tion of the carcinogenic substance byhumans.
Pathogen: An agent, such as a bacterium orvirus, capable of causing disease.
Salmonella: Any of a genus of gram-negativebacteria that are pathogenic for man andother warm-blooded animals, usuallycausing intestinal disease such as foodpoisoning.
Subtherapeutic: The use of drugs where thedoses given are less than that whichwould be used if disease were present. Inthe context of the use of antibiotics inanimal feeds, these uses include preven-tion of disease and the weight-promotionand feed-efficiency effects of certain anti-biotics.
Therapeutic: Treatment of known diseasewith drug doses that are high enough toeradicate or control the disease agent.
Weight promotion: The use of certain drugswhich results in animals growing fasterthan animals not given such drugs overthe same time period and for the sameamount of feed consumed.
Chapter I
SUMMARY
INTRODUCTION
Over the past three decades drugs havebeen used increasingly in the rearing of ani-mals for human consumption. The drugs canbe administered via drinking water or feed,they can be injected, or pellets can be in-serted under the animal’s skin. This is donefor five reasons:
1 , As nutritional supplementation such asvitamins and minerals are given,
2. For treating disease,3. For preventing disease,4. For increasing weight gain,5. For improving feed efficiency.
More than 40 percent of the antibacteri-als* produced in the United States are usedas animal feed additives and for other non-human purposes, Nearly 100 percent of poul-try, 90 percent of swine and veal calves, and60 percent of cattle receive antibacterial feedsupplementation. About 70 percent of U.S.beef by carcass weight comes from cattlethat have received weight-promoting feedsupplement tion.
This widespread use of drugs in livestockproduction has led to increasing concern overpotential adverse effects on human health fortwo reasons:
I. Many of the same antibacterial areused both in human therapy and in ani-mal feeds. The use of these drugs as feedadditives contributes to a growing poolof drug-resistant bacteria, Physiciansare now reporting reduced effectivenessof these same drugs in treating humandisease. Some bacteria are resistant to
.—_-———*The term “anti bacteria]s ” includes antibiotics and
chemicals w’i !h similar action, Other technical termsa re defined i n t h e g 1 oss a r v.
2
several antibacterial ; others requirehigher doses to control or kill them. Re-search findings point to animal feeds asa contributory source of rnanv of thesedrug-resistant bacteria.
Residues of other drugs found in animalproducts such as meat and eggs are po-t en t i a l ly ca rc inogen ic and may bepassed on to consumers.
There is much disagreement among scien-tists as to the validity of many of the findingsand the weight that should be attributed tothem when considering a ban or restrictionson the use of these drugs. The two main areasof dispute are:
I, What the effects are on human morbid-ity and mortality,
2. What tradeoffs there should properly bebetween risks and benefits.
Therefore, at the request of the Chairmanof the Senate Committee on Agriculture, Nu-trition, and Forestry, the Office of TechnologyAssessment (OTA) undertook an assessmentof the use of drugs as feed additives in live-stock and poultry production, with particularemphasis on the following concerns:
● The benefits to livestock producers fromthe use of each category of drugs used asfeed additives,The established or potential risks fromthe use of each category of drugs,The available alternatives to the con-tinued use of each category of drugs,The acceptable risks in the use of eachcategory of drugs,The options available to Congress to im-prove regulation of drugs used in live-stock feeds.
3
This report summarizes the evidence onrisks and benefits and the relevant regulatoryand public-policy background against whichthis assessment takes place. Since the use ofdrugs in animal feeds either as nutritionalsupplements or for therapeutic purposes isrelatively noncontroversial, t h i s r e p o r tfocuses on the addition of low levels of anti-bacterial to feeds and on diethylstilbestrol(DES), a synthetic estrogenic hormone whichis a proven human carcinogen. DES pelletsare implanted under the skin or added to the
diet to increase feed efficiency and promotegrowth in beef cattle.
Since estimates on risks and benefits ofsupplemental drugs in animal production arebased on numerous complex factors, no oneset of figures can confidently be used in anyquantitative estimates of risks versus bene-fits. This difficulty in assigning precisefigures has contributed greatly to the com-plexity of the debate over the safety of drugsin animal feeds.
HOW THE DRUGS ARE USED
Doses lower than the usual therapeuticlevel are given to poultry, cattle, swine, andcalves to promote weight gain, to prevent dis-ease, and to increase feed efficiency, thus in-creasing the meat yield per pound of feedused. The drugs most often used are: tetracy-cline, penicillins, sulfas, nitrofurans, andDES. DES is different from other drugs usedin animal feeds, as it is not an antibacterialbut rather a synthetic estrogen.
It is not known precisely how the antibac-terial work to increase weight gain and feedefficiency. At least three modes of actionhave been postulated, but there is still dis-agreement among scientists on this point:
1.
2.
3.
A Nutrient-Sparing Effect in which thedrugs reduce the animal’s dietary re-quirements either by stimulating thegrowth of beneficial organisms that syn-thesize vitamins and other essential nu-trients or by depressing the organismsthat compete with the host animal fornutrients, or by increasing the capacityof the animal’s intestinal tract to absorbnutrients.A Metabolic Effect in which the antibac-terial directly affects the rate or patternof metabolic processes in the animal.A Disease-Control Effect in which thedrugs suppress those organisms thatcause disease in animals of such a lowlevel that symptoms are not apparentbut the animal’s weight gain is reduced.
It is thought that the disease-control effectis the most responsible for growth promotion.
4
It has been demonstrated that the degree ofresponse to antibacterial feed supplements isinversely related to the general well-being ofthe experimental animals. Healthy, well-nourished animals do not respond to antibac-terial when housed in carefully cleaned anddisinfected quarters that have not previouslyhoused other animals. While such a level ofsanitation is usually not practical for thelarge-scale animal producer, it does suggestthat it is through the prevention of diseasesthat drugs promote growth.
When FDA approves a use of an antibacte-rial for a purpose other than the treatment ofdisease, the Agency specifies whether thedrug is approved for growth promotion, feedefficiency, or disease prevention. However,these are somewhat artificial distinctions,since it is impossible to point to growth pro-motion or increased feed efficiency or diseasecontrol as being responsible for the improvedproduct yield. It is possible that the effect is aresult of all three. Furthermore, a completedfeed mix may well contain drugs approved forall three uses anyway.
The safety debate arises from the wide-spread continuous use of antibacterial. Thedeleterious effects of the drugs appear re-gardless of the uses for which they are ap-proved. Thus the actions of the drugs are sooverlapping that distinctions based on in-tended purpose are irrelevant insofar assafety is concerned.
BENEF
The benefits of using antibacterial in ani-mal feeds are:
. The prevention of disease,c The promotion of growth, and● The improvement of feed efficiency.
The evidence points to the disease-preven-tion effect as being primarily responsible forincreased weight gain.
While increased weight gain resulting fromlow doses of antibacterial and DES is not indispute, the amount of gain is. Even thoughdrugs may increase weight gain by only a fewpercentage points, the absolute increase islarge because of the size of the livestock mar-ket.
Present levels of livestock production donot depend specifically on the use of DES andthe addition of low levels of tetracycline,penicillins, sulfa, and nitrofurans to feeds be-cause substitute drugs are available. In addi-tion, if adopted, the current Food and DrugAdministration (FDA) proposal to restrict butnot totally ban the most widely used anti-biotic, tetracycline, could mitigate the impactof banning or restricting other drugs used forthis purpose,
The economic consequences of such deci-sions, however, are a separate matter be-cause marginal increases or decreases inproduction may make the critical differencein the profitability of the livestock industry,Economic dislocations within subsectors ofthe livestock market could be significant over
ITS
the short term. Such economic effects areoften raised in objections to proposedchanges in regulations, but present statutoryauthority limits FDA’s decisionary basis toscientific evidence of effectiveness and safe-ty. Although under present law FDA doesconsider the practicality of achieving thedesired result of regulatory changes, FDAdoes not explicitly consider the economic con-sequences of these changes. When FDA’sproposed regulations have been successfullychallenged, i t has usua l ly been on thegrounds that FDA’s procedures, rather thanthe substance of the law, were faulty.
There may soon be an opportunity to ob-serve whether or not the banning of antibac-terial will result in significant changes inproduction. FDA has withdrawn approval ofone of the four nitrofurans, an antibacterialoriginally approved for food animal use, andwill soon enter hearings on the remaining ap-provals. One of these, furazolidone, is themost widely used. Predictions point to no ef-fect on beef and pork production but to sig-nificant short-term effects on poultry produc-tion. (See tables 23 and 24, ) Penicillin andtetracycline are also widely used in poultry,and their uses overlap extensively with the ni-trofurans. (See tables I, 2, 4, 5, and 9.) Even ifpenicillin were banned subsequently, tetracy-cline would remain available, since FDA’sproposal would allow its continued use ifalternatives were unavailable. If these anti-bacterial cannot replace nitrofurans, effectsshould be observed immediately.
RISKS FROM CONTINUED USE OF THE DRUGS
The risks from the use of antibacterial inanimal feeds stem from an increase in bac-terial resistance to the drugs. Drug-sensitivebacteria are killed or inhibited by the drug,allowing res i s t an t bac te r i a , which haveadapted to the presence of the drug, to growin their place, While drug-resistant variantsexist even in the absence of antibacterial,they do not generally flourish unless a changein their environment favors their survival.
When antibacterial are given, the drug-re-sistant bacteria are the fittest to survive intheir presence, and they soon become the ma-jority,
Genes for antibiotic resistance as well asits transfer are carried on structures calledplasmids, which are bits of DNA that functionindependently of the organism’s main geneticapparatus. Plasmids can transfer resistance
5
between bacteria of the same or of differentspecies. Thus harmless resident bacteria,such as E. co]i, which are present in the in-testines of humans and animals, can becomeresistant in the presence of the drugs and canthen transfer their resistance to a still sen-sitive strain of a more virulent pathogen suchas Salmonella. The result of such a transferwould be a strain of Salmonella that wasresistant to one or more antibacterial. Theresident bacteria in the intestines of animalsand humans receiving antibacterial are soonreplaced with resistant resident bacteria andthus serve as a reservoir for the spread ofplasmid-mediated resistance to antibacteri-a l .
While research attention was originallyfocused on the transfer of drug resistancefrom E. coli to other intestinal microorga-nisms, principally Salmonella, it is now evi-dent that the spread is wider. There is nowstrong evidence that similar transfers occurbetween H. influenza and N. gonorrhea andresistant E. coli. Thus the risks are no longerrestricted to people who may have picked upSalmonella directly from animals or their edi-ble products.
N. gonor rhea and H. in~luenza are har-bored by humans. For these bacteria to haveacquired plasmids for the transfer of resist-ance means that the plasmids are traveling ina wider radius than was originally predicted.For instance, identical plasmids have beenisolated in parts of the world as distant asEngland and Vietnam,
In a sampling of E. co]i from a freshwaterriver system and within the saltwater bayinto which it emptied, it was found that near-ly all the freshwater sites and about half thesaltwater sites sampled contained resistantcoliforms. Twenty percent of the strains con-tained resistance plasmids carrying multipledrug resistance transferable to sensitive E.coli and to S, typhimurium and S. dysenteriae(the bacteria which cause typhoid and dysen-tery).
Furthermore, plasmids are now carryinggenes for resistance to more than one drug.Whereas formerly this was rare, it is nowcommon, if not usual, for bacteria to be resist-ant to several drugs at a time. It is now neces-
sary for physicians to run sensitivity tests todetermine alternative drugs to which a givenstrain of bacteria is still sensitive. Certainstrains of gonorrhea and typhoid, amongothers, have proven more difficult to treatthan formerly as a result of resistance to thestandard drug of choice.
The extent of the decrement in perform-ance of antibacterial used in treating humanand animal disease is still relatively un-known, The relationship between decreasedsensitivity and decreased effectiveness intreating disease is complicated because manyvariables such as species, general health,and numbers of invading bacteria influencewhether known pathogenic bacteria willcause observable disease and whether a spe-cific drug will make the difference in outcomewhen disease does occur, This is particularlytrue for Salmonella, the bacteria on whichmuch attention has been focused, However,FDA estimated that in 27 percent of the Sal-monella cases treated each year, the first an-tibacterial chosen for treatment proved to beineffective because the disease was causedby antibacterial-resistant bacteria.
Another risk from the use of antibacterialfeed additives is that it eventually compro-mises therapeutic and prophylactic effects ofthe same drugs. Even though stopping the useof an antibacterial can be expected to resultin the loss of dominance of resistant bacterialstrains, these strains can persist in dimin-ished but significant numbers. If growth pro-motion and feed efficiency are closely de-pendent on disease prevention, the effective-ness of supplemental antibacterial feedingwill decline.
Noncarcinogenic drug residues pose littledirect risk to consumers if tolerances areadequately established and the residues arebelow tolerance levels. But the sulfametha-zine findings discussed in this report indicatethat the majority of concentrations of resi-dues above allowable limits results from theunintended cross-contamination of feeds dur-ing mixing. This may be occurring particu-larly with penicillin and tetracycline, sincethey are widely used and mixing is not limitedto certified feed mills or done under a veteri-narian’s prescription, Cross-contamination
6
would increase the risk of plasmid-mediateddrug resistance because such cross-contami-nation would mean that the extent of supple-mental feeding of antibacterial is evenhigher than that of recognized, approveduses, Because tissue residues in general maynot be good indicators of cross-contamina-tion, the extent of cross-contamination needsto be monitored directly.
The risk from resistant plasmids of animalorigin is not quantifiable even by the rough
estimates made for Salmonella infections.The majority of resistance in human bacterialpopulations is probably caused by wide-spread use of antibacterial in humans (someof which are unnecessary), but the enormouspool of R-plasmids that now exists in animals,together with the ability of an R-plasmid to bepromiscuously transferred among bacterialspecies, must be regarded as a threat to thetherapeutic value of ant ibacterial in thetreatment of both human and animal dis-eases.
CARCINOGENIC DRUG RESIDUES
DES and the nitrofurans pose risks be-cause they are carcinogenic and may leaveresidues in animal products such as meat andeggs. The effort to determine carcinogenicrisks from drug residue is complicated by twofactors:
1, The difficulty of extrapolating data ob-tained from animal experiments to man,and
2. Analytical problems in measuring a “noresidue’ level.
Although carcinogenesis in laboratory ani-mals is accepted as proof of a probable carci-nogenic effect in humans, extrapolation tech-niques to determine the amount of cancersexpected in humans are still embryonic innature and subject to validation on a case-by-case basis. To conduct the tests using dosescomparable to that ingested by humanswould require a far larger sample—hun-dreds of thousands as opposed to hundreds—of animals, Therefore, tests are conductedwith much larger doses and the results ex-trapolated back down.
Because of the increasing sensitivity ofnewer assay methods to smaller amounts ofresidue, FDA is attempting to define “no res-idue’ on the basis of a “practical thresh-old” —i.e., that threshold below which therisk of cancer is statistically negligible ratherthan on the basis of absolute zero residue.Otherwise, standards must be revised withthe appearance of each new assay methodthat can detect the presence of a minute levelwhich the previous method was not quite sen-
sitive enough to detect. Accordingly, FDAproposes to define “no residue” as the quan-tity leading to an extra risk of 1 in I million(1/10’) of developing cancer over a lifetime ofexposure,
Furazolidone is assumed to cause cancerby heritable damage to the genetic system ofthe host cells that eventually leads to tumorformation. Thus there is probably no level atwhich it is absolutely safe. Using a modelwhich assumes that there is no safe thresholdto extrapolate from animal data to humans,an extra risk of l/l OG from furazolidone canbe correlated to furazolidone residue levels infoods consumed by humans. Assuming thatfoods contain at least as much furazolidoneas would be detected by FDA’s proposedquanti tat ive assay standards for furazoli-done and using average consumption figures,the risks to humans from ingestion of foodscon ta in ing furazolidone residues are lessthan the 1/10’ Iifetime exposure risk. Usingthe high consumption population as the groupat risk, the risk may approach 1/106.
DES, a female hormone, has been associ-ated with cancer in the daughters of womenwho took the hormone during pregnancy. Incontrast to furazolidone, there is evidencethat DES’s carcinogenic action is through pro-moting the effect of substances that can pro-duce cancer directly. This would mean thatits carcinogenic action is caused not byheritable genetic damage but more likely byits estrogenic action. It is therefore likely thata threshold exists below which DES content
7
1
will not be sufficient to cause tumors. Usingan extrapolation model for estimating risksthat assumes such a threshold, the tissuelevel obtained falls in the approximate rangeFDA has set as associated with the “no resi-due” level. Obviously, such a measurement isnot absolute, but rather is relative to risk. If,on the other hand, no threshold is assumedand if any level is considered carcinogenic,
different extrapolation models would be usedand would predict for the same tissue levelsof DES risks from 10 to 100 times the I/IOtilifetime exposure risk associated with the“practical threshold” level. However, atpresent, there is no assay method presentlyapproved that is sensitive enough to measureDES at these levels.
ASSESSING AND QUANTIFYING RISKS AND BENEFITS
Risk-benefit assessments, in view of thekinds of evidence on benefits and risks re-viewed in this report, are not only difficult toconduct but also difficult to use in makingregulatory decisions or in revising the under-lying statutory authorities.
The risks and benefits of drugs used to in-crease food animal production share somecommon attributes: (I) laboratory evidenceprovides scientific support for the identifiedbenefits and risks; (z) effects expected in ac-tual use can be shown in selected experi-ments, but it is often unclear whether the pre-cise biochemical and or metabolic processesobserved in the laboratory setting are respon-sible; and (3) quantification of the effects,whether it be extra pounds of meat or extracases of cancer produced, are too impreciseto yield reliable figures, although such figuresa r e use fu l fo r p red ic t ing the genera lmagnitude of the expected effects . Suchquantitative estimates of risks or benefitsoften are made with a degree of precisionthat is justified only within the statisticalboundaries of a particular experiment. Onceremoved from the structured experimentalsetting, these numbers retain an aura of legit-imacy that may not be warranted. This is notonly true for the kinds of simple calculationsincluded in this report for the risk from Sal-monella infections or the risk of cancer fromDES or furazolidone but also for the expected
effectiveness of the drugs discussed in thisreport. Typically, the experiments that quan-tify the effect of antibacterial or DES onweight gain and feed efficiency measurethese effects up to a hundredth of a percent(0.0001). Yet the gain is on the order of gramsper day for small animals such as chickens orturkeys and fractions of a pound per day forlarge animals such as pigs and cattle.
Even if precise measurements could be val-idly obtained, they would still be of limiteduse in addressing policy issues because theserisks and benefits cannot be approachedthrough a simple balance-sheet type of as-sessment. No common denominator is gener-ally acceptable for comparing human illnessand death with pounds of meat. Rather thanusing monetary values as a common denom-inator, opposing advocates usually seek tomake their case or ridicule their opponents inthe most exaggerated terms. For example,one advocate might say that if one life issaved, that is worth whatever it costs in de-creased meat production, and Americans eattoo much meat anyway. The other advocatemight seek to dismiss the risk of gettingcancer from a certain product by saying thatit is equal to drinking 800 12-ounce cans ofdiet soda daily over a lifetime. Such tacticsclearly do not address the issue of risks ver-sus benefits.
CURRENT REGULATORY POLICY
Present Federal regulation of animaldrugs is based on evidence of effectivenessand safety.
Animal drugs, as in the case of humandrugs, must be shown to be both effec-tive and safe.Residues in food, such as animal drugs inmeat, must only be shown to be safe.Food-additive regulation is focused onsafety. However, food additives alsomust be shown to have the intended ef-fect or to be reasonably expected to be-come a component or affect the charac-teristics of food.The statutes and the implementing regu-lations set criteria for demonstrating ef-fectiveness and safety that are inde-pendent of each other. There are no ex-plicit guidelines for determining whenthe evidence on either effectiveness orsafety overrides the evidence on theother.
If a food additive is found to be carcino-genic, it must be banned regardless ofhow little is present in the food,
Drugs may be carcinogenic and their usestill allowed if effectiveness overridesthe risks,
When an animal-derived food productmay contain residues of a carcinogenicsubstance (e. g., an animal drug), the lawprovides some leeway in determining anadequate assay procedure to demon-strate “no residue. ” FDA has attemptedto define “no residue” in terms of ac-ceptable risk as extrapolated from ani-mal experiment data, It is an attempt todefine safety in practical instead of ab-solute terms, since definitions in ab-solute terms must continually be revisedas newer assay methods are able tomeasure smaller and smaller residues ofless than one part per billion,
FINDINGS AND CONCLUSIONS
1. Drugs in animal feed are targeted for mul-tiple purposes —40 percent of all antibac-terial produced are used for animal feed.
Drugs are added to livestock feeds fornutritional supplementation, treatmentof disease, prevention of disease, weightpromotion, and feed efficiency.In addition to their use for therapeuticpurposes, antibacterial are used to pre-vent disease by eliminating the carrierstatus of animals and egg-transmitted in-fections or by suppressing infections inthe very young bird or animal.Low concentrations of antibacterialalso are commonly approved to hastenweight gain and to increase the amountof weight gained per unit of feed.It is not clear whether these weight-prmmotion and feed-efficiency effects areseparate from or dependent on the dis-ease-prevention effect. Commonly, how-ever, one concentration of an antibacte-rial is approved only for disease pre-
vention, while another concentration ofthe same antibacterial is approved onlyfor weight promotion and feed efficien-cy.
