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 Office

Washington, D.C. 20402
Foreword

This report addresses the question of the continued use of certain

drugs in livestock feed.

The assessment was undertaken at the request of Senator Herman

E. Talmadge, Chairman of the Senate Committee on Agriculture, Nutrition, and Forestry.

The Office of Technology Assessment utilized a diverse range of

personnel and methodologies for this assessment. An overall assessment advisory panel was appointed and individual papers dealing with

the key issues were commissioned. This work was supplemented by a

review of Food and Drug Administration documents, input from public

participation meetings, and critical review of draft reports by a wide

spectrum of individuals. These wide-ranging inputs from public interest

and consumer representatives, agribusiness and producers, scientific

experts, and Government officials helped shape the study and the congressional options. To all of these people OTA acknowledges a deep

debt. Without their individual and institutional assistance and cooperation the report would not have been possible. This report is an OTA staff

synthesis and does not necessarily reflect the position or views of any

particular individual.

/yzL#&-

JOHN H. GIBBONS

Director

. . . 111
OTA Food Program Staff

Joyce C. Lashof, Assistant Director

Health and Life Sciences Division

J. B. Cordaro, Group Manager

Phyllis Balan Elizabeth Galloway Yvonne Noel

Contractors

Lawrence Miike

Samuel Iker Walter Wilcox Marietta Whittlesey

Winrock International Livestock Research and Training Center

T. C. Byerly, Principal Investigator

E. K. Byington H. A. Fitzhugh

OTA Publishing Staff

John C. Holmes, Publishing Officer

Kathie S. Boss Joanne Heming

v
OTA Food Advisory Committee

David Call

Dean, College of Agricultural

and Life Sciences

Cornell University

Cy Carpenter

President

Mimesota Farmers Union

Martin E. Abel, Chairman

Senior Vice President, Schnittker Associates

Johanna Dwyer, Vice Chairmm

Director, Frances Stern Nutrition Center

Eliot Coleman

Director

Coolidge Center for the

Study of Agriculture

Almeta Edwards Fleming

Social Program Coordinator

Florence County, S.C.

Lorne Greene

Chairman of the Board

American Freedom From

Hunger Foundation

Richard L. Hall

Vice President, Science and

Technology

McCormick & Company, Inc.

Laura Heuser

Member, Board of Directors

Agricultural Council of America

Arnold Mayer

Legislative Representative

Amalgamated Meat Cutters and

Butcher Workmen of North

America

Max Milner

Executive Director

American Institute of Nutrition

Robert O. Nesheim

Vice President, Science and

Technology

The Quaker Oats Company

Advisory Working Group

H. R. Bird

Professor of Poultry Science

University of Wisconsin

David B. Clayson

Deputy Director

Eppley Institute for Research on

Cancer and Allied Diseases

W. W. Cochrane

Professor of Agricultural

Economics

University of Minnesota

Ruth Desmond

President

American Federation of

Homemakers

vi

Lauren Seth, Chairman

Agricultural Consultant

Charles M. Dobbins

Associate Dean

College of Veterinary Medicine

University of Georgia

S. T. Donta

Director of Infectious Disease

Services

Department of Medicine

University of Iowa Medical School

C. M. Hardin

Director of Research

Ralston-Purina Feed Company

Kenneth Monfort

Chairman of the Board

Monfort of Colorado

Kathleen O’Reilly

Director

Consumer Federation of America

R. Demis Rouse

Dean, School of Agriculture

Auburn University

Lauren Seth

Agricultural Consultant

Thomas Sporleder

Professor of Agricultural

Economics

Texas A&M University

Sylvan Wittwer

Director and Assistant Dean

College of Agriculture and

Natural Resources

Michigan State University

Sheldon Murphy

Professor and Director, Division

of Toxicology

Department of Pharmacology

University of Texas Medical

School

Pauline Paul

Acting Head, Foods and Nutrition

Human Resources and Family

Studies

University of Illinois

Virgil Rosendale

President

Pork Producers Council

James S. Turner

Co-Director

Consumer Action for Improved

Drugs
Attendance at Public Participation Meeting

September 12, 1977

Lauren Seth, Chairman

OTA: J.B. Cordaro

Walter Wilcox

John B. Adams

National Milk Producers Federation

George Allen

Economic Research Service

U.S. Department of Agriculture

Selma P. Baron

Committee on Animal Nutrition

National Research Council

National Academy of Sciences

James R. Bean

Office of Toxic Substances

Environmental Protection Agency

John J. Birdsall

American Meat Institute

Ann Bornstein

National Farmers Organization

Jerry Brunton

Animal Health Institute

Grace Clark

Food Safety and Quality Service

U.S. Department of Agriculture

Mitchell L. Cohen

Bacterial Disease Division

Center for Disease Control

U.S. Department of Health,

Education. and Welfare

Stephanie C. Crocco

Department of Foods and Nutrition

American Medical Association

Robert Elder

Office of Science

Food and Drug Administration

U.S. Department of Health,

Education, and Welfare

Burton Eller

National Cattlemen’s Association

W. G. Flamm

National Cancer Institute

National Institutes of Health

U.S. Department of Health,

Education, and Welfare

Frank Frazier

American Agribusiness Associates

J. Marvin Garner

National Pork Producers Council

Roger J. Gerrits

Livestock and Veterinary Science

Agriculture Research Service

U.S. Department of Agriculture

Mary T. Goodwin

Montgomery Count y Health

Department

State of Maryland

Richard H. Gustafson

American Cyanamid Company

Donald L. Houston

Meat and Poultry Inspection Program

Food Safety and Quality Service

U.S. Department of Agriculture

C. D. Van Houweling

Bureau of Veterinary Medicine

Food and Drug Administration

U.S. Department of Health,

Education, and Welfare

Robert W. Keirs

Poultry & Egg Institute of America

Terry B. Kinney

Agricultural Research Service

U.S. Department of Agriculture

Catherine A. Koob

Koob Associates

Robert Lenahan

U.S. Department of Agriculture

Fred H. McDiarmid

Biochemical Department

DuPont Company

Ian McNett

Free-lance Writer

Kirk Miller

American Farm Bureau Federation

Natalie Pargas

Food Chemical News

Maryln K. Perez

Bureau of Foods

Food and Drug Administration

U.S. Department of Health,

Education, and Welfare

Bill Roenigk

National Broiler Council

Phillip Ross

Board on Agriculture and Renewable

Resources

National Academy of Sciences

John W. Thomas

American Veterinary Medical

Association

G. L. Waits

National Turkey Federation

Winrock International Livestock

Research and Training Center:

T. C. Byerly, Principal Investigator

E, K. Byington

H. A. Fitzhugh

Charles E. Wismer, Jr,

vii
Attendance at Public Participation Meeting

April 21, 1978

Lauren Seth, Chairman

Agricultural Consultant

OTA: J, B. Cordaro

Nancy Ikeda

Walter Wilcox

Cathie Woteki

L. E. Barnes

Diamond Shamrock Company

Jerry Brunton

Animal Health Institute

Clark R. Burbee

Economics, Statistics, and

Cooperatives Service,

U.S. Department of Agriculture

Nancj’ J. Cole

National Cotton Council

Stephanie C. Crocco

Department of Foods and Nutrition

American Medical Association

Ruth G. Desmond

Federation of Homemakers

Burton Eller

National Cattlemen’s Association

John Farnham

American Cyanamid Company

Ann Cottrell Free

Rachel Carson Trust

Roger J. Gerrits

Livestock and Veterinary Science

Agriculture Research Service

U.S. Department of Agriculture

Rosa Gryder

Bureau of Veterinary Medicine

Food and Drug Administration

U.S. Department of Health,

Education, and Welfare

Richard H. Gustafson

American Cyanamid Company

Frederick S. Hird, Jr.

Vineland Laboratories, Inc.

Harry W, Jamison, Jr.

American Cyanamid Company

Cornell Johnson

Diamond Shamrock Company

Fritz Kessinger

Animal Health Institute

Irene Kiefer

American Chemical Society

Robert L. Koob

Koob Associates

Robert Lenahan

U.S. Department of Agriculture

Kirk Miller

American Farm Bureau Federation

Patty Mitchell

Food Chemical News

Neil Robin

Consumer Affairs

The White House

Thomas B. Smith

Community Nut rition Institute

I.A. Solomons

Pfizer Company

John W. Thomas

American Veterinary Medical

Association

Ann W. Turner

Rachelle Labs

C, D. Van Houweling

Bureau of Veterinary Medicine

Food and Drug Administration

U.S. Department of Health,

Education, and Welfare

G. L. Waits

National Turkey Federation

Winrock International Livestock

Research and Training Center:

T. C. Byerly, Principal Investigator

E. 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. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . , ..., , . . . . . . .

Appendix

Commissioned Papers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1

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36

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63

64

Fig[frt:J\’f). P(lpc

1. Comparisonsof S;] feDoses[~ompllte(l FronltheL lantel-Brvan Procedure and

Froma Proce(lure13:ised on the hlultistagc klo(iel, , . . . . . . . . . . . . . . . . . . . . . . . . . 53

ix
LIST OF TABLES

Table No, Page

l, Approved Uses for Penicillin in Chicken Feeds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

2. ApprovedUses forPenicillin inTurkeyFeeds ..,... . . . . . . . . . . . . . . . . . . . . . . . . 23

3. ApprovedUses forPenicillin inSwineFeeds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

4. ApprovedUses forTetracycline inChickenFeeds. . . . . . . . . . . . . . . . . . . . . . . . . ., 24

5. ApprovedUses forTetracycline inTurkeyFeeds . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

6. ApprovedUses forTetracycline inSwineFeeds . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

7. ApprovedUses forTetracycline inCattleand SheepFeeds . . . . . . . . . . . . . . . . . . . 24

8. ApprovedUses for Sulfa inAnimalFeeds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

9. ApprovedUses forNitrofurans inAnimalFeeds . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

10. ApprovedUses forDiethylstilbestrol inFoodAnimals . . . . . . . . . . . . . . . . . . . . . . . 25

11. Effect ofChlortetracycline onWeightGainsofPigsin Different Environments. . . . 30

12. ResponseofChicks to Chlortetracycline (CTC) and Penicillin inNewand

PreviouslyUsed Environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

13. Relationship Between Growth Rate ofControl Animals and Animals Fed

Antibiotics(Pigs) ....,. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

14. Relationship Between Growth Rate ofControl Pigs and Pigs Fed a Combination

ofPenicillinand Streptomycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

15. Effect ofa ’’Nonspecific Infection’’ onChickGrowth. . . . . . . . . . . . . . . . . . . . . . . . . 31

16. ResponseofPigs toAntibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

17, Continued Effectiveness ofTetracyclinein Swine . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

18. ResponseofChickens toAntibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

19. ImprovementinChick Performance: AllYearsVersus Since 1970, . . . . . . . . . . . . . 33

20, Effect of Selected Antibiotics onEggProduction, FeedPerDozenEggs, and

Matchability. ....,.... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

21. ReponseofTurkeysto Antibiotics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

22. Production ofMeatAnimals, 1976 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

23. Estimated Percentage Change in Livestock Production From Banning

Selected Antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

24. EstimatedDecreasein LivestockProductionFrom BanningSelectedAntibiotics . . 35

25. PercentChangeinQuantity ofMeatFromaBanonthe UseofSelectedAntibiotics 36

26. Percent ChangeinFarm Prices From aBanonthe Subtherapeutic Usesof

SelectedAntibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

27. Percent Change in Retail PriceFroma Ban on the Subtherapeutic Uses ofSelected

Antibiotics ....,..,. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

28. NoDrugVersusMGA VersusDESVersus Estrogen Implant. . . . . . . . . . . . . . . . . . . 38

29. Percent Changeson the Supply, Farm Prices, and Retail PricesofBeefFrom

aDESBan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

30. HomologyBetweenPlasmids ofAnimal andHumanOrigin. . . . . . . . . . . . . . . . . . . . 44

31. Antibiotic Resistance in Salmonella Isolated From Hospitalized Patients . . . . . . . . 45

32. Incidence ofViolations Among Different Antibiotics inKidneys From

Food Animals.....,.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

33. Occurrence andLatent Periods of Mammary Carcinoma inMiceFedVarying

Concentrations ofDESinthe Diet. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54

34. Extra RiskofMammary Tumors ataDoseofO.02ppb. . . . . . . . . . . . . . . . . . . . . . . . 55

35. Estimates ofDosage(ppb) ofDESRequired ToEffect anAddedCarcinogen

Responseof l/lOb. .,.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55

36. Summary ofTumorigenic and Carcinogenic Results From Four Experiments

WithFurazolidone, . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56

37. Levels ofSignificance of Various Goodness-of-Fit Tests PerformedonDatain

Table 36.,....,.,,,.. , . .,, ., . .,, . .,, .,,,... . . . . . . . . . . . . . . . . . . . . . . . . . 56

38. Estimates ofExtraRisk Froma DoseofTwoPartsPer Billion of FurazolidoneUsing

theDatainTable36 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

39. 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 bacteria

constituting the greater part of the intestinal flora of man and other animals and

occasionally pathogenic for man.

Enteric: Of or relating to the intestines.

Feed efficiency: The use of certain drugs

which results in animals gaining more

weight than animals not given such drugs

for the same amount of feed consumed.

Genotoxic: A toxic effect on the chromosomes—for example, mutation. In the context of cancer-causing agents, the hypothesis is that the agent acts directly on the

chromosomes to cause cancer.

Gram-negative or gram-positive: A method of

identifying bacteria, related to the color

they retain in the gram’s method of staining for microscopic examination. Bacteria

are usually identified as being either

gram-negative or gram-positive.

H. influenza: A species of gram-negative bacteria that may cause meningitis in infants

and young children related to a respiratory tract infection.

N. gonorrhea: A species of gram-negative

bacteria that is the specific causative

agent of gonorrhea.

Nongenotoxic: In the context of cancer-causing agents, the hypothesis is that the

agent acts indirectly to cause cancer. For

example, the agent may enhance or promote the ability of a genotoxic agent to

cause cancer but cannot cause cancer by

itself.

Nonpathogen: An agent not usually capable

of causing disease.

1/106 extra lifetime risk of cancer: A method

of quantifying risk to humans from exposure (e.g., ingestion) to a specified amount

of a cancer-causing substance over a lifetime for regulatory purposes. It is derived

from extrapolation of cancer rates in laboratory animals (e.g., rats) exposed to the

substance over their lifetimes. For example, if a daily dose of x over the animals’

lifetimes leads to a cancer rate of 1/100 in

the experimental animals, the extrapolation model might be used to predict what

daily dose over the human lifetime would

lead to a cancer rate of 1/10’. Alternatively, the model might be used to predict

what the cancer rate would be in humans

for the average daily lifetime consumption of the carcinogenic substance by

humans.

Pathogen: An agent, such as a bacterium or

virus, capable of causing disease.

Salmonella: Any of a genus of gram-negative

bacteria that are pathogenic for man and

other warm-blooded animals, usually

causing intestinal disease such as food

poisoning.

Subtherapeutic: The use of drugs where the

doses given are less than that which

would be used if disease were present. In

the context of the use of antibiotics in

animal feeds, these uses include prevention of disease and the weight-promotion

and feed-efficiency effects of certain antibiotics.

Therapeutic: Treatment of known disease

with drug doses that are high enough to

eradicate or control the disease agent.

Weight promotion: The use of certain drugs

which results in animals growing faster

than animals not given such drugs over

the same time period and for the same

amount of feed consumed.
Chapter I

SUMMARY

INTRODUCTION

Over the past three decades drugs have

been used increasingly in the rearing of animals for human consumption. The drugs can

be administered via drinking water or feed,

they can be injected, or pellets can be inserted under the animal’s skin. This is done

for five reasons:

1, As nutritional supplementation such as

vitamins 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 antibacterials* produced in the United States are used

as animal feed additives and for other nonhuman purposes, Nearly 100 percent of poultry, 90 percent of swine and veal calves, and

60 percent of cattle receive antibacterial feed

supplementation. About 70 percent of U.S.

beef by carcass weight comes from cattle

that have received weight-promoting feed

supplement tion.

This widespread use of drugs in livestock

production has led to increasing concern over

potential adverse effects on human health for

two reasons:

I. Many of the same antibacterial are

used both in human therapy and in animal feeds. The use of these drugs as feed

additives contributes to a growing pool

of drug-resistant bacteria, Physicians

are now reporting reduced effectiveness

of these same drugs in treating human

disease. Some bacteria are resistant to

.—_-———

*The term “anti bacteria]s ” includes antibiotics and

chemicals w’i !h similar action, Other technical terms

a re defined i n t h e g 1 oss a r v.

2

several antibacterial; others require

higher doses to control or kill them. Research findings point to animal feeds as

a contributory source of rnanv of these

drug-resistant bacteria.

Residues of other drugs found in animal

products such as meat and eggs are potentially carcinogenic and may be

passed on to consumers.

There is much disagreement among scientists as to the validity of many of the findings

and the weight that should be attributed to

them when considering a ban or restrictions

on the use of these drugs. The two main areas

of dispute are:

I, What the effects are on human morbidity and mortality,

2. What tradeoffs there should properly be

between risks and benefits.

Therefore, at the request of the Chairman

of the Senate Committee on Agriculture, Nutrition, and Forestry, the Office of Technology

Assessment (OTA) undertook an assessment

of the use of drugs as feed additives in livestock and poultry production, with particular

emphasis on the following concerns:

● The benefits to livestock producers from

the use of each category of drugs used as

feed additives,

The established or potential risks from

the use of each category of drugs,

The available alternatives to the continued use of each category of drugs,

The acceptable risks in the use of each

category of drugs,

The options available to Congress to improve regulation of drugs used in livestock feeds.

3
This report summarizes the evidence on

risks and benefits and the relevant regulatory

and public-policy background against which

this assessment takes place. Since the use of

drugs in animal feeds either as nutritional

supplements or for therapeutic purposes is

relatively noncontroversial, this report

focuses on the addition of low levels of antibacterial to feeds and on diethylstilbestrol

(DES), a synthetic estrogenic hormone which

is a proven human carcinogen. DES pellets

are implanted under the skin or added to the

diet to increase feed efficiency and promote

growth in beef cattle.

Since estimates on risks and benefits of

supplemental drugs in animal production are

based on numerous complex factors, no one

set of figures can confidently be used in any

quantitative estimates of risks versus benefits. This difficulty in assigning precise

figures has contributed greatly to the complexity of the debate over the safety of drugs

in animal feeds.