Feed premixes often contain a combina-tion of antibacteriaIs, and these pre-mixes may be approved for some or alluses. For example, one combination ap-proved for swine feeds contains pro-caine penicillin, chlortetracycline, andsulfamethazine for disease treatment,disease prevention, growth promotion,and feed efficiency.
Other drugs, including DES for beef cat-tle, also are used in feed or administeredthrough subcutaneous implants forweight promotion and feed efficiency,
2. Because of the attendant risks, regulatoryattention has focused on the addition oflow levels of antibacterial in animal feedsand on DES, a proven human carcinogen.
9
● The continuous use of low-level antibac-terial as feed supplements producesdrug-resistant bacteria that may causedisease in animals and humans andtransfer drug resistance to other bacte-ria. The use of one antibacterial mayresult in the transfer of genes carryingres i s t ance to seve ra l o the r antibac-terial as well,—Development and interchange of re-
sistance have been confined largely togram-negative bacteria, although anincreasing body of data is accumulat-ing that indicates transferable drugresistance in the gram-positive bac-teria.(a) E, coli, common bacteria found inthe intestinal tract of both humansand animals and throughout the envi-ronment, are the largest reservoir ofdrug resistance. Drug resistance de-veloped in E. coli can be transferred toother gram-negative bacteria thatmay be more pathogenic.(b) Salmonella, intestinal bacteria thatcan cause clinical disease, can devel-op resistance directly from the use ofa n t i b a c t e r i a l o r h a v e r e s i s t a n c etransferred to them from E. coli.(c) Other gram-negative bacteria, suchas H. in~]uenzae and N. gonorrhea, re-cently have been found to have drug-resistant properties that apparentlyhave been transferred from drug-re-sistant E. coli.
—The use of tetracycline, widely usedas an t ibac te r i a l in an imal f eeds ,leads to the dominance of bacteriawith multiple drug resistance. Penicil-lin and, to a lesser extent, the sulfasare the other primary antibacterialwhose uses are being examined.
. DES, a synthetic estrogen used in beefcattle to promote growth and increasefeed efficiency, and nitrofurans, anti-bacterial widely used in poultry, areproven or suspected carcinogens.—DES has been shown to be carcino-
genic in both animals and humans,The use of DES by women during preg-nancy has been associated with theappearance of vaginal or cervicalcancers in the daughters with whom
they were pregnant at the time. Re-cen t s tud ies c l ea r ly show an in -creased rate of genital abnormalitiesin similarly exposed sons. So far therehave been no definitive findings re-garding testicular cancer or fertilityin these men.
—Furazolidone, one of the nitrofurans,has been shown to cause cancer inlaboratory animals.
3. The health risks from the development ofbacterial resistance to antibacterial infeed are of greater concern than the risksof cancer from DES and furazolidone asused in livestock practices.
● The proposed FDA regulations woulddefine “no residue” as an added cancerrisk of one in one million per lifetime ex-posure. As determined under presentstandards of detection from presentlevels of use, the residue concentrationsof DES and furazolidone expected infood animal byproducts border on thisgeneral range of acceptable risk. ButFDA has indicated that, according tonewer methods of measurement, the po-tential cancer risks from both DES andfurazolidone will be higher than this pro-posed target risk.
● Loss of effectiveness of the most widelyused antibacterial (i. e., tetracyclineand penicillins) and of other antibacteri-al with plasmid-mediated resistancesposes risks to both human and animalhealth, Therapeutic failure with theseantibacterial would lead to large butpresently unquantifiable morbidity andmortality in humans and animals. Oncesignificant effects on human and animalhealth do become widely observable andquantifiable, it may be too late to ad-dress the problem. The development ofalternative antibacterial may be oneapproach to alleviating increased mor-bidity and mortality, but this approachrequires a great deal of time and wouldnot be of immediate use, and it is likelythat in time a resistance problem woulddevelop in them as well.—The percent of bacteria that are re-
sistant to one or more antibacterial
10
has been increasing. The portion ofthis increase attributable to the sub-therapeutic use of antibacterial infood animals and the portion attribu-table to human use, especially inappropriate or unnecessary use, cannotbe measured directly. However, thefact that antibacterial are used forfood animals in such large amountsand that animals and humanscananddo exchange bacteria with actual orpotential drug-resistance propertiesleads to the conclusion that the addi-tion of drugs to animal feed is a sig-nificant contributor to the increase inantibacterial-resistant bacteria.
4. Most of these drugs could be replacedwith alternative drugs that are already ap-proved by FDA.
c In addition, the FDA proposals would notban tetracycline in cases where replace-ment antibacterial were not available.
5. The economic consequences of removingthese drugs could be significant over theshort term. Production may be decreasedin the period immediately following a ban,but higher prices may offset the decreasein quantity and may lead to higher produc-er incomes. But consumer prices wouldalso be higher.
● The long-term consequences are lesscertain, probably resulting in small de-creases or no changes in production andsmall increases in both consumer pricesand overall producer incomes.
6. The tradeoff is therefore between imme-diate economic benefits and future healthrisks. These decisions involve value judg-ments that cannot be based simply onmonetary considerations. And the lack ofscientific certainty on the magnitude ofboth the probable health risks and the at-tributed increases in meat productionmakes the formulation of a balance-sheetapproach difficult.
CONGRESSIONAL OPTIONS
Option 1Allow FDA to Decide the Issues, Subject
to Congressional Oversight
FDA’s proposed actions include:
1!
2.
3.
4.
ban the addition of low levels of penicil-lin in animal feeds,restrict similar uses of tetracycline tosituations where replacement antibacte-rial are not available,monitor cross-contamination of feeds byantibacterial, andban all uses of nitrofurans and DES.
As an alternative to the actions on penicillinand tetracycline, FDA has proposed thattheir distribution in feed premixes be limitedto feed mills holding approved medicated feedapplications and to licensed veterinarians.The purpose of these proposals is to alleviatethe drug-resistance problem by reducing thecontinuous use of these antibacterial.
The possibility exists that total penicillinand tetracycline use may be unchanged afterthe initial period of adjustment, as producersmay increase drinking water and/or thera-peutic uses. The impact of everyday use indrinking water would be comparable to thesustained antibacterial pressure from feedpremixes. But therapeutic use may not reflectsimilar risks even though the total amountused might equal that for feed additive uses.Therapeutic use involves higher doses formuch shorter periods of time.
Other, less controversial, steps can betaken to decrease continuous exposure to an-tibacterial, Close monitoring of cross-con-tamination of feeds and subsequent correc-tive actions should lead to decreased uninten-tional antibacterial exposure. Most of the evi-dence on the effectiveness of drug use indisease prevention, weight promotion, andfeed efficiency reveals that the young bird oranimal benefits the most. Some decrease in
11
use could probably be achieved if the periodof use is limited to the early part of a bird’s oranimal’s life and carefully monitored toassure that such use does not extend beyondthat period.
The replacement antibacterial availablefor penicillin and tetracycline include somethat also cause gram-negative bacterial re-sistance, but usually not as much as penicillinand tetracycline cause. Others may select forresistance among gram-positive bacteria,which at this time present less of a knownproblem than gram-negative bacteria. Otherantibacterial are not known to select for re-sistance among ei ther gram-negative orgram-positive bacteria.
For the nitrofurans and DES, the outcomesdepend on FDA’s current attempts: (1) toadopt new methods of measuring residue con-centrations and (2) to define carcinogenic “noresidue” as residue concentrations that re-sult in added cancer risks of 1/106 per lifetimeexposure. Calculations of added risk basedon the limits of current methods to measureresidue concentrations indicate that the risksborder on the 1/10’ target. However, FDA hasindicated that, according to newer methodsof detecting residues and their metabolicproducts, bo th DES and the nitrofuranswould exceed the target risk of 1/106.
Option 2Enact Legislation Requiring Economic as
Well as Scientific Assessments ofBenefits and Risks
Objections filed against proposed regula-tions by FDA often raise economic issues.Apart from the laws under FDA’s administra-tion, most Federal agencies involved in reg-ulating health problems can or are requiredto consider the economic impacts of their ac-tions. A comparative examination of thoseFederal agencies using and not using sucheconomic criteria may show whether or notthese different criteria lead to different con-clusions. Or the law could be changed to re-quire the explicit evaluation of economic im-pacts along with scientific data on benefitsand risks.
Much of the impetus for legislating suchchanges has come from those who want themonetary worth of benefits to be considered.However, if monetary values were estab-lished for benefits, they also have to be estab-lished for the risks, It is far more difficult toreach agreement on monetary values forrisks than it is for benefits in this instance.Moreover, even if monetary values are estab-lished for benefits and risks, that does notresolve the fundamental problem of decidingwhen risks or benefits should prevail.
Option 3Enact Legislation Removing the Special
Approach to Carcinogens in FoodRegulation
Present legislation already provides an ex-emption for drug residues in meat and otheredible byproducts of food animals. The all-or-nothing approach of the Delaney clause willbe avoided if FDA succeeds in implementingits target risk approach (defined as an addedlifetime exposure risk of 1/10’ of developingcancer). In assessing risks from carcinogenicagents, the techniques for defining the targetrisk are still in a primitive state. There aremajor problems in setting an appropriate tar-get risk, in deciding on methods of extrapola-tion, and in detecting residues of some sub-stances even at the target-risk level. But theseare all problems related to setting the level ofuse, not to determining whether a substanceshould be banned,
Option 4Require FDA to Decrease Therapeutic
Use of Antibacterial in Human andVeterinary Medicine as Well as in
Food Animal Production
Both human and animal antibacterial usescontribute to the problem of drug-resistantorganisms. Of the antibacterial produced inthe United States, nearly half are used inanimal feeds or for other nonhuman pur-poses. The review of the evidence on risks hasshown that humans and animals serve ascommon hosts for bacteria and that resist-
12
ance transfer is not limited to those animalsand humans in close proximity to animalsgiven low-level doses of antibacterial in theirfood.
The majority of resistance in human bacte-rial populations is probably caused by wide-spread use of antibacterial in humans, inwhich overuse undoubtedly occurs as it doesin both therapeutic and supplemental animaluses, However, regardless of why antibacte-rial are given, the key facts concerning theplasmid problem are that: (I) at any point intime, the number of animals exposed to anti-bacterial far exceeds the number of humansexposed, and (2) the length of therapy inhumans averages less than 10 days, while an-tibacterial-supplemented animal feed use isoften continuous.
As for methods of decreasing therapeuticand subtherapeutic uses of antibacterial, itwould be easier to control and monitor the ad-dition of antibacterial to feeds than it wouldbe to regulate the practices of veterinariansand physicians.
Option 5Approve Future Drugs Only if They Are
More or Equally Effective as ThoseAlready Approved
It is the most widely used antibacterialthat are contributing to antibacterial resist-ance, and a limitation based on relative effec-tiveness would most likely aggravate theproblem by discouraging the development ofnew antibacterial,
13
Chapter II
FEDERAL REGULATIONS
Chapter II
FEDERAL REGULATIONS
REGULATORY BASIS
Except for minor involvement by severalother Federal agencies, the safety, whole-someness, and proper labeling of the foodsupply are the responsibility of the Food andDrug Administration (FDA) of the Departmentof Health, Education, and Welfare (HEW),and of the U.S. Department of Agriculture(USDA), USDA has concurrent jurisdictionwith FDA over certain meat and poultry prod-ucts through the Federal Meat InspectionAct ] and the Poultry Products Inspection Act.z
USDA is authorized to conduct its own in-quiry into the safety of such products, buteither through law or administrative defer-ence, USDA’s activities regarding safety in-volve enforcing decisions that have beenmade by FDA (USDA, 1978).
FDA*s authority over substances added toanimal feeds and over animal drugs comesprimarily from two sections of the FederalFood, Drug, and Cosmetic Act (FFDCA):] (1)food additives, and (2) new animal drugs.
A substance is considered a food additiveif:
., . [Its]. . . intended use . . . results or mayreasonably be expected to result, directly orindirectly, in its becoming a component orotherwise affecting the characteristics ofany food . . . if such substance is not general-ly recognized . . . to be safe under the condi-tions of intended use .. ..4
To avoid regulation as a food additive, thepetitioner must either provide evidence thatthe substance does not become a componentor otherwise affect the characteristics of
121 U,S. C. 601 et seq.‘21 U. SC. 451 et seq.‘21 U.S. C. 301 et seq.‘21 U.S.C. 321(s).
food or, if it does, provide evidence that it isgenerally recognized as safe under the condi-tions of intended use.
The FFDCA expressly excludes “new ani-mal drugs” from the definition of “food addi-tive” and regulates them under a separatesection of the law. New animal drugs aretreated in the same way as new drugs forhuman use. An application must contain:
1. Full reports of investigations whichhave been made to show whether or not suchdrug is safe and effective for use:
2. A full list of the articles used as compo-nents of such drug;
3. A full statement of the composition ofsuch drug;
4. A full description of the methods usedin, and the facilities and controls used for,the manufacture, processing, and packing ofsuch drug;
5. Such samples of such drug and of the ar-ticles used as components thereof, of any ani-mal feed for use in or on which such drug isintended, and of the edible portions or prod-ucts (before or after slaughter) o-f animals towhich such drug (directly or in or on animalfeed) is intended to be administered, as theSecretary may require:
6. Specimens of the labeling proposed tobe used for such drug, or in case such drug isintended for use in animal feed, proposed la-beling appropriate for such use, and speci-mens of the labeling for the drug to be manu-factured, packed, or distributed by the appli-cant;
7. A description of practicable methods -fordetermining the quantity, if any, of such drugin or on food, and any substance formed in oron food, because of its use; and
8. The proposed tolerance or withdrawalperiod or other use restrictions for such drugif any tolerance or withdrawal period orother use restrictions are required in order to
17
assure that the proposed use of such drugwill be safe (emphasis added), ’
Some of the grounds for refusing the appli-cation include:
(A) [T]he investigations . . . do not includeadequate tests by all methods reasonably ap-plicable to show whether or not such drug issafe for use under the conditions prescribed,recommended, or suggested in the proposedlabeling thereof;
(B) [T]he results of such tests show thatsuch drug is unsafe for use under such condi-tions or do not show that such drug is safe foruse under such conditions; . . .
(D) IU]pon the basis of the information sub-mitted , . . or upon the basis of any other in-formation . . . with respect to such drug . . ,there is insufficient information to determinewhether such drug is safe for use under suchconditions;
(E) [Evaluated on the basis of the informa-tion submitted . . . and any other informationwith respect to such drug, there is a lack ofsubstantial evidence that the drug will havethe effect it purports or is represented tohave under the conditions of use prescribed,recommended, or suggested in the proposedlabeling thereof; ., .
(H) [S]uch drug induces cancer when in-gested by man or animal or. after tests whichare appropriate for the evaluation of thesafety of such drug, induces cancer in manor animal, except that the foregoing provi-sions of this subparagraph shall not applywith respect to such drug if the Secretaryfinds that, under the conditions of use speci-fied in proposed labeling and reasonably cer-tain to be followed in practice (i) such drugwill not adversely affect the animals forwhich it is intended, and (ii) no residue ofsuch drug will be found (by methods of exam-ination prescribed or approved by the Secre-tary by regulations ., .) in any edible portionof such animals after slaughter or in anyfood yielded by or derived from the living ani-mals . . . .h
The last reason for refusal enumeratedabove is one of the Delaney clauses in FFDCAthat bans the use of carcinogenic substancesthat enter the food supply. The clause is simi-lar to that applicable to food additives. In thelatter, the exception to a total ban is for “the
use of a substance as an ingredient of feed foranimals which are raised for food produc-tion. ”
For animal feed ingredients and animaldrugs, the law directs the Secretary to pro-mulgate regulations defining when “no resi-due” will be found, (It should be noted thatfor noncarcinogens, residues are allowed,subject to safety considerations [see numbers5, 7, and 8, supra, on information to be con-tained in new animal drug applications]). Forfood additives generally, the definition itselfincludes the finding that the substance be-comes or may reasonably be expected to be-come a component of food. Thus once a sub-stance is legally labeled a food additive and isfound to be a carcinogen, it is automaticallybanned because, by definition, it is present inthe food.
Finally, some of the grounds for withdraw-ing approval for animal drugs include: (1) ex-perience or scientific data showing that suchdrug is unsafe for use under the conditions ofuse on which the application was approved;(z) new evidence, evaluated together with theevidence available when the application wasapproved, showing that the drug is not shownto be safe under the approved conditions ofuse; and (3) new evidence, evaluated togetherwith the evidence available when the applica-tion was approved, showing that there is alack of substantial evidence that the drug willhave the effect claimed under the conditionsof use.7
In order to avoid food additive status, asubstance must be “generally recognized assafe” (GRAS) “under the conditions of in-tended use” if it enters the food. But a foodadditive is unsafe and prohibited from useunless a regulation is issued “prescribing theconditions under which such additive may besafely used. ” Although the language is nearlyidentical, the practical difference is that foodadditive status gives FDA authority to pre-scribe the actual conditions of use.
For drugs, FFDCA requires that the appli-cant provide adequate data on both the safetyand effectiveness of the drug under the in-
’21 U.S,C. 360(b).‘)21 U.S.C. 360(b)(d)(l).
18
721 U.S.C. 360( b(e)(l).
tended conditions of use, but FDA may denyor withdraw the approval on either safety oreffectiveness grounds. For example, FDAmay deny the use of a drug for some purposesand approve it for others, even if it is safe tobe used under all of the petitioned conditions.Here, effectiveness would be the ultimate de-terminant of approval. Or, conversely, FDAmay deny use of a drug for some purposesand approve it for others even if it were effec-tive for all the petitioned conditions. Heresafety would be the ultimate determinant ofapproval.
Some have criticized FDA for failing to con-sider socioeconomic benefits and costs in de-terminations allowing or disapproving the useof food additives and drugs. These criticsclaim that present law allows the considera-tion of such costs and benefits. Whether ornot the law should include these considera-tions is a separate question. But FFDCA isquite conspicuous in its absence of languagesupporting such claims.
The law is clear that safety and effective-ness will be determined by scientific assess-ments:
In determining whether such drug is safefor use under the conditions prescribed, rec-ommended, or suggested in the proposed la-beling thereof, the Secretary shall consider,
among other relevant factors, (A] the prob-able consumption of such drug and of anysubstance formed in or on food because ofthe use of such drug, (B] the cumulative ef-fect on man or animal of such drug, takinginto account any chemically or pharmacolo-gically related substance, (C) safety factorswhich in the opinion of experts, qualified byscientific training and experience to eval-uate the safety of such drugs, are appropri-ate for the use.
. . . [The] term substantial evidence meansevidence consisting of adequate and well-controlled investigations, including field in-vestigation, by experts qualified by scientifictraining and experience to evaluate the ef-fectiveness of the drug involved, on the basisof which it could fairly and reasonably beconcluded by such experts that the drug willhave the effect it purports or is representedto have under the conditions of use pre-scribed, recommended, or suggested in thelabeling or proposed labeling thereof.n
Although the statute presents these as in-dependent assessments and does not provideany guide for FDA to decide when effective-ness outweighs safety and vice versa, thesedecisions are in reality risk-benefit assess-ments limited to scientific considerations.
’21 U. S. C.360(b(d)(2-3).
CURRENT ACTIVITIES
Antibacterial used in human treatmenta r[: often used in animals, and limitations onuse have been proposed for animal antibacte-rial, particularly for their subtherapeuticuses in animal feed. Over 40 percent of all theantibacterial produced in this country areused as feed additives or for other nonhumanpurposes. Research on antibacterial-resist-ant bacteria has shown that, in some cases,genes for antibacterial resistance can betransferred between bacterial types and thathumans and animals are interchangeablehosts for such bacteria.
Another major concern has been the possi-bility of more direct, adverse human healtheffects from eating meat, eggs, etc., contain-
ing residues of drugs. The health effect pri-marily at issue here is carcinogenesis. Feder-al law prohibits the use of carcinogenic foodadditives and also requires that food prod-ucts from animals given carcinogenic sub-stances for any purpose (e. g., therapeutic,growth promotant, etc. ) cannot contain anyresidue of such carcinogens, Among the ani-mal drugs in use, furazolidone and DES areknown carcinogens,
The antibacterial problem began to be ad-dressed in the 1960’s in the United States andother countries. One consequence was GreatBritain’s decision in 1971 to restrict the useof antibacterial for food animals and, in par-ticular, their feed-additive uses.
19
Similar reviews were ini t iated in theUnited States by the FDA (FDA, 1966, 1972,1977). The general thrust of these reportswas similar tothe report leading toGreatBri-tain’s curtailment of antibacterial for foodanimal uses, although they differedin the em-phasis placed on specif ic ant ibacterial .There were also differences on specific con-clusions and recommendations between theSubcommittee on Antibiotics in AnimalFeeds, its parent National Advisory Food andDrug Committee to the FDA, and the FDAitself. (See USDA, 1978, for a chronicle ofthese events.)
As a consequence of these reviews, in 1973FDA began a series of actions to update theeffectiveness and safety data of approvedanimal antibacterial and to extend the cri-teria to new antibacterial.’ These effortssubsequently were focused on the penicillinsand tetracycline which, in the words of theFDA Commissioner, “were chosen as the ini-tial subjects of regulation because of their im-portance in the treatment of human disease”(Kennedy, 1977).