HOW THE DRUGS ARE USED

Doses lower than the usual therapeutic

level are given to poultry, cattle, swine, and

calves to promote weight gain, to prevent disease, and to increase feed efficiency, thus increasing the meat yield per pound of feed

used. The drugs most often used are: tetracycline, penicillins, sulfas, nitrofurans, and

DES. DES is different from other drugs used

in animal feeds, as it is not an antibacterial

but rather a synthetic estrogen.

It is not known precisely how the antibacterial work to increase weight gain and feed

efficiency. At least three modes of action

have been postulated, but there is still disagreement among scientists on this point:

1.

2.

3.

A Nutrient-Sparing Effect in which the

drugs reduce the animal’s dietary requirements either by stimulating the

growth of beneficial organisms that synthesize vitamins and other essential nutrients or by depressing the organisms

that compete with the host animal for

nutrients, or by increasing the capacity

of the animal’s intestinal tract to absorb

nutrients.

A Metabolic Effect in which the antibacterial directly affects the rate or pattern

of metabolic processes in the animal.

A Disease-Control Effect in which the

drugs suppress those organisms that

cause disease in animals of such a low

level that symptoms are not apparent

but the animal’s weight gain is reduced.

It is thought that the disease-control effect

is the most responsible for growth promotion.

4

It has been demonstrated that the degree of

response to antibacterial feed supplements is

inversely related to the general well-being of

the experimental animals. Healthy, wellnourished animals do not respond to antibacterial when housed in carefully cleaned and

disinfected quarters that have not previously

housed other animals. While such a level of

sanitation is usually not practical for the

large-scale animal producer, it does suggest

that it is through the prevention of diseases

that drugs promote growth.

When FDA approves a use of an antibacterial for a purpose other than the treatment of

disease, the Agency specifies whether the

drug is approved for growth promotion, feed

efficiency, or disease prevention. However,

these are somewhat artificial distinctions,

since it is impossible to point to growth promotion or increased feed efficiency or disease

control as being responsible for the improved

product yield. It is possible that the effect is a

result of all three. Furthermore, a completed

feed mix may well contain drugs approved for

all three uses anyway.

The safety debate arises from the widespread continuous use of antibacterial. The

deleterious effects of the drugs appear regardless of the uses for which they are approved. Thus the actions of the drugs are so

overlapping that distinctions based on intended purpose are irrelevant insofar as

safety is concerned.
BENEF

The benefits of using antibacterial in animal feeds are:

. The prevention of disease,

c The promotion of growth, and

● The improvement of feed efficiency.

The evidence points to the disease-prevention effect as being primarily responsible for

increased weight gain.

While increased weight gain resulting from

low doses of antibacterial and DES is not in

dispute, the amount of gain is. Even though

drugs may increase weight gain by only a few

percentage points, the absolute increase is

large because of the size of the livestock market.

Present levels of livestock production do

not depend specifically on the use of DES and

the addition of low levels of tetracycline,

penicillins, sulfa, and nitrofurans to feeds because substitute drugs are available. In addition, if adopted, the current Food and Drug

Administration (FDA) proposal to restrict but

not totally ban the most widely used antibiotic, tetracycline, could mitigate the impact

of banning or restricting other drugs used for

this purpose,

The economic consequences of such decisions, however, are a separate matter because marginal increases or decreases in

production may make the critical difference

in the profitability of the livestock industry,

Economic dislocations within subsectors of

the livestock market could be significant over

ITS

the short term. Such economic effects are

often raised in objections to proposed

changes in regulations, but present statutory

authority limits FDA’s decisionary basis to

scientific evidence of effectiveness and safety. Although under present law FDA does

consider the practicality of achieving the

desired result of regulatory changes, FDA

does not explicitly consider the economic consequences of these changes. When FDA’s

proposed regulations have been successfully

challenged, it has usually been on the

grounds that FDA’s procedures, rather than

the substance of the law, were faulty.

There may soon be an opportunity to observe whether or not the banning of antibacterial will result in significant changes in

production. FDA has withdrawn approval of

one of the four nitrofurans, an antibacterial

originally approved for food animal use, and

will soon enter hearings on the remaining approvals. One of these, furazolidone, is the

most widely used. Predictions point to no effect on beef and pork production but to significant short-term effects on poultry production. (See tables 23 and 24, ) Penicillin and

tetracycline are also widely used in poultry,

and their uses overlap extensively with the nitrofurans. (See tables I, 2, 4, 5, and 9.) Even if

penicillin were banned subsequently, tetracycline would remain available, since FDA’s

proposal would allow its continued use if

alternatives were unavailable. If these antibacterial cannot replace nitrofurans, effects

should be observed immediately.

RISKS FROM CONTINUED USE OF THE DRUGS

The risks from the use of antibacterial in

animal feeds stem from an increase in bacterial resistance to the drugs. Drug-sensitive

bacteria are killed or inhibited by the drug,

allowing resistant bacteria, which have

adapted to the presence of the drug, to grow

in their place, While drug-resistant variants

exist even in the absence of antibacterial,

they do not generally flourish unless a change

in their environment favors their survival.

When antibacterial are given, the drug-resistant bacteria are the fittest to survive in

their presence, and they soon become the majority,

Genes for antibiotic resistance as well as

its transfer are carried on structures called

plasmids, which are bits of DNA that function

independently of the organism’s main genetic

apparatus. Plasmids can transfer resistance

5
between bacteria of the same or of different

species. Thus harmless resident bacteria,

such as E. co]i, which are present in the intestines of humans and animals, can become

resistant in the presence of the drugs and can

then transfer their resistance to a still sensitive strain of a more virulent pathogen such

as Salmonella. The result of such a transfer

would be a strain of Salmonella that was

resistant to one or more antibacterial. The

resident bacteria in the intestines of animals

and humans receiving antibacterial are soon

replaced with resistant resident bacteria and

thus serve as a reservoir for the spread of

plasmid-mediated resistance to antibacteria l .

While research attention was originally

focused on the transfer of drug resistance

from E. coli to other intestinal microorganisms, principally Salmonella, it is now evident that the spread is wider. There is now

strong evidence that similar transfers occur

between H. influenza and N. gonorrhea and

resistant E. coli. Thus the risks are no longer

restricted to people who may have picked up

Salmonella directly from animals or their edible products.

N. gonorrhea and H. in~luenza are harbored by humans. For these bacteria to have

acquired plasmids for the transfer of resistance means that the plasmids are traveling in

a wider radius than was originally predicted.

For instance, identical plasmids have been

isolated in parts of the world as distant as

England and Vietnam,

In a sampling of E. co]i from a freshwater

river system and within the saltwater bay

into which it emptied, it was found that nearly all the freshwater sites and about half the

saltwater sites sampled contained resistant

coliforms. Twenty percent of the strains contained resistance plasmids carrying multiple

drug resistance transferable to sensitive E.

coli and to S, typhimurium and S. dysenteriae

(the bacteria which cause typhoid and dysentery).

Furthermore, plasmids are now carrying

genes for resistance to more than one drug.

Whereas formerly this was rare, it is now

common, if not usual, for bacteria to be resistant to several drugs at a time. It is now necessary for physicians to run sensitivity tests to

determine alternative drugs to which a given

strain of bacteria is still sensitive. Certain

strains of gonorrhea and typhoid, among

others, have proven more difficult to treat

than formerly as a result of resistance to the

standard drug of choice.

The extent of the decrement in performance of antibacterial used in treating human

and animal disease is still relatively unknown, The relationship between decreased

sensitivity and decreased effectiveness in

treating disease is complicated because many

variables such as species, general health,

and numbers of invading bacteria influence

whether known pathogenic bacteria will

cause observable disease and whether a specific drug will make the difference in outcome

when disease does occur, This is particularly

true for Salmonella, the bacteria on which

much attention has been focused, However,

FDA estimated that in 27 percent of the Salmonella cases treated each year, the first antibacterial chosen for treatment proved to be

ineffective because the disease was caused

by antibacterial-resistant bacteria.

Another risk from the use of antibacterial

feed additives is that it eventually compromises therapeutic and prophylactic effects of

the same drugs. Even though stopping the use

of an antibacterial can be expected to result

in the loss of dominance of resistant bacterial

strains, these strains can persist in diminished but significant numbers. If growth promotion and feed efficiency are closely dependent on disease prevention, the effectiveness of supplemental antibacterial feeding

will decline.

Noncarcinogenic drug residues pose little

direct risk to consumers if tolerances are

adequately established and the residues are

below tolerance levels. But the sulfamethazine findings discussed in this report indicate

that the majority of concentrations of residues above allowable limits results from the

unintended cross-contamination of feeds during mixing. This may be occurring particularly with penicillin and tetracycline, since

they are widely used and mixing is not limited

to certified feed mills or done under a veterinarian’s prescription, Cross-contamination

6
would increase the risk of plasmid-mediated

drug resistance because such cross-contamination would mean that the extent of supplemental feeding of antibacterial is even

higher than that of recognized, approved

uses, Because tissue residues in general may

not be good indicators of cross-contamination, the extent of cross-contamination needs

to be monitored directly.

The risk from resistant plasmids of animal

origin is not quantifiable even by the rough

estimates made for Salmonella infections.

The majority of resistance in human bacterial

populations is probably caused by widespread use of antibacterial in humans (some

of which are unnecessary), but the enormous

pool of R-plasmids that now exists in animals,

together with the ability of an R-plasmid to be

promiscuously transferred among bacterial

species, must be regarded as a threat to the

therapeutic value of antibacterial in the

treatment of both human and animal diseases.

CARCINOGENIC DRUG RESIDUES

DES and the nitrofurans pose risks because they are carcinogenic and may leave

residues in animal products such as meat and

eggs. The effort to determine carcinogenic

risks from drug residue is complicated by two

factors:

1, The difficulty of extrapolating data obtained from animal experiments to man,

and

2. Analytical problems in measuring a “no

residue’ level.

Although carcinogenesis in laboratory animals is accepted as proof of a probable carcinogenic effect in humans, extrapolation techniques to determine the amount of cancers

expected in humans are still embryonic in

nature and subject to validation on a case-bycase basis. To conduct the tests using doses

comparable to that ingested by humans

would require a far larger sample—hundreds of thousands as opposed to hundreds—

of animals, Therefore, tests are conducted

with much larger doses and the results extrapolated back down.

Because of the increasing sensitivity of

newer assay methods to smaller amounts of

residue, FDA is attempting to define “no residue’ on the basis of a “practical threshold” —i.e., that threshold below which the

risk of cancer is statistically negligible rather

than on the basis of absolute zero residue.

Otherwise, standards must be revised with

the appearance of each new assay method

that can detect the presence of a minute level

which the previous method was not quite sensitive enough to detect. Accordingly, FDA

proposes to define “no residue” as the quantity leading to an extra risk of 1 in I million

(1/10’) of developing cancer over a lifetime of

exposure,

Furazolidone is assumed to cause cancer

by heritable damage to the genetic system of

the host cells that eventually leads to tumor

formation. Thus there is probably no level at

which it is absolutely safe. Using a model

which assumes that there is no safe threshold

to extrapolate from animal data to humans,

an extra risk of l/l OG from furazolidone can

be correlated to furazolidone residue levels in

foods consumed by humans. Assuming that

foods contain at least as much furazolidone

as would be detected by FDA’s proposed

quantitative assay standards for furazolidone and using average consumption figures,

the risks to humans from ingestion of foods

containing furazolidone residues are less

than the 1/10’ Iifetime exposure risk. Using

the high consumption population as the group

at risk, the risk may approach 1/106.

DES, a female hormone, has been associated with cancer in the daughters of women

who took the hormone during pregnancy. In

contrast to furazolidone, there is evidence

that DES’s carcinogenic action is through promoting the effect of substances that can produce cancer directly. This would mean that

its carcinogenic action is caused not by

heritable genetic damage but more likely by

its estrogenic action. It is therefore likely that

a threshold exists below which DES content

7

1
will not be sufficient to cause tumors. Using

an extrapolation model for estimating risks

that assumes such a threshold, the tissue

level obtained falls in the approximate range

FDA has set as associated with the “no residue” level. Obviously, such a measurement is

not absolute, but rather is relative to risk. If,

on the other hand, no threshold is assumed

and if any level is considered carcinogenic,

different extrapolation models would be used

and would predict for the same tissue levels

of DES risks from 10 to 100 times the I/IOti

lifetime exposure risk associated with the

“practical threshold” level. However, at

present, there is no assay method presently

approved that is sensitive enough to measure

DES at these levels.

ASSESSING AND QUANTIFYING RISKS AND BENEFITS

Risk-benefit assessments, in view of the

kinds of evidence on benefits and risks reviewed in this report, are not only difficult to

conduct but also difficult to use in making

regulatory decisions or in revising the underlying statutory authorities.

The risks and benefits of drugs used to increase food animal production share some

common attributes: (I) laboratory evidence

provides scientific support for the identified

benefits and risks; (z) effects expected in actual use can be shown in selected experiments, but it is often unclear whether the precise biochemical and or metabolic processes

observed in the laboratory setting are responsible; and (3) quantification of the effects,

whether it be extra pounds of meat or extra

cases of cancer produced, are too imprecise

to yield reliable figures, although such figures

a r e useful for predicting the genera l

magnitude of the expected effects. Such

quantitative estimates of risks or benefits

often are made with a degree of precision

that is justified only within the statistical

boundaries of a particular experiment. Once

removed from the structured experimental

setting, these numbers retain an aura of legitimacy that may not be warranted. This is not

only true for the kinds of simple calculations

included in this report for the risk from Salmonella infections or the risk of cancer from

DES or furazolidone but also for the expected

effectiveness of the drugs discussed in this

report. Typically, the experiments that quantify the effect of antibacterial or DES on

weight gain and feed efficiency measure

these effects up to a hundredth of a percent

(0.0001). Yet the gain is on the order of grams

per day for small animals such as chickens or

turkeys and fractions of a pound per day for

large animals such as pigs and cattle.

Even if precise measurements could be validly obtained, they would still be of limited

use in addressing policy issues because these

risks and benefits cannot be approached

through a simple balance-sheet type of assessment. No common denominator is generally acceptable for comparing human illness

and death with pounds of meat. Rather than

using monetary values as a common denominator, opposing advocates usually seek to

make their case or ridicule their opponents in

the most exaggerated terms. For example,

one advocate might say that if one life is

saved, that is worth whatever it costs in decreased meat production, and Americans eat

too much meat anyway. The other advocate

might seek to dismiss the risk of getting

cancer from a certain product by saying that

it is equal to drinking 800 12-ounce cans of

diet soda daily over a lifetime. Such tactics

clearly do not address the issue of risks versus benefits.
CURRENT REGULATORY POLICY

Present Federal regulation of animal

drugs is based on evidence of effectiveness

and safety.

Animal drugs, as in the case of human

drugs, must be shown to be both effective and safe.

Residues in food, such as animal drugs in

meat, must only be shown to be safe.

Food-additive regulation is focused on

safety. However, food additives also

must be shown to have the intended effect or to be reasonably expected to become a component or affect the characteristics of food.

The statutes and the implementing regulations set criteria for demonstrating effectiveness and safety that are independent of each other. There are no explicit guidelines for determining when

the evidence on either effectiveness or

safety overrides the evidence on the

other.

If a food additive is found to be carcinogenic, it must be banned regardless of

how little is present in the food,

Drugs may be carcinogenic and their use

still allowed if effectiveness overrides

the risks,

When an animal-derived food product

may contain residues of a carcinogenic

substance (e. g., an animal drug), the law

provides some leeway in determining an

adequate assay procedure to demonstrate “no residue. ” FDA has attempted

to define “no residue” in terms of acceptable risk as extrapolated from animal experiment data, It is an attempt to

define safety in practical instead of absolute terms, since definitions in absolute terms must continually be revised

as newer assay methods are able to

measure smaller and smaller residues of

less than one part per billion,

FINDINGS AND CONCLUSIONS

1. Drugs in animal feed are targeted for multiple purposes—40 percent of all antibacterial produced are used for animal feed.

Drugs are added to livestock feeds for

nutritional supplementation, treatment

of disease, prevention of disease, weight

promotion, and feed efficiency.

In addition to their use for therapeutic

purposes, antibacterial are used to prevent disease by eliminating the carrier

status of animals and egg-transmitted infections or by suppressing infections in

the very young bird or animal.

Low concentrations of antibacterial

also are commonly approved to hasten

weight gain and to increase the amount

of weight gained per unit of feed.

It is not clear whether these weight-prm

motion and feed-efficiency effects are

separate from or dependent on the disease-prevention effect. Commonly, however, one concentration of an antibacterial is approved only for disease prevention, while another concentration of

the same antibacterial is approved only

for weight promotion and feed efficiency.

Feed premixes often contain a combination of antibacteriaIs, and these premixes may be approved for some or all

uses. For example, one combination approved for swine feeds contains procaine penicillin, chlortetracycline, and

sulfamethazine for disease treatment,

disease prevention, growth promotion,

and feed efficiency.

Other drugs, including DES for beef cattle, also are used in feed or administered

through subcutaneous implants for

weight promotion and feed efficiency,

2. Because of the attendant risks, regulatory

attention has focused on the addition of

low levels of antibacterial in animal feeds

and on DES, a proven human carcinogen.

9
● The continuous use of low-level antibacterial as feed supplements produces

drug-resistant bacteria that may cause

disease in animals and humans and

transfer drug resistance to other bacteria. The use of one antibacterial may

result in the transfer of genes carrying

resistance to several other antibacterial as well,

—Development and interchange of resistance have been confined largely to

gram-negative bacteria, although an

increasing body of data is accumulating that indicates transferable drug

resistance in the gram-positive bacteria.

(a) E, coli, common bacteria found in

the intestinal tract of both humans

and animals and throughout the environment, are the largest reservoir of

drug resistance. Drug resistance developed in E. coli can be transferred to

other gram-negative bacteria that

may be more pathogenic.

(b) Salmonella, intestinal bacteria that

can cause clinical disease, can develop resistance directly from the use of

antibacterial or have resistanc e

transferred to them from E. coli.

(c) Other gram-negative bacteria, such

as H. in~]uenzae and N. gonorrhea, recently have been found to have drugresistant properties that apparently

have been transferred from drug-resistant E. coli.

—The use of tetracycline, widely used

as antibacterial in animal feeds,

leads to the dominance of bacteria

with multiple drug resistance. Penicillin and, to a lesser extent, the sulfas

are the other primary antibacterial

whose uses are being examined.