In 1977, FDA proposed to withdraw ap-proval of the use of penicillin and to restrictthe use of tetracycline in feed premixes. Thereasons for the proposed ban on the use ofpenicillin were that: (1) the new evidence onthe hazards of bacterial resistance hadshown that such use of penicillin was notsafe, and (2) the applicants had failed to meetthe record maintenance requirements of thelaw.10 Similar reasons were given for the pro-posed restrictions on tetracycline, wherethey would be prohibited except where ade-quate substitutes for disease prevention werenot available. 1 ]
As a corollary action, the FDA had pro-posed to limit the distribution of animal feedpremixes containing penicillin and/or tetracy-cline to feed mills holding approved medi-cated feed applications for manufacturingthese medicated feeds and to restrict furtherthe distribution of those feeds to the order ofa licensed veterinarian as part of the recordmaintenance requirements of the law.12 Pub-
1’21 CFR 558.15‘(’42 F. R., 43772, Aug. 30, 1977.“42 F.R. 56264, Oct. 21, 1977.’143 F.R. 3032, Jan. 20, 1978.
lic hearings on the proposal raised concernsover such matters as the inadequacy of thenumbers, distribution, and kinds of veteri-narians available to diagnose and write pre-scriptions under the proposed requirements;the economic disadvantage of the proposal tosmall producers; circumvention of the pro-posed restrictions, s ince soluble powderdosage forms would not be subject to the pro-posal; and allegations that it would interferewith the practice of veterinary medicine andState control over the feed industry. The FDACommissioner therefore decided to delay adecision until such issues were resolved.ls
Meanwhile, the U.S. Congress has takenseveral actions to delay the final outcome ofthese proposals. In May 1978 the House Ap-propriations Subcommittee on Agricultureand Related Agencies earmarked $250,000for fiscal year 1979 for a study on antibacte-rial used in animal feed, to be conducted bythe National Academy of Sciences. In July1978 the House Agriculture Committee approved a resolution to delay the proposed banuntil new research studies could be com-pleted and formal evidentiary hearings held.And in September 1978 House and Senateconferees agreed to require the FDA to holdup the proposals until such research and evi-dentiary hearings were completed.
The congressional actions have led theDirector of the FDA’s Bureau of VeterinaryMedicine to conclude that the outcome ofthese proposals would not be reached before1980 and that “(p)ublic and industry reactionto these proposals have made it abundantlyclear that livestock producers are desirous ofhaving penicillin, tetracycline, and similarantibiotics remain in animal feeds. Unlesssubstitutions of antibiotics currently on themarket are more readily accepted and unlessviable alternatives to potentially restrictedantibiotics can be developed, most likely thepublic outcry will continue regarding the pr~posed regulations. These are practicalitiesthat are incident to the national acceptanceof the proposed regulations” (Food ChemicalNews, Sept. 25, 1978).
Two other classes of antibacterial raiseseparate safety issues, in addition to the
‘ ’43 F.R. 35059, Aug. 8, 1978.
20
safety problems reflected in these proposalsto restrict the use of penicillin and tetra-cycline. The sulfa drugs (i. e., sulfamethazinefor swine feed and drinking water) have beenfound to have a high violation rate for resi-dues in slaughtered hogs. And one of the ni-trofurans, furazolidone, is carcinogenic inlaboratory animals.
Specific tolerances for residues of sulfadrugs in edible tissues of food-producinganimals are set at O to 0.1 parts per million(PPm). ” For sulfamethazine the to le rancelevel in swine is 0,1 ppm. These tolerancesare accomplished by specified withdrawalt ime periods between last t reatment andslaughter. For the last 6 months of 1977,USDA had found that the percentage of sam-pled hogs in violation of the t).1-ppm residualtolerance averaged 13.1 percent. An FDAstudy concluded that 54 percent of the viola-tions were probably caused by contaminationof the withdrawal feed (which should not con-tain the drug) through insufficient cleanout ofequipment, 26 percent were probably causedby failure to observe the withdrawal period,12 percent were caused by feeding or feed-mixing errors, and 9 percent from othercauses (FDA, 1979). New research data ledFDA to change the preslaughter withdrawaltime for sulfamethazine in swine feed anddrinking water from 5, 7, or 10 days to 15days. ” FDA also expected to issue a proposalto establish action levels for cross-contamina-tion carryover of animal drugs (including butnot limited to sulfamethazine in swine feed)by the end of 1978 (Food Chemical News, Oct.16, 1978).
Three nitrofurans were approved previ-ously for feed premixes; furazolidone (themost widely used), nihydrazone, and nitrofur-azone. Furaltadone, a nitrofuran, is used ininjectable form to treat mastitis in lactatingcows, Assay methods to meet the “no resi-due” requirement have not been approved forthe nitrofurans. Furazolidone has producedcancer in laboratory animals. The other threecompounds are suspected of being carcino-gens but have not been adequately tested. Alluses of nihydrazone were revoked because no
“21 CFR 566.625-.700.“43 F.R. 19385, hlav 5, 1978.
hearings were requested. Of the two spon-sors of furaltadone, one approval was re-voked because a hearing was also not re-quested.l’ Actions were pending against fura-zolidone and ni trofurazone as of January1979.
The “no residue” exception to the ban oncarcinogenic substances added to food issometimes referred to as the “DES excep-tion. ” DES has been known to be carcinogenicalmost from the time it was first produced in1938 (DES Task Force Report, 1978), its car-cinogenic effect generally attributed to itsestrogenic propert ies . The Food Addit iveAmendments of 195817 contained the firstDelaney clause barring carcinogenic food ad-ditives. In order to allow the continued use ofDES in food animals, a “no residue” excep-tion was inserted in the Animal Drug Amend-ments of 1968.1B
DES is added to feed or used in implants tofatten beef cattle. To a lesser extent, im-plants are used in lambs. Other drugs used tofatten cattle include: (1) melengesteroi ace-tate (MGA) in feed for heifers, with the addi-tional purpose of suppressing estrus; (2) mon-ensin in feed, authorized only for increasingfeed efficiency, although it also is authorizedfor disease prevention and growth promotionin poultry; (3) estradiol benzoate plus testos-terone proprionate for heifers by implants: (4)estradiol benzoate plus progesterone forsteers by implants; and (5) zeranol implantsfor calves, cattle, and lambs. Estradiol mono-palmitate injections are authorized for use inroasting chickens. ’g In addition to DES andthe estradiols, zeranol has direct estrogenicactivity, MGA (a synthetic progesterone) andprogesterone result in increased estrogenproduction in treated heifers. Monensin is acompound produced by the bacterium Strep-tomyces cinnamonensis and is still used as ananticoccidial in poultry.
Starting in 1972, FDA first banned the useof DES in feeds and, later, in implants, onevidence of residues in beef livers detected
“42 F.R. 17526, Apr. 1, 1977; 42 F.R. 18619, Apr. 8,1977.
“Public Law 85-929.‘“Public Law 90-3w.“21 CFR 522, 21 CFR 558.
21
by a new method. The withdrawal was va-cated in 1974 by court order on the groundsthat an insufficient notice of opportunity forhearing had been given to the affected par-ties because FDA had relied on a method oftesting that it had not approved. Administra-tive hearings have been concluded and inSeptember 1978 the administrative law judgerecommended that DES be banned from feedand as an ear implant (CNI Weekly Report,Oct. 5, 1978). FDA’s decision had not beenmade as of January 1979,
A closely related issue has been the meth-od by which “no residue” would be deter-mined. The increasing sensitivity of methodsused to detect such residues has led FDA toseek methods “to keep the agency fromalways chasing zero in terms of an allowabletolerance of substances that will be adminis-tered to food-producing animals” (Food Chem-ical News, Oct. 16, 1978).
In early 1977, FDA issued new proceduresand criteria for evaluating the assays for car-cinogenic residues in edible products of ani-reals . zo Essentially, the intention of the newregulations was to cease trying to quantifythe actual amount of carcinogenic residuebecause of the problem of chasing zero
‘{’42 F.R. 10412, Feb. 11, 1977.
(newer methods were able to identify sub-stances at less than one part per biIlion). In-stead, the new regulations adopted a methodwhereby “no residue” would be definedthrough extrapolation from animal test datato man so that the lifetime risk to an individ-ual would be less than 1 in 1 million (l/l Oti or10-”). The published regulation stated that“such a risk level can properly be consideredof insignificant public health concern. ” Ac-cording to an FDA spokesman, the new meth-od would “provide a mechanism whereby areasonably safe level may be established andthen, irrespective of further analytical devel-opments, there will be that expectation thatthe originally set level will remain until toxi-cological evidence rather than analytical evi-dence demonstrates that to be an incorrecttolerance” (Food Chemical News, Oct. 16,1978).
These regulations were revoked by FDA21after the U.S. District Court for the District ofColumbia remanded the case to FDA “for fur-ther findings to rectify the omissions in thecurrent record. ”zz FDA expects to issue pro-posed new regulations in 1979.
“43 F.R. 22675, May 26, 1978,“Animal Heu]th Institue v. Food and Drug Adminis-
tration, Civil No. 77-806, D. D. C., Feb. 8, 1978,
APPROVED USES
Subtherapeutic uses of penicillin, tetracy-cline, sulfas, and nitrofurans vary accordingto the food animal. They may be used alone orin combination with each other or with otherdrugs. These other drugs may be antibacteri-a l , anticoccidials, antihelminthics, o r non-antibacterials, such as DES or other growthpromotants, One drug may be approved foronly some uses, but when combined withother drugs, the resulting feed mix may coverall uses.
penicillin is used extensively in poultryfeeding programs and, to a lesser extent, inswine feeds, usually in combination withother drugs (sulfa, tetracycline, bacitracin,etc.). There are no approved uses for pen-
22
icillin in animal feed for cattle or sheep.Penicillin may be used alone for all possibleindications—i.e., growth promotion, feed effi-ciency, disease prevention, and disease treat-ment. It also may be used in combination withother drugs.
Tables 1, 2, and 3 summarize the use ofpenicillin in animal feeds for chickens, tur-keys, and swine. In chickens and turkeys,penicillin, when used alone, is approved forthe separate uses of growth promotion, feedefficiency, disease prevention, or diseasetreatment, The amount of penicillin per ton offeed would vary for these uses, It may also becombined with other antibacterial so thatthe completed feed is approved for all uses,
———— .—
Table 1. –Approved Uses for Penicillin in Chicken Feeds
/r) ccWnb/flaf/ofl Wfh
StreptomyclnCStreptomycin C
StreptomyclncStreptomyclnCAmproltum~Amprollum~ and streptomyclncAmprollumd and ethopabatefiAmprollum, d ethopabate, ’ and
streptomyclncBacttracln methylene
dlsallcylatec
BacNracln methylenedlsallcylatec
Bacltracln zlnccBuqulnolatee .,Hygromyc(n BfHygromycln B{ and
streptomyclncHygromycln Bf and bacltraclnc
Usesa bGrowth promotion, feed efficiencyDisease preventionDisease treatmentGrowth promotion, feed efficiencyMaintain or Increase egg productionDfsease preventionDisease treatmentGrowth promotion, feed efficiencyTreatment of dcseaseGrowth promotion, feed efficiency
Treatment of disease.
Malntalnlng or Increasing hatchablllty ofeggs
Treatment of diseaseTreatment of diseaseGrowth promot[on, feed efficiencyTreatment of disease
Treatment of diseaseTreatment of disease
‘For a sDecltlc food animal di f ferent ccmcenlrat!ons o same drug may be approved fordlflerent purposes –e g for chickens one concentration IS approved for qrowth promoflon andfeed efficiency anolher concenfrat(on for prevention of disease
‘Speclflc d!seases omlHedcSame (odlca!lons for use as penlcl’llndFor development of act[ve lmmuntty to or prevention of Loccld(osls‘For prevention of cocctdos(s‘For control of worms
SOURCE 21 CFP 558 and related sec’(ens
even though the separate antibacterial arenot. In swine, when penicillin is combinedwith tetracycline and sulfa, the completedfeed is approved for all uses.
Tetracycline, as oxytetracycline or chlor-tetracycline, is used in all food animals. Likepenicillin, it maybe used alone or in combina-tion with other drugs, and for all or only someof the approved uses. Tables 4, 5, 6, and 7summarize the use of tetracycline in animalfeed for chickens, turkeys, swine, cattle, andsheep, Tetracycline is the most widely usedantibacterial in feed.
Sulfa drugs are used primarily in swine incombination with penicillin and tetracycline(tables 3 and 6) for disease treatment, diseaseprevention, growth promotion, and feed effi-ciency, or with tylosin for disease prevention.They also are used in combination with tetra-cycline for disease prevention in cattle (table7). Sulfaethoxypyridazine premixes are usedfor disease treatment in swine and cattle foruse by or on the order of a licensed veterinar-ian.2J Sulfadimethoxine is used in chicken and
“21 CFR 558.579.
Table 2.–Approved Uses for Penicillin in Turkey Feeds
/n cornfl/?(3r/o/J w/lh Usesa b
Growth promotion, feed efficiencyDisease prevention,Disease treatment
S t r e p t o m y c i n Growth promotion, feed efficiencyAmprollumd Growth promotion, feed efficiency.Amprollumd and streptomyclnc Disease treatmentAmproliumd and bacltraclnc Disease treatmentBacitracin methylene
disallcylatec Disease treatmentBacltracln zincc Disease treatment
aFOr a Speclflc food animal d{ fferent concentrations of the same drug may be approved fo!ddferent purposes
bSpecdlc d!seases omtttedcSame Indlcallons for use as pen{c(lllndFor development of act!ve Immunlfy 10 or prevention Of coccldlosls
SOURCE 21 CFR 558 and related secilons
Table 3.–Approved Uses for Penicillin in Swine Feeds
In combination with
StreptomyclncStreptomyclncStreptomyclnCChlorletracyclinec and
sulfamethazinec
Chlortetracycllnec andsulfathlazolec
Bacltracln methylenedlsallcylatec
Bacitracin zlncc
.Vsesa b —Growth promotion, feed efficiencyGrowth promotion feed eff!clencyDisease prevenhonDisease treatment
Growth promotion, feed efflclency,disease prevenhon, dtseasetreatment
Growth promotion. feed efflclency,disease prevention, diseasetreatment.
Disease treatmentDisease treatment
aFor a Speclflc food anlma( different concenfratlons of the same drug may be approved fordifferent purposes
bSpeclflc diseases om
weeks after farrowing. It is also used for dis- DES is used to promote growth and in-ease-prevention and treatment purposes. It is crease feed efficiency in cattle and, to a less-concurrently approved for growth promotion er extent, in sheep. In feeds, it is given alonewhen the swine are on the medication for the or in combination with antibiotics. It is admin-purposes outlined. These uses are summa- istered separately by ear implantation. Theserized in table 9. uses are summarized in table 10.
Table 4.–Approved Uses for Tetracycline in Chicken Feeds
/fl cornbmafm With
--------Monensind (as coccidiostat).Nequinated . . . . ,Robenidine h y d r o c h l o r i d e.
Amproliume .,Amprolium and ethopabatef .Buquinolate9 . . . . . . .Clopidolf .,Decoquinateh ... . .Hygromycln B{ . . .Roxarsonel. .Zoalene k ., : : : ‘ : :
Uses~ CGrowth promotion, feed efficiency.Disease prevention.Disease treatment.Disease prevention, disease treatment.Disease prevention, disease treatment.Disease prevention,Disease treatment.Disease prevention, disease treatment,Disease prevention, disease treatment,Disease prevention.Disease prevention, disease treatment.Disease treatment.Growth promotion, feed efficiency.Disease prevention, disease treatment.
ach)ofletracycllne or oxyfetracycllnebFor a spec(f[c food animal, different concentrahons of the same drug May be approved for
different purposescSpeclflc dtseases omdfeddsame Ind!cattons for use as Pentclll!neFor development of active Immunliy [0 Or pWt?nhOn of coccldloslsfFor Preven[lon of coccldloslsgFor prevention of coccldlosls growfh promoflon, and feed efhciencyhFor prevenhon ancj freafment of disease
‘For confrol of wormsIFor growth promohon, feed dflClenCy
kFor development of acflve ImiTIun{ty to coccldlosls
SOURCE 21 CFR 558 and relafed sections
Table 6,–Approved Uses for Tetracycline in Swine Feeds
in combination with Uses~ C.- Growth promotion, feed efficiency,
- - - - Disease prevention.- - - - Disease treatment.Penicillin and
sulfamethazined . Growth promot ion, feed e f f ic iency,disease prevention, diseasetreatment.
Penicillin and sulfathiazoled Growth promotion, feed efficiency,disease prevention, diseasetreatment.
Hygromycin Be. . , . . . D i s e a s e t r e a t m e n t .
achlofletracycllne or oxytetracyclmebDlfferent concentrations of the same drug may be approved for different PurPosescSpeclflc diseases omlffeddsame ~5e5 as for tetracycline
‘For control of wormsSOURCE 21 CFR 558 and related sections
Table 7.–Approved Uses for Tetracycline inCattle and Sheep Feeds
Table 5.–Approved Uses for Tetracycline in Turkey Feeds
Animal In combination withIn comb/nat/on wWr Usesb C
Growth promotion, feed efficiency.Cattle. . . ----- - - -
- - - - Disease prevention,Disease treatment.
SulfamethazinedDiethystilbestrole . ,
Roxarsoned . . . . , G r o w t h p r o m o t i o n , f e e d e f f i c i e n c y , Sheep ----disease prevention,
Usesb CGrowth promotion, feed efficiency,
disease prevention.Disease prevention.Disease prevention.Disease prevention, feed efficiency.
achlofletracycllne or oxyfetracychneachlofletracycllne or oxyfefracyclme bDlfferent concentrations of the same drug may be approved fOr different PurPose5bolflerent concentraflons of the same drug may be approved for different PurPoses cSpeclflc diseases omlffed
dsame uses as for tetracyctmecSpeclflc diseases omNfeddFor growfh promoflon feed efklency eFo r growfh promotton, feed eff!clency
SOURCE 21 CFR 558 and related secflons SOURCE 21 CFR 558 and related sections
24
Table 8.–Approved Uses for Sulfaa in Animal Feeds Table 9,–Approved Uses for Nitrofuransa in Animal Feeds
An/ma/Chickens
Turkeys
Swine
Cattle
In combination with Uses~COrmetopnmd Disease preventionOrmetopflmd and3-nifro-4-
hydroxy-phenylarsonlcacide Dlseaseprevenhon
Ormetopflmd Disease preventionOrmetopnmd and
Ipronldazolef Olsease preventionDisease treatment (only for use
by or on order of a Ilcensedvetertnarlan )
Penlcllllnd and tetracycline Growth promotion, feedefficiency, disease preven -hon, disease treatment
Tyloslnd. D!sease preventionDisease treatment (only for use
by or on order of a Ilcensedveterinarian)
Tetracycllned Disease prevention
Animal In comb/na(/on w/th llses~ CChickens andt u r k e y s - - - - Growth promotion, feed efficiency
Disease preventionGrowth promotion, feed efflclency,
disease preventionDisease prevention, dtseasetreatment
Swine ---- Disease prevention, growthpromotion
Disease treatment, growth promotion.
aFu,azolldone or mtrofurazonebDlffe(ent ~oncentratlons Of the same drug may be approved for different PurPoses
cSpeclf[c d[seases omdtedSOURCE 21 CFR 55815 and 558262
aldent,ty of Speclflc sulfonamide derlvatwes o~lftedbDlfferenl ~oncen[ra[lons of the ~ame d~~g may be approved IOF different purposes
cSpec(flc diseases omlfted‘Same uses as for sulfaeFo( growth promollon feed efftclency
fpre Jent(on of blackhead I hlSIOMOnlaSIS I
SOURCE 21 CFR 558 and relafed secftons
Table 10.–Approved Uses for Diethylstilbestrol in Food Animals
An/real Roule of acfm/n/sVa(/on In combinaf/on w/th UsesCattle. Feed ---- Growth promotion, feed efficiency.
F e e d Bacitracin methylene disalicylatea Growth promotion, feed efficiencyF e e d Bacitracln zincb Growth promotion, feed efficiencyF e e d Tetracycllnec Growth promotion, feed efficiencyEar Implant. ---- Growth promotion, feed efficiency
Sheep Feed ---- Growth promotion, feed efficiencyEar implant (lambs) ---- Growth promotion, feed efficiency.
aFor disease preventionb For growth ~rornotton feed efficiencyCAS Ch(offetracycllne or oxytefracycllne for disease PrevenflonSOURCE 21 CFR 522640 and 558225
25
Chapter III
BENEFIT’S
Chapter III
BENEFITS
ANTI BACTERIALS
Mode of Action
The subtherapeutic uses of antibacterialfor food animals include not only diseaseprevention but also weight promotion andfeed efficiency. All antibacterial have theability to suppress or inhibit the growth ofcertain micro-organisms, but their chemicalcomposition and effectiveness against specif-ic organisms may vary widely. Yet there is nodirect correlation between chemical composi-tion and the weight-promotion and feed-effi-ciency effects, so even though specific, non-antimicrobial effects can be shown for cer-tain antibacterial , there is disagreementover how low levels of antibacterial bringabout increased growth and feed efficiency.
At least three modes of actions have beenpostulated, and each has varying degrees ofresearch support.
1.
2.
3.
A metabolic effect, where the antibacte-rial directly affects the rate or patternof the metabolic processes in the hostanimal.
A nutrient-sparing effect, where anti-bacterial reduce the dietary require-ment for certain nutrients by stimulatingthe growth of desirable organisms thatsynthesize vitamins or amino acids, bydepressing the organisms that competewith the host animal for nutrients, by in-creasing the availability of nutrients viachelation mechanisms, or by improvingthe absorptive capacity of the intestinaltract.