. DES, a synthetic estrogen used in beef

cattle to promote growth and increase

feed efficiency, and nitrofurans, antibacterial widely used in poultry, are

proven or suspected carcinogens.

—DES has been shown to be carcinogenic in both animals and humans,

The use of DES by women during pregnancy has been associated with the

appearance of vaginal or cervical

cancers in the daughters with whom

they were pregnant at the time. Recent studies clearly show an increased rate of genital abnormalities

in similarly exposed sons. So far there

have been no definitive findings regarding testicular cancer or fertility

in these men.

—Furazolidone, one of the nitrofurans,

has been shown to cause cancer in

laboratory animals.

3. The health risks from the development of

bacterial resistance to antibacterial in

feed are of greater concern than the risks

of cancer from DES and furazolidone as

used in livestock practices.

● The proposed FDA regulations would

define “no residue” as an added cancer

risk of one in one million per lifetime exposure. As determined under present

standards of detection from present

levels of use, the residue concentrations

of DES and furazolidone expected in

food animal byproducts border on this

general range of acceptable risk. But

FDA has indicated that, according to

newer methods of measurement, the potential cancer risks from both DES and

furazolidone will be higher than this proposed target risk.

● Loss of effectiveness of the most widely

used antibacterial (i. e., tetracycline

and penicillins) and of other antibacterial with plasmid-mediated resistances

poses risks to both human and animal

health, Therapeutic failure with these

antibacterial would lead to large but

presently unquantifiable morbidity and

mortality in humans and animals. Once

significant effects on human and animal

health do become widely observable and

quantifiable, it may be too late to address the problem. The development of

alternative antibacterial may be one

approach to alleviating increased morbidity and mortality, but this approach

requires a great deal of time and would

not be of immediate use, and it is likely

that in time a resistance problem would

develop in them as well.

—The percent of bacteria that are resistant to one or more antibacterial

10
has been increasing. The portion of

this increase attributable to the subtherapeutic use of antibacterial in

food animals and the portion attributable to human use, especially inap

propriate or unnecessary use, cannot

be measured directly. However, the

fact that antibacterial are used for

food animals in such large amounts

and that animals and humanscanand

do exchange bacteria with actual or

potential drug-resistance properties

leads to the conclusion that the addition of drugs to animal feed is a significant contributor to the increase in

antibacterial-resistant bacteria.

4. Most of these drugs could be replaced

with alternative drugs that are already approved by FDA.

c In addition, the FDA proposals would not

ban tetracycline in cases where replacement antibacterial were not available.

5. The economic consequences of removing

these drugs could be significant over the

short term. Production may be decreased

in the period immediately following a ban,

but higher prices may offset the decrease

in quantity and may lead to higher producer incomes. But consumer prices would

also be higher.

● The long-term consequences are less

certain, probably resulting in small decreases or no changes in production and

small increases in both consumer prices

and overall producer incomes.

6. The tradeoff is therefore between immediate economic benefits and future health

risks. These decisions involve value judgments that cannot be based simply on

monetary considerations. And the lack of

scientific certainty on the magnitude of

both the probable health risks and the attributed increases in meat production

makes the formulation of a balance-sheet

approach difficult.

CONGRESSIONAL OPTIONS

Option 1

Allow 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 penicillin in animal feeds,

restrict similar uses of tetracycline to

situations where replacement antibacterial are not available,

monitor cross-contamination of feeds by

antibacterial, and

ban all uses of nitrofurans and DES.

As an alternative to the actions on penicillin

and tetracycline, FDA has proposed that

their distribution in feed premixes be limited

to feed mills holding approved medicated feed

applications and to licensed veterinarians.

The purpose of these proposals is to alleviate

the drug-resistance problem by reducing the

continuous use of these antibacterial.

The possibility exists that total penicillin

and tetracycline use may be unchanged after

the initial period of adjustment, as producers

may increase drinking water and/or therapeutic uses. The impact of everyday use in

drinking water would be comparable to the

sustained antibacterial pressure from feed

premixes. But therapeutic use may not reflect

similar risks even though the total amount

used might equal that for feed additive uses.

Therapeutic use involves higher doses for

much shorter periods of time.

Other, less controversial, steps can be

taken to decrease continuous exposure to antibacterial, Close monitoring of cross-contamination of feeds and subsequent corrective actions should lead to decreased unintentional antibacterial exposure. Most of the evidence on the effectiveness of drug use in

disease prevention, weight promotion, and

feed efficiency reveals that the young bird or

animal benefits the most. Some decrease in

11
use could probably be achieved if the period

of use is limited to the early part of a bird’s or

animal’s life and carefully monitored to

assure that such use does not extend beyond

that period.

The replacement antibacterial available

for penicillin and tetracycline include some

that also cause gram-negative bacterial resistance, but usually not as much as penicillin

and tetracycline cause. Others may select for

resistance among gram-positive bacteria,

which at this time present less of a known

problem than gram-negative bacteria. Other

antibacterial are not known to select for resistance among either gram-negative or

gram-positive bacteria.

For the nitrofurans and DES, the outcomes

depend on FDA’s current attempts: (1) to

adopt new methods of measuring residue concentrations and (2) to define carcinogenic “no

residue” as residue concentrations that result in added cancer risks of 1/106 per lifetime

exposure. Calculations of added risk based

on the limits of current methods to measure

residue concentrations indicate that the risks

border on the 1/10’ target. However, FDA has

indicated that, according to newer methods

of detecting residues and their metabolic

products, both DES and the nitrofurans

would exceed the target risk of 1/106.

Option 2

Enact Legislation Requiring Economic as

Well as Scientific Assessments of

Benefits and Risks

Objections filed against proposed regulations by FDA often raise economic issues.

Apart from the laws under FDA’s administration, most Federal agencies involved in regulating health problems can or are required

to consider the economic impacts of their actions. A comparative examination of those

Federal agencies using and not using such

economic criteria may show whether or not

these different criteria lead to different conclusions. Or the law could be changed to require the explicit evaluation of economic impacts along with scientific data on benefits

and risks.

Much of the impetus for legislating such

changes has come from those who want the

monetary worth of benefits to be considered.

However, if monetary values were established for benefits, they also have to be established for the risks, It is far more difficult to

reach agreement on monetary values for

risks than it is for benefits in this instance.

Moreover, even if monetary values are established for benefits and risks, that does not

resolve the fundamental problem of deciding

when risks or benefits should prevail.

Option 3

Enact Legislation Removing the Special

Approach to Carcinogens in Food

Regulation

Present legislation already provides an exemption for drug residues in meat and other

edible byproducts of food animals. The all-ornothing approach of the Delaney clause will

be avoided if FDA succeeds in implementing

its target risk approach (defined as an added

lifetime exposure risk of 1/10’ of developing

cancer). In assessing risks from carcinogenic

agents, the techniques for defining the target

risk are still in a primitive state. There are

major problems in setting an appropriate target risk, in deciding on methods of extrapolation, and in detecting residues of some substances even at the target-risk level. But these

are all problems related to setting the level of

use, not to determining whether a substance

should be banned,

Option 4

Require FDA to Decrease Therapeutic

Use of Antibacterial in Human and

Veterinary Medicine as Well as in

Food Animal Production

Both human and animal antibacterial uses

contribute to the problem of drug-resistant

organisms. Of the antibacterial produced in

the United States, nearly half are used in

animal feeds or for other nonhuman purposes. The review of the evidence on risks has

shown that humans and animals serve as

common hosts for bacteria and that resist12
ance transfer is not limited to those animals

and humans in close proximity to animals

given low-level doses of antibacterial in their

food.

The majority of resistance in human bacterial populations is probably caused by widespread use of antibacterial in humans, in

which overuse undoubtedly occurs as it does

in both therapeutic and supplemental animal

uses, However, regardless of why antibacterial are given, the key facts concerning the

plasmid problem are that: (I) at any point in

time, the number of animals exposed to antibacterial far exceeds the number of humans

exposed, and (2) the length of therapy in

humans averages less than 10 days, while antibacterial-supplemented animal feed use is

often continuous.

As for methods of decreasing therapeutic

and subtherapeutic uses of antibacterial, it

would be easier to control and monitor the addition of antibacterial to feeds than it would

be to regulate the practices of veterinarians

and physicians.

Option 5

Approve Future Drugs Only if They Are

More or Equally Effective as Those

Already Approved

It is the most widely used antibacterial

that are contributing to antibacterial resistance, and a limitation based on relative effectiveness would most likely aggravate the

problem by discouraging the development of

new antibacterial,

13
Chapter II

FEDERAL REGULATIONS
Chapter II

FEDERAL REGULATIONS

REGULATORY BASIS

Except for minor involvement by several

other Federal agencies, the safety, wholesomeness, and proper labeling of the food

supply are the responsibility of the Food and

Drug Administration (FDA) of the Department

of Health, Education, and Welfare (HEW),

and of the U.S. Department of Agriculture

(USDA), USDA has concurrent jurisdiction

with FDA over certain meat and poultry products through the Federal Meat Inspection

Act ] and the Poultry Products Inspection Act.z

USDA is authorized to conduct its own inquiry into the safety of such products, but

either through law or administrative deference, USDA’s activities regarding safety involve enforcing decisions that have been

made by FDA (USDA, 1978).

FDA*s authority over substances added to

animal feeds and over animal drugs comes

primarily from two sections of the Federal

Food, Drug, and Cosmetic Act (FFDCA):] (1)

food additives, and (2) new animal drugs.

A substance is considered a food additive

if:

., . [Its]. . . intended use . . . results or may

reasonably be expected to result, directly or

indirectly, in its becoming a component or

otherwise affecting the characteristics of

any food . . . if such substance is not generally recognized . . . to be safe under the conditions of intended use .. ..4

To avoid regulation as a food additive, the

petitioner must either provide evidence that

the substance does not become a component

or 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 is

generally recognized as safe under the conditions of intended use.

The FFDCA expressly excludes “new animal drugs” from the definition of “food additive” and regulates them under a separate

section of the law. New animal drugs are

treated in the same way as new drugs for

human use. An application must contain:

1. Full reports of investigations which

have been made to show whether or not such

drug is safe and effective for use:

2. A full list of the articles used as components of such drug;

3. A full statement of the composition of

such drug;

4. A full description of the methods used

in, and the facilities and controls used for,

the manufacture, processing, and packing of

such drug;

5. Such samples of such drug and of the articles used as components thereof, of any animal feed for use in or on which such drug is

intended, and of the edible portions or products (before or after slaughter) o-f animals to

which such drug (directly or in or on animal

feed) is intended to be administered, as the

Secretary may require:

6. Specimens of the labeling proposed to

be used for such drug, or in case such drug is

intended for use in animal feed, proposed labeling appropriate for such use, and specimens of the labeling for the drug to be manufactured, packed, or distributed by the applicant;

7. A description of practicable methods -for

determining the quantity, if any, of such drug

in or on food, and any substance formed in or

on food, because of its use; and

8. The proposed tolerance or withdrawal

period or other use restrictions for such drug

if any tolerance or withdrawal period or

other use restrictions are required in order to

17
assure that the proposed use of such drug

will be safe (emphasis added), ’

Some of the grounds for refusing the application include:

(A) [T]he investigations . . . do not include

adequate tests by all methods reasonably applicable to show whether or not such drug is

safe for use under the conditions prescribed,

recommended, or suggested in the proposed

labeling thereof;

(B) [T]he results of such tests show that

such drug is unsafe for use under such conditions or do not show that such drug is safe for

use under such conditions; . . .

(D) IU]pon the basis of the information submitted , . . or upon the basis of any other information . . . with respect to such drug . . ,

there is insufficient information to determine

whether such drug is safe for use under such

conditions;

(E) [Evaluated on the basis of the information submitted . . . and any other information

with respect to such drug, there is a lack of

substantial evidence that the drug will have

the effect it purports or is represented to

have under the conditions of use prescribed,

recommended, or suggested in the proposed

labeling thereof; ., .

(H) [S]uch drug induces cancer when ingested by man or animal or. after tests which

are appropriate for the evaluation of the

safety of such drug, induces cancer in man

or animal, except that the foregoing provisions of this subparagraph shall not apply

with respect to such drug if the Secretary

finds that, under the conditions of use specified in proposed labeling and reasonably certain to be followed in practice (i) such drug

will not adversely affect the animals for

which it is intended, and (ii) no residue of

such drug will be found (by methods of examination prescribed or approved by the Secretary by regulations ., .) in any edible portion

of such animals after slaughter or in any

food yielded by or derived from the living animals . . . .h

The last reason for refusal enumerated

above is one of the Delaney clauses in FFDCA

that bans the use of carcinogenic substances

that enter the food supply. The clause is similar to that applicable to food additives. In the

latter, the exception to a total ban is for “the

use of a substance as an ingredient of feed for

animals which are raised for food production. ”

For animal feed ingredients and animal

drugs, the law directs the Secretary to promulgate regulations defining when “no residue” will be found, (It should be noted that

for noncarcinogens, residues are allowed,

subject to safety considerations [see numbers

5, 7, and 8, supra, on information to be contained in new animal drug applications]). For

food additives generally, the definition itself

includes the finding that the substance becomes or may reasonably be expected to become a component of food. Thus once a substance is legally labeled a food additive and is

found to be a carcinogen, it is automatically

banned because, by definition, it is present in

the food.

Finally, some of the grounds for withdrawing approval for animal drugs include: (1) experience or scientific data showing that such

drug is unsafe for use under the conditions of

use on which the application was approved;

(z) new evidence, evaluated together with the

evidence available when the application was

approved, showing that the drug is not shown

to be safe under the approved conditions of

use; and (3) new evidence, evaluated together

with the evidence available when the application was approved, showing that there is a

lack of substantial evidence that the drug will

have the effect claimed under the conditions

of use.7

In order to avoid food additive status, a

substance must be “generally recognized as

safe” (GRAS) “under the conditions of intended use” if it enters the food. But a food

additive is unsafe and prohibited from use

unless a regulation is issued “prescribing the

conditions under which such additive may be

safely used. ” Although the language is nearly

identical, the practical difference is that food

additive status gives FDA authority to prescribe the actual conditions of use.

For drugs, FFDCA requires that the applicant provide adequate data on both the safety

and effectiveness of the drug under the in-

’21 U.S,C. 360(b).

‘

)

21 U.S.C. 360(b)(d)(l).

18

7

21 U.S.C. 360( b(e)(l).
tended conditions of use, but FDA may deny

or withdraw the approval on either safety or

effectiveness grounds. For example, FDA

may deny the use of a drug for some purposes

and approve it for others, even if it is safe to

be used under all of the petitioned conditions.

Here, effectiveness would be the ultimate determinant of approval. Or, conversely, FDA

may deny use of a drug for some purposes

and approve it for others even if it were effective for all the petitioned conditions. Here

safety would be the ultimate determinant of

approval.

Some have criticized FDA for failing to consider socioeconomic benefits and costs in determinations allowing or disapproving the use

of food additives and drugs. These critics

claim that present law allows the consideration of such costs and benefits. Whether or

not the law should include these considerations is a separate question. But FFDCA is

quite conspicuous in its absence of language

supporting such claims.

The law is clear that safety and effectiveness will be determined by scientific assessments:

In determining whether such drug is safe

for use under the conditions prescribed, recommended, or suggested in the proposed labeling thereof, the Secretary shall consider,

among other relevant factors, (A] the probable consumption of such drug and of any

substance formed in or on food because of

the use of such drug, (B] the cumulative effect on man or animal of such drug, taking

into account any chemically or pharmacologically related substance, (C) safety factors

which in the opinion of experts, qualified by

scientific training and experience to evaluate the safety of such drugs, are appropriate for the use.

. . . [The] term substantial evidence means

evidence consisting of adequate and wellcontrolled investigations, including field investigation, by experts qualified by scientific

training and experience to evaluate the effectiveness of the drug involved, on the basis

of which it could fairly and reasonably be

concluded by such experts that the drug will

have the effect it purports or is represented

to have under the conditions of use prescribed, recommended, or suggested in the

labeling or proposed labeling thereof.n

Although the statute presents these as independent assessments and does not provide

any guide for FDA to decide when effectiveness outweighs safety and vice versa, these

decisions are in reality risk-benefit assessments limited to scientific considerations.

’21 U. S. C.360(b(d)(2-3).

CURRENT ACTIVITIES

Antibacterial used in human treatment

a r[: often used in animals, and limitations on

use have been proposed for animal antibacterial, particularly for their subtherapeutic

uses in animal feed. Over 40 percent of all the

antibacterial produced in this country are

used as feed additives or for other nonhuman

purposes. Research on antibacterial-resistant bacteria has shown that, in some cases,

genes for antibacterial resistance can be

transferred between bacterial types and that

humans and animals are interchangeable

hosts for such bacteria.

Another major concern has been the possibility of more direct, adverse human health

effects from eating meat, eggs, etc., containing residues of drugs. The health effect primarily at issue here is carcinogenesis. Federal law prohibits the use of carcinogenic food

additives and also requires that food products from animals given carcinogenic substances for any purpose (e. g., therapeutic,

growth promotant, etc. ) cannot contain any

residue of such carcinogens, Among the animal drugs in use, furazolidone and DES are

known carcinogens,

The antibacterial problem began to be addressed in the 1960’s in the United States and

other countries. One consequence was Great

Britain’s decision in 1971 to restrict the use

of antibacterial for food animals and, in particular, their feed-additive uses.

19
Similar reviews were initiated in the

United States by the FDA (FDA, 1966, 1972,

1977). The general thrust of these reports

was similar tothe report leading toGreatBritain’s curtailment of antibacterial for food

animal uses, although they differedin the emphasis placed on specific antibacterial.

There were also differences on specific conclusions and recommendations between the

Subcommittee on Antibiotics in Animal

Feeds, its parent National Advisory Food and

Drug Committee to the FDA, and the FDA

itself. (See USDA, 1978, for a chronicle of

these events.)

As a consequence of these reviews, in 1973

FDA began a series of actions to update the

effectiveness and safety data of approved

animal antibacterial and to extend the criteria to new antibacterial.’ These efforts

subsequently were focused on the penicillins

and tetracycline which, in the words of the

FDA Commissioner, “were chosen as the initial subjects of regulation because of their importance in the treatment of human disease”

(Kennedy, 1977).

In 1977, FDA proposed to withdraw approval of the use of penicillin and to restrict

the use of tetracycline in feed premixes. The

reasons for the proposed ban on the use of

penicillin were that: (1) the new evidence on

the hazards of bacterial resistance had

shown that such use of penicillin was not

safe, and (2) the applicants had failed to meet

the record maintenance requirements of the

law.10 Similar reasons were given for the proposed restrictions on tetracycline, where

they would be prohibited except where adequate substitutes for disease prevention were

not available. 1 ]

As a corollary action, the FDA had proposed to limit the distribution of animal feed

premixes containing penicillin and/or tetracycline to feed mills holding approved medicated feed applications for manufacturing

these medicated feeds and to restrict further

the distribution of those feeds to the order of

a licensed veterinarian as part of the record

maintenance requirements of the law.12 Pub1

’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 concerns

over such matters as the inadequacy of the

numbers, distribution, and kinds of veterinarians available to diagnose and write prescriptions under the proposed requirements;

the economic disadvantage of the proposal to

small producers; circumvention of the proposed restrictions, since soluble powder

dosage forms would not be subject to the proposal; and allegations that it would interfere

with the practice of veterinary medicine and

State control over the feed industry. The FDA

Commissioner therefore decided to delay a

decision until such issues were resolved.ls

Meanwhile, the U.S. Congress has taken

several actions to delay the final outcome of

these proposals. In May 1978 the House Appropriations Subcommittee on Agriculture

and Related Agencies earmarked $250,000

for fiscal year 1979 for a study on antibacterial used in animal feed, to be conducted by

the National Academy of Sciences. In July

1978 the House Agriculture Committee ap

proved a resolution to delay the proposed ban

until new research studies could be completed and formal evidentiary hearings held.

And in September 1978 House and Senate

conferees agreed to require the FDA to hold

up the proposals until such research and evidentiary hearings were completed.

The congressional actions have led the

Director of the FDA’s Bureau of Veterinary

Medicine to conclude that the outcome of

these proposals would not be reached before

1980 and that “(p)ublic and industry reaction

to these proposals have made it abundantly

clear that livestock producers are desirous of

having penicillin, tetracycline, and similar

antibiotics remain in animal feeds. Unless

substitutions of antibiotics currently on the

market are more readily accepted and unless

viable alternatives to potentially restricted

antibiotics can be developed, most likely the

public outcry will continue regarding the pr~

posed regulations. These are practicalities

that are incident to the national acceptance

of the proposed regulations” (Food Chemical

News, Sept. 25, 1978).

Two other classes of antibacterial raise

separate safety issues, in addition to the

‘ ’43 F.R. 35059, Aug. 8, 1978.

20
safety problems reflected in these proposals

to restrict the use of penicillin and tetracycline. The sulfa drugs (i. e., sulfamethazine

for swine feed and drinking water) have been

found to have a high violation rate for residues in slaughtered hogs. And one of the nitrofurans, furazolidone, is carcinogenic in

laboratory animals.

Specific tolerances for residues of sulfa

drugs in edible tissues of food-producing

animals are set at O to 0.1 parts per million

(PPm). ” For sulfamethazine the toleranc e

level in swine is 0,1 ppm. These tolerances

are accomplished by specified withdrawal

time periods between last treatment and

slaughter. For the last 6 months of 1977,

USDA had found that the percentage of sampled hogs in violation of the t).1-ppm residual

tolerance averaged 13.1 percent. An FDA

study concluded that 54 percent of the violations were probably caused by contamination

of the withdrawal feed (which should not contain the drug) through insufficient cleanout of

equipment, 26 percent were probably caused

by failure to observe the withdrawal period,

12 percent were caused by feeding or feedmixing errors, and 9 percent from other

causes (FDA, 1979). New research data led

FDA to change the preslaughter withdrawal

time for sulfamethazine in swine feed and

drinking water from 5, 7, or 10 days to 15

days. ” FDA also expected to issue a proposal

to establish action levels for cross-contamination carryover of animal drugs (including but

not limited to sulfamethazine in swine feed)

by the end of 1978 (Food Chemical News, Oct.

16, 1978).

Three nitrofurans were approved previously for feed premixes; furazolidone (the

most widely used), nihydrazone, and nitrofurazone. Furaltadone, a nitrofuran, is used in

injectable form to treat mastitis in lactating

cows, Assay methods to meet the “no residue” requirement have not been approved for

the nitrofurans. Furazolidone has produced

cancer in laboratory animals. The other three

compounds are suspected of being carcinogens but have not been adequately tested. All

uses of nihydrazone were revoked because no

“21 CFR 566.625-.700.

“43 F.R. 19385, hlav 5, 1978.

hearings were requested. Of the two sponsors of furaltadone, one approval was revoked because a hearing was also not requested.l’ Actions were pending against furazolidone and nitrofurazone as of January

1979.

The “no residue” exception to the ban on

carcinogenic substances added to food is

sometimes referred to as the “DES exception. ” DES has been known to be carcinogenic

almost from the time it was first produced in

1938 (DES Task Force Report, 1978), its carcinogenic effect generally attributed to its

estrogenic properties. The Food Additive

Amendments of 1958

17 contained the first

Delaney clause barring carcinogenic food additives. In order to allow the continued use of

DES in food animals, a “no residue” exception was inserted in the Animal Drug Amendments of 1968.1B

DES is added to feed or used in implants to

fatten beef cattle. To a lesser extent, implants are used in lambs. Other drugs used to

fatten cattle include: (1) melengesteroi acetate (MGA) in feed for heifers, with the additional purpose of suppressing estrus; (2) monensin in feed, authorized only for increasing

feed efficiency, although it also is authorized

for disease prevention and growth promotion

in poultry; (3) estradiol benzoate plus testosterone proprionate for heifers by implants: (4)

estradiol benzoate plus progesterone for

steers by implants; and (5) zeranol implants

for calves, cattle, and lambs. Estradiol monopalmitate injections are authorized for use in

roasting chickens. ’g In addition to DES and

the estradiols, zeranol has direct estrogenic

activity, MGA (a synthetic progesterone) and

progesterone result in increased estrogen

production in treated heifers. Monensin is a

compound produced by the bacterium Streptomyces cinnamonensis and is still used as an

anticoccidial in poultry.

Starting in 1972, FDA first banned the use

of DES in feeds and, later, in implants, on

evidence 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 vacated in 1974 by court order on the grounds

that an insufficient notice of opportunity for

hearing had been given to the affected parties because FDA had relied on a method of

testing that it had not approved. Administrative hearings have been concluded and in

September 1978 the administrative law judge

recommended that DES be banned from feed

and as an ear implant (CNI Weekly Report,

Oct. 5, 1978). FDA’s decision had not been

made as of January 1979,

A closely related issue has been the method by which “no residue” would be determined. The increasing sensitivity of methods

used to detect such residues has led FDA to

seek methods “to keep the agency from

always chasing zero in terms of an allowable

tolerance of substances that will be administered to food-producing animals” (Food Chemical News, Oct. 16, 1978).

In early 1977, FDA issued new procedures

and criteria for evaluating the assays for carcinogenic residues in edible products of anireals. 

zo Essentially, the intention of the new

regulations was to cease trying to quantify

the actual amount of carcinogenic residue

because of the problem of chasing zero

‘{’42 F.R. 10412, Feb. 11, 1977.

(newer methods were able to identify substances at less than one part per biIlion). Instead, the new regulations adopted a method

whereby “no residue” would be defined

through extrapolation from animal test data

to man so that the lifetime risk to an individual would be less than 1 in 1 million (l/l Oti or

10-”). The published regulation stated that

“such a risk level can properly be considered

of insignificant public health concern. ” According to an FDA spokesman, the new method would “provide a mechanism whereby a

reasonably safe level may be established and

then, irrespective of further analytical developments, there will be that expectation that

the originally set level will remain until toxicological evidence rather than analytical evidence demonstrates that to be an incorrect

tolerance” (Food Chemical News, Oct. 16,

1978).

These regulations were revoked by FDA21

after the U.S. District Court for the District of

Columbia remanded the case to FDA “for further findings to rectify the omissions in the

current record. ”zz FDA expects to issue proposed new regulations in 1979.

“43 F.R. 22675, May 26, 1978,

“Animal Heu]th Institue v. Food and Drug Administration, Civil No. 77-806, D. D. C., Feb. 8, 1978,

APPROVED USES

Subtherapeutic uses of penicillin, tetracycline, sulfas, and nitrofurans vary according

to the food animal. They may be used alone or

in combination with each other or with other

drugs. These other drugs may be antibacterial, anticoccidials, antihelminthics, or nonantibacterials, such as DES or other growth

promotants, One drug may be approved for

only some uses, but when combined with

other drugs, the resulting feed mix may cover

all uses.

penicillin is used extensively in poultry

feeding programs and, to a lesser extent, in

swine feeds, usually in combination with

other drugs (sulfa, tetracycline, bacitracin,

etc.). There are no approved uses for pen22

icillin in animal feed for cattle or sheep.

Penicillin may be used alone for all possible

indications—i.e., growth promotion, feed efficiency, disease prevention, and disease treatment. It also may be used in combination with

other drugs.

Tables 1, 2, and 3 summarize the use of

penicillin in animal feeds for chickens, turkeys, and swine. In chickens and turkeys,

penicillin, when used alone, is approved for

the separate uses of growth promotion, feed

efficiency, disease prevention, or disease

treatment, The amount of penicillin per ton of

feed would vary for these uses, It may also be

combined with other antibacterial so that

the completed feed is approved for all uses,
Table 1. –Approved Uses for Penicillin in Chicken Feeds

/r) ccWnb/flaf/ofl Wfh

StreptomyclnC

Streptomycin C

Streptomyclnc

StreptomyclnC

Amproltum~

Amprollum~ and streptomyclnc

Amprollumd and ethopabatefi

Amprollum, d ethopabate, ’ and

streptomyclnc

Bacttracln methylene

dlsallcylatec

BacNracln methylene

dlsallcylatec

Bacltracln zlncc

Buqulnolatee .,

Hygromyc(n Bf

Hygromycln B{ and

streptomyclnc

Hygromycln Bf and bacltraclnc

Usesa b

Growth promotion, feed efficiency

Disease prevention

Disease treatment

Growth promotion, feed efficiency

Maintain or Increase egg production

Dfsease prevention

Disease treatment

Growth promotion, feed efficiency

Treatment of dcsease

Growth promotion, feed efficiency

Treatment of disease.

Malntalnlng or Increasing hatchablllty of

eggs

Treatment of disease

Treatment of disease

Growth promot[on, feed efficiency

Treatment of disease

Treatment of disease

Treatment of disease

‘For a sDecltlc food animal different ccmcenlrat!ons o same drug may be approved for

dlflerent purposes –e g for chickens one concentration IS approved for qrowth promoflon and

feed efficiency anolher concenfrat(on for prevention of disease

‘Speclflc d!seases omlHed

cSame (odlca!lons for use as penlcl’lln

dFor 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 are

not. In swine, when penicillin is combined

with tetracycline and sulfa, the completed

feed is approved for all uses.

Tetracycline, as oxytetracycline or chlortetracycline, is used in all food animals. Like

penicillin, it maybe used alone or in combination with other drugs, and for all or only some

of the approved uses. Tables 4, 5, 6, and 7

summarize the use of tetracycline in animal

feed for chickens, turkeys, swine, cattle, and

sheep, Tetracycline is the most widely used

antibacterial in feed.

Sulfa drugs are used primarily in swine in

combination with penicillin and tetracycline

(tables 3 and 6) for disease treatment, disease

prevention, growth promotion, and feed efficiency, or with tylosin for disease prevention.

They also are used in combination with tetracycline for disease prevention in cattle (table

7). Sulfaethoxypyridazine premixes are used

for disease treatment in swine and cattle for

use by or on the order of a licensed veterinarian.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 efficiency

Disease prevention,

Disease treatment

Streptomyci n Growth promotion, feed efficiency

Amprollumd Growth promotion, feed efficiency.

Amprollumd and streptomyclnc Disease treatment

Amproliumd and bacltraclnc Disease treatment

Bacitracin methylene

disallcylatec Disease treatment

Bacltracln zincc Disease treatment

aFOr a Speclflc food animal d{ fferent concentrations of the same drug may be approved fo!

ddferent purposes

bSpecdlc d!seases omttted

cSame Indlcallons for use as pen{c(llln

dFor 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

Streptomyclnc

Streptomyclnc

StreptomyclnC

Chlorletracyclinec and

sulfamethazinec

Chlortetracycllnec and

sulfathlazolec

Bacltracln methylene

dlsallcylatec

Bacitracin zlncc

.

Vsesa b —

Growth promotion, feed efficiency

Growth promotion feed eff!clency

Disease prevenhon

Disease treatment

Growth promotion, feed efflclency,

disease prevenhon, dtsease

treatment

Growth promotion. feed efflclency,

disease prevention, disease

treatment.

Disease treatment

Disease treatment

aFor a Speclflc food anlma( different concenfratlons of the same drug may be approved for

different purposes

bSpeclflc diseases om![ted

cSame !ndlcahons for use as perwctllhn

SOURCE 21 CFR 558 and related sechons

turkey feeds for disease prevention. In chicken feed, it may be combined with a growth

promotion and feed efficiency drug,z” There

are no approved uses for sheep feed, These

uses of sulfa are summarized in table 8.

Nitrofurans are use d extensively in

chickens and turkeys and to a lesser extent in

swine, Of the two nitrofurans still approved

for use in feeds, furazolidone is the most

widely used. It and, to a lesser extent, nitrofurazone are used in poultry for all four purposes— i.e., growth promotion, feed efficiency, disease prevention, and disease treatment. Furazolidone is used in sows for prevention of bacterial scours in baby pigs and is

added to feed I week before farrowing and z

“21 CFR 558.575.

23

1 - 11- -
weeks after farrowing. It is also used for dis- DES is used to promote growth and inease-prevention and treatment purposes. It is crease feed efficiency in cattle and, to a lessconcurrently approved for growth promotion er extent, in sheep. In feeds, it is given alone

when the swine are on the medication for the or in combination with antibiotics. It is adminpurposes outlined. These uses are summa- istered separately by ear implantation. These

rized 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 hydrochlorid e

.

Amproliume .,

Amprolium and ethopabatef 

.

Buquinolate9 . . . . . . .

Clopidolf .,

Decoquinateh ... . .

Hygromycln B{ . . .

Roxarsonel. .

Zoalene k 

., : : : ‘ : :

Uses~ C

Growth 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 oxyfetracycllne

bFor a spec(f[c food animal, different concentrahons of the same drug May be approved for

different purposes

cSpeclflc dtseases omdfed

dsame Ind!cattons for use as Pentclll!n

eFor development of active Immunliy [0 Or pWt?nhOn of coccldlosls

fFor Preven[lon of coccldlosls

gFor prevention of coccldlosls growfh promoflon, and feed efhciency

hFor prevenhon ancj freafment of disease

‘For confrol of worms

IFor 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 promotion, feed efficiency,

disease prevention, disease

treatment.

Penicillin and sulfathiazoled Growth promotion, feed efficiency,

disease prevention, disease

treatment.

Hygromycin Be. ., ... Disease treatment .

achlofletracycllne or oxytetracyclme

bDlfferent concentrations of the same drug may be approved for different PurPoses

cSpeclflc diseases omlffed

dsame ~5e5 as for tetracycline

‘For control of worms

SOURCE 21 CFR 558 and related sections

Table 7.–Approved Uses for Tetracycline in

Cattle and Sheep Feeds

Table 5.–Approved Uses for Tetracycline in Turkey Feeds

Animal In combination with

In comb/nat/on wWr Usesb C

Growth promotion, feed efficiency.

Cattle. . . ----

--- -

--- - Disease prevention,

Disease treatment.

Sulfamethazined

Diethystilbestrole . ,

Roxarsoned ... ., Growth promotion, feed efficiency, Sheep ----

disease prevention,

Usesb C

Growth promotion, feed efficiency,

disease prevention.

Disease prevention.

Disease prevention.

Disease prevention, feed efficiency.

achlofletracycllne or oxyfetracychne

achlofletracycllne or oxyfefracyclme bDlfferent concentrations of the same drug may be approved fOr different PurPose5

bolflerent concentraflons of the same drug may be approved for different PurPoses cSpeclflc diseases omlffed

cSpeclflc diseases omNfed dsame uses as for tetracyctme

dFor growfh promoflon feed efklency eFor 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~C

Ormetopnmd Disease prevention

Ormetopflmd and3-nifro-4-

hydroxy-phenylarsonlc

acide Dlseaseprevenhon

Ormetopflmd Disease prevention

Ormetopnmd and

Ipronldazolef Olsease prevention

Disease treatment (only for use

by or on order of a Ilcensed

vetertnarlan )

Penlcllllnd and tetracycline Growth promotion, feed

efficiency, disease preven -

hon, disease treatment

Tyloslnd. D!sease prevention

Disease treatment (only for use

by or on order of a Ilcensed

veterinarian)

Tetracycllned Disease prevention

Animal In comb/na(/on w/th llses~ C

Chickens and

turkeys --- - Growth promotion, feed efficiency

Disease prevention

Growth promotion, feed efflclency,

disease prevention

Disease prevention, dtsease

treatment

Swine ---- Disease prevention, growth

promotion

Disease treatment, growth promotion.

aFu,azolldone or mtrofurazone

bDlffe(ent ~oncentratlons Of the same drug may be approved for different PurPoses

cSpeclf[c d[seases omdted

SOURCE 21 CFR 55815 and 558262

aldent,ty of Speclflc sulfonamide derlvatwes o~lfted

bDlfferenl ~oncen[ra[lons of the ~ame d~~g may be approved IOF different purposes

cSpec(flc diseases omlfted

‘Same uses as for sulfa

eFo( 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 Uses

Cattle. Feed ---- Growth promotion, feed efficiency.

Fee d Bacitracin methylene disalicylatea Growth promotion, feed efficiency

Fee d Bacitracln zincb Growth promotion, feed efficiency

Fee d Tetracycllnec Growth promotion, feed efficiency

Ear Implant. ---- Growth promotion, feed efficiency

Sheep Feed ---- Growth promotion, feed efficiency

Ear implant (lambs) ---- Growth promotion, feed efficiency.

a

For disease prevention

b Fo

r growth ~rornotton feed efficiency

CAS Ch(offetracycllne or oxytefracycllne for disease Prevenflon

SOURCE 21 CFR 522640 and 558225

25
Chapter III

BENEFIT’S
Chapter III

BENEFITS

ANTI BACTERIALS

Mode of Action

The subtherapeutic uses of antibacterial

for food animals include not only disease

prevention but also weight promotion and

feed efficiency. All antibacterial have the

ability to suppress or inhibit the growth of

certain micro-organisms, but their chemical

composition and effectiveness against specific organisms may vary widely. Yet there is no

direct correlation between chemical composition and the weight-promotion and feed-efficiency effects, so even though specific, nonantimicrobial effects can be shown for certain antibacterial, there is disagreement

over how low levels of antibacterial bring

about increased growth and feed efficiency.