A disease-control effect, through sup-pression of organisms causing diseasethat reduce weight gain but result in noobvious symptoms of disease in the hostanimal,
There is much evidence that metabolic re-actions in the host animal are influenced byantibacterial. For example, tetracycline af-fects water and nitrogen excretion in rat liverhomogenates (Brody et al., 19!54). But the rateof metabolism may be influenced by systemicand digestive tract infections and absorptionof microbially produced toxins from the gas-trointestinal tract, so the metabolic effectcould be attributed to a disease-control ef-fect. Furthermore, the metabolic effects can-not account for the growth promotion in ani-mals fed diets supplemented with moderatelevels of antibacterial in view of the natureof the animal responses, the tissue levels ofan t ibac te r i a l when added to the diet atgrowth-promotant levels, and the levels nec-essary to mediate such biochemical proc-esses. And, as to be discussed short ly, adirect metabolic effect should not vary great-ly with environmental conditions.
The nutrient-sparing effect has consider-able research support, but it could also beclassified as a type of disease-control effect.Certain intestinal organisms synthesize vita-mins and amino acids that are essential toanimals, and other bacteria require and com-pete with the host animal for these essentialnutrients. Diets containing penicillin may in-crease the number of intestinal coliformsother than E. coli (Anderson et al., 1952), andthese organisms may synthesize nutrientsthat are dietary essentials for the host ani-mal. If a diet is deficient in a specific nutri-ent, it could be partially corrected by micro-bial synthesis.
A n t i b a c t e r i a l m a y a l s o d e p r e s s t h egrowth of organisms competing with the hostanimal for nutrients. The bacteria most af-fec ted by chlortetracyclines are the lacto-bacilli (March and Biely, 1952). The lacto-
29
bacilli require amino acids in relatively simi-lar proportional amounts as do pigs, and thelevels and sources of protein that supportmaximum growth in pigs are also near opti-mum for the multiplication of lactobacilli inthe intestinal tract (Kellogg et al., 1964).Those antibacterial most effective in reduc-ing the number of these organisms in the in-testinal tract are also the most effective asroutine growth promotants (Kellogg et al.,1966).
Antibacterial may also improve absorption of nutrients by the host animal (Catron etal., 1953). Structural ly, this seems to berelated to thickness of the intestinal wall,which is thinner with rations containing an-tibacterial versus no antibacterial (Coates,1953; Russoff et al., 1954, Braude et al . ,1955). The thinner wall implies a potential forimproved absorption and is assumed to resultfrom the inhibition of the organisms thatdamage or produce toxins that damage the in-testinal tissue.
The nutritive and antibacterial responserelationships still appear secondary to thedisease-control effect. Early in the history ofantibacterial supplements to animal feeds, itwas noted that the degree of response to anti-bacterial was inversely related to the gener-al well-being of the experimental animals.Healthy, well-nourished animals do not re-spond to antibacterial supplements whenhoused in carefully cleaned and disinfectedquarters that have not previously housedother animals (Speer et al., 1950; Catron etal., 1951; Coates et al., 1951; Hill et al, 1952).
Studies involving clean and contaminatedenvironments illustrate that the response toantibacterial is greater in contaminated orpreviously used environments. For example,pigs housed in an old barn had an increasedgrowth rate of 14.2 percent versus 7.5 per-cent in the new barn (table 11). The responseof chicks to chlortetracycline in a new envi-ronment was a 12.6-percent improvementversus 18.2 percent for chicks from the samehatch that were reared in a previously usedenvironment, and 1.6 percent versus 23.9percent when penicillin was used (table 12).The relative improvements in growth ratesfrom supplementing diets with antibacterialoften are inversely related to the growth rate
Table 11. –Effect of Chlortetracycline on Weight Gains of Pigsin Different Environments
Enwromnerrf andchlortefracychne tedNew barn:C o n t r o lChlortetracycltne (9 g/ton )Old barn:C o n t r o lChlortetracycllne ‘(9 g/ton)
Dally gain Feed effmer?cp
A v e r a g e /rnprove- /rnprove-(9) ment (Yo) A v e r a g e ment (Yo)
604 – 4.15 –649 7 5 3 9 2 5 5
604 – 4.21 –690 142 3 7 8 102
aJ P Bowland 1956 Influence of environment on response of sw(ne lo anllblot(c and/orVlgofac supplements Umv .4/berfa Press Ml 41 (2) 12 Alberla Canada
bun,t~ of feed per unit of gain
SOURCE Hays 1978 table 7
Table 12. –Response of Chicks to Chlortetracycline (CTC) andPenicillin in New and Previously Used Environment
4-week /mprovernentEnwronment Treatment we/ght (g) (%)Bird et al. aNew house Control 254 –
CTC, 10 ppm 286 12.6Previously used house Control 176 –
CTC, 10 ppm 208 182Coa/es O( a/. bGreenford Lab C Control 184 –
Pemcillin 187 1.6Reading Lab C Control 155 –
Penicillin 192 23.9
aH R Bird R J LWe and J R Slzemore 1952 Enwronment and shmulat(on of chickg r o w t h b y anltb!otlcs Poulmy SCI 3 1 9 0 7
bM E Coates c D Olckinson G F Harr)son S K Kon S H Cummlns and W F JCulhbertson 1951 Mode of action of an!lblot[cs In stimulating growfh of chicks Na!ure168332
cReadlng Lab had been previously used to house chicks bul the Greenford Lab had notSOURCE Hays 1978 table 8
of the controls—i. e., the difference in anti-bacterial response in clean versus contam-inated environments is often the result of thecontrols in the contaminated environment do-ing poorly in comparison with controls in theclean environment. Tables 13 and 14 summa-rize this relationship across a number of ex-periments.
The growth-depressing effect can alsobuild up over time with the continued use ofspecific animal facilities. This effect fromnonspecific infections in a chick-starting fa-cility is summarized in table 15. Emptying,cleaning, and fumigating the facility im-proved performance but did not approach thelevel of performance of the first hatch.
Effectiveness
What is the quantitative gain in livestockproduction with the use of antibacterial infeed? Have they continued to be effective?
30
Table 13. –Relationship Between Growth Rate of Control Animalsand Animals Fed Antibiotics (Pigs)
Response toDa//y ga/n /n weight (g) ant/b/et/c
Ant/b/of/c-ledNo. of fests Corflrol anunak anvnak Improvement (%)
4 . . 94 245 1611 136 227 67
12 182 336 8513 227 340 501 6 272 449 653 1 318 481 511 2 363 499 381 8 409 563 3816 454 572 2636 < 499 572 1532 545 627 153 9 590 636 84 8 636 713 1220 681 735 822 726 790 9
1 772 881 14
aA~aPled f,O~ R Braude ~ D W a l l a c e a n d T J Cunha 1953 The value of armb!otlcs Inthe nutntlon of swine a review An(Ib/o/Ics and Chemotherapy 3271
SOURCE Hays 1978 fable 13
Table 14.–Relationship Between Growth Rate of Control Pigsand Pigs Fed a Combination of Penicillin and Streptomycin
Da//y gan /n we/ghtof controls (g)
91 to 1821 8 1 t o 2 7 2272 to 363363 to 454.454 to 545545 to 636636 to 726.726
No ofcomparisons
234799
207
T o t a l 61Average Improvement. 0/0
Improvement over controls byp/gs fed anl/b/ot/cs
Ga/n /n Feedwe/ght (0/0) eff/c/ency (Yo)
2 2 0 8 22 7 0 4 52 0 4 5 6161 11 1123 6 49 4 1 95 6 4 73 8 1 8—
107 5 1
aDa(a summar(~ed trom agrlcutfural e x p e r i m e n t s!atton repofls 1960 to 1967 V W HaysB(ologlcal bass for the use of ant(b(otlcs m I(vesfock production The Use of Druqs /n Antmal
F e e d s Proc S y m p Publ 1679 D 11 (Washl nqlon D C Vatlonal Academy of Sctences1969 I
SOURCE Hays 1978 fable 14
How effective are specific antibacterialcompared to others? These questions are dif-ficult to answer with any degree of precision,but the general conclusions can be made thatantibacterial continue to be effective for in-creasing production and that some antibac-terial are clearly more effective in specificfood animals than in others.
There are a number of confounding factorsthat make an evaluation of the quantitativeeffect difficult. First, antibacterial now areso widely used that most of the experimentaldata comes from the early years of use—i,e.,
Table 15.–Effect of a “Nonspecific Infection” on Chick Growtha
Hatch no. Average ga/n, O to 7days (g) Relat/ve gain (Yo)1 44.2 100.02 42.7 96.63 . . . . . 41,5 93,94, 40,1 90.75,, 4 2 8 96.86 . 41 8 94.67 . 4 0 9 9 2 58 . . 4 0 2 91 09 3 9 5 89.4
1 0 3 5 2 7 9 7Depopulation and fumigation11 ., 37.7 8 5 31 2 26,2 5 9 3Depopulation and fumigation1 3 3 8 2 86.41 4 3 4 5 78115 ., 2 8 3 6 4 0
aH M Scott 19 6 2 T h e effect of a non-speclflc InfectIon on chick growth Proc I l l NutrConf p 23 Umverslty of Illhno(s Urbana
SOURCE Hays 1978 fable 1 f
from the 1950’s and early 1960’s. For experi-ments conducted later, especially those inwhich field trials were used, it is often dif-ficult to tell whether the animals used werepreviously fed feeds containing antibacteri-al. And as discussed earlier, the housingconditions of the animals also contribute tothe effect of antibacterial usage; previouslyused faci l i t ies usual ly resul t in greaterresponse.
Second, controlled experimental conditionsoften produce results less than those found infield conditions. Aside from cleaner housingin controlled experiments, often less animalsare housed per facility, and runt animals usu-ally are not included.
Third, the degree of increased productionalso may depend on the animal’s lifecycle andthe conditions of feeding. Responses may varydepending on whether it is calves or heifers/steers being fed, whether they are on high-roughage (hay) or high-energy (grain) diets,whether it is the first few weeks of life versusthe whole lifespan of the animal in whichfeeds are supplemented with antibacterial,etc. Animals are often fed antibacterial-sup-plemented feed throughout their lifespan, andthe effects may be attributable mostly to cer-tain periods of that time.
Cattle. Antibacterial approved for growthpromotion and feed efficiency are the tetracy-cline and bacitracins. Cattle show a greaterresponse to tetracycline on high-roughage,
31
low-energy rations than on high-grain, high-energy diets. However, increased use of high-grain rations for the finishing of cattle in-creases the incidence of liver abscesses, andantibacterial are used continuously for pre-vention. The tetracycline are the most wide-ly used, but tylosin and bacitracin are alsoapproved for such use. Although related tohigh-grain diets, t he e t io logy o f t heseabscesses isunknown.
The responseto antibacterials varies withthe type offeed, feedlot conditions, stress fac-tors, and disease level of the cattle, so resultsare not consistent. A summary of a largenumber of experiments shows that tetracy-cline at a level of 70 to 80 mgm daily peranimal have on the average increased weightgain 6 percent and improved feed efficiency(feed per pound gained)4 percent (Beeson,1978). The incidence of liver abscesses fromhigh-grain, high-energy diets is not known,butsopercentor more of the livers could beexpected to be abscessed without the use ofantibacterial, andsuchabscesses also causereductions in weight gain. Davis (1978) esti-mates that the use of antibacterial reducesthe incidenceof liver abscesses from over 50percent toapproximately 18percent.
Inits reporton the economic impacts ofaban on antibacterials, USDA (1978) used thefollowing criteria for weight gain:(l) 700-lbyearlingcattleare fed for 156dayswithanti-bacterial-supplemented feed, (2)with amar-keting weightof l,050tol,0621bs with anti-bacterials, and (3) a marketing weight of1,038 lbswithout antibacterials. This wouldresult in a reduced marketing weightof 12to241bsperanima~ or a differenceof 1.2t02.3percent.
Sheep. Antibiotics are not generally usedon a subtherapeutic basis but rather fortreating specific diseases. Only the tetracy-cline have been found to be beneficial forweightgain and feed efficiency, and they areprimarily used in lambs. The major responseoccurs initially in the feeding period (Beeson,1978).
Pigs. Table 16 provides rough comparisonsof different antibacterial at different timesin the feeding life of pigs. In the experimentssummarized in the table: (1) “starter” pigs
32
initially weighed 11 to 27 lbs, with finishedweights of 30 to 110 lbs; (2) “grower-devel-oper” pigs initially weighed 34 to 45 lbs, withfinished weights of 90 to 114 lbs; and (3)“growing-finishing” pigs initially weighed 32to 59 lbs, with finished weights of 134 to 2 0 7lbs. Responses were generally greater inyoung pigs. Excluding combinations that in-cluded penicillin or tetracycline, responsesequal to tetracycline or penicillin were ob-tained with tylosin, virginiamycin, mecadox,tylan-sulfa, bacitracin, a n d lincomycin.Bacitracin had a smaller feed-efficiency ef-fect, but the others were comparable to peni-cillin or tetracycline.
Table 17 summarizes the effect of tetracy-cline over three decades for swine at similarstages in the production cycle as covered intable 16. Effectiveness has been maintainedfor starter pigs and diminished but still posi-tive for more mature swine.
Poultry. Table 18 summarizes the responseto different antibacterial by chickens to 4weeks and 8 weeks from hatch. The greatestresponse takes place early in the growth cy-cle. After 8 weeks from hatch, there is only asmall difference between birds fed and notfed antibacterial-supplemented feeds. Sever-al antibacterial produce similar results astetracycline and penicillin—namely, virginia-mycin, streptomycin, erythromycin, andlincomycin.
Table 19 averages the effectiveness of tet-racycline, penicillin, bacitracin, and the ar-senical for chicks up to 4 weeks of age forspecific years. Effectiveness in the earlyphase of the growth cycle has been main-tained.
Table 20 summarizes the effectiveness ofselected antibacterial on egg production andmatchability. Of the six antibacterial listed,tetracycline has the greatest effect, followedby bambermycin and penicillin.
The results for turkeys are generally simi-lar to those for chickens (table 21).
Effect on Production
The effects of tetracycline,sulfa, and nitrofurans on product
penicillin,on of meat
Table 16.–Response of Pigs to Antibiotics
Average dady gam (% Improvement) Feed/gain (% Improvement)Grower- Growing- Grower- Grow\ng -
Antlblohc Starter developer flnlshing Starter developer finlshlngT e t r a c y c l i n e , 10.84 1093 6,58 6 2 5 3 8 8 2 5 5Penlcdltn 9 4 5 — — 8 6 8 — —Penlclllin-streptomy cin 1485 — 3.87 7.42 — 1,74Tetracycline-penicillin-
sulfamethazine 2250 1746 — 8.48 — 6 3 9Bacltracln 9,72 5 1 0 2.50 3 2 6 2 5 0 2 6 7Tylosln 1481 10,94 4 6 4 6 0 3 4 2 0 1,47Vlrginiamycln 1100 10.69 5 7 3 5 0 2 6 6 0 3 2 5Bambermycin 0 0 0 2.45 1 89 – 099 1 17 1 17Tylan-sulfa 1765 5 1 2 — 6 7 6 2 1 5 —M e c a d o x 18.56 1513 8 6 4 6.91Lincomycln
—11 11 — — 7 5 7 —
Nitrofuran 8,00 — 1 42 2 3 3 — O 58
SOURCE V W Hays Effectiveness of Feed Add(flve Usage of Arrtlbacferlal Agents tn Swine and Poultry prepared for the Olflce of TechnologyAssessment U S Congress 1978 (typescript) fables 5 26 and 27
Table 17.–Continued Effectiveness of Tetracycline in Swine
Average dally gain (% Improvement) Feed/gain (0/o improvement}
Grower- Grow/rig - Grower- Growing -Tlme period Starter developer hrflshmg Starter developer hnlshlng1950-56 8 7 0 1736 9 4 0 5 4 5 6.27 4 5 51957-66, ., 11 69 6.02 5 8 8 7 9 3 1 95 1 141 9 6 7 - 7 7 1063 5 9 7 4 5 5 2.99 2 4 2 0 9 2
SOURCE V W Hays Effectiveness of Feed Addlttve Usage of Antlbacterlal Agents tn Sw{ne and Poultry prepared for the Off Ice of TechnologyAssessment U S Congress 1978 (tyoescrlpt) tables 5 26 and 27
Table 19.–lmprovement in Chick Performance: All Years VersusSince 1970 (To Approximately 4 Weeks of Age)
Table 18. –Response of Chickens to Antibiotics
14elght gain Feed/gain(% Improvement) (% Improvement)
Antlblohc 4 weeksTetracycline 7 3 3Penlclllln 811Bacltracln 6 3 0Arsenlcals 4 9 4Bambermycin 3 7 7Llncomycln 9.25Ndrofuran – 328Oleandomycln 501Streptomycin 7 2 6Vlrglnlamycln 1598Erythromycin 7 2 0Tylosln 2.82
8 weeks3 6 92 9 30.953442 3 54 4 81 984 4 8
—
——
4 weeks5 0 94.463 2 47011 808 2 8
– 2612 2 51 899.065.051 00
8 weeks2312 7 62 2 03 1 51,943.301.471.78
———
SOURCE V W Hays Effectiveness of Feed Addlflve Usage of Antlbacterlal Agents In Swineand Poulfry prepared for the Off Ice of Technology Assessment U S Congress t978(typescript) tables 35 and 36
PVelght gain Feed/ga/n(% Improvement) (LYo Improvement)
Anliblotlc Al/years Since 1970 Allyears Since 1970Tetracycline 7.33 6.79 5.09 5 3 8Penlcillln . , 811 1220 4 4 6 7 1 4Bacitracin 631 7.34 3 2 4 2.75A r s e n i c a l 4.94 471 701 4.81
SOURCE V W Hays Effectiveness of Feed Addmve Usage of Anflbacterlal Agents In Swineand Poultry prepared for the Otftce of Technology Assessment U S Congress 1978(typescript) table 37
Table 20.–Effect of Selected Antibiotics on Egg Production,Feed Per Dozen Eggs, and Matchability (in % Improvement)
Anhblotic Eggproduchon Feed/dozen eggs HatchabdltyTetracycline 11.91 891 147P e n i c i l l i n 5.52 5 0 4 3 9 7Bacltracln 0.95 2 2 8 6 9 7Arsenical : : 2.34 1 29 581Bambermycin 879 11.73 2 4 9Erythromycln 1.36 136 0 3 5
SOURCE V W Hays Effecllveness of Feed Addltwe Usage of Arrhbactenal Agents In Swineand Poultry prepared for the Off Ice of Technology Assessment U S Congress 1978[typescript) fables 39
33
Table 21 .–Response of Turkeys to Antibiotics
Welghf gam (% improvement) Feed/gain (% improvement)
To market To marketAnfhoffc 4 weeks 8 weeks weight 4 weeks 8 weeks weightT e t r a c y c l i n e . 1489 13.21 — 8.37 5.88 —
P e n i c i l l i n 1531 10.24 5.73 7.87 5.62 2,64Bacltracin 9.82 4,97 7.23 4,71 2.73 1.59S t r e p t o m y c i n 8 1 4 4 5 3 — 4 6 9 1 9 2 —
SOURCE V W Hays, Etfecttveness of Feed Addltwe Usage of Ant! bacterial Agents In Swine and Poultry, prepared for the Office of TechnologyAssessment U S Congress 1978 (typescript). tables 41, 42, and 43
have been estimated recently by USDA (1978)and Headley (1978). These estimates were de-signed primarily to estimate the effects on theincome of livestock producers and on consum-er prices. Both estimates were generatedfrom the same model. However, the expectedeffects differ in magnitude and time trend be-cause of the application of different assum-ptions (e.g., demand elasticities) to the basicmodel. The USDA analysis projected impactsfor 5 years, and Headley’s projected impactsfor 10 years from the time of banning. In theUSDA analysis, the initial decrease in pro-duction was expected to increase net pro-ducer revenues because of higher prices.Both production and prices of most affectedspecies were projected to recover to approx-imately their baseline levels by the fifth year.Headley’s analysis concluded that the ban-ning of selected or all four antibacterialwould increase aggregate farm income andincrease consumer expenditures from $5.7oto $19 per capita.
In both analyses, the effects were assumedto be additive, and no consideration wasgiven to the availability of alternative anti-bacterial. Both analyses mention that the es-timated effects would be less if these wereconsidered. Alternatively, the hypothesis thatsmall producers may be forced out of busi-ness was not considered. Production de-creases would be greater for the short term ifthis factor had been included. The long-termeffects, however, might not have been af-fected.
The economic consequences for producersand consumers and the long-term effectspostulated are obviously matters over whichmuch disagreement exists. However, the esti-mates of immediate consequences of selectedor complete banning of these four antibacteri-al can serve as first-order, rough approx-
34
imations of the kinds of production increasesattributable to these antibacterial. As notedabove, the availability of replacement anti-bacterial (see tables 16, 18, 19, 20, and 21) isnot considered.
USDA’s analysis estimated the effects ofthe four antibacterial separately for beef,pork, chickens, and turkeys. It also examinedthe effects on egg production, dairy calves,and lambs. Headley’s analysis estimated theeffects on beef, pork, chickens, and turkeysfrom a ban on (a) tetracycline and penicillin,(b) nitrofuran and sulfa, and (c) all four anti-bac te r i a l . S ince bo th ana lyses a s sumedthese effects to be additive, they were com-parable. Lambs, dairy calves, and egg pro-duction are not addressed here.
The percent changes in production arecomparable and both use 1976 data, but theanalyses differed slightly in the measure ofproduction. Both used ready-to-cook weightsfor chickens (broilers) and turkeys, but Head-ley used carcass weights for beef and pork,while USDA used live weights at times ofslaughter. USDA’s estimates are thereforeadjusted to reflect carcass weights. Head-ley’s translation from percentage to poundsdiffers slightly from that obtained in USDA’sanalysis, so the former is adjusted to coincidewith the latter.
Table 22 summarizes 1976 production fig-ures for beef, pork, broiler chickens, and tur-
Table 22.–Production of Meat Animals, 1976
Arvmal products Mdlions of poundsBeefa. 25,969Porka, 12,425B r o i l e r chickensb. 8,970Turkeys b : : 1,960
aCarcass wetghtbReady-to-cook weightSOURCE Extracled from USDA, 1978 and Headley, 1978
keys. Table 23 compares USDA’s with Head-ley’s est imates on the effect of banningselected antibacterial expressed in percent-age decreases. The analyses are comparablefor each meat product, although the effect ofspecific antibacterial may differ, such as fornitrofurans on chickens and turkeys,
Using USDA’s separate analyses for eachfood animal and each antibacterial, table 24summarizes the range of impacts for each an-tibacterial. Among the individual antibacteri-al, the greatest impact relative to total pro-duction would be through banning tetracy-cline; pork and chicken would be the most af-fected,
As mentioned earlier, USDA’s and Head-ley’s analyses differed in the estimated im-pact of banning these antibacterial. Thoughbanning of the four antibacterial is esti-mated to decrease production by the percent-ages and pounds summarized in tables 23 and
24, the effect on the total market over anumber of years would not be equivalent tothese estimates. For both USDA’s and Head-ley’s analyses, table 25 summarizes the per-cent change in the quantity of meat producedor consumed, table 26 summarizes the per-cent change in farm prices, and table 27 sum-marizes changes in retail prices. Headley’sanalysis was for a lo-year period following aban, while USDA’s analysis extended only 5years beyond the initial year of the hypo-thetical ban. The primary difference betweenthe two analyses is that Headley consistentlyestimates a larger impact than USDA on de-creased production, increased farm prices,and increased retail prices. Headley’s esti-mates drop slightly after the first 2 years, butremain at a fairly constant level over thefollowing years, while the USDA analysis hasa high initial impact that diminishes over the5-year period. Both analyses predict the min-imal impact to be on beef and the maximumimpact on poultry.
Table 23. –Estimated Percentage Change in Livestock Production From Banning Selected Antibiotics(First Year)
CurnulalweArvmal product ProjectIon F’emcdhrr TeUacycllr7e N!tro~~rafl Sulfa effectB e e f USDA NAb – O 4 to – 0.8 NA NA – O 4 to – O 8
Headley - l o — NA — – 1.0Pork U S D A NA – 34 to – 15.6 NA – 1 5to – 22 – 4 9 tO – 1 7 8
Headley : – 4.0 — – 2,5 — - 6 5Broiler chicken U S D A – 21 to – 3.8 – 64 to – 11.5 + 02 to – 5.7 NA – 8.3 to – 210
Headley – 2 2 — – 120 — – 14.2Turkey USDA – 1 4 to – 28 – 2.8 to – 46 – 1 9 to – 8.7 NA – 61 to – 161
Headley – 3.2 — – 120 — – 152
apenlclllln \e[racycllne and sulfa consldefed banned at subfherapeutlc levels and nttrofurans considered banned at ail levels
bNot applicableS O U R C E USOA 1978 Headley 1978
Table 24.–Estimated Decrease in Livestock Production From Banning Selected Antibiotics(First Year) (millions of pounds)
Tofal productmnAmmal product (f976) Penlcdhrr Tetracychne Nitrofuran SulfaBeef~ 25,969 NA 104 to 208 NA NAPorkb 12,425 NA 422 to 1,938 NA 186 to 273Broiler chlckenC 8.970 188 to 341 574 to 1,032 18to511 NAT u r k e yC . 1,960 27 to 55 55 to 90 37 to 171 NA
apenlcl[lln Ielracycllne and sulfa considered banned at subtherapeullc levels and nltrofurans considered banned at all levelsbCarcass we(ghtcReady to cook weightSOURCE Table 22 and USOA percent estlmafes table 23
35
Table 25. –Percent Change in Quantity of Meata From a Ban on the Use of Selected Antibiotics
Beef Pork Broiler-chicken Turkey
Yearc USDA Headley USDA Headley USDA Headley USDA Headley1. ... ., ... –0,19to – 0,28 – 0.9 -4.86 to – 17,90 – 5.8 – 8.24 to – 22.70 – 15.4 – 5.98to – 1470 – 21,82.. . . . – 0,04 to + 0,04 –1 1 – 3.86 to – 14.17 – 55 – 3.61 to – 9.10 – 8,9 – 4.23 to – 10.45 – 19.33., . . . + 0,10 to + 0,25 – 0.7 – 2.68to – 9 . 8 6 – 5.8 – 2,27 to – 5.75 – 9.7 – 3.54 to – 8.74 – 17.74 .., ., . . . ., + 0.14 to + 0,24 – 0,4 – 1,40to – 5.15 – 6.2 – 2.15 to – 5.46 – 9,1 -2.71 to – 6,66 -15,95,. + 0.30 to + 0,56 – 0,4 –0.84to – 3.02 – 6 . 0 –2.16to– 5 . 5 0 – 7 . 7 –2.62to– 6 . 4 4 – 1 6 . 7
aUSDA’s IIgures based on quantity of meat produced Headley’s f~gures based on annual cwlhan Consumption Only first 5 years Of Headley’s analY$sls includedbpenlclilln tetracycline and sulfa considered banned at subtherapeutlc levels and nltrOfUranS considered banned al all levelsCyear of banning equats year 0
SOURCE USDA 1978 table 17 Headley, 1978 table 10
Table 26.–Percent Change in Farm Prices From a Ban on the Subtherapeutic Uses of Selected Antibiotics
Fed beef Hogs Broiler-chickens Turkeys(liveweight prjce) (Iiveweight price) (wholesale price) (Iweweight prjce)
Yearb USDA Headley USDA Headley USDA Headley USDA Headley1, .,....,. + 4,30 to + 15,34 + 4,7 + 5,02 to + 16.13 + 18.5 + 12.99 to + 35.65 + 51.8 + 11.61 to + 25.64 + 37,62, ., : : + 3,30 to + 11.27 +37 + 3.83 to + 1297 + 12.2 + 6.94 to + 20.00 + 28.4 + 6.70to + 16.42 + 28,43 .., . + 2.00to + 5.03 + 4.0 + 2.34 to + 800 + 12.4 + 3.09 to + 8.98 + 38.4 + 3,42 to + 8.88 + 38.44 . . , .,,,,..,, + 1.00 to + 2,00 + 2,8 + 1,59 to + 524 + 14.0 + 2.67 to + 7.46 +31.3 + 3,51 to + 8,79 + 31.35.. , : Oto + 0.96 + 2.3 + 1 14to + 353 + 15.5 + 2.25to + 6.04 + 35.0 + 3,54 to + 8,88 + 35.0
apenlclllln tetracyc[lne, and sulfa considered banned al subtherapeuhc levels and mtrofurans considered banned al all levelsbyear of banning equals Year O
SOURCE USDA, 1978 table 16, Headley 1978 table 11
Table 27.–Percent Change in Retail Pricea From a Ban on the Subtherapeutic Usesof Selected Antibiotics
PoultryBeet Pork (chickens & turkey
YeaP USDA Headley USDA Headley USDA Headley1. + 2.7 to + 10.4 + 3 6 + 4 5 to + 14.7 + 168 + 10.3 to + 276 + 13,32, : : : : + 2.2to + 7.7 + 2.8 + 3,5 to + 11,8 + 11 6 + 57 to + 15,9 + 8,73 ,. ., + 1.4 to + 3.4 + 3.2 + 2 1 to + 7.3 + 11 8 + 26 to + 7.4 + 10.34.. + o,7to + 14 + 2 2 + 1.4 to + 4.8 + 125 + 24 to + 6,5 + 10,05 0 to + 0.7 + 1.8 + 1 0 to + 3.2 + 135 + 2.2 to + 5.6 + 9,7
—aUSDA based on consumer price tndex Headley based on retail PflCe indexbpenlcl[lln [etracyc[lne and sulfa considered banned at subtherapeutlc levels and mtrofurans considered banned al all levelsCyear of banning ewals w 0
SOURCE USDA f978 table 2f Headley 1978 table 12
DIETHYLSTILBESTROL (DES)
Mode of Action
DES is a synthetic estrogen that differs instructure and metabolism from naturally oc-curring estrogen, but there is no evidencethat natural or other synthetic estrogens dif-fer substantially in their harmful or toxic ef-fects (DES Report, 1978). DES has a potency10 times that of the standard estradiol, and itis this relative potency that has made it thepreferred drug for growth promotion andfeed efficiency.
DES increases cellulose digestion by bovinerumen micro-organisms in vitro and in vivo.
36
Stilbestrol has been shown to increase the co-efficients of digestibility of cellulose in sheepfrom 41.9 to 48.7 percent and the crude pro-tein digestibility from 37.5 to 44.7 percent[Brooks et al., 1954). However, the followingevidence supports the hypothesis that the sys-tematic growth-promotion and feed-efficiencyeffects of DES are the result of endogenousandrogen (male hormone) production:
● DES accelerates protein anabolic proc-esses in cattle and results in an increasein nitrogen retention (Clegg and Cole,1954).
●
●
●
Introduction of exogenous estrogen trig-gers endogenous androgen secretion asa compensatory mechanism (Gassner etal., 1951; Whitehair et al., 1953).Melengestrol acetate (MGA), a syntheticprogesteronal s t e ro id a l so used fo rgrowth promotion and feed efficiency,produces biological effects closely re-lated to the effect of naturally occurringprogesterone. The effect of naturally oc-curring progesterone is cyclic and per-mits ovulation in the nonpregnant heifer.In the pregnant heifer endogenous pro-gesterone maintains the corpus luteum,which prevents ovulation. MGA inhibitsestrus and ovulation and allows the de-velopment of mature fol l icles in theovary. These persistent, mature folliclesproduce increased amounts of estrogen,which in turn stimulate weight gain andimprove feed efficiency. The interrup-tion of estrus i s t empora ry , normalestrus usually returning after MGA isdiscontinued. MGA will not stimulateweight gain in nonovulating, spayed, orpregnant heifers, in steers, or in bulls(Beeson, 1978).Testosterone also can be used to pro-mote growth and increase feed efficienc-y. This can be accomplished by addingtestosterone to the feed or by not cas-trating bull calves.
Effectiveness
Dose responses from different levels ofDES are not linear. Excessive levels willdepress performance and lead to undesirableside effects. Steers (castrated males) andheifers (immature females) respond different-ly, and response varies with the type of feed(e.g., pasture vs. grain) and whether DES isgiven orally or under the skin. Approved oraldoses of DES are 5 to 20 mg per head per dayfor cattle. ’ The approved implant levels forcattle are 30 or 36 mg. z
The effects of DES are limited to increasedweight gain and feed efficiency. The effect onmilk production has been inconsistent and itis not used for that purpose. Feedlots account
’21 CFR 558.225.221 CFR 522,690.
for most use. DES increases weight gain from15 to 19 percent and feed efficiency from 7 to12 percent in steers, and 10 percent forweight gain and 7 percent for feed efficiencyin heifers (Beeson, 1978).
In addition to DES, several other drugs areused for fattening cattle. As previously dis-cussed, these include melengesterol acetate(MGA), monensin, zeranol, and estradiol ben-zoate plus testosterone or progesterone. MGAis a progesteronal steroid that is effectiveonly in heifers. Studies covering a lo-yearperiod (1968-77) show that it produces moreweight gain and feed efficiency than eitheroral DES or estrogen implants. Table 28 sum-marizes these results. Monensin improvesfeed efficiency by 10 percent but has no ef-fect on weight gain in cattle. Implants of zera-nol, an estrogen-like compound, have from 30to 50 percent of the growth-promotion andfeed-efficiency effects of DES. Implants ofestradiol-progesterone for steers and estradi-ol-testosterone for heifers have similar quan-titative effects as DES. Beeson (1978) con-cludes that the data generally show that thequantitative effects are similar and recentlyreconfirmed previous research showing thatestradiol-progesterone implants are equal toDES implants for improving weight gain andfeed efficiency in steers (Beeson et al., 1977).Finally, the use of uncastrated young bullswill partially substitute for DES and othersimilar growth stimulants, improving bothweight gain and feed efficiency about 10 per-cent (Beeson, 1978). But bulls are difficult tocarry over as yearlings to be fed-out, andthere is a consumer prejudice against bullmeat.
Thus DES can be replaced by severalalready-approved drugs to promote weightgain and feed efficiency in cattle.
Effect on Production
Headley’s 1978 estimates on the effect onmeat production of a ban on selected antibac-terial also included estimates of a DES ban.A downward shift in supply of 3.75 percentwas predicted for the first year. As for anti-bacterial, the long-term effect was predictedas a rise in total producer income, and a risein consumer prices of $7.75 per capita.
37
Table 28.–No Drug Versus MGA Versus DES Versus Estrogen Implant (1968 -77)a
(47exper\ments) (36 experiments) (12experiments) (experiments)
EstrogenItem No drug MGA Oral DES MGA No drug DESb MGA No drug Implant MGAD a i l y gainlb 2.24 2.47 2.38 2.53 2.25 2,35 251 2,40 2.49 2.63Improvement ‘Yo
— 10.3 – 6.3 – 4.4 11,6 3.8 9.6Feed/lb gain lb : : : :
—
9.95 9.30 8.85 8.44 8.78 8.59 8 2 3 7 5 5 7,34 7,14Improvement % – 6.5 – 4,9 – 2,2 63 — 2 8 5.4
asummarlzlng experlmenis conducted by unwerslttes teed manufacturers and Commercial feedlotsbpercenf improvement not equal 10 that Clled In text because lhese were comparison experiments and were not necessarily testln9 the maximum resPonse from OESSOURCE W M Beeson Use of Drugs and Chem!cals as Feed Addltwes 10 Increase the Productwlty of Cattle and Sheep prepared for the Off Ice of Technology Assessment U S Congress 1978
(typescrtpf) table 5
However, Headley estimated that 90 per-cent of fed cattle received DES or MGA. Aspokesman for the National Cattlemen’s As-sociation estimates that DES and similargrowth stimulants such as zeranol are used inabout 80 percent of fed cattle (CNI WeeklyReport, Oct. 5, 1978) Therefore, if Headley’sfigures are adjusted by eight-ninth’s and applied to a total 1976 production of 25,969 mil-lion lbs carcass weight of beef (see table 22),DES is estimated to increase beef productionby 3.33 percent, or 865 million lbs. This esti-mate is still high, because DES does not ac-count for all growth-stimulant use.
As in the case of banning selected anti-bacterial, Headley estimated the effects of aban on DES over a lo-year period from thetime of banning. The combined response ofantibacterial and DES approaches an addi-tive effect in beef cattle meat production, butthe effect on costs is not additive. When ana-lyzed apart from a ban on the subtherapeuticuse of antibacterial , the per capita con-sumer cost of a DES ban was estimated to be$ 7 . 7 5 . I f pen ic i l l in , t e t r acyc l ine , su l fa ,nitrofurans, and DES were simultaneouslybanned, per capita consumer costs wereestimated at $21.90. If only the antibacterialwere banned, per capita costs would be $19,Thus when added to an antibacterial ban,
DES was estimated to add only $2.90 to percapita consumer costs, in contrast to $7.75 i fonly DES were banned.
Table 29 summarizes Headley’s estimatesof a DES ban on the percent changes in avail-able beef supplies, farm prices, and retailprices. After 5 years, supply is slightly in-creased over supply before the ban, with de-creases in farm prices and consumer prices.After 10 years, supplies are slightly de-c reased and fa rm pr ices and consumerprices increased, but none of these changes isas large as that expected in the 2 years imme-diately following the ban on DES.
Table 29,–Percent Change on the Supply, Farm Prices,and Retail Prices of Beef From a DES Ban
(Farm prices, hveweight)Yeara supply Fed cattle Nonted cattle Retadprmes1,. . – 3 7 + 11,9 + 15,2 + 9.12 .., ., – 3 2 + 8.6 + 12.5 + 6,73 – 1 5 + 5,7 + 7 7 + 4.74,, .,,, – 0.5 + 2,1 + 2,6 + 1.95 . + 0.5 - 2 5 – 3.6 – 1,76.. ,, + 0 2 – 1,4 – 2,8 – 0.87,, .,,. – 0.9 + 4,0 + 4.3 + 3.38. . . . – 1,7 + 8.1 + 1029
+ 6,5– 1 9 + 10,4 + 13,7 + 8.4
1 0 . – 1,2 + 6 9 + 9.5 + 5,8
ayear of bannma eauals vear OSOURCE Headl& 1978’ tables 1 2 and 3
38
Chapter IV
RISKS
Chapter IV
RISKS
INFECTIOUS DISEASES
Antibacterial-Related Risks
The increasing pool of drug-resistant bac-terial pathogens is the greatest health riskposed by the widespread use of antibacteri-alsin animal feeds. It isalso the most difficultto evaluate in terms of:
I, quantifying the pool of drug-resistantbacterial pathogens,
2. assessing the relative contributionto thepool from the use of antibacterial inanimal feeds, and
3. determining causality between the useof antibacterial in animal feeds andhuman disease.
Hazards to the food animals themselvesfrom such use of antibacterial are closely re-lated to these human health concerns be-cause the development of resistant pathogensand subsequent failure or diminished effec-tiveness of antibacterial therapy are prob-lems for both human and animal health. How-ever, this sharing of potential, long-term,adverse consequences is obscured by the pre-dicted short-term consequences for the live-stock industries of limiting the subthera-peutic uses of certain antibacterial.
On the other hand, the long-term conse-quences for these industries might be signifi-cantly different. With limited use, althoughthe supply of certain food animals could di-minish, shifts in supply and demand for dif-ferent foods (primarily beef, pork, and chick-en) may produce little change in total incomefor producers and modest rises in consumerprices (USDA, 1978; Headley, 1978).
The threat to human health has been theprimary reason why current efforts at lim-iting widespread use are underway. But suchwidespread use poses an identical threat to
the health of livestock and poultry and mayeven occur earlier and more visibly than thethreat to human health. Present production isconcen t ra ted in high-volume, crowded,stressful environments, made possible in partby the routine use of antibacterial in feed.Thus the current dependency on low-level useof antibacterial to increase or maintain pro-duction, while of immediate benefit, alsocould be the Achilles’ heel of present produc-tion methods.
Adverse effects on human health are possi-ble from contact with treated livestock or theantibacterial themselves and through eatingfood products containing residues of animaldrugs. Illness can result from poor manage-ment and sanitation practices in violation ofstandards, but this report is not concernedwith such causes except when the circum-stances show that prevention is not possiblethrough standard-set t ing and compliance-monitoring. Nor is this report concerned withall disease acquired from ingesting contami-nated foods but only when: (1) drug residuesrepresent the threat or (z) antibacterial inthe feed result in disease or threatened dis-ease from antibacterial-resistant bacteria.
Human disease from contact with treatedlivestock or with the antibacterial(s) itself ismore significant for building a case for thegeneral risk of such uses than it is for con-cluding that direct disease transmission ispresently a significant problem, That is, dis-ease transmitted directly from food animalschronically fed antibacterial-supplementedfeed is not of epidemic proportions, and iso-lated cases or limited epidemics have been soinfrequently detected that they are news-worthy items even in the scientific communi-ty, But taken together with the growing num-
41
ber of research findings of asymptomaticspread of drug-resistant organisms from foodanimals to humans, they are significant indocumenting the risk to human health fromdrug-resistant pathogenic bacteria.
Risks From Infectious Diseases
A large body of literature shows that cer-tain infect ious diseases are t ransmit teddirectly from animals to humans. Such dis-eases are not limited to bacterial etiologiesbut cover the whole spectrum of infections—e.g., tapeworms, trichinosis, psittacosis, tu-berculosis, etc. Some diseases are occupa-tional hazards in the meat industry and carrycommon names such as “pork infection, ”“swine erysipelas, ” and “fish poisoning. ”
While the causal chain between food ani-mals or their edible products and disease inhumans may not be completely demonstratedin any given case, each step in the chain hasbeen documented repeatedly. With the addedcriterion that the infectious agent in theanimal or its edible product be shown to becaused by antibacterial supplements in thefeed, the causal chain is even more difficult toprove in any specific case. Thus there isdisagreement over the interpretation of anyspecific case but no real disagreement overthe overall conclusions that food animals arethe source of some infections in humans andthat the use of antibacterial in feeds is onecause of the growing pool of drug-resistantpathogenic bacteria. Instead, the disagree-ment is over the exact risk from this enlargingpool and the contribution of antibacterial inanimal feeds to the problem.
The proliferation of antibacterial-resistantbacteria is encouraged by the presence ofsuch drugs. Sensitive bacteria are killed or in-hibited, allowing resistant strains or spon-taneous mutations of sensitive-to-resistantbacteria to grow into the vacated environ-ment. The situation is complicated becausesome resistant strains can transfer the resist-ant genes to other bacteria. Antibacterial re-sistance (and other properties of bacteria)are sometimes carried on bits of DNA thatfunction independently of the organism’schromosomes. T h e s e extrachromosomalpieces of DNA are called plasmids.