At least three modes of actions have been

postulated, and each has varying degrees of

research support.

1.

2.

3.

A metabolic effect, where the antibacterial directly affects the rate or pattern

of the metabolic processes in the host

animal.

A nutrient-sparing effect, where antibacterial reduce the dietary requirement for certain nutrients by stimulating

the growth of desirable organisms that

synthesize vitamins or amino acids, by

depressing the organisms that compete

with the host animal for nutrients, by increasing the availability of nutrients via

chelation mechanisms, or by improving

the absorptive capacity of the intestinal

tract.

A disease-control effect, through suppression of organisms causing disease

that reduce weight gain but result in no

obvious symptoms of disease in the host

animal,

There is much evidence that metabolic reactions in the host animal are influenced by

antibacterial. For example, tetracycline affects water and nitrogen excretion in rat liver

homogenates (Brody et al., 19!54). But the rate

of metabolism may be influenced by systemic

and digestive tract infections and absorption

of microbially produced toxins from the gastrointestinal tract, so the metabolic effect

could be attributed to a disease-control effect. Furthermore, the metabolic effects cannot account for the growth promotion in animals fed diets supplemented with moderate

levels of antibacterial in view of the nature

of the animal responses, the tissue levels of

antibacterial when added to the diet at

growth-promotant levels, and the levels necessary to mediate such biochemical processes. And, as to be discussed shortly, a

direct metabolic effect should not vary greatly with environmental conditions.

The nutrient-sparing effect has considerable research support, but it could also be

classified as a type of disease-control effect.

Certain intestinal organisms synthesize vitamins and amino acids that are essential to

animals, and other bacteria require and compete with the host animal for these essential

nutrients. Diets containing penicillin may increase the number of intestinal coliforms

other than E. coli (Anderson et al., 1952), and

these organisms may synthesize nutrients

that are dietary essentials for the host animal. If a diet is deficient in a specific nutrient, it could be partially corrected by microbial synthesis.

Antibacterial may also depress th e

growth of organisms competing with the host

animal for nutrients. The bacteria most affected by chlortetracyclines are the lactobacilli (March and Biely, 1952). The lacto29
bacilli require amino acids in relatively similar proportional amounts as do pigs, and the

levels and sources of protein that support

maximum growth in pigs are also near optimum for the multiplication of lactobacilli in

the intestinal tract (Kellogg et al., 1964).

Those antibacterial most effective in reducing the number of these organisms in the intestinal tract are also the most effective as

routine growth promotants (Kellogg et al.,

1966).

Antibacterial may also improve absorp

tion of nutrients by the host animal (Catron et

al., 1953). Structurally, this seems to be

related to thickness of the intestinal wall,

which is thinner with rations containing antibacterial versus no antibacterial (Coates,

1953; Russoff et al., 1954, Braude et al.,

1955). The thinner wall implies a potential for

improved absorption and is assumed to result

from the inhibition of the organisms that

damage or produce toxins that damage the intestinal tissue.

The nutritive and antibacterial response

relationships still appear secondary to the

disease-control effect. Early in the history of

antibacterial supplements to animal feeds, it

was noted that the degree of response to antibacterial was inversely related to the general well-being of the experimental animals.

Healthy, well-nourished animals do not respond to antibacterial supplements when

housed in carefully cleaned and disinfected

quarters that have not previously housed

other animals (Speer et al., 1950; Catron et

al., 1951; Coates et al., 1951; Hill et al, 1952).

Studies involving clean and contaminated

environments illustrate that the response to

antibacterial is greater in contaminated or

previously used environments. For example,

pigs housed in an old barn had an increased

growth rate of 14.2 percent versus 7.5 percent in the new barn (table 11). The response

of chicks to chlortetracycline in a new environment was a 12.6-percent improvement

versus 18.2 percent for chicks from the same

hatch that were reared in a previously used

environment, and 1.6 percent versus 23.9

percent when penicillin was used (table 12).

The relative improvements in growth rates

from supplementing diets with antibacterial

often are inversely related to the growth rate

Table 11. –Effect of Chlortetracycline on Weight Gains of Pigs

in Different Environments

Enwromnerrf and

chlortefracychne ted

New barn:

Contro l

Chlortetracycltne (9 g/ton )

Old barn:

Contro l

Chlortetracycllne ‘(9 g/ton)

Dally gain Feed effmer?cp

Average /rnprove- /rnprove-

(9) ment (Yo) Average 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/or

Vlgofac 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) and

Penicillin in New and Previously Used Environment

4-week /mprovernent

Enwronment Treatment we/ght (g) (%)

Bird et al. a

New house Control 254 –

CTC, 10 ppm 286 12.6

Previously used house Control 176 –

CTC, 10 ppm 208 182

Coa/es O( a/. b

Greenford Lab C Control 184 –

Pemcillin 187 1.6

Reading Lab C Control 155 –

Penicillin 192 23.9

aH R Bird R J LWe and J R Slzemore 1952 Enwronment and shmulat(on of chick

growth by anltb!otlcs Poulmy SCI 31907

bM E Coates c D Olckinson G F Harr)son S K Kon S H Cummlns and W F J

Culhbertson 1951 Mode of action of an!lblot[cs In stimulating growfh of chicks Na!ure

168332

cReadlng Lab had been previously used to house chicks bul the Greenford Lab had not

SOURCE Hays 1978 table 8

of the controls—i. e., the difference in antibacterial response in clean versus contaminated environments is often the result of the

controls in the contaminated environment doing poorly in comparison with controls in the

clean environment. Tables 13 and 14 summarize this relationship across a number of experiments.

The growth-depressing effect can also

build up over time with the continued use of

specific animal facilities. This effect from

nonspecific infections in a chick-starting facility is summarized in table 15. Emptying,

cleaning, and fumigating the facility improved performance but did not approach the

level of performance of the first hatch.

Effectiveness

What is the quantitative gain in livestock

production with the use of antibacterial in

feed? Have they continued to be effective?

30
Table 13. –Relationship Between Growth Rate of Control Animals

and Animals Fed Antibiotics (Pigs)

Response to

Da//y ga/n /n weight (g) ant/b/et/c

Ant/b/of/c-led

No. of fests Corflrol anunak anvnak Improvement (%)

4 . . 94 245 161

1 136 227 67

12 182 336 85

13 227 340 50

1 6 272 449 65

3 1 318 481 51

1 2 363 499 38

1 8 409 563 38

16 454 572 26

36 < 499 572 15

32 545 627 15

3 9 590 636 8

4 8 636 713 12

20 681 735 8

22 726 790 9

1 772 881 14

aA~aPled f,O~ R Braude ~ D Wallace and T J Cunha 1953 The value of armb!otlcs In

the 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 Pigs

and Pigs Fed a Combination of Penicillin and Streptomycin

Da//y gan /n we/ght

of controls (g)

91 to 182

181 to 2 7 2

272 to 363

363 to 454.

454 to 545

545 to 636

636 to 726.

726

No of

comparisons

2

3

4

7

9

9

20

7

Tota l 61

Average Improvement. 0/0

Improvement over controls by

p/gs fed anl/b/ot/cs

Ga/n /n Feed

we/ght (0/0) eff/c/ency (Yo)

2 2 0 8 2

2 7 0 4 5

2 0 4 5 6

161 11 1

123 6 4

9 4 1 9

5 6 4 7

3 8 1 8 —

107 5 1

aDa(a summar(~ed trom agrlcutfural experiment s!atton repofls 1960 to 1967 V W Hays

B(ologlcal bass for the use of ant(b(otlcs m I(vesfock production The Use of Druqs /n Antmal

Feeds Proc Symp Publ 1679 D 11 (Washl nqlon D C Vatlonal Academy of Sctences

1969 I

SOURCE Hays 1978 fable 14

How effective are specific antibacterial

compared to others? These questions are difficult to answer with any degree of precision,

but the general conclusions can be made that

antibacterial continue to be effective for increasing production and that some antibacterial are clearly more effective in specific

food animals than in others.

There are a number of confounding factors

that make an evaluation of the quantitative

effect difficult. First, antibacterial now are

so widely used that most of the experimental

data 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 44.2 100.0

2 42.7 96.6

3 . . . . . 41,5 93,9

4, 40,1 90.7

5,, 4 2 8 96.8

6 . 41 8 94.6

7 . 4 0 9 9 2 5

8 . . 4 0 2 91 0

9 3 9 5 89.4

1 0 3 5 2 7 9 7

Depopulation and fumigation

11 ., 37.7 8 5 3

1 2 26,2 5 9 3

Depopulation and fumigation

1 3 3 8 2 86.4

1 4 3 4 5 781

15 ., 2 8 3 6 4 0

aH M Scott 1962 The effect of a non-speclflc InfectIon on chick growth Proc Ill Nutr

Conf p 23 Umverslty of Illhno(s Urbana

SOURCE Hays 1978 fable 1 f

from the 1950’s and early 1960’s. For experiments conducted later, especially those in

which field trials were used, it is often difficult to tell whether the animals used were

previously fed feeds containing antibacterial. And as discussed earlier, the housing

conditions of the animals also contribute to

the effect of antibacterial usage; previously

used facilities usually result in greater

response.

Second, controlled experimental conditions

often produce results less than those found in

field conditions. Aside from cleaner housing

in controlled experiments, often less animals

are housed per facility, and runt animals usually are not included.

Third, the degree of increased production

also may depend on the animal’s lifecycle and

the conditions of feeding. Responses may vary

depending on whether it is calves or heifers/

steers being fed, whether they are on highroughage (hay) or high-energy (grain) diets,

whether it is the first few weeks of life versus

the whole lifespan of the animal in which

feeds are supplemented with antibacterial,

etc. Animals are often fed antibacterial-supplemented feed throughout their lifespan, and

the effects may be attributable mostly to certain periods of that time.

Cattle. Antibacterial approved for growth

promotion and feed efficiency are the tetracycline and bacitracins. Cattle show a greater

response to tetracycline on high-roughage,

31
low-energy rations than on high-grain, highenergy diets. However, increased use of highgrain rations for the finishing of cattle increases the incidence of liver abscesses, and

antibacterial are used continuously for prevention. The tetracycline are the most widely used, but tylosin and bacitracin are also

approved for such use. Although related to

high-grain diets, the etiology of thes e

abscesses isunknown.

The responseto antibacterials varies with

the type offeed, feedlot conditions, stress factors, and disease level of the cattle, so results

are not consistent. A summary of a large

number of experiments shows that tetracycline at a level of 70 to 80 mgm daily per

animal have on the average increased weight

gain 6 percent and improved feed efficiency

(feed per pound gained)4 percent (Beeson,

1978). The incidence of liver abscesses from

high-grain, high-energy diets is not known,

butsopercentor more of the livers could be

expected to be abscessed without the use of

antibacterial, andsuchabscesses also cause

reductions in weight gain. Davis (1978) estimates that the use of antibacterial reduces

the incidenceof liver abscesses from over 50

percent toapproximately 18percent.

Inits reporton the economic impacts ofa

ban on antibacterials, USDA (1978) used the

following criteria for weight gain:(l) 700-lb

yearlingcattleare fed for 156dayswithantibacterial-supplemented feed, (2)with amarketing weightof l,050tol,0621bs with antibacterials, and (3) a marketing weight of

1,038 lbswithout antibacterials. This would

result in a reduced marketing weightof 12to

241bsperanima~ or a differenceof 1.2t02.3

percent.

Sheep. Antibiotics are not generally used

on a subtherapeutic basis but rather for

treating specific diseases. Only the tetracycline have been found to be beneficial for

weightgain and feed efficiency, and they are

primarily used in lambs. The major response

occurs initially in the feeding period (Beeson,

1978).

Pigs. Table 16 provides rough comparisons

of different antibacterial at different times

in the feeding life of pigs. In the experiments

summarized in the table: (1) “starter” pigs

32

initially weighed 11 to 27 lbs, with finished

weights of 30 to 110 lbs; (2) “grower-developer” pigs initially weighed 34 to 45 lbs, with

finished weights of 90 to 114 lbs; and (3)

“growing-finishing” pigs initially weighed 32

to 59 lbs, with finished weights of 134 to 2 0 7

lbs. Responses were generally greater in

young pigs. Excluding combinations that included penicillin or tetracycline, responses

equal to tetracycline or penicillin were obtained with tylosin, virginiamycin, mecadox,

tylan-sulfa, bacitracin, and lincomycin.

Bacitracin had a smaller feed-efficiency effect, but the others were comparable to penicillin or tetracycline.

Table 17 summarizes the effect of tetracycline over three decades for swine at similar

stages in the production cycle as covered in

table 16. Effectiveness has been maintained

for starter pigs and diminished but still positive for more mature swine.

Poultry. Table 18 summarizes the response

to different antibacterial by chickens to 4

weeks and 8 weeks from hatch. The greatest

response takes place early in the growth cycle. After 8 weeks from hatch, there is only a

small difference between birds fed and not

fed antibacterial-supplemented feeds. Several antibacterial produce similar results as

tetracycline and penicillin—namely, virginiamycin, streptomycin, erythromycin, and

lincomycin.

Table 19 averages the effectiveness of tetracycline, penicillin, bacitracin, and the arsenical for chicks up to 4 weeks of age for

specific years. Effectiveness in the early

phase of the growth cycle has been maintained.

Table 20 summarizes the effectiveness of

selected antibacterial on egg production and

matchability. Of the six antibacterial listed,

tetracycline has the greatest effect, followed

by bambermycin and penicillin.

The results for turkeys are generally similar 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 finlshlng

Tetracycline , 10.84 1093 6,58 6 2 5 3 8 8 2 5 5

Penlcdltn 9 4 5 — — 8 6 8 — —

Penlclllin-streptomy cin 1485 — 3.87 7.42 — 1,74

Tetracycline-penicillinsulfamethazine 2250 1746 — 8.48 — 6 3 9

Bacltracln 9,72 5 1 0 2.50 3 2 6 2 5 0 2 6 7

Tylosln 1481 10,94 4 6 4 6 0 3 4 2 0 1,47

Vlrginiamycln 1100 10.69 5 7 3 5 0 2 6 6 0 3 2 5

Bambermycin 0 0 0 2.45 1 89 – 099 1 17 1 17

Tylan-sulfa 1765 5 1 2 — 6 7 6 2 1 5 —

Mecado x 18.56 1513 8 6 4 6.91

Lincomycln

—

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 Technology

Assessment 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 hnlshlng

1950-56 8 7 0 1736 9 4 0 5 4 5 6.27 4 5 5

1957-66, ., 11 69 6.02 5 8 8 7 9 3 1 95 1 14

1967-7 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 Technology

Assessment U S Congress 1978 (tyoescrlpt) tables 5 26 and 27

Table 19.–lmprovement in Chick Performance: All Years Versus

Since 1970 (To Approximately 4 Weeks of Age)

Table 18. –Response of Chickens to Antibiotics

14elght gain Feed/gain

(% Improvement) (% Improvement)

Antlblohc 4 weeks

Tetracycline 7 3 3

Penlclllln 811

Bacltracln 6 3 0

Arsenlcals 4 9 4

Bambermycin 3 7 7

Llncomycln 9.25

Ndrofuran – 328

Oleandomycln 501

Streptomycin 7 2 6

Vlrglnlamycln 1598

Erythromycin 7 2 0

Tylosln 2.82

8 weeks

3 6 9

2 9 3

0.95

344

2 3 5

4 4 8

1 98

4 4 8 —

—

—

4 weeks

5 0 9

4.46

3 2 4

701

1 80

8 2 8

– 261

2 2 5

1 89

9.06

5.05

1 00

8 weeks

231

2 7 6

2 2 0

3 1 5

1,94

3.30

1.47

1.78

—

—

—

SOURCE V W Hays Effectiveness of Feed Addlflve Usage of Antlbacterlal Agents In Swine

and 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 1970

Tetracycline 7.33 6.79 5.09 5 3 8

Penlcillln . , 811 1220 4 4 6 7 1 4

Bacitracin 631 7.34 3 2 4 2.75

Arsenica l 4.94 471 701 4.81

SOURCE V W Hays Effectiveness of Feed Addmve Usage of Anflbacterlal Agents In Swine

and 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 Hatchabdlty

Tetracycline 11.91 891 147

Penicilli n 5.52 5 0 4 3 9 7

Bacltracln 0.95 2 2 8 6 9 7

Arsenical : : 2.34 1 29 581

Bambermycin 879 11.73 2 4 9

Erythromycln 1.36 136 0 3 5

SOURCE V W Hays Effecllveness of Feed Addltwe Usage of Arrhbactenal Agents In Swine

and 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 market

Anfhoffc 4 weeks 8 weeks weight 4 weeks 8 weeks weight

Tetracycline . 1489 13.21 — 8.37 5.88 —

Penicilli n 1531 10.24 5.73 7.87 5.62 2,64

Bacltracin 9.82 4,97 7.23 4,71 2.73 1.59

Streptomyci 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 Technology

Assessment U S Congress 1978 (typescript). tables 41, 42, and 43

have been estimated recently by USDA (1978)

and Headley (1978). These estimates were designed primarily to estimate the effects on the

income of livestock producers and on consumer prices. Both estimates were generated

from the same model. However, the expected

effects differ in magnitude and time trend because of the application of different assumptions (e.g., demand elasticities) to the basic

model. The USDA analysis projected impacts

for 5 years, and Headley’s projected impacts

for 10 years from the time of banning. In the

USDA analysis, the initial decrease in production was expected to increase net producer revenues because of higher prices.

Both production and prices of most affected

species were projected to recover to approximately their baseline levels by the fifth year.

Headley’s analysis concluded that the banning of selected or all four antibacterial

would increase aggregate farm income and

increase consumer expenditures from $5.7o

to $19 per capita.

In both analyses, the effects were assumed

to be additive, and no consideration was

given to the availability of alternative antibacterial. Both analyses mention that the estimated effects would be less if these were

considered. Alternatively, the hypothesis that

small producers may be forced out of business was not considered. Production decreases would be greater for the short term if

this factor had been included. The long-term

effects, however, might not have been affected.