Resistance plasmids (R-plasmids) may codeboth for antibacterial resistance and for theability to transfer to other bacteria, or thetwo functions may be separate on differentplasmids. Resistance to multiple antibacteri-al is frequently found on an R-plasmid. As inthe case of single resistance, multiple resist-ance may or may not be transferable depend-ing on whether the transfer code is associ-ated with the resistance code—i, e., resist-ance to a specific antibacterial may be trans-ferred alone or along with resistance to oneor more other antibacterial.
Gram-negative and gram-positive bacteriaalso differ in plasmid-mediated transfer. R-plasmid transfer has not been found to occurbetween these two types of bacteria. The R-plasmid of gram-positives are not so freelytransferred as those in gram-negative spe-cies, nor are linked, multiple resistances sofrequently found in them.
For any antibacterial there may be: (1) noknown plasmid-mediated transfer of resist-ance in either gram-positive or gram-negativebacteria, (z) transferred resistance only inone bacteria type but not in the other, or (3)varying degrees of linkages with other anti-bacterial resistances, For example: (a) bam-bermycin has no known effect on gram-posi-tive or gram-negative bacterial resistancepatterns; (b) tylosin and virginiamycin selectfor erythromycin-resistant staphylococci andstreptococci (gram positives), but their effecton the resistance patterns of gram-negativesis essentially nonexistent; and (c) tetracyclineselects for resistance not only to itself butalso for resistance to other antibacteriallinked to it in both gram-positive and gram-negative bacteria (Falkow, 1978) .
Resistance can be transferred from non-pathogenic as well as from pathogenic bac-teria. Although resistant nonpathogenic bac-teria will not cause disease, they may be ableto transfer antibacterial resistance to bacte-ria that can cause disease but which werepreviously responsive to antibacterial ther-apy. Thus a growing pool of plasmid-mediatedresistance in nonpathogenic bacteria, eventhough of no direct clinical significance,poses a large threat because of the transferof that resistance to pathogenic bacteria.
42
Plasmids have also been identified wheredrug resistance and pathogenicity are linked.Since the first reports on drug resistance andenteropathogenicity linkage in swine, similaroccurrences have been found in human toxi-genic E. coli. In E. coli that cause diarrhealdisease by the production of an exotoxin, ithas been shown that the intestinal toxin in-volved is often encoded by plasmids (Ent-plas-mids) that can be transferred from strain tostrain (Smith and Linggood, 1972; Gyles et al.,1974; So et al., 1975). A second plasmid-coded gene product, the K-antigen, whichenables the organism to adhere to the wall ofthe intestine, is also required for pathogenici-ty of the organism by exotoxins. Although theK-antigen shows some species specificity, theEnt-plasmid does not.
The incidence of R-plasmids is very highamong enterotoxigenic E. coli strains for bothanimals and humans (Gyles et al., 1974). Thecoexistence of Ent- and R-plasmids within thesame cells raises the possibility of recombina-tion between the plasmids, translocation, ori n d e p e n d e n t cotransfer. Independen t co-transfer has been shown in vitro. In an E. colistrain responsible for a hospital epidemic ofinfantile diarrhea, one plasmid was associ-ated with the production of heat-stable en-terotoxin, and another plasmid determineddrug resistance against seven antibacterial.When the R-plasmid was transferred, theEnt-plasmid was also transferred to 36 per-cent of the drug-resistant recipients (Wachs-muth et al., 1976).
E. coli isolated from piglets with diarrheahave been found with Ent- and R-plasmidscombined, presumably by recombination ortranslocation, These plasmids were conjuga-tive (transfer by direct contact between bac-terial cells) and determined the production ofenterotoxin and resistance to multiple anti-bacterial ( tetracycline, sulfonamide, andstreptomycin) (Gyles et al., 1977). In addition,a conjugative plasmid encoding a K-antigenhas also been found to carry resistance genes(So et al., 1976). These findings portend thepossibility of a complete plasmid in the senseof combining conjugative, enterotoxigenic(Ent), adhesive (K), and resistance (R) proper-ties in one package for transfer to completelynonpathogenic, gram-negative bacteria.
Humans and other animals are hosts tomany of the same bacteria. It is now widelyaccepted that E. coli, some of the most ubiqui-tous gram-negative bacteria, are not com-posed of stably differentiated strains that arespecific colonizers or pathogenic for separateanimal species. Cross-colonization studies,serotyping, drug-resistance patterns, andplasmid types show extensive overlappingsets of human and animal organisms (Lintonet al., 1977a, 1977b; Howe et al., 1976) Cross-colonization may be enhanced by plasmid-mediated factors. Colicin is a substance thatkills E. coli except for the type producing it,thus giving competitive advantage to the pro-ducer. Oral administration of two colicin-positive bovine E. coli strains resulted in 100-percent replacement of the resident coliformflora in humans, whereas colicin-negativederivatives of these two strains were unableto colonize the same humans (Smith and Hug-gins, 1976).
Conjugative, colicin-positive plasmids car-rying resistance genes are known to exist(Delhalle and Gratia, 1976). The potentialtherefore exists for animal feeding of anti-bacterial to cause a direct increase in thepathogenicity of E. coli in humans.
A single Sahnonella serotype, S. typhirnuri-um, is the most common cause of Salmonellainfection in both animals and humans (CDCSalmonella Summary Report, 1973). Six of themost common human serotypes were amongthe ten most common animal serotypes in arecent CDC survey (CDC Report, 1974). In ad-dition to shared serotypes between animalsand humans, plasmids from E. coli can betransferred to Salmonella and other gram-negative bacteria.
In Connecticut in 1976, S. Heidelberg fromcalves infected humans, who in turn second-arily infected three infants, The organismwas resistant to six antibacterial, E, coliwith identical resistance patterns were iso-lated frGm two infected calves and from onehuman, This particular resistance patternwas not seen in over 10,000 pathogenicstrains of E. coli isolated from the Northeast-ern United States in the same year, including42 strains isolated from controls in the study(Cohen et al., 1977).
43
In a sampling of E. coli from a freshwaterriver system and within the saltwater bayinto which it emptied: (a) nearly all the fresh-water sites and about half of the saltwatersites sampled contained antibacterial-resist-ant coliforms, and (b) zo percent of the 194strains tested contained R-plasmids carryingmultiple antibacterial resistance transfer-able to sensitive E. coli, Salmonella typhimuri-um, and Shigella dysenteriae (Feary, et al.,1972),
DNA base sequence homology studies ofplasmids from different parts of the worldhave shown striking compatibility of plas-mids. Plasmids with molecular weights of 57million, one isolated from a bovine S. typhi-murium in England in 1972, and the otherfrom a human S. typhi in Vietnam in 1974,showed 100-percent homology. Table 30 sum-marizes these results (Anderson, et al., 1975).
Finally, a more serious occurrence thantransferred resistance between E, coli andSalmonella has recently appeared. R-plas-mids determining resistance in newly discov-ered ampicillin-resistant strains of 1-1. in~lu-enza (Elwell et al., 1975) and in penicillin-resistant strains of N. gonorrhea (Elwell etal., 1977) are identical to plasmids previouslyfound in E. coli. It must be assumed that theseidentical plasmids have a common origin.
Magnitude of the Risk
What proportion of antibacterial resist-ance is caused by subtherapeutic use in foodanimals as opposed to therapeutic use in bothanimals and humans is unknown. Thus thisrisk is not yet possible to fully quantify. Forsome aspects of the problem, such as thedegree of compromise in treating Salmonellainfection, it is possible to arrive at some quan-titative notion of the magnitude of humanrisk. But for the overall risk to humans fromincreased antibacterial resistance, not only isit unclear what the final deleterious eventshould be whose frequency would be esti-mated, but there are also complicated inter-actions among human and animal populationswith which we must contend.
As a rule the transmission of Salmonella in-fection is from animals to man, and the Sal-monella reservoir in animals is consideredthe direct source of most of the Salmonella in-fections in humans (Sickenga, 1964). The anti-bacterial-mediated reservoir of resistant E.coli in animals provides a source of R-plas-mids that can transfer to Salmonella.
A continuous increase in antibacterial re-sistance has been noted among Salmonellaisolated from farm animals. There has been adramatic increase in resistance to antibacte-
Table 30a.—Homology Between Plasmids of Animal and Human Origin
I The values fnd[cate the deqree of reassocldllon d! ~’I ‘C of 3H Id beled Plasfllld DNA with unlabeled ol~slllld DNA rela!l ~e 10 Ihe reassoclalton both with ONA of the same plasmldI = 100 I dnd wtth E COI( K 1 ? chromosomal DNA I = 01
Unlabeled DNA fromstrains bear!nq plasmlds Labeled plasm[d DNA
~{
~Human (H)
3 f Fll 1, N H, H, )or ammal (A) Plasmld ~ ~
Group orlgm no { 240 R I . 1 9 K . TP1 66>~J eTP1 58’ ‘ T P 1 2 3 T P 1 5 3 T P 1 5 >~TP1 16
Fll H 2 4 0 1 0 0 57 64 13 0 0 3–H R1 -19K. - 1 0 0 93 :4 – – – 17 –A TP166 6 4 8 5 100 9 10 10 – 17 6
It H TP102 13 – 11 1 0 0 75 7 4 2–A A 15 – 11 6 5 1 0 0 1 o– —
N H T P 1 2 0 l– 4 0 1 1 0 0 94 5–A T P 1 5 8 l– 3 1 0 101 100 10 —
H, H T P 1 2 3 10 17 2 4 0 0 9 6 1 0 0 91H TP153 – 6 12 – — — 3 IWH T P 1 6 3 10 6 9 1 0 8 4 s 96A TPI 71 – — — — — — — 1 0 0A T P 1 5 4 6 0 8 0 0 7 12 8 7 9 2
H , H TP1 16 2––– 0 8– 4 0A TP167 – — — — — — — — o
4—
5
34
0—
919s82
100
——
o—
9
—o
0—
857
—
o
10081
3—
4
—o
2—
o05
—
o
65100
Note—The broken Ime encloses reactions of Iabelled plasmld DNA wtth unlabeled plasmlds from the same compatlbidy group—, Not done
a~derson et al , J @n Mlcroblol 9 1 3 7 6 . 3 6 2 , 1975, table 3
44
—..
rials in human Salmonella infections, A re-view of several studies of human infectionsconducted over a period of years indicatesthat resistance of Salmonella to tetracyclinehas increased continuously from l-percentresistant organisms prior to 1948 to morethan 40-percent resistance in 1973.1 A com-parison of antibacterial resistance in Salmo-nella isolated from hospitals in 1967 and 1975conducted by the Department of Health, Edu-cation, and Welfare’s (HEW) Center for Dis-ease Control showed overall resistance to atleast one antibacterial increased from 41,1 to69.4 percent, Multiple resistance to six ormore antibacterial increased from 0,8 to 9,2percent (table 31),
FDA estimated that there are 2.5 millioncases of Salmonella infection in the UnitedStates each year; about 30 percent were se-vere enough to be seen by a physician, andapproximately 1 percent of these develop life-threatening septicemia where appropriateantibacterial therapy is critical. In 27 per-cent of the cases treated, the first antibacte-rial chosen for treatment proves to be ineffec-tive because the disease was caused by anti-bacterial-resistant bacteria.z Thus there arecurrently about 2,500,000 x 0.3 x 0.01 x0.27 = 2,025 Americans who annually con-tract a life-threatening Sahnonella infectionthat requires antibacterial treatment and forwhom treatment is compromised to some ex-
Table 31. –Antibiotic Resistance in Sa/mone//a IsolatedFrom Hospitalized Patients
1967400 strains
Resistance to one or more antlblotlcsS typhlmurfum 41 170
Other serotypes 15870All strains 22 2Y0
Resistance to two or more antlblotlcs 15 OYO(60 strains)
Resistance to six or more antlb!otlcs O 80/0(3 strains)
1975754 strains
69 4Y043 9yo49 7Y026 5%
(200 strains)9 20/0
(69 strains)
SO IJRCE 42 F R 5027? W’ 2 ‘ 1977
’42 F.R. 56272, Oct. 21, 1977.‘Ibid.
tent by antibacterial resistance of the infect-ing Salmonella strain. Additionally, there isan even larger number of people with nonsys-temic infections who are treated with anti-bacterial and for whom treatment is alsocompromised.
All Salmonella infections cannot be as-cribed to antibacterial use in food animals,but the risk is also not a static situation. If therisk were static, the lifetime risk of contract-ing systemic Salmonella infection and thesubsequent treatment being compromised byantibacterial resistance could be approx-imated as (2,025 people/year x 70 years) -200,000,000 = l/1,411, But in view of therapid rise in multiple resistance, it must beassumed that both the degree and extent towhich treatment is compromised are increas-ing at a rapid rate.
The risk from resistance plasmids of ani-mal origin is not quantifiable even by therough estimates made for Salmonella infec-tions. The majority of resistance in humanbacterial populations is probably caused bywidespread use of antibacterial in humans(some of which is unnecessary), but the enor-mous pool of R-plasmids as now exists in ani-mals, together with the ability of an R-plas-mid to be promiscuously transferred amongbacterial species, must be regarded as athreat to the therapeutic value of antibacteri-al in the treatment of both human and ani-mal diseases.
In assessing the risks to humans from theuse of antibacterial in animals, the cumula-tive nature of these risks cannot be over-looked nor the importance of understandingthe time rate of change of these risks. Al-though penicillin and tetracycline have bothbeen used for over 25 years in animaI feedswithout seriously compromising the effective-ness of these drugs in the treatment of humandisease, it cannot be assumed that there willbe no problems in the future. Both the acquir-ing of resistance in animals and the passingof resistance from animals to humans are cu-mulative processes, and perhaps the pointhas not been reached, but will be at somefuture time, where significant deleterious ef-fects will be observed in humans.
45
DRUG RESIDUES
Types of Risk
Monitoring of drug residues focuses on thedirect harm to humans from consumption ofedible animal byproducts. There are twotypes of risks that are addressed: carcino-genic residues and residues with other healtheffects. As discussed earlier, there can be noresidue of carcinogenic substances, with “noresidue” determined by a method prescribedor approved of by the Secretary of HEW. Cri-teria by which the acceptability of a methodwill be judged have not been finalized, but theFood and Drug Administration (FDA) con-tinues to proceed with regulations that wouldavoid the problem of always “chasing zero”that results from the increasing ability tomeasure extremely minute amounts of sub-stances. There are approved drugs that areregulated on a “no residue” basis becausethey are known or suspect carcinogens.There are official methods for these drugs,although there is disagreement on whether ornot these methods are adequate when re-viewed by current scientific standards.
Residues of noncarcinogenic drugs do nothave to meet the “no residue” requirementapplicable to carcinogens but are governedby safety factors as described in the law.These factors include the probable consump-tion of the drug and of any substance formedin or on food, the cumulative effect, othersafety factors deduced by scientific expertsf rom an imal exper imenta t ion da ta , andwhether the conditions of use are reasonablycertain to be followed in practice.3 In prac-tice, FDA sets specific tolerances for residuesbased on these safety factors and the avail-ability of a practical analytical method todetermine the quantity of residue. Chronicstudies are required to support a finite toler-ance. Acute toxicity studies of 90 days’ dura-tion are minimally required for a negligibletolerance. If it is determined that negligibleresidues will probably not occur, no toleranceis required. And if the drug may be metabo-lized and/or assimilated in such form that anypossible residue would be indistinguishable
from normal tissue constituents, no toleranceis required.4
The treatment of carcinogens differs fromthat of noncarcinogens in that: (1) if finite res-idues are present, carcinogens are bannedand noncarcinogens are not, the latter contin-gent on establishment of a tolerance, and (2)if it is not possible to determine whether resi-dues will be present (a) for carcinogens, themanufacturer fails the burden-of-proof testfor safety and the drug is not approved orwithdrawn, whereas (b) for noncarcinogens,negligible tolerances or no tolerances are set,based on a showing that residues are ex-pected to be below a level of potential tox-icological significance. The judgments are notmade without toxicological data. For carcino-gens, even this distinction is somewhat artifi-cial because in the case of either measurableor unmeasurable residues, the drug is not ap-proved or withdrawn. FDA’s current attemptto extrapolate from animal test data to man,so that “no residue” would be defined by risk,would be one method of regulating carcino-gens on a more rational basis.
Noncarcinogenic Risks
Tolerances for noncarcinogenic drug resi-dues are determined by the general criteriafor safety enumerated earlier and by the re-quirement that the residue level cannot be sethigher than that reflected by the permitteduse of the drug. When a specified level of res-idue is determined to be safe through toxico-logical data, a withdrawal period prior toslaughter of the animal may be requiredbefore the drug can be approved. Most ap-proved drugs require a withdrawal periodonly because they are approved on a negligi-ble-tolerance basis instead of on a finite-toler-ance basis, Because the safety factor appliedto establish a negligible as opposed to a finitetolerance is very large, withdrawal periodsare necessary for residues to deplete below-tolerance levels. The withdrawal period for aspecific drug may vary for different animalspecies or production classes and also may
’21 U.S.C. 360 b[d]2].
46
’21 CFR 556.1.
vary depending on its combination with otherdrugs.
Sulfamethazine residues in swine havecaused the greatest problem in this area,with tissue residues in excess of the 0.1 ppmlimitation averaging 13.1 percent of the sam-ples tested in the latter half of 1977. As ex-plained earlier, more than half of these viola-tions were probably caused by contaminationof the withdrawal feed. If so, then increasingthe withdrawal time will have little effect onviolation rates without parallel action in de-creasing cross-contamination of feeds,
FDA subsequently did increase the with-drawal period for all uses of sulfamethazineto 15 days and was nearing completion of aproposal to set action levels for cross-contam-ination at the end of 1978. Prior to this action,the withdrawal period had been 5 days whenin combination with tylosin and 7 days in com-bination with penicillin and tetracycline.These withdrawal periods had been estab-lished prior to new regulations issued in 1975that established a lo-day withdrawal periodfor sulfonamides not already subject to regu-lation.’ The 10-day period was set becausethe judgment was made at that time that 10days would probably be adequate to assurethat residues would be below 0.1 ppm and be-cause of the degree of thyroid response to sul-fonamide drugs,
Other sulfonamides have not been affectedby the new withdrawal period. The with-drawal period for sulfathiazole, also usedwith tetracycline and penicillin in swine feed,remains at 7 days.~ Sulfaethoxypyridazine isused for therapeutic purposes in swine andcattle for use by or on the order of a licensedveterinarian. The withdrawal period remains10 days.’ Sulfamerazine is used in trout, witha withdrawal period of 3 weeks. ~
Residue violations from other antibacteri-al have not been significant. Most of the resi-due problems result from therapeutic and notfrom feed-supplement use. The incidence ofviolations for some antibacterial is summa-rized in table 32.
521 CFR 510.450.“21 CFR 558.155,721 CFR 558.579.’21 CFR 558.582.
Antibacterial residues were previouslyconsidered important in the development ofantibacterial-resistant bacteria because ofingestion by humans, but this is now consid-ered the least likely contributor. However,the evidence that violative residues of sulfa-methazine were caused largely by contamina-tion of the withdrawal feed may bring a newperspective to this issue, As previously dis-cussed, the contribution of antibacterial-sup-plemented feed to the growth of drug-resist-ant bacteria comes primarily from selectionand promotion of resistant strains of themicro-organisms in animals, not humans. Soantibacterial residues in edible animal prod-ucts are the wrong indicator of this potentialproblem if the level of such residues does notreflect dependably the antibacterial contami-nation.
Cross-contamination of feeds may also beoccurring for other antibacterial, particu-larly penicillin and tetracycline, because theyare widely used and mixing is not limited tocertified feed mills or under the direction of al icensed veterinarian. The sulfamethazineproblem was detected because contaminationled to violative tissue residues. For other an-tibacterial, cross-contamination may be oc-curring but may not be reflected in increasedconcentrations of tissue residues. Thus, reli-ance on tissue residues as an indicator ofcross-contamination of feed may not be ap-propriate, and direct monitoring of supposed-ly antibacterial-free feeds would have to beundertaken to eliminate cross-contaminationas a possible significant contributor to the de-velopment of drug-resistant bacteria. A lim-ited amount of this feed monitoring is pres-ently conducted by FDA.
Carcinogenic Risks
General Considerations
Current reliance is on testing in small ani-mals for both cause and effect and quantita-tive extrapolation to humans, All substancesdemonstrated to be carcinogenic in animalsare regarded as potential human carcino-gens. No clear distinctions exist betweenthose that cause cancer in laboratory ani-mals and those that cause it in humans. How-ever, the accurateness of extrapolation from
47
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laboratory animal results to humans to quan-tify the effect is less certain (Cancer TestingTechnology and Saccharin, 1977).
Short-term tests are developing as aids inevaluating the potential of substances tocause cancer. Short-term tests are based onthe presumption that cancer is related tocellular DNA changes and that detection ofsuch changes is predictive for a substance’spotential carcinogenicity. These tests exam-ine the capacity of a substance to cause muta-tions or other genetic alterations. Severalhundred known animal carcinogens and non-carcinogens have been tested in the Salmonel-la/Ames test, which at this time is the mostextensively studied short-term test. About 90percent of the known carcinogens are posi-tive in this test, in contrast to positive resultsin about 10 percent of substances that are notcarcinogenic in animal tests (McCann et al.,1975; Purchase et al., 1976; Sugimura et al.,1976).
Typically, animal experiments use on theorder of 100 animals at each experimentaldose. If a part icular experimental dosecauses a lifetime increase in cancer risk of1/10, this increase can be measured with asmall degree of accuracy using 100 animals.If background or spontaneous carcinogenesisis present, even larger numbers of animalswill be required. On the other hand, the extrahuman risk that we may want to estimate re-sulting from environmental exposure is usual-ly much smaller than 1/100 for any givenchemical , perhaps on the order of 1/10’.Clearly, it would not be practical to conductan experiment with enough animals to mea-sure directly an increase in risk this small.
For these reasons the procedure has beendeveloped of conducting lifetime animal-feed-ing experiments using, in addition to a controldose of zero, several doses at which the pro-jected extra cancer risk may be 1/10 orlarger. The high-dose data are used to esti-mate a dose where the risk may be no largerthan, say, 1/10’. That is, the high-dose data isused to estimate the risk at dose levels con-siderably below a level at which effects couldbe discerned from practical experimentalfeeding studies. An equally important variantto this problem is the calculation of the so-
called “safe” dose, for which there is somemeasure of statistical assurance that the ex-tra risk at that dose is no more than, say,1/10’. These problems are often referred tocollectively in the literature as the “low doseextrapolation problem.
The most common animals used are ratsand mice, and these species, as well as dif-ferent inbred strains of them, often vary intheir sensitivity to the substance being tested.Also, the number of animals used in these ex-periments is a compromise between largeenough numbers of them to detect positive ef-fects and the costs and time of conductingthese experiments. Rats and mice live for 2 to3 years, and when this time is added to thetime needed to set up the experiment, exam-ine tissues, write up the results, etc. a typicalexperiment takes about 4 years. And statisti-cally speaking, the law of probabilities tellsus that positive results cannot be expected allof the time even when the substance beingtested is carcinogenic.
For these reasons, when both positive andnegative results are obtained in different ex-periments and there is no known reason forthe discrepancy, more weight is given to thepositive results. Scientists would agree thatstatistically positive results obtained in atleast two animal species by appropriate testsare reasonably conclusive evidence that thesubstance is likely to be a human carcinogen.Clearly positive results in one valid and ap-propriate animal species are also consideredby a majority of scientists to be a sufficientbasis for labeling a substance a carcinogen.In addition, short-term tests may be helpful inpredicting that a substance is genotoxic andmay, therefore, aid in the identification of asubstance’s carcinogenic potential.
Carcinogens may act in a variety of ways,ranging from a genotoxic interaction of theagent with the cell genome to the enhance-ment of the expression of tumorigenesis initi-ated by other known or unknown agents. Sci-ence is progressing rapidly in the elucidationof the mechanisms of carcinogenic action, butit is seldom possible at this stage to be certainby what mechanisms an individual agentacts.
49
The concept of a threshold below which acarcinogen may be ineffective has been thesubject of debate. It is not possible to deter-mine by experiment whether such a thresholdexists because of the vast numbers of animalsand the consequently large facilities and res-ervoir of trained personnel required. Never-theless, there is substantial evidence that thelower the exposure to a carcinogen, the lowerthe risk of developing cancer. This estab-lished fact is the justification for attempts toextrapolate from the effects of carcinogens athigh doses to their postulated effects at muchlower doses. And even if threshold issueswere resolved—i. e., for a given substancethere is or is not a threshold—how to deter-mine the threshold with a high degree of con-fidence would remain as a major issue.
In the absence of contrary data, it is pru-dent in extrapolating from the results of ani-mal experiments to humans to give the mostweight to the results of the most sensitiveanimal experiments. The general rationale isto err on the side of safety. Laboratory ani-mals are deliberately inbred to have uniformcharacteristics so that confounding factorsrelating to individual animal variability areminimized within a specific experiment. Gen-erally, these experiments attempt to intro-duce only one variable—the substance to betested—so that causality can be deduced be-tween it and the resulting carcinogenic ef-fect.
When the risks from animal experimentsare extrapolated to expected incidence inhumans, the results are usually expressed inrisks per lifetime exposure, the usual expo-sure period of present animal tests. Yet life-time exposure is not a necessary preconditionfor carcinogenesis, since even single expo-sures to potent carcinogens can produce can-cer. Lifetime exposure is intended to elicit themaximum response to a particular concentra-tion of the tested substance.
Lifetime exposure to large doses by experi-mental animals and the use of these findingsto extrapolate to low doses in humans areoften misunderstood. The usual misunder-standing is to equate the concentrations usedin the experiments with that consumed byhumans. For example, in announcing the re-
sults of positive carcinogenic tests on sac-charin and its intention to ban it as a food ad-ditive, the initial press release from FDAmade the statement that “The dosages of sac-charin fed the rats in the Canadian studywere in excess of the amount that a consumerwould receive from drinking eight hundred(800) 12 oz. diet sodas daily over a lifetime”(FDA Press Release, Mar. 9, 1977).
These misunderstandings leave the impres-sion that animal experiments predict unreal-istically high carcinogenic effects in humans.Yet these experiments are conducted in care-fully controlled conditions where other car-cinogens are not present, in contrast to theconditions of human exposure. There is arough similarity between (I) the correlationof experimental conditions with environment-al exposure to which humans are subject and(2) the correlation of experimental with fieldresults on the effectiveness of antibacterialfor growth promotion and feed efficiency infood animals. In the latter, the quantitativeeffect in the field is greater than under con-trolled, experimental conditions, though theprecise mechanisms are not known. Perhapsa similar result might be hypothesized forcarcinogenic effects, but at the minimum, theconditions are not so radically different thatin carcinogenic testing the opposite resultshould be expected. That is, there is no strongargument that animal data overstate the riskto humans.
Quantification of Risk
It is not scientifically possible to determinethe slope of the carcinogenesis dose-responsecurve for any carcinogen at low exposure lev-els. Therefore, performing a low-dose extrap-olation involves the choice of a mathematicalfunction to model the dose-carcinogenic re-sponse relationship and the choice of statis-tical procedures to apply to the mathematicalfunction. The choice for this mathematicalfunction turns out to be extremely crucial tothe outcome of low-dose risk estimation. If theassumed relationship between tumor occur-rence and dose does not apply in the regionsto which the extrapolation is being made, aserious overestimate of the “safe” dose mayresult (Mantel and Bryan, 1961). For exam-ple, a comparison of five standard dose-re-
50
sponse models showed that they could differby many orders of magnitude at low doselevels for which extra risks are on the orderof 1/10’ (Chand and Heel, 1974),
It is theoretically possible to discriminateamong the various potential dose-responsefunctions on the basis of experimental data;however, two different dose-response func-tions can often fit experimental data equallywell but still differ by several orders ofmagnitude at very low doses. Moreover, evenif a particular dose-response function were togive a significantly better fit to data thanseveral others, this would still not furnishassurances that this function would neces-sarily correlate in any way with the true doseresponse at very low doses where it is notfeasible to measure the true extra risk direct-ly. As a consequence of the great disparity ofdose-response functions at low doses, thedose-response function should reflect knownor at least plausible information regardingthe biological mechanisms through which achemical induces or promotes cancer and notsolely on the basis of how well it can be madeto fit “experimental data. ”
For genotoxic carcinogens probably thesubstance itself or a metabolize acts directlyat the cellular level and produces a heredita-ble change that eventually leads to tumor for-mation (Crump et al., 1977), Carcinogens thatare carcinogenic by reason of their mutagen-icity should fall into this category. Therefore,carcinogens that test positively in the Sahno-nelJa/Ames mutagenicity screening test arevery likely to be genotoxic. As 90 percent ofthe known carcinogens tested have beenfound to be mutagenic, most known carcino-gens are probably genotoxic.
A partial solution to the low-dose extrap-olation problem for the case of genotoxicchemical carcinogens has been given (Crumpet al,, 1976; Guess and Crump, 1976; Pete,1977). The key result is that, at least as longas background carcinogenesis is present, thedose-response curve should not be expectedto be absolutely flat at zero dose. What thismeans is simply that when risk is plottedagainst dose response on ordinary linearscales, the tangent line to the dose-responsecurve at zero dose should have a positive
slope. When a dose-response function hasthis property, it is linear at low dose. Thissimple property can have far-reaching conse-quences on low-dose extrapolation. For exam-ple, consider the two potential dose-responsefunctions (1) 0.1 [(99/999) x d + (900/999) x
dz] and 0.1 x dz for the dose intervalos d s 3, Both of these curves give a risk of1/10 at a dose of d = 1 and are practicably in-distinguishable at higher doses. However, ata dose of d = 1/103 (1) predicts a risk of 1/105
and (2) predicts a risk of 1/107, a difference oftwo orders of magnitude.
One explanation of why the dose-responsefunction should be linear at low dose whenbackground is present is that the cellularmechanism through which the test agent pro-duces cancer should already be operative inproducing background tumors. When this istrue, the effect of the test agent is to add to analready ongoing process (Crump et al., 1976;Pete, 1977). If background carcinogenesis isallowed for by positing an effective back-ground dose, the wide range of risks obtainedusing different models effectively disappears.This does not imply that the dose-responsecurve is not expected to be linear at low dosein the absence of background carcinogenesis(Crumpet al., 1976; Watson, 1977).
The evidence for low-dose linearity givenabove applies mainly to genotoxic carcino-gens. A nongenotoxic carcinogen might causesome gross physiological change such as sup-pression of ovulation, which could predisposethe subject to cancer. For such carcinogensthe shape of the dose-response curve at lowdose is highly speculat ive. There couldpossibly be a threshold dose below which theagent has no carcinogenic effect at all on anindividual. However, even if a thresholdmechanism is operative, there is likely to beconsiderable variation in individual thresh-olds in a large population. Consequently, thedose-response curve for the entire populationcould still exhibit a linear trend at risks aslow as 1/10’ or lower,
The effects of metabolic activation and de-toxification on carcinogenic dose responsehave been recently considered through a ki-netic model that encompasses free toxic sub-stance, metabolize, deactivator, and the inter-
51
actions of these substances (Cornfield, 1977).Only a steady state situation is studied in thatvariation over time of the concentrations ofthese agents is not considered. The modelpredicts a threshold dose below which thereis no carcinogenic risk under the assumptionthat the deactivator is 100 percent efficient indeactivating the carcinogen. However, in anaturally occurring process it is likely thatdeactivation would not be perfect and wouldbe less than 100 percent effective in alwayscombining with 100 percent of the carcinogenbefore an amount of the active metabolizereaches a cancer target site. Any of a numberof modifications to the model to allow fornonperfect deactivation would rule out athreshold and would lead directly to a modelfor which carcinogenic response varieslinearly with dose at low doses. Cornfield’sown modification of perfect deactivation, thatof allowing the deactivating reaction to bereversible, leads, as Cornfield points out, to amodel that is linear at low dose. This occursregardless of how slowly the reverse reactiontakes place, as long as the possibility is noteliminated entirely. Furthermore, even in theextremely unlikely case of perfect deactiva-tion, an otherwise realistic model should stillimply low-dose linearity, since the theoreticaltime required for perfect deactivation wouldnot be zero and would likely be infinite.
For most, perhaps all, carcinogens, themechanisms through which cancer is pro-duced are not sufficiently understood so thatthe shape of the carcinogenic response curvecan be predicted with certainty. As pointedout earlier, experiments of sufficient sizecannot be conducted that would permit directexperimental investigation of the dose-re-sponse curve at low doses. There are plaus-ible arguments that the dose-response curveis linear at low dose for many carcinogens. Inview of these uncertainties, it would seemreasonable to base estimates of added risk ofcancer on a mathematical model that encom-passes low-dose linearity unless the mech-anism through which the carcinogen operatesis sufficiently understood so that low-doselinearity can be conclusively ruled out. Oncethe principle of low-dose linearity is ac-cepted, the problem of estimation of risks atlow doses is nearly solved. This is because the
disagreement between the upper statisticalconfidence bounds on risk at low doses basedon a model that incorporates low-dose linear-ity, and one that does not is typically severalorders of magnitude; whereas the corre-sponding disagreement between two reason-able models, both of which incorporate low-dose linearity, is usually much less than this.
The new procedures and criteria for evalu-ating the assays for carcinogenic residues inedible products of animals that FDA is at-tempting to implement (see chapter II) origi-nally adopted the Mantel-Bryan mathemati-cal model (Mantel and Bryan, 1961; Mantel etal., 1975) to quantify the residue level corre-sponding to a risk of 1/105 in test animals.This residue level, or So, is expressed as afraction of the total diet—i.e., in parts perbillion (ppb). This level is adjusted to accountfor the respective portion of the human dietthat is represented by the various food prod-ucts containing residues of the carcinogen be-ing tested, the transfer from animals to manbeing made on a fraction-of-total-diet basis.The resulting dose level, Sm, is “the level oftotal residue of carcinogenic concern thatcan be operationally defined as satisfying theno-residue requirement of the Act for specifictissues. ”g The dose level Sm represents theupper bound to the lowest limit of reliablemeasurement that an approved assay methodmust satisfy. The specific mathematicalmodel chosen is thus an integral part of defin-ing “no residue. ”
Crump (1978) discusses the Mantel-Bryanmodel, simple linear extrapolation models tolow doses (Heel et al., 1975; Brown, 1976),and multistage dose-response models (Guessand Crump, 1976, 1978; Crump et al., 1977;Hartley and Sielkin, 1977). In the Mantel-Bryan procedure, the mathematical modelused for the dose-response model is what istermed the “probit” function. The Mantel-Bryan procedure, as was to be applied in theFDA regulations, rules out linearity at lowdose in favor of a “flatness property” at lowdoses. This results in “safe” dose estimatesthat are considerably higher than those ob-tained using the multistage model because it
’42 F.R. 10422, Feb. 22, 1977.
52
assumes away linearity at low dose, an as-sumption that is probably unwarranted forthe majority of carcinogens, which appear tobe genotoxic. Figure 1 illustrates this dif-ference. Note that for the data reflected in
Figure 1.— C o m p a r i s o n s o f “ S a f e ” D o s e s C o m p u t e dFrom the Mantel-Bryan Procedure and From a
Procedure Based On the Mult istage Modela
1
1
%~
1
0-1Multistage maximumlikelihood curve
Mante l -Bryan“safe” dose
0.3 — curve
()-5 —
Multistage “safe”dose curve
108 1 ()-6
AcMedrisk10”4
10-2
Source Crump K S 1977 Response to ODen Query Theoret ical Problemsm the Mod!fled Mantel. B~an Procedure &omefr/cs 33 752 755
this graph, the Mantel-Bryan “safe” dose liesabove the multistage “safe” dose at values ofadded risk below 5 x 10 -4, When the Mantel-Bryan method predicts that a cancer risk isno greater than 1/10 6 the true risk could easi-ly be one or two orders of magnitude higher,or between 1/10’ and 1/105 (Crump, 1978).
FDA has now proposed that linear extrap-olation be used, rather than the Mantel-Bryan procedure, because, among other rea-sons, linear extrapolation is least likely tounderestimate the risk.
Since extrapolation based on the multi-stage model will often be linear at low doses,the question arises as to how different theresult will be from simple linear extrapola-tion. For some data the difference will beminimal, but for other data sets the differ-ence could be considerable, For example,
1044 F.R. 17070, Mar. 20, 1979.
from DES data in C3H female mice (Gass et al,1964), the “safe” dose based on linear ex-trapolation is lower than the “safe” dosebased on the multistage model by a factor ofabout five and there are doubtless caseswhere the difference could be greater thanan order of magnitude (10 x ).
Diethylstilbestrol (DES)
DES has been shown to be carcinogenic inboth animals and humans. The associationbetween the use of DES by women duringpregnancy and the appearance of clear-celladenocarcinoma of the vagina or cervix intheir exposed daughters was recently re-viewed by a task force at the National In-stitutes of Health (DES Task Force Report,1978). The main conclusions were as follows:
1.
2.
3,
DES daughters. A clear association be-tween in utero exposure to DES andclear-cell adenocarcinoma of the vaginaor cervix is established. Estimates arethat the incidence will be between 0.14to 1.4 per 1,000 through age 24 amongthe exposed daughters. Cancers of thistype and histological sites were almostunknown in women of that age group pri-or to this discovery. (The eventual inci-dence as these women grow older obvi-ously is unknown. )DES mothers. A relationship betweenDES during pregnancy and risk of can-cer in the mothers is unproved. How-ever, existing studies indicate that thispopulation, like others exposed to highlevels of estrogens, may in the futuredevelop excessive incidence of specifictumors.DES sons. Until recently, DES effects onexposed sons had not been reported. Re-cent studies clearly show an excess ofgenital abnormalities in these individ-uals. As yet, there is no definitive in-formation on the fertility implications ofthese findings nor firm evidence of anassociation between DES exposure insons and an increased risk of testicularcancer.
The animal data currently available oncarcinogenic dose response to DES consistsprimarily of mice data (Gass et al., 1964; Gasset al., 1974), although new experiments at the
53
National Center for Toxicological Research inJefferson, Ark., are nearing completion. DESwas given in the diet beginning from 4 to 6weeks after birth and continued throughouttheir lives. (Note that this is less than max-imum lifetime exposure, so the cancer re-sponse might have been greater.) The 1964micedata are summarizedin table 33.
Crump(1978) analyzed these data setsac-cording to specified methods for analyzinga n i m a l carcinogenicity data (Grump et al.,1977) to estimate the risks to mice at doselevels comparable to those encountered byhumans through DES residues in beef. 13e-cause suppression of appetite at the twohighest doses was reported, thedataat 500ppb and 1,000 ppb were omitted from anal-ysis.
The average food intake of Americans isabout 24 lbs a week (Riedman, 1971), about2.31bsof which is beef (CAST report, 1977).The lowest limits of reliable measurement ofthe FDA-approved mouse uterine method formeasuringDES residuesis 2ppb. Theconcen-tration of DES residues in liver is about 10times that in beef muscle (U.S. Congress,1971). Tested livers cannot exceed 2 ppb;otherwise DES would be detected and thepresent “no residue” test would be violated.Thus the average DES residue in beef musclemightbe 0.2 ppb. This gives an average doseof DES to Americans from DES residues inbeef muscle to be:
(2.3 lbs a week) X (0.2 ppb) = 0.02 ppb[24 lbs a week)
Table 34 summarizes the estimates of ex-tra cancer risks at the dose of 0.02 ppb basedon applying the multistage model and relatedstatistical theory to these mice data. The mostsensitive mice data predict a risk of I/13,000,and the least sensitive a risk of 1/82,000. Asexplained earlier, when the Mantel-Bryanmodel predicts a risk of 1/106, the true riskcould easily be between 1/10 4 and 1/10 5, orwithin the same range as summarized in table34.
Assuming that the population at risk is 200million people, lifetime exposure to DES inmeats at 0.02 ppb would result in 15,385 ex-tra cancers as derived from the most-sensi-tive mice strain (2OO million x 1/13,000), and3,390 or 2,439 extra cancers as derived fromthe less-sensitive mice results from table 34.These estimates should be compared with200 extra cancers, which would be the “noresidue” level of the 1/106 target risk from theproposed FDA regulation.
Table 35 summarizes the doses derivedfrom these same experimental data that re-sult in an added carcinogen response of 1/106,the target “no-residue” level of the proposedFDA regulation. In contrast to the 0.02 ppbestimate exposure to DES from present con-sumption of food, these doses are in the rangeof 0.001 to 0.0003 ppb, or 1/20 to 3/200 theestimated exposure.
The evidence for DES’s carcinogenicitypoints to a nongenotoxic mechanism, so an ef-fect at low doses can be disputed (Weisbur-ger, 1977). In addition, the response might be
Table 33. –Occurrence and Latent Period of Mammary Carcinoma in Mice Fed Varying Concentrationsof DES in the Diet (Gass et al., 1964)
C3H females C3H males Strain A castrate males
Percent Latent Percent Latent Percent LatentDES /n diet with period m with period In with period In
ppba No, ofmlce tumors weeks No of mice tumors weeks No. ofmlce tumors weekso 121 3 3 0 49,12 115 0 — 136 0 —6.25 56 4 8 2 49.96 59 0 — 78 0 —
125 60 4 3 3 46.57 58 17 – 78 1.3 620025 60 4 3 3 51.07 62 0 — 70 2 9 48,5050 68 5 2 9 45.19 62 4 8 66.00 77 3.9 69,66
100 64 6 5 6 42.19 60 5.0 4467 74 8.1 61.33500 59 8 4 7 30.66 60 38.3 3995 52 13,5 5400
1,000 58 86.2 31.40 71 42.3 36.03 76 19.7 4780
aMlce coflsu~ed approx[ma!ely 2 5 to 3 6 g Of food per day ammals recelvtng the two highest concentraflons consumed sllghtly leSS due 10 eStr09enlcsuppression of appeflfe ppb = parts per b[ll[on
SOURCE Crump 1978
54
Table 34.–Extra Risk of Mammary Tumors at a Dose of 0.02 ppb(Mice Data, Gass et al., 1964)
A40s/ //kc/y Upper 57 50/0M/cc slfaln es(lmale cmfdeme lmufld
L *JH fem[iles 1 / 13 ,000 118000C’3H males 1 8? 000 1 ’47 000S[r d n A castf Ate mdles 1 ~ndes 59000 1 ‘.37 000
Table 35.–Estimates of Dosage (ppb) of DES Required To Effectan Added Carcinogen Response of 1/108
(Mice Data, Gass et al., 1964)
Mosl //kc/y 10~ver 97 5%Mice s[rJ, “ t51/rna/e roh f)dence bound
C’3H Iemales [1 000258 0000162C’3H rTI+ e5 O 00164 0000944Sfr.j(n A caslr,ite mal?s 0170117 0000748
I 1. [ 1,1, I ‘?
largely limited to females. However, in bothanimal experiments and from what is knownabout DES effects in humans: (1) cancer isknown to occur even in the absence of con-tinuous DES stimulation, and (2) effects inmales have been observed, The rough esti-mates for the number of extra cases expectedin humans are for lifetime exposure risks. IfDES has a carcinogenic effect at low doses,these estimates would n(Jt be overstating [heef feet.