The economic consequences for producers

and consumers and the long-term effects

postulated are obviously matters over which

much disagreement exists. However, the estimates of immediate consequences of selected

or complete banning of these four antibacterial can serve as first-order, rough approx34

imations of the kinds of production increases

attributable to these antibacterial. As noted

above, the availability of replacement antibacterial (see tables 16, 18, 19, 20, and 21) is

not considered.

USDA’s analysis estimated the effects of

the four antibacterial separately for beef,

pork, chickens, and turkeys. It also examined

the effects on egg production, dairy calves,

and lambs. Headley’s analysis estimated the

effects on beef, pork, chickens, and turkeys

from a ban on (a) tetracycline and penicillin,

(b) nitrofuran and sulfa, and (c) all four antibacterial. Since both analyses assumed

these effects to be additive, they were comparable. Lambs, dairy calves, and egg production are not addressed here.

The percent changes in production are

comparable and both use 1976 data, but the

analyses differed slightly in the measure of

production. Both used ready-to-cook weights

for chickens (broilers) and turkeys, but Headley used carcass weights for beef and pork,

while USDA used live weights at times of

slaughter. USDA’s estimates are therefore

adjusted to reflect carcass weights. Headley’s translation from percentage to pounds

differs slightly from that obtained in USDA’s

analysis, so the former is adjusted to coincide

with the latter.

Table 22 summarizes 1976 production figures for beef, pork, broiler chickens, and turTable 22.–Production of Meat Animals, 1976

Arvmal products Mdlions of pounds

Beefa. 25,969

Porka, 12,425

Broiler chickensb. 8,970

Turkeys b : : 1,960

aCarcass wetght

bReady-to-cook weight

SOURCE Extracled from USDA, 1978 and Headley, 1978
keys. Table 23 compares USDA’s with Headley’s estimates on the effect of banning

selected antibacterial expressed in percentage decreases. The analyses are comparable

for each meat product, although the effect of

specific antibacterial may differ, such as for

nitrofurans on chickens and turkeys,

Using USDA’s separate analyses for each

food animal and each antibacterial, table 24

summarizes the range of impacts for each antibacterial. Among the individual antibacterial, the greatest impact relative to total production would be through banning tetracycline; pork and chicken would be the most affected,

As mentioned earlier, USDA’s and Headley’s analyses differed in the estimated impact of banning these antibacterial. Though

banning of the four antibacterial is estimated to decrease production by the percentages and pounds summarized in tables 23 and

24, the effect on the total market over a

number of years would not be equivalent to

these estimates. For both USDA’s and Headley’s analyses, table 25 summarizes the percent change in the quantity of meat produced

or consumed, table 26 summarizes the percent change in farm prices, and table 27 summarizes changes in retail prices. Headley’s

analysis was for a lo-year period following a

ban, while USDA’s analysis extended only 5

years beyond the initial year of the hypothetical ban. The primary difference between

the two analyses is that Headley consistently

estimates a larger impact than USDA on decreased production, increased farm prices,

and increased retail prices. Headley’s estimates drop slightly after the first 2 years, but

remain at a fairly constant level over the

following years, while the USDA analysis has

a high initial impact that diminishes over the

5-year period. Both analyses predict the minimal impact to be on beef and the maximum

impact on poultry.

Table 23. –Estimated Percentage Change in Livestock Production From Banning Selected Antibiotics

(First Year)

Curnulalwe

Arvmal product ProjectIon F’emcdhrr TeUacycllr7e N!tro~~rafl Sulfa effect

Bee f USDA NAb – O 4 to – 0.8 NA NA – O 4 to – O 8

Headley - l o — NA — – 1.0

Pork USD A NA – 34 to – 15.6 NA – 1 5to – 22 – 49 tO – 178

Headley : – 4.0 — – 2,5 — - 6 5

Broiler chicken USD A – 21 to – 3.8 – 64 to – 11.5 + 02 to – 5.7 NA – 8.3 to – 210

Headley – 2 2 — – 120 — – 14.2

Turkey 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 applicable

SOURCE USOA 1978 Headley 1978

Table 24.–Estimated Decrease in Livestock Production From Banning Selected Antibiotics

(First Year) (millions of pounds)

Tofal productmn

Ammal product (f976) Penlcdhrr Tetracychne Nitrofuran Sulfa

Beef~ 25,969 NA 104 to 208 NA NA

Porkb 12,425 NA 422 to 1,938 NA 186 to 273

Broiler chlckenC 8.970 188 to 341 574 to 1,032 18to511 NA

Turke y

C

. 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 levels

bCarcass we(ght

cReady to cook weight

SOURCE 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 Headley

1. ... ., ... –0,19to – 0,28 – 0.9 -4.86 to – 17,90 – 5.8 – 8.24 to – 22.70 – 15.4 – 5.98to – 1470 – 21,8

2.. . . . – 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 – 19.3

3., . . . + 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 – 17.7

4 .., ., . . . ., + 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 -15,9

5,. + 0.30 to + 0,56 – 0,4 –0.84to – 3.02 –6.0 –2.16to– 5.50 – 7.7 –2.62to– 6.44 –16. 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 included

bpenlclilln tetracycline and sulfa considered banned at subtherapeutlc levels and nltrOfUranS considered banned al all levels

Cyear 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 Headley

1, .,....,. + 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 + 37,6

2, ., : : + 3,30 to + 11.27 +37 + 3.83 to + 1297 + 12.2 + 6.94 to + 20.00 + 28.4 + 6.70to + 16.42 + 28,4

3 .., . + 2.00to + 5.03 + 4.0 + 2.34 to + 800 + 12.4 + 3.09 to + 8.98 + 38.4 + 3,42 to + 8.88 + 38.4

4 . ., .,,,,..,, + 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 + 31.3

5.. , : 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 levels

byear 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 Uses

of Selected Antibiotics

Poultry

Beet Pork (chickens & turkey

YeaP USDA Headley USDA Headley USDA Headley

1. + 2.7 to + 10.4 + 3 6 + 4 5 to + 14.7 + 168 + 10.3 to + 276 + 13,3

2, : : : : + 2.2to + 7.7 + 2.8 + 3,5 to + 11,8 + 11 6 + 57 to + 15,9 + 8,7

3 ,. ., + 1.4 to + 3.4 + 3.2 + 2 1 to + 7.3 + 11 8 + 26 to + 7.4 + 10.3

4.. + o,7to + 14 + 2 2 + 1.4 to + 4.8 + 125 + 24 to + 6,5 + 10,0

5 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 index

bpenlcl[lln [etracyc[lne and sulfa considered banned at subtherapeutlc levels and mtrofurans considered banned al all levels

Cyear 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 in

structure and metabolism from naturally occurring estrogen, but there is no evidence

that natural or other synthetic estrogens differ substantially in their harmful or toxic effects (DES Report, 1978). DES has a potency

10 times that of the standard estradiol, and it

is this relative potency that has made it the

preferred drug for growth promotion and

feed efficiency.

DES increases cellulose digestion by bovine

rumen micro-organisms in vitro and in vivo.

36

Stilbestrol has been shown to increase the coefficients of digestibility of cellulose in sheep

from 41.9 to 48.7 percent and the crude protein digestibility from 37.5 to 44.7 percent

[Brooks et al., 1954). However, the following

evidence supports the hypothesis that the systematic growth-promotion and feed-efficiency

effects of DES are the result of endogenous

androgen (male hormone) production:

● DES accelerates protein anabolic processes in cattle and results in an increase

in nitrogen retention (Clegg and Cole,

1954).
●

●

●

Introduction of exogenous estrogen triggers endogenous androgen secretion as

a compensatory mechanism (Gassner et

al., 1951; Whitehair et al., 1953).

Melengestrol acetate (MGA), a synthetic

progesteronal steroid also used for

growth promotion and feed efficiency,

produces biological effects closely related to the effect of naturally occurring

progesterone. The effect of naturally occurring progesterone is cyclic and permits ovulation in the nonpregnant heifer.

In the pregnant heifer endogenous progesterone maintains the corpus luteum,

which prevents ovulation. MGA inhibits

estrus and ovulation and allows the development of mature follicles in the

ovary. These persistent, mature follicles

produce increased amounts of estrogen,

which in turn stimulate weight gain and

improve feed efficiency. The interruption of estrus is temporary, norma l

estrus usually returning after MGA is

discontinued. MGA will not stimulate

weight gain in nonovulating, spayed, or

pregnant heifers, in steers, or in bulls

(Beeson, 1978).

Testosterone also can be used to promote growth and increase feed efficiency. This can be accomplished by adding

testosterone to the feed or by not castrating bull calves.

Effectiveness

Dose responses from different levels of

DES are not linear. Excessive levels will

depress performance and lead to undesirable

side effects. Steers (castrated males) and

heifers (immature females) respond differently, and response varies with the type of feed

(e.g., pasture vs. grain) and whether DES is

given orally or under the skin. Approved oral

doses of DES are 5 to 20 mg per head per day

for cattle. ’ The approved implant levels for

cattle are 30 or 36 mg.

 z

The effects of DES are limited to increased

weight gain and feed efficiency. The effect on

milk production has been inconsistent and it

is not used for that purpose. Feedlots account

’21 CFR 558.225.

2

21 CFR 522,690.

for most use. DES increases weight gain from

15 to 19 percent and feed efficiency from 7 to

12 percent in steers, and 10 percent for

weight gain and 7 percent for feed efficiency

in heifers (Beeson, 1978).

In addition to DES, several other drugs are

used for fattening cattle. As previously discussed, these include melengesterol acetate

(MGA), monensin, zeranol, and estradiol benzoate plus testosterone or progesterone. MGA

is a progesteronal steroid that is effective

only in heifers. Studies covering a lo-year

period (1968-77) show that it produces more

weight gain and feed efficiency than either

oral DES or estrogen implants. Table 28 summarizes these results. Monensin improves

feed efficiency by 10 percent but has no effect on weight gain in cattle. Implants of zeranol, an estrogen-like compound, have from 30

to 50 percent of the growth-promotion and

feed-efficiency effects of DES. Implants of

estradiol-progesterone for steers and estradiol-testosterone for heifers have similar quantitative effects as DES. Beeson (1978) concludes that the data generally show that the

quantitative effects are similar and recently

reconfirmed previous research showing that

estradiol-progesterone implants are equal to

DES implants for improving weight gain and

feed efficiency in steers (Beeson et al., 1977).

Finally, the use of uncastrated young bulls

will partially substitute for DES and other

similar growth stimulants, improving both

weight gain and feed efficiency about 10 percent (Beeson, 1978). But bulls are difficult to

carry over as yearlings to be fed-out, and

there is a consumer prejudice against bull

meat.

Thus DES can be replaced by several

already-approved drugs to promote weight

gain and feed efficiency in cattle.

Effect on Production

Headley’s 1978 estimates on the effect on

meat production of a ban on selected antibacterial also included estimates of a DES ban.

A downward shift in supply of 3.75 percent

was predicted for the first year. As for antibacterial, the long-term effect was predicted

as a rise in total producer income, and a rise

in 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)

Estrogen

Item No drug MGA Oral DES MGA No drug DESb MGA No drug Implant MGA

Daily gainlb 2.24 2.47 2.38 2.53 2.25 2,35 251 2,40 2.49 2.63

Improvement ‘Yo — 10.3 – 6.3 – 4.4 11,6 3.8 9.6

Feed/lb gain lb : : : :

—

9.95 9.30 8.85 8.44 8.78 8.59 8 2 3 7 5 5 7,34 7,14

Improvement % – 6.5 – 4,9 – 2,2 63 — 2 8 5.4

asummarlzlng experlmenis conducted by unwerslttes teed manufacturers and Commercial feedlots

bpercenf improvement not equal 10 that Clled In text because lhese were comparison experiments and were not necessarily testln9 the maximum resPonse from OES

SOURCE 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 percent of fed cattle received DES or MGA. A

spokesman for the National Cattlemen’s Association estimates that DES and similar

growth stimulants such as zeranol are used in

about 80 percent of fed cattle (CNI Weekly

Report, Oct. 5, 1978) Therefore, if Headley’s

figures are adjusted by eight-ninth’s and ap

plied to a total 1976 production of 25,969 million lbs carcass weight of beef (see table 22),

DES is estimated to increase beef production

by 3.33 percent, or 865 million lbs. This estimate is still high, because DES does not account for all growth-stimulant use.

As in the case of banning selected antibacterial, Headley estimated the effects of a

ban on DES over a lo-year period from the

time of banning. The combined response of

antibacterial and DES approaches an additive effect in beef cattle meat production, but

the effect on costs is not additive. When analyzed apart from a ban on the subtherapeutic

use of antibacterial, the per capita consumer cost of a DES ban was estimated to be

$7.75. If penicillin, tetracycline, sulfa ,

nitrofurans, and DES were simultaneously

banned, per capita consumer costs were

estimated at $21.90. If only the antibacterial

were banned, per capita costs would be $19,

Thus when added to an antibacterial ban,

DES was estimated to add only $2.90 to per

capita consumer costs, in contrast to $7.75 if

only DES were banned.

Table 29 summarizes Headley’s estimates

of a DES ban on the percent changes in available beef supplies, farm prices, and retail

prices. After 5 years, supply is slightly increased over supply before the ban, with decreases in farm prices and consumer prices.

After 10 years, supplies are slightly decreased and farm prices and consume r

prices increased, but none of these changes is

as large as that expected in the 2 years immediately 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 Retadprmes

1,. . – 3 7 + 11,9 + 15,2 + 9.1

2 .., ., – 3 2 + 8.6 + 12.5 + 6,7

3 – 1 5 + 5,7 + 7 7 + 4.7

4,, .,,, – 0.5 + 2,1 + 2,6 + 1.9

5 . + 0.5 - 2 5 – 3.6 – 1,7

6.. ,, + 0 2 – 1,4 – 2,8 – 0.8

7,, .,,. – 0.9 + 4,0 + 4.3 + 3.3

8. . . . – 1,7 + 8.1 + 102

9

+ 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 O

SOURCE 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 bacterial pathogens is the greatest health risk

posed by the widespread use of antibacterialsin animal feeds. It isalso the most difficult

to evaluate in terms of:

I, quantifying the pool of drug-resistant

bacterial pathogens,

2. assessing the relative contributionto the

pool from the use of antibacterial in

animal feeds, and

3. determining causality between the use

of antibacterial in animal feeds and

human disease.

Hazards to the food animals themselves

from such use of antibacterial are closely related to these human health concerns because the development of resistant pathogens

and subsequent failure or diminished effectiveness of antibacterial therapy are problems for both human and animal health. However, this sharing of potential, long-term,

adverse consequences is obscured by the predicted short-term consequences for the livestock industries of limiting the subtherapeutic uses of certain antibacterial.

On the other hand, the long-term consequences for these industries might be significantly different. With limited use, although

the supply of certain food animals could diminish, shifts in supply and demand for different foods (primarily beef, pork, and chicken) may produce little change in total income

for producers and modest rises in consumer

prices (USDA, 1978; Headley, 1978).

The threat to human health has been the

primary reason why current efforts at limiting widespread use are underway. But such

widespread use poses an identical threat to

the health of livestock and poultry and may

even occur earlier and more visibly than the

threat to human health. Present production is

concentrated in high-volume, crowded,

stressful environments, made possible in part

by the routine use of antibacterial in feed.

Thus the current dependency on low-level use

of antibacterial to increase or maintain production, while of immediate benefit, also

could be the Achilles’ heel of present production methods.

Adverse effects on human health are possible from contact with treated livestock or the

antibacterial themselves and through eating

food products containing residues of animal

drugs. Illness can result from poor management and sanitation practices in violation of

standards, but this report is not concerned

with such causes except when the circumstances show that prevention is not possible

through standard-setting and compliancemonitoring. Nor is this report concerned with

all disease acquired from ingesting contaminated foods but only when: (1) drug residues

represent the threat or (z) antibacterial in

the feed result in disease or threatened disease from antibacterial-resistant bacteria.

Human disease from contact with treated

livestock or with the antibacterial(s) itself is

more significant for building a case for the

general risk of such uses than it is for concluding that direct disease transmission is

presently a significant problem, That is, disease transmitted directly from food animals

chronically fed antibacterial-supplemented

feed is not of epidemic proportions, and isolated cases or limited epidemics have been so

infrequently detected that they are newsworthy items even in the scientific community, But taken together with the growing num41
ber of research findings of asymptomatic

spread of drug-resistant organisms from food

animals to humans, they are significant in

documenting the risk to human health from

drug-resistant pathogenic bacteria.

Risks From Infectious Diseases

A large body of literature shows that certain infectious diseases are transmitted

directly from animals to humans. Such diseases are not limited to bacterial etiologies

but cover the whole spectrum of infections—

e.g., tapeworms, trichinosis, psittacosis, tuberculosis, etc. Some diseases are occupational hazards in the meat industry and carry

common names such as “pork infection, ”

“swine erysipelas, ” and “fish poisoning. ”

While the causal chain between food animals or their edible products and disease in

humans may not be completely demonstrated

in any given case, each step in the chain has

been documented repeatedly. With the added

criterion that the infectious agent in the

animal or its edible product be shown to be

caused by antibacterial supplements in the

feed, the causal chain is even more difficult to

prove in any specific case. Thus there is

disagreement over the interpretation of any

specific case but no real disagreement over

the overall conclusions that food animals are

the source of some infections in humans and

that the use of antibacterial in feeds is one

cause of the growing pool of drug-resistant

pathogenic bacteria. Instead, the disagreement is over the exact risk from this enlarging

pool and the contribution of antibacterial in

animal feeds to the problem.

The proliferation of antibacterial-resistant

bacteria is encouraged by the presence of

such drugs. Sensitive bacteria are killed or inhibited, allowing resistant strains or spontaneous mutations of sensitive-to-resistant

bacteria to grow into the vacated environment. The situation is complicated because

some resistant strains can transfer the resistant genes to other bacteria. Antibacterial resistance (and other properties of bacteria)

are sometimes carried on bits of DNA that

function independently of the organism’s

chromosomes. These extrachromosomal

pieces of DNA are called plasmids.

Resistance plasmids (R-plasmids) may code

both for antibacterial resistance and for the

ability to transfer to other bacteria, or the

two functions may be separate on different

plasmids. Resistance to multiple antibacterial is frequently found on an R-plasmid. As in

the case of single resistance, multiple resistance may or may not be transferable depending on whether the transfer code is associated with the resistance code—i, e., resistance to a specific antibacterial may be transferred alone or along with resistance to one

or more other antibacterial.

Gram-negative and gram-positive bacteria

also differ in plasmid-mediated transfer. Rplasmid transfer has not been found to occur

between these two types of bacteria. The Rplasmid of gram-positives are not so freely

transferred as those in gram-negative species, nor are linked, multiple resistances so

frequently found in them.