Nitrofurans
In 1964, in the course of conducting toxici-ty studies, scientists at the University ofWisconsin discovered that a substantial num-IJ~I’ of mammary tumors had developed inrats fed nitrofurazone. Subsequent studies in1966 and 1967 sho~ted that animals fed nitro-furans had significantly higher incidence oftumors, Sinre that time, Norwich PharmacalCompany has conducted four chronic toxicitystudies to assess the tumorigenic and car-cinogenic effects of one of these nitrofurans,furazolidone. In all of these studies, the ex-periments were started when the animalswer[~ about 2 months of age, and three ofthese studies fed furazolidone for a limitedperiod, followed by a furazolidone-free dietuntil the experiment was terminated. A morepronounced carcinogenic effect might havebeen observed if the doses had been con-tinued throu~hout the experiment.
Brief descriptions of these experiments fol-low:
1.
2
3.
4.
The High-Dose Sprague-Dawley R a tStudy .’’—Four hundred Sprague-Daw-ley rats approximately 2 months of agewere divided into four groups of 50 maleand 50 female rats each. The diet of thefour groups contained furazolidone inthe feed in the amounts of O ppm, 250ppm, 500 ppm, and 1,000 ppm for ap-proximately 18 months. All groups werethen maintained on a furazolidone-freed ie t un t i l mor ta l i t y in each g roupreached 90 percent, at which time theremaining animals were sacrificed.The Fischer Rat Study .’Z—This studywas performed identically to the High-Dose Sprague-Dawley Rat Study exceptthat Fischer 344 rats were used insteadof Sprague-Dawley rats.T h e L o w - D o s e Sprague-Dawley RatStudy .’3—Three hundred and twentySprague-Dawley rats approximately 2months old were divided into four groupsof 40 male and 40 female rats each. Thediet of the four groups contained fura-zolidone in the feed in the amounts of Oppm, 17.6 ppm, 87,9 ppm, and 264 .4ppm. These are average amounts sincethe concentrations of furazolidone in thediet were increased as the animals con-t inued to grow. The an imals weretreated continuously until the experi-ment was terminated after 2 years.The Mouse S tudy .’’—Four hundredSwiss MBRIICR mice approximately 2months of age were divided into fourgroups of 50 male and 50 female miceeach. The diets of the four groups con-tained furazolidone in the feed in theamounts of O ppm, 75 ppm, 150 ppm, and300 ppm for approximately 13 months.
‘‘“Tumorigenesis Evaluation of Nh’- 180 in Spra~ue-Dawley and Fischer Rats, Part 1. S~~r:~~~lc-Il:]\\l[:\ Eval-uation. ” Nov. 9, 1973, Projert No, 475.091),
‘“‘Tumorigenesis Evaluation of NF-180 in Spra~ue-Dawley and Fischer Rats, Part II, Fischer 344 Ev;~lua-tion, ” Jan. 31, 1974, Project No. 475.09D.
1‘i’Chronic Toxicopathologic Safety Study [two \’ears]of NF-180 in Rats,’” Nov. 9, 1973, Projert No. 475.09C.
““Tumorigenesis Evaluation [twentv-three months]of Furazolidone [NF- 180] in If ice. J:in. 31, 1974, Proj-ect No. 475.09E.
5 5
The four groups were then maintainedon a furazolidone-free diet for 10 addi-tional months, at which time the experi-ment was terminated and the survivinganimals were sacrificed.
Table 36 summarizes the tumorigenic andcarcinogenic findings. There is a high rate ofspontaneous tumors in all four groups. Themice results are the most sensitive. Althoughexposed to the lowest concentrations of fura-zolidone, they developed the greatest percent-ages of tumors, particularly when malignanttumors were separated from nonmalignantones.
The results of various statistical tests per-formed on the data are given in table 37. Achi-square goodness-of-fit test of no carcino-genic-dose-related effect is significant at the0.01 level of significance for four of the datasets. More importantly, a test of no dose-re-lated effect versus the alternative of a one-stage effect (a multistage model) is significantat the 0.01 level for six of the data sets in-cluding all four of the data sets for mice. Thusfurazolidone had a statistically significant ef-fect in mice. A chi-square goodness-of-fit testfor compatibility with the one-stage model ofcarcinogenesis was significant at the 0.05level in only z of the 16 data sets. The twodata sets for which significance was found
Table 36.–Summary of Tumorigenic and Carcinogenic ResultsFrom Four Experiments With Furazolidone (N F-180)
(Data is presented in the form “no. responders/no animalstested”)
High-doseSprague-Dawley RatStudy
Fischer 344Rat Study
Low-doseSprague-Dawley RatStudy
Mice Study
Dose(ppm)
o250500
1,000
0250500
1,000
01 7 68 7 9
2644
075
150300
SOURCE CrumD 1978
All neoplasms Malignant neoplasms. . . .Males29/5033/4935/5040/49
48/4949/5045/5044/49
21 /341 3/341 7/3523/32
25/493014836/5046/51
females44/9946/5048/5045/50
39/4946/5050/5045/50
26/3424/3529/3333/35
35/5035/5040/4742/48
Males10/5012/491 5/501 3/49
1 5/492/50
1 5/5013/49
3/345/349/356/32
21 /4926/4832/5043/51
~emales11 /496/50
12/5013/50
14/4910/5011 /5016/50
7/3411 /359/33
12/35
32/5028/5037/4740/48
Table 37.–Levels of Significance of Various Goodness-of-FitTests Performed on Data in Table 36
Test 1 Chl-square goodness-of-fit test (3 d, f.) of no dose-related effect.Test 2 Test of the hypothesis no dose-related effect versus the alter-
native hypothesis of a one-stage model (Crump, Guess, and Deal,1977)
Test 3 Cht-square goodness-of-fit test (2 d.f ) of a one-stage model
Test 1 Test 2 Test 3
High-dose Sprague -Dawley ratsAll neoplasms Males 31 < 01 92
F e m a l e s 64 49 47Mallgnant neoplasms Males 73 .21 64
Females 38 .18 25
Fischer ratsAll neoplasms Males 13 .50 06
Females. C 01 .05 01M a l i g n a n t neoplasms M a l e s < 0 1 28 < , 0 1
F e m a l e s 48 ,26 37
All neoplasms Males ,F e m a l e s .
M a l i g n a n t neoplasms M a l e sF e m a l e s
A l l neoplasms M a l e sFemales
Mallgnant neoplasms M a l e sFemales
SOURCE Crump 1978
Low-dose Sprague -Dawley rats03 .03 0703 < 0 1 4729 16 2361 17 61
SWISS MER IIBR mice< 01 < 01 72
05 < 01 47< (I1 < 01 76
.01 < 0 1 14
were quite anomalous and would likely not becompatible with any dose-response functionfor which the risk increases with increasingdose.
Before using these data to estimate extrarisks for furazolidone residues, it is firstnecessary to assess the level of furazolidoneresidue likely to occur in food products fromanimals exposed to furazolidone. In 1971 itwas announced by FDA that a method formeasuring residues of furazolidone would berequired that would reliably measure res-idues as low as 2 ppb. The FDA concluded in1976 that there was at that time no methodavailable for reliably measuring residues of 2ppb.15 Thus there currently is no way to knowif food products from animals treated withfurazolidone do not have at least 2 ppb inthem.
Table 38 presents estimates of extra risk ata dose of 2 ppb based on the rodent data intable 36. Since these estimates are all very
“41 F.R. 19919, May 13, 1976.
56
Table 38. –Estimates of Extra Risk From a Dose of Two Parts PerBillion of Furazolidone Using the Data in Table 36
Most hkeiy Upper 97 5%eslimate of confidence llmlLsextra risk for exfra nsk
H(gh-dose Sprague -Dawley ratsAll neoplasms Males 1/1 500000 1 /760 000
Females 1 /375 000,000 1/4 800000Mallgnant neoplasms Males 1/6 900,000 1/1 900,000
Females 1/6 900000 1/2 100,000
Fischer ratsAll neoplasms Males o 1/5 500,000Malignanl neoplasms Females 1 /9,400 000 1 /2,200,000
Low-dose Sprague -Daw/ey ratsAll neoplasms Males 1 /490,000 1 /21 0000
Females 1 /260,000 1 / 130,000Mallgnant neoplasms Males 1 i 1 300000 1 /430,000
Females 1 /’1 30(J 000 I f39(3 ()()(J
SWISS MBR IIBR mmeAll neoplasms Males 1 / 200,000 1 / 1 20,000”
Females 1 /470 000 I 1230,000Maltgnant neoplasms Males 1 /220,000 1 / 130000
Females 1 /420,000 1 /21 0000
nearly linear with dose at risks below 1 per-cent, risk estimates for other doses can bedetermined from the table by simply multiply-ing by the appropriate factor. For example, tocompute risks at zo ppb, multiply the resultsin table 38 by 10.
The risk estimates in table 38 are based onthe statistical procedures of Crump et al.(1977] associated with a multistage model. Toobtain the “most likely estimates, ” the par-ticular multistage model was selected (Guessand Crump, 1976) that maximized the likeli-hood of the data. Risk estimates are not givenfor the Fischer rats for “females, all neo-p lasm,” nor fo r “males, malignant neo-p l a s m , ” because these data are not consist-ent with the multistage model. For the mostsensitive result—namely, in the mice—theextra risk at a dose of 2 ppb furazolidone ex-ceeds the proposed regulatory “no residue”risk level of 1/ 10h by two to five times.
It should be noted that the estimates of riskare higher for the mice and low-dose ratsthan for the high-dose rats because the high-dose rats had lower or approximately equiv-alent tumor rates as rats and mice in theother experiments. High-dose rats were fed2 5 0 ppm, 500 ppm, or 1,000 ppm furazoli-done. Low-dose rats were fed approximately
17.6 ppm, 87.9 ppm, or 264.4 ppm furazoli-done; and the mice were fed 75 ppm, 150ppm, or 300 ppm furazolidone. When extrap-olated to extra risks from a dose of 2 ppbfurazolidone (table 38), the low-dose experi-ments result in higher incidence of tumorsthan the high-dose experiments.
Two ppb may be the residue level in meat,but it is not the dose to which humans are ex-posed. These risks can be translated at lowdoses for mice into comparable risks for hu-mans in the following way: Furazolidone isused extensively in chickens and turkeys andfor limited periods in swine, In the estimatesof effects from banning selected antibacteri-al, banning nitrofurans (of which furazoli-done is one) was estimated to have an effecton chickens and turkeys but not on pork. (Seetable 23.) Thus, human exposure from meatconsumption comes from chickens and tur-keys.
For DES, Americans were assumed to con-sume an average of 2,3 lbs of beef a week and24 lbs of food a week. Thus beef was assumedto average about 0.2 ppb DES, for an averagedose of 0.02 ppb, Taking a population of ap-proximately 200 million and a total beef sup-ply in 1976 of 25,969 million lbs (see table 22),the average amount of beef consumed byAmericans was approximately 2.3 Ibs a week(25,969 million lbs of beef - 200 million peo-ple - 52 weeks). This correlates with the 2.3lbs used in calculating the DES risk, whereaverage dose from DES residues was 0.02ppb.
A comparable calculation for furazolidoneis as follows: Total chicken and turkey pro-duction in 1976 was 10,930 million Ibs (table22). The average weekly consumption perperson was therefore:
I0,g30 million lbs 1.05 lbs— - 52 weeks = {l ~~,e[>k200 million people .,
Using the same caluclation as used forDES, the average dose of furazolidone perperson from residues in chicken and turkeymeat would he:
57
The estimates of extra risk in table 38 for adose of z ppb can be used to estimate therisks for other doses by multiplying by the ap-propriate factor, 0.09/2, or approximatelyI/ZO. Taking the most sensitive animal data,that for Swiss MBRIIBR mice, and multiply-ing by I/20, these risks are approximately 1- (4 x 10”); 1 - (9,4 x 10”); 1 - (4.4 x1O[)); and 1 - (8.4 x 10’). Thus the risk tohumans from furazolicione in poultry is 4 to 10times less than the target “no residue” risk of1/10’. In contrast to expected extra cancersof 200 for the “no residue” risk of l/l Ob, theseexposures to furazolidone are estimated toproduce 20 to 50 extra cases of cancer.
These estimates also can be illustrated bycontrasting the calculated exposure of hu-mans to furazolidone with estimates of thedose of furazolidone required to produce anextra risk of 1/10” (table 39). The most sen-sitive mice data result in doses of 0.41 to 0.95ppb, as contrasted to the 0.09 ppb dose calcu-lated for human exposure.
The mice and rat strains used in these ex-periments all had rather high spontaneousrates of both tumors and malignancies, Man-tel (1977) has not recommended using the
Table 39.–Estimates of Dose in Parts Per Billion of FurazolidoneRequired To Produce an Extra Risk of 1 /10’ Using the
Data in Table 36
H/g/) (fiJSt? s’~l,lgiwfl{~wk’y rdis
All neopldsms Males 30 1 5Females 750 9 5
Mallqnant neoplasms Males 137 39Females 139 41
F/scher rd(sAli neoplasrns Males — 402 ppmMaltgnant neoplasms Females 189 4 3
Low-dose Sprague l)dwley rdisA I neoplasms Males O 988 0429
Females O 527 0253M,]llgndnl neoplasms Mdles ? 58 0862
Females ? 56 0783
SIt/ss MBR 1 /t?f7 miceAll neoplasms Males 0410 0247
Fcmales O 946 0454Mallgndnt neophsms Males 0431 0265
Females O 836 0424
Mantel-Bryan procedure for data with highspontaneous rates, In his analysis of the ex-periments described here,lfi Mantel selected a“cut off” time and only considered tumors de-tected prior to this time. This modification ofthe data used by Mantel was applied to themice data and was found to have relativelylittle effect, the maximum change in the up-per confidence bounds on risk being less thana factor or two (Crump, 1978). Therefore, therisk estimates in table 38 would not havebeen significantly different if the test animalshad had a lower spontaneous rate of tumorproduction or if the data had been modifiedso as to discount tumors that occur late inlife.
There should be neither statistical northeoretical grounds for rejecting the riskestimates in table 38 as unreasonable esti-mates of rodent risk at 2 ppb. Each of the 14nitrofurans tested with the Salmonella/Amestest were mutagenic (McCann et al., 1975).Consequently, furazolidone should be con-sidered to be a genotoxic carcinogen with theproperty of being linear at low dose. The up-per confidence bounds on risk computed fromthe multistage model also have this property.(See figure 1.) Moreover, as is shown in table37, the multistage model cannot be ruled outon the basis of a chi-square goodness-of-fittest for those data sets for which risk esti-mates are listed in table 38,
Since the carcinogenic effect of furazoli-done in man has not been measured directly,data such as in table 36 constitute the cur-rently available dose-response informationfor estimating the carcinogenic risk to man.
The assumptions underlying the kinds ofrisk estimates as calculated for DES andfurazolidone are not unanimously accepted,and calculations based on different assump-tions could lead to different estimates. Thepoint of the foregoing quantitative exercisewas to test the usefulness of a target risk ap-proach to the definition of “no residue” andwhether that approach would avoid the prob-lem caused by using actual physical presenceof residues for the definition. As discussedearlier, technical improvements in measuring
I F [ 1! [, ‘ ~ ‘OIbid.
58
very minute quantities of residue have led toproblems in continuing to use the physicalpresence approach.
Present tI’DA regulatory authority is risk-oriented. A regulated substance must beshown to have its intended effect, but moreimportantly for this discussion, risks must beestimated because safety as well as effective-ness is a regulatory criterion. Thus, even ifthere were agreement that the 1/10’ ) a d d e dlifetime exposure risk of (~ancer was an ap-propriate definition of “no residue, ” deter-mining the amount of drug that correspondsto that risk level remains a problem.
Similar differences exist among research-ers in quantifying the benefits of using animaldrugs. The estimates summarized in the pre-vious chapter on benefits of thf~ use of certainantibacterial and DES produced differentquantitative results, even though the USDAand Headley analyses began with the samemodel,
In contrast to risk assessment, FDA’s regu-latory decisionmaking basis does not includea quantification of benefits. Furthcrrnore,FDA will not make an official estimate ofrelative effectiveness of the different drugsthey approve for similar uses, FDA’s positionis that the Agency does not deal in relative ef-fectiveness and that any product with thesame claims may be used interchangeably asa substitute for the others (FDA, 1979). TheUSDA and Headley analyses on benefits leadto different results, although starting fromthe same model. If FDA had to quan!ify bene-fits, it most likely would have reached ctiffer-ent quantitative results.
FDA does have to estimate risks. In con-trast to the estimate of cancer risks from DESand furazolidone included in this report, FDAhas indicated that, according to the estimatesthey have made, present DES and furazoli-done uses would lead to cancer risks in ex-cess of the proposed target risk of 1/10’) (FDA,1979). The difference in results comes pri-marily from two different assumptions. FDAuses the ninth decile for consumption distri-bution rather than average per capita con-
sumption “to provide protection for the vastmajority of the population. But use of aver-age per capita consumption does Ilot neces-sarily underestimate the risk to humans. Theestimates used here assumed all beef con-tained at least 2 ppb of DES, when in fact DESor other weight-promoting chemicals aregiven to about 80 percent of fed cattle. andFDA itself reports that DES has dropped con-siderably in the dollar-volume s;iles list.
Second, FDA is also concerned that risksoccur from both the parent drugs and theirmetabolizes and that for both DES and furo-zolidone, the parent drug represents only :)small percentage of the total residue, whichhas not been well-characterized or shown tobe safe. FDA states that: “VVithout identifica-tion and testing of the compounds which com-prise the residue, no estimates of risk are ofmuch value in judgin~ the safety of thp druguse. At best it may be said that the informa-tion available gives rise to the possibility thatresidue exposure may greatly exceed an ac-cepta ble level of risk from cancer’ (FDA,1979). The estimates used here were basedon residue levels that were at the limits ofdetection by methods presently approved byFDA, whereas FDA’s estimates ~re based onnewer methods not yet approved. In addition,if FDA’s use of the target-risk approach leadsto no practical difference on how regulatorydecisions are made, the FDA statement thatno estimates of risk are of much value with-out identification and testing of the metab-olizes raises the question of whether a target-risk approach is any improvement over physi-ca l p resence c r i t e r i a . Furthermore+ thiswould be a contradiction to the previouslyquoted statement by FDA’s Director of theBureau of Veterinary Medicine that the newmethod would “ p r o v i d e a m e c h a n i s mwhereby a reasonably safe level ma~ be es-tablished and then, irrespective of furtheranalytical developments, there will be thatexpectation that the originally set level willremain until toxicological evidence ratherthan analytical evidence [demonstrates that tobe an incorrect tolerance” (FCKJd ChemicalNews, oct. 16,1978).
59
APPENDIX
Commissioned PapersReferences
COMMISSIONED PAPERS
Chapters III and IV, which summarize the evidence on the benefits ancl risks of the use ofdrugs in livestock feeding, were based on reviews commissioned by the office of TechnologyAssessment and on a paper originally prepared for the Council for Agricultural Science andTechnology’s Task Force on Antibiotics in Animal Feeds. The authors and their reviews are asfol lows: -
W. M. BeesonProfessor Emeritus, Animal NutritionDepartment of Animal SciencePurdue University
Kenny S, CrumpProfessor of Mathematics and StatisticsLouisiana Technical University
George K. Davis, Professor of Animal ScienceInstitute of Food and Agricultural SciencesUniversity of Florida
L.C. Grumbles, HeadDepartment of Veterinary Microbiology and
ParasitologyCollege of Veterinary MedicineTexas A&M University
Virgil W. HaysProfessor and ChairmanDepar~ment of Animal SciencesUniversity of Kentucky
J.C. HeadleyProfessor of Production EconomicsUnivcrsit y of Missouri
Richard P. Novick, ChiefDepartment of Plasmid BiologyPublic Health Research InstituteCity of New York
}. H, ~’eisburger, Vice-PresidentResearch
American Health FoundationValhalla, New York
“Use of Drugs and Chemicals as FeedAdditives to Increase the Productivity ofCattle and Sheep”
“Estimating Human Risks From Drug FeedAdditives”
“Drugs and Chemicals as Feed Additives forthe Protection of the Health of Cattle, Sheep,and Goats’
“Protection of the Health and Performance ofPoultry and Swine by the Use of Drugs andChemicals as Feed Additives”
“Effectiveness of Feed Additive Usage ofAntibacterial Agents in Swine and PoultryProduction”
“Economic Aspects of Drug and ChemicalFeed Additives”
“Transmission of Bacterial Pathogens FromAnimals to Man With Special Reference toAntibiotic Resistance” (originally preparedfor the Council for Agricultural Science andTechnology’s Task Force on Antibiotics inAnimal Feeds, Ames, Iowa)
“Comments on the Physiological andPathological Effects of Diethylstilbestrol(DES)”
These papers are available from OTA on request.
63
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