For any antibacterial there may be: (1) no

known plasmid-mediated transfer of resistance in either gram-positive or gram-negative

bacteria, (z) transferred resistance only in

one bacteria type but not in the other, or (3)

varying degrees of linkages with other antibacterial resistances, For example: (a) bambermycin has no known effect on gram-positive or gram-negative bacterial resistance

patterns; (b) tylosin and virginiamycin select

for erythromycin-resistant staphylococci and

streptococci (gram positives), but their effect

on the resistance patterns of gram-negatives

is essentially nonexistent; and (c) tetracycline

selects for resistance not only to itself but

also for resistance to other antibacterial

linked to it in both gram-positive and gramnegative bacteria (Falkow, 1978) .

Resistance can be transferred from nonpathogenic as well as from pathogenic bacteria. Although resistant nonpathogenic bacteria will not cause disease, they may be able

to transfer antibacterial resistance to bacteria that can cause disease but which were

previously responsive to antibacterial therapy. Thus a growing pool of plasmid-mediated

resistance in nonpathogenic bacteria, even

though of no direct clinical significance,

poses a large threat because of the transfer

of that resistance to pathogenic bacteria.

42
Plasmids have also been identified where

drug resistance and pathogenicity are linked.

Since the first reports on drug resistance and

enteropathogenicity linkage in swine, similar

occurrences have been found in human toxigenic E. coli. In E. coli that cause diarrheal

disease by the production of an exotoxin, it

has been shown that the intestinal toxin involved is often encoded by plasmids (Ent-plasmids) that can be transferred from strain to

strain (Smith and Linggood, 1972; Gyles et al.,

1974; So et al., 1975). A second plasmidcoded gene product, the K-antigen, which

enables the organism to adhere to the wall of

the intestine, is also required for pathogenicity of the organism by exotoxins. Although the

K-antigen shows some species specificity, the

Ent-plasmid does not.

The incidence of R-plasmids is very high

among enterotoxigenic E. coli strains for both

animals and humans (Gyles et al., 1974). The

coexistence of Ent- and R-plasmids within the

same cells raises the possibility of recombination between the plasmids, translocation, or

independent cotransfer. Independent cotransfer has been shown in vitro. In an E. coli

strain responsible for a hospital epidemic of

infantile diarrhea, one plasmid was associated with the production of heat-stable enterotoxin, and another plasmid determined

drug resistance against seven antibacterial.

When the R-plasmid was transferred, the

Ent-plasmid was also transferred to 36 percent of the drug-resistant recipients (Wachsmuth et al., 1976).

E. coli isolated from piglets with diarrhea

have been found with Ent- and R-plasmids

combined, presumably by recombination or

translocation, These plasmids were conjugative (transfer by direct contact between bacterial cells) and determined the production of

enterotoxin and resistance to multiple antibacterial (tetracycline, sulfonamide, and

streptomycin) (Gyles et al., 1977). In addition,

a conjugative plasmid encoding a K-antigen

has also been found to carry resistance genes

(So et al., 1976). These findings portend the

possibility of a complete plasmid in the sense

of combining conjugative, enterotoxigenic

(Ent), adhesive (K), and resistance (R) properties in one package for transfer to completely

nonpathogenic, gram-negative bacteria.

Humans and other animals are hosts to

many of the same bacteria. It is now widely

accepted that E. coli, some of the most ubiquitous gram-negative bacteria, are not composed of stably differentiated strains that are

specific colonizers or pathogenic for separate

animal species. Cross-colonization studies,

serotyping, drug-resistance patterns, and

plasmid types show extensive overlapping

sets of human and animal organisms (Linton

et al., 1977a, 1977b; Howe et al., 1976) Crosscolonization may be enhanced by plasmidmediated factors. Colicin is a substance that

kills E. coli except for the type producing it,

thus giving competitive advantage to the producer. Oral administration of two colicinpositive bovine E. coli strains resulted in 100-

percent replacement of the resident coliform

flora in humans, whereas colicin-negative

derivatives of these two strains were unable

to colonize the same humans (Smith and Huggins, 1976).

Conjugative, colicin-positive plasmids carrying resistance genes are known to exist

(Delhalle and Gratia, 1976). The potential

therefore exists for animal feeding of antibacterial to cause a direct increase in the

pathogenicity of E. coli in humans.

A single Sahnonella serotype, S. typhirnurium, is the most common cause of Salmonella

infection in both animals and humans (CDC

Salmonella Summary Report, 1973). Six of the

most common human serotypes were among

the ten most common animal serotypes in a

recent CDC survey (CDC Report, 1974). In addition to shared serotypes between animals

and humans, plasmids from E. coli can be

transferred to Salmonella and other gramnegative bacteria.

In Connecticut in 1976, S. Heidelberg from

calves infected humans, who in turn secondarily infected three infants, The organism

was resistant to six antibacterial, E, coli

with identical resistance patterns were isolated frGm two infected calves and from one

human, This particular resistance pattern

was not seen in over 10,000 pathogenic

strains of E. coli isolated from the Northeastern United States in the same year, including

42 strains isolated from controls in the study

(Cohen et al., 1977).

43
In a sampling of E. coli from a freshwater

river system and within the saltwater bay

into which it emptied: (a) nearly all the freshwater sites and about half of the saltwater

sites sampled contained antibacterial-resistant coliforms, and (b) zo percent of the 194

strains tested contained R-plasmids carrying

multiple antibacterial resistance transferable to sensitive E. coli, Salmonella typhimurium, and Shigella dysenteriae (Feary, et al.,

1972),

DNA base sequence homology studies of

plasmids from different parts of the world

have shown striking compatibility of plasmids. Plasmids with molecular weights of 57

million, one isolated from a bovine S. typhimurium in England in 1972, and the other

from a human S. typhi in Vietnam in 1974,

showed 100-percent homology. Table 30 summarizes these results (Anderson, et al., 1975).

Finally, a more serious occurrence than

transferred resistance between E, coli and

Salmonella has recently appeared. R-plasmids determining resistance in newly discovered ampicillin-resistant strains of 1-1. in~luenza (Elwell et al., 1975) and in penicillinresistant strains of N. gonorrhea (Elwell et

al., 1977) are identical to plasmids previously

found in E. coli. It must be assumed that these

identical plasmids have a common origin.

Magnitude of the Risk

What proportion of antibacterial resistance is caused by subtherapeutic use in food

animals as opposed to therapeutic use in both

animals and humans is unknown. Thus this

risk is not yet possible to fully quantify. For

some aspects of the problem, such as the

degree of compromise in treating Salmonella

infection, it is possible to arrive at some quantitative notion of the magnitude of human

risk. But for the overall risk to humans from

increased antibacterial resistance, not only is

it unclear what the final deleterious event

should be whose frequency would be estimated, but there are also complicated interactions among human and animal populations

with which we must contend.

As a rule the transmission of Salmonella infection is from animals to man, and the Salmonella reservoir in animals is considered

the direct source of most of the Salmonella infections in humans (Sickenga, 1964). The antibacterial-mediated reservoir of resistant E.

coli in animals provides a source of R-plasmids that can transfer to Salmonella.

A continuous increase in antibacterial resistance has been noted among Salmonella

isolated from farm animals. There has been a

dramatic increase in resistance to antibacteTable 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 plasmld

I = 100 I dnd wtth E COI( K 1 ? chromosomal DNA I = 01

Unlabeled DNA from

strains bear!nq plasmlds Labeled plasm[d DNA

~

{

~

Human (H) 3

f Fll 1, N H, H, )

or ammal (A) Plasmld ~ ~

Group orlgm no { 240 RI.19K . TP1 66> ~J eTP1 58’ ‘TP12 3 TP153 TP15 > ~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 TP120 l– 4 0 1 1 0 0 94 5–

A TP158 l– 3 1 0 101 100 10 —

H, H TP123 10 17 2 4 0 0 9 6 1 0 0 91

H TP153 – 6 12 – — — 3 IW

H TP163 10 6 9 1 0 8 4 s 96

A TPI 71 – — — — — — — 1 0 0

A TP154 6 0 8 0 0 7 12 8 7 9 2

H , H TP1 16 2––– 0 8– 4 0

A TP167 – — — — — — — — o

4

—

5

3

4

0

—

91

9s

82

100

——

o

—

9

—

o

0

—

8

5

7

—

o

100

81

3

—

4

—

o

2

—

o

0

5

—

o

65

100

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 91 376.362, 1975, table 3

44
rials in human Salmonella infections, A review of several studies of human infections

conducted over a period of years indicates

that resistance of Salmonella to tetracycline

has increased continuously from l-percent

resistant organisms prior to 1948 to more

than 40-percent resistance in 1973.1 A comparison of antibacterial resistance in Salmonella isolated from hospitals in 1967 and 1975

conducted by the Department of Health, Education, and Welfare’s (HEW) Center for Disease Control showed overall resistance to at

least one antibacterial increased from 41,1 to

69.4 percent, Multiple resistance to six or

more antibacterial increased from 0,8 to 9,2

percent (table 31),

FDA estimated that there are 2.5 million

cases of Salmonella infection in the United

States each year; about 30 percent were severe enough to be seen by a physician, and

approximately 1 percent of these develop lifethreatening septicemia where appropriate

antibacterial therapy is critical. In 27 percent of the cases treated, the first antibacterial chosen for treatment proves to be ineffective because the disease was caused by antibacterial-resistant bacteria.z Thus there are

currently about 2,500,000 x 0.3 x 0.01 x

0.27 = 2,025 Americans who annually contract a life-threatening Sahnonella infection

that requires antibacterial treatment and for

whom treatment is compromised to some exTable 31. –Antibiotic Resistance in Sa/mone//a Isolated

From Hospitalized Patients

1967

400 strains

Resistance to one or more antlblotlcs

S typhlmurfum 41 170

Other serotypes 15870

All 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)

1975

754 strains

69 4Y0

43 9yo

49 7Y0

26 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 infecting Salmonella strain. Additionally, there is

an even larger number of people with nonsystemic infections who are treated with antibacterial and for whom treatment is also

compromised.

All Salmonella infections cannot be ascribed to antibacterial use in food animals,

but the risk is also not a static situation. If the

risk were static, the lifetime risk of contracting systemic Salmonella infection and the

subsequent treatment being compromised by

antibacterial resistance could be approximated as (2,025 people/year x 70 years) -

200,000,000 = l/1,411, But in view of the

rapid rise in multiple resistance, it must be

assumed that both the degree and extent to

which treatment is compromised are increasing at a rapid rate.

The risk from resistance plasmids of animal origin is not quantifiable even by the

rough estimates made for Salmonella infections. The majority of resistance in human

bacterial populations is probably caused by

widespread use of antibacterial in humans

(some of which is unnecessary), but the enormous pool of R-plasmids as now exists in animals, together with the ability of an R-plasmid to be promiscuously transferred among

bacterial species, must be regarded as a

threat to the therapeutic value of antibacterial in the treatment of both human and animal diseases.

In assessing the risks to humans from the

use of antibacterial in animals, the cumulative nature of these risks cannot be overlooked nor the importance of understanding

the time rate of change of these risks. Although penicillin and tetracycline have both

been used for over 25 years in animaI feeds

without seriously compromising the effectiveness of these drugs in the treatment of human

disease, it cannot be assumed that there will

be no problems in the future. Both the acquiring of resistance in animals and the passing

of resistance from animals to humans are cumulative processes, and perhaps the point

has not been reached, but will be at some

future time, where significant deleterious effects will be observed in humans.

45
DRUG RESIDUES

Types of Risk

Monitoring of drug residues focuses on the

direct harm to humans from consumption of

edible animal byproducts. There are two

types of risks that are addressed: carcinogenic residues and residues with other health

effects. As discussed earlier, there can be no

residue of carcinogenic substances, with “no

residue” determined by a method prescribed

or approved of by the Secretary of HEW. Criteria by which the acceptability of a method

will be judged have not been finalized, but the

Food and Drug Administration (FDA) continues to proceed with regulations that would

avoid the problem of always “chasing zero”

that results from the increasing ability to

measure extremely minute amounts of substances. There are approved drugs that are

regulated on a “no residue” basis because

they are known or suspect carcinogens.

There are official methods for these drugs,

although there is disagreement on whether or

not these methods are adequate when reviewed by current scientific standards.

Residues of noncarcinogenic drugs do not

have to meet the “no residue” requirement

applicable to carcinogens but are governed

by safety factors as described in the law.

These factors include the probable consumption of the drug and of any substance formed

in or on food, the cumulative effect, other

safety factors deduced by scientific experts

from animal experimentation data, and

whether the conditions of use are reasonably

certain to be followed in practice.3 In practice, FDA sets specific tolerances for residues

based on these safety factors and the availability of a practical analytical method to

determine the quantity of residue. Chronic

studies are required to support a finite tolerance. Acute toxicity studies of 90 days’ duration are minimally required for a negligible

tolerance. If it is determined that negligible

residues will probably not occur, no tolerance

is required. And if the drug may be metabolized and/or assimilated in such form that any

possible residue would be indistinguishable

from normal tissue constituents, no tolerance

is required.4

The treatment of carcinogens differs from

that of noncarcinogens in that: (1) if finite residues are present, carcinogens are banned

and noncarcinogens are not, the latter contingent on establishment of a tolerance, and (2)

if it is not possible to determine whether residues will be present (a) for carcinogens, the

manufacturer fails the burden-of-proof test

for safety and the drug is not approved or

withdrawn, whereas (b) for noncarcinogens,

negligible tolerances or no tolerances are set,

based on a showing that residues are expected to be below a level of potential toxicological significance. The judgments are not

made without toxicological data. For carcinogens, even this distinction is somewhat artificial because in the case of either measurable

or unmeasurable residues, the drug is not approved or withdrawn. FDA’s current attempt

to extrapolate from animal test data to man,

so that “no residue” would be defined by risk,

would be one method of regulating carcinogens on a more rational basis.

Noncarcinogenic Risks

Tolerances for noncarcinogenic drug residues are determined by the general criteria

for safety enumerated earlier and by the requirement that the residue level cannot be set

higher than that reflected by the permitted

use of the drug. When a specified level of residue is determined to be safe through toxicological data, a withdrawal period prior to

slaughter of the animal may be required

before the drug can be approved. Most approved drugs require a withdrawal period

only because they are approved on a negligible-tolerance basis instead of on a finite-tolerance basis, Because the safety factor applied

to establish a negligible as opposed to a finite

tolerance is very large, withdrawal periods

are necessary for residues to deplete belowtolerance levels. The withdrawal period for a

specific drug may vary for different animal

species 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 other

drugs.

Sulfamethazine residues in swine have

caused the greatest problem in this area,

with tissue residues in excess of the 0.1 ppm

limitation averaging 13.1 percent of the samples tested in the latter half of 1977. As explained earlier, more than half of these violations were probably caused by contamination

of the withdrawal feed. If so, then increasing

the withdrawal time will have little effect on

violation rates without parallel action in decreasing cross-contamination of feeds,

FDA subsequently did increase the withdrawal period for all uses of sulfamethazine

to 15 days and was nearing completion of a

proposal to set action levels for cross-contamination at the end of 1978. Prior to this action,

the withdrawal period had been 5 days when

in combination with tylosin and 7 days in combination with penicillin and tetracycline.

These withdrawal periods had been established prior to new regulations issued in 1975

that established a lo-day withdrawal period

for sulfonamides not already subject to regulation.’ The 10-day period was set because

the judgment was made at that time that 10

days would probably be adequate to assure

that residues would be below 0.1 ppm and because of the degree of thyroid response to sulfonamide drugs,

Other sulfonamides have not been affected

by the new withdrawal period. The withdrawal period for sulfathiazole, also used

with tetracycline and penicillin in swine feed,

remains at 7 days.~ Sulfaethoxypyridazine is

used for therapeutic purposes in swine and

cattle for use by or on the order of a licensed

veterinarian. The withdrawal period remains

10 days.’ Sulfamerazine is used in trout, with

a withdrawal period of 3 weeks. ~

Residue violations from other antibacterial have not been significant. Most of the residue problems result from therapeutic and not

from feed-supplement use. The incidence of

violations for some antibacterial is summarized in table 32.

5

21 CFR 510.450.

“21 CFR 558.155,

7

21 CFR 558.579.

’21 CFR 558.582.

Antibacterial residues were previously

considered important in the development of

antibacterial-resistant bacteria because of

ingestion by humans, but this is now considered the least likely contributor. However,

the evidence that violative residues of sulfamethazine were caused largely by contamination of the withdrawal feed may bring a new

perspective to this issue, As previously discussed, the contribution of antibacterial-supplemented feed to the growth of drug-resistant bacteria comes primarily from selection

and promotion of resistant strains of the

micro-organisms in animals, not humans. So

antibacterial residues in edible animal products are the wrong indicator of this potential

problem if the level of such residues does not

reflect dependably the antibacterial contamination.

Cross-contamination of feeds may also be

occurring for other antibacterial, particularly penicillin and tetracycline, because they

are widely used and mixing is not limited to

certified feed mills or under the direction of a

licensed veterinarian. The sulfamethazine

problem was detected because contamination

led to violative tissue residues. For other antibacterial, cross-contamination may be occurring but may not be reflected in increased

concentrations of tissue residues. Thus, reliance on tissue residues as an indicator of

cross-contamination of feed may not be appropriate, and direct monitoring of supposedly antibacterial-free feeds would have to be

undertaken to eliminate cross-contamination

as a possible significant contributor to the development of drug-resistant bacteria. A limited amount of this feed monitoring is presently conducted by FDA.

Carcinogenic Risks

General Considerations

Current reliance is on testing in small animals for both cause and effect and quantitative extrapolation to humans, All substances

demonstrated to be carcinogenic in animals

are regarded as potential human carcinogens. No clear distinctions exist between

those that cause cancer in laboratory animals and those that cause it in humans. However, the accurateness of extrapolation from

47
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laboratory animal results to humans to quantify the effect is less certain (Cancer Testing

Technology and Saccharin, 1977).

Short-term tests are developing as aids in

evaluating the potential of substances to

cause cancer. Short-term tests are based on

the presumption that cancer is related to

cellular DNA changes and that detection of

such changes is predictive for a substance’s

potential carcinogenicity. These tests examine the capacity of a substance to cause mutations or other genetic alterations. Several

hundred known animal carcinogens and noncarcinogens have been tested in the Salmonella/Ames test, which at this time is the most

extensively studied short-term test. About 90

percent of the known carcinogens are positive in this test, in contrast to positive results

in about 10 percent of substances that are not

carcinogenic in animal tests (McCann et al.,

1975; Purchase et al., 1976; Sugimura et al.,

1976).

Typically, animal experiments use on the

order of 100 animals at each experimental

dose. If a particular experimental dose

causes a lifetime increase in cancer risk of

1/10, this increase can be measured with a

small degree of accuracy using 100 animals.

If background or spontaneous carcinogenesis

is present, even larger numbers of animals

will be required. On the other hand, the extra

human risk that we may want to estimate resulting from environmental exposure is usually much smaller than 1/100 for any given

chemical, perhaps on the order of 1/10’.

Clearly, it would not be practical to conduct

an experiment with enough animals to measure directly an increase in risk this small.

For these reasons the procedure has been

developed of conducting lifetime animal-feeding experiments using, in addition to a control

dose of zero, several doses at which the projected extra cancer risk may be 1/10 or

larger. The high-dose data are used to estimate a dose where the risk may be no larger

than, say, 1/10’. That is, the high-dose data is

used to estimate the risk at dose levels considerably below a level at which effects could

be discerned from practical experimental

feeding studies. An equally important variant

to this problem is the calculation of the socalled “safe” dose, for which there is some

measure of statistical assurance that the extra risk at that dose is no more than, say,

1/10’. These problems are often referred to

collectively in the literature as the “low dose

extrapolation problem.

The most common animals used are rats

and mice, and these species, as well as different inbred strains of them, often vary in

their sensitivity to the substance being tested.

Also, the number of animals used in these experiments is a compromise between large

enough numbers of them to detect positive effects and the costs and time of conducting

these experiments. Rats and mice live for 2 to

3 years, and when this time is added to the

time needed to set up the experiment, examine tissues, write up the results, etc. a typical

experiment takes about 4 years. And statistically speaking, the law of probabilities tells

us that positive results cannot be expected all

of the time even when the substance being

tested is carcinogenic.

For these reasons, when both positive and

negative results are obtained in different experiments and there is no known reason for

the discrepancy, more weight is given to the

positive results. Scientists would agree that

statistically positive results obtained in at

least two animal species by appropriate tests

are reasonably conclusive evidence that the

substance is likely to be a human carcinogen.

Clearly positive results in one valid and appropriate animal species are also considered

by a majority of scientists to be a sufficient

basis for labeling a substance a carcinogen.

In addition, short-term tests may be helpful in

predicting that a substance is genotoxic and

may, therefore, aid in the identification of a

substance’s carcinogenic potential.

Carcinogens may act in a variety of ways,

ranging from a genotoxic interaction of the

agent with the cell genome to the enhancement of the expression of tumorigenesis initiated by other known or unknown agents. Science is progressing rapidly in the elucidation

of the mechanisms of carcinogenic action, but

it is seldom possible at this stage to be certain

by what mechanisms an individual agent

acts.

49
The concept of a threshold below which a

carcinogen may be ineffective has been the

subject of debate. It is not possible to determine by experiment whether such a threshold

exists because of the vast numbers of animals

and the consequently large facilities and reservoir of trained personnel required. Nevertheless, there is substantial evidence that the

lower the exposure to a carcinogen, the lower

the risk of developing cancer. This established fact is the justification for attempts to

extrapolate from the effects of carcinogens at

high doses to their postulated effects at much

lower doses. And even if threshold issues

were resolved—i. e., for a given substance

there is or is not a threshold—how to determine the threshold with a high degree of confidence would remain as a major issue.

In the absence of contrary data, it is prudent in extrapolating from the results of animal experiments to humans to give the most

weight to the results of the most sensitive

animal experiments. The general rationale is

to err on the side of safety. Laboratory animals are deliberately inbred to have uniform

characteristics so that confounding factors

relating to individual animal variability are

minimized within a specific experiment. Generally, these experiments attempt to introduce only one variable—the substance to be

tested—so that causality can be deduced between it and the resulting carcinogenic effect.

When the risks from animal experiments

are extrapolated to expected incidence in

humans, the results are usually expressed in

risks per lifetime exposure, the usual exposure period of present animal tests. Yet lifetime exposure is not a necessary precondition

for carcinogenesis, since even single exposures to potent carcinogens can produce cancer. Lifetime exposure is intended to elicit the

maximum response to a particular concentration of the tested substance.

Lifetime exposure to large doses by experimental animals and the use of these findings

to extrapolate to low doses in humans are

often misunderstood. The usual misunderstanding is to equate the concentrations used

in the experiments with that consumed by

humans. For example, in announcing the results of positive carcinogenic tests on saccharin and its intention to ban it as a food additive, the initial press release from FDA

made the statement that “The dosages of saccharin fed the rats in the Canadian study

were in excess of the amount that a consumer

would receive from drinking eight hundred

(800) 12 oz. diet sodas daily over a lifetime”

(FDA Press Release, Mar. 9, 1977).

These misunderstandings leave the impression that animal experiments predict unrealistically high carcinogenic effects in humans.

Yet these experiments are conducted in carefully controlled conditions where other carcinogens are not present, in contrast to the

conditions of human exposure. There is a

rough similarity between (I) the correlation

of experimental conditions with environmental exposure to which humans are subject and

(2) the correlation of experimental with field

results on the effectiveness of antibacterial

for growth promotion and feed efficiency in

food animals. In the latter, the quantitative

effect in the field is greater than under controlled, experimental conditions, though the

precise mechanisms are not known. Perhaps

a similar result might be hypothesized for

carcinogenic effects, but at the minimum, the

conditions are not so radically different that

in carcinogenic testing the opposite result

should be expected. That is, there is no strong

argument that animal data overstate the risk

to humans.

Quantification of Risk

It is not scientifically possible to determine

the slope of the carcinogenesis dose-response

curve for any carcinogen at low exposure levels. Therefore, performing a low-dose extrapolation involves the choice of a mathematical

function to model the dose-carcinogenic response relationship and the choice of statistical procedures to apply to the mathematical

function. The choice for this mathematical

function turns out to be extremely crucial to

the outcome of low-dose risk estimation. If the

assumed relationship between tumor occurrence and dose does not apply in the regions

to which the extrapolation is being made, a

serious overestimate of the “safe” dose may

result (Mantel and Bryan, 1961). For example, a comparison of five standard dose-re50
sponse models showed that they could differ

by many orders of magnitude at low dose

levels for which extra risks are on the order

of 1/10’ (Chand and Heel, 1974),

It is theoretically possible to discriminate

among the various potential dose-response

functions on the basis of experimental data;

however, two different dose-response functions can often fit experimental data equally

well but still differ by several orders of

magnitude at very low doses. Moreover, even

if a particular dose-response function were to

give a significantly better fit to data than

several others, this would still not furnish

assurances that this function would necessarily correlate in any way with the true dose

response at very low doses where it is not

feasible to measure the true extra risk directly. As a consequence of the great disparity of

dose-response functions at low doses, the

dose-response function should reflect known

or at least plausible information regarding

the biological mechanisms through which a

chemical induces or promotes cancer and not

solely on the basis of how well it can be made

to fit “experimental data. ”

For genotoxic carcinogens probably the

substance itself or a metabolize acts directly

at the cellular level and produces a hereditable change that eventually leads to tumor formation (Crump et al., 1977), Carcinogens that

are carcinogenic by reason of their mutagenicity should fall into this category. Therefore,

carcinogens that test positively in the SahnonelJa/Ames mutagenicity screening test are

very likely to be genotoxic. As 90 percent of

the known carcinogens tested have been

found to be mutagenic, most known carcinogens are probably genotoxic.

A partial solution to the low-dose extrapolation problem for the case of genotoxic

chemical carcinogens has been given (Crump

et al,, 1976; Guess and Crump, 1976; Pete,

1977). The key result is that, at least as long

as background carcinogenesis is present, the

dose-response curve should not be expected

to be absolutely flat at zero dose. What this

means is simply that when risk is plotted

against dose response on ordinary linear

scales, the tangent line to the dose-response

curve at zero dose should have a positive

slope. When a dose-response function has

this property, it is linear at low dose. This

simple property can have far-reaching consequences on low-dose extrapolation. For example, consider the two potential dose-response

functions (1) 0.1 [(99/999) x d + (900/999) x

dz] and 0.1 x dz for the dose interval

os d s 3, Both of these curves give a risk of

1/10 at a dose of d = 1 and are practicably indistinguishable at higher doses. However, at

a dose of d = 1/103 (1) predicts a risk of 1/105

and (2) predicts a risk of 1/107, a difference of

two orders of magnitude.

One explanation of why the dose-response

function should be linear at low dose when

background is present is that the cellular

mechanism through which the test agent produces cancer should already be operative in

producing background tumors. When this is

true, the effect of the test agent is to add to an

already ongoing process (Crump et al., 1976;

Pete, 1977). If background carcinogenesis is

allowed for by positing an effective background dose, the wide range of risks obtained

using different models effectively disappears.

This does not imply that the dose-response

curve is not expected to be linear at low dose

in the absence of background carcinogenesis

(Crumpet al., 1976; Watson, 1977).

The evidence for low-dose linearity given

above applies mainly to genotoxic carcinogens. A nongenotoxic carcinogen might cause

some gross physiological change such as suppression of ovulation, which could predispose

the subject to cancer. For such carcinogens

the shape of the dose-response curve at low

dose is highly speculative. There could

possibly be a threshold dose below which the

agent has no carcinogenic effect at all on an

individual. However, even if a threshold

mechanism is operative, there is likely to be

considerable variation in individual thresholds in a large population. Consequently, the

dose-response curve for the entire population

could still exhibit a linear trend at risks as

low as 1/10’ or lower,

The effects of metabolic activation and detoxification on carcinogenic dose response

have been recently considered through a kinetic model that encompasses free toxic substance, metabolize, deactivator, and the inter51
actions of these substances (Cornfield, 1977).

Only a steady state situation is studied in that

variation over time of the concentrations of

these agents is not considered. The model

predicts a threshold dose below which there

is no carcinogenic risk under the assumption

that the deactivator is 100 percent efficient in

deactivating the carcinogen. However, in a

naturally occurring process it is likely that

deactivation would not be perfect and would

be less than 100 percent effective in always

combining with 100 percent of the carcinogen

before an amount of the active metabolize

reaches a cancer target site. Any of a number

of modifications to the model to allow for

nonperfect deactivation would rule out a

threshold and would lead directly to a model

for which carcinogenic response varies

linearly with dose at low doses. Cornfield’s

own modification of perfect deactivation, that

of allowing the deactivating reaction to be

reversible, leads, as Cornfield points out, to a

model that is linear at low dose. This occurs

regardless of how slowly the reverse reaction

takes place, as long as the possibility is not

eliminated entirely. Furthermore, even in the

extremely unlikely case of perfect deactivation, an otherwise realistic model should still

imply low-dose linearity, since the theoretical

time required for perfect deactivation would

not be zero and would likely be infinite.

For most, perhaps all, carcinogens, the

mechanisms through which cancer is produced are not sufficiently understood so that

the shape of the carcinogenic response curve

can be predicted with certainty. As pointed

out earlier, experiments of sufficient size

cannot be conducted that would permit direct

experimental investigation of the dose-response curve at low doses. There are plausible arguments that the dose-response curve

is linear at low dose for many carcinogens. In

view of these uncertainties, it would seem

reasonable to base estimates of added risk of

cancer on a mathematical model that encompasses low-dose linearity unless the mechanism through which the carcinogen operates

is sufficiently understood so that low-dose

linearity can be conclusively ruled out. Once

the principle of low-dose linearity is accepted, the problem of estimation of risks at

low doses is nearly solved. This is because the

disagreement between the upper statistical

confidence bounds on risk at low doses based

on a model that incorporates low-dose linearity, and one that does not is typically several

orders of magnitude; whereas the corresponding disagreement between two reasonable models, both of which incorporate lowdose linearity, is usually much less than this.

The new procedures and criteria for evaluating the assays for carcinogenic residues in

edible products of animals that FDA is attempting to implement (see chapter II) originally adopted the Mantel-Bryan mathematical model (Mantel and Bryan, 1961; Mantel et

al., 1975) to quantify the residue level corresponding to a risk of 1/105 in test animals.

This residue level, or So, is expressed as a

fraction of the total diet—i.e., in parts per

billion (ppb). This level is adjusted to account

for the respective portion of the human diet

that is represented by the various food products containing residues of the carcinogen being tested, the transfer from animals to man

being made on a fraction-of-total-diet basis.

The resulting dose level, Sm, is “the level of

total residue of carcinogenic concern that

can be operationally defined as satisfying the

no-residue requirement of the Act for specific

tissues. ”g The dose level Sm represents the

upper bound to the lowest limit of reliable

measurement that an approved assay method

must satisfy. The specific mathematical

model chosen is thus an integral part of defining “no residue. ”

Crump (1978) discusses the Mantel-Bryan

model, simple linear extrapolation models to

low doses (Heel et al., 1975; Brown, 1976),

and multistage dose-response models (Guess

and Crump, 1976, 1978; Crump et al., 1977;

Hartley and Sielkin, 1977). In the MantelBryan procedure, the mathematical model

used for the dose-response model is what is

termed the “probit” function. The MantelBryan procedure, as was to be applied in the

FDA regulations, rules out linearity at low

dose in favor of a “flatness property” at low

doses. This results in “safe” dose estimates

that are considerably higher than those obtained using the multistage model because it

’42 F.R. 10422, Feb. 22, 1977.

52
assumes away linearity at low dose, an assumption that is probably unwarranted for

the majority of carcinogens, which appear to

be genotoxic. Figure 1 illustrates this difference. Note that for the data reflected in

Figure 1.— Comparisons of “Safe” Doses Computed

From the Mantel-Bryan Procedure and From a

Procedure Based On the Multistage Modela

1

1

%

~

1

0-1

Multistage maximum

likelihood curve

Mantel-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 Theoretical Problems

m the Mod!fled Mantel. B~an Procedure &omefr/cs 33 752 755

this graph, the Mantel-Bryan “safe” dose lies

above the multistage “safe” dose at values of

added risk below 5 x 10-4, When the MantelBryan method predicts that a cancer risk is

no greater than 1/106 the true risk could easily be one or two orders of magnitude higher,

or between 1/10’ and 1/105 (Crump, 1978).

FDA has now proposed that linear extrapolation be used, rather than the MantelBryan procedure, because, among other reasons, linear extrapolation is least likely to

underestimate the risk.

Since extrapolation based on the multistage model will often be linear at low doses,

the question arises as to how different the

result will be from simple linear extrapolation. For some data the difference will be

minimal, but for other data sets the difference 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 extrapolation is lower than the “safe” dose

based on the multistage model by a factor of

about five and there are doubtless cases

where the difference could be greater than

an order of magnitude (10 x ).

Diethylstilbestrol (DES)

DES has been shown to be carcinogenic in

both animals and humans. The association

between the use of DES by women during

pregnancy and the appearance of clear-cell

adenocarcinoma of the vagina or cervix in

their exposed daughters was recently reviewed by a task force at the National Institutes of Health (DES Task Force Report,

1978). The main conclusions were as follows:

1.

2.

3,

DES daughters. A clear association between in utero exposure to DES and

clear-cell adenocarcinoma of the vagina

or cervix is established. Estimates are

that the incidence will be between 0.14

to 1.4 per 1,000 through age 24 among

the exposed daughters. Cancers of this

type and histological sites were almost

unknown in women of that age group prior to this discovery. (The eventual incidence as these women grow older obviously is unknown. )

DES mothers. A relationship between

DES during pregnancy and risk of cancer in the mothers is unproved. However, existing studies indicate that this

population, like others exposed to high

levels of estrogens, may in the future

develop excessive incidence of specific

tumors.

DES sons. Until recently, DES effects on

exposed sons had not been reported. Recent studies clearly show an excess of

genital abnormalities in these individuals. As yet, there is no definitive information on the fertility implications of

these findings nor firm evidence of an

association between DES exposure in

sons and an increased risk of testicular

cancer.

The animal data currently available on

carcinogenic dose response to DES consists

primarily of mice data (Gass et al., 1964; Gass

et al., 1974), although new experiments at the

53
National Center for Toxicological Research in

Jefferson, Ark., are nearing completion. DES

was given in the diet beginning from 4 to 6

weeks after birth and continued throughout

their lives. (Note that this is less than maximum lifetime exposure, so the cancer response might have been greater.) The 1964

micedata are summarizedin table 33.

Crump(1978) analyzed these data setsaccording to specified methods for analyzing

animal carcinogenicity data (Grump et al.,

1977) to estimate the risks to mice at dose

levels comparable to those encountered by

humans through DES residues in beef. 13ecause suppression of appetite at the two

highest doses was reported, thedataat 500

ppb and 1,000 ppb were omitted from analysis.

The average food intake of Americans is

about 24 lbs a week (Riedman, 1971), about

2.31bsof which is beef (CAST report, 1977).

The lowest limits of reliable measurement of

the FDA-approved mouse uterine method for

measuringDES residuesis 2ppb. Theconcentration of DES residues in liver is about 10

times that in beef muscle (U.S. Congress,

1971). Tested livers cannot exceed 2 ppb;

otherwise DES would be detected and the

present “no residue” test would be violated.

Thus the average DES residue in beef muscle

mightbe 0.2 ppb. This gives an average dose

of DES to Americans from DES residues in

beef 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 extra cancer risks at the dose of 0.02 ppb based

on applying the multistage model and related

statistical theory to these mice data. The most

sensitive mice data predict a risk of I/13,000,

and the least sensitive a risk of 1/82,000. As

explained earlier, when the Mantel-Bryan

model predicts a risk of 1/106, the true risk

could easily be between 1/104 and 1/105

, or

within the same range as summarized in table

34.

Assuming that the population at risk is 200

million people, lifetime exposure to DES in

meats at 0.02 ppb would result in 15,385 extra cancers as derived from the most-sensitive mice strain (2OO million x 1/13,000), and

3,390 or 2,439 extra cancers as derived from

the less-sensitive mice results from table 34.

These estimates should be compared with

200 extra cancers, which would be the “no

residue” level of the 1/106 target risk from the

proposed FDA regulation.

Table 35 summarizes the doses derived

from these same experimental data that result in an added carcinogen response of 1/106,

the target “no-residue” level of the proposed

FDA regulation. In contrast to the 0.02 ppb

estimate exposure to DES from present consumption of food, these doses are in the range

of 0.001 to 0.0003 ppb, or 1/20 to 3/200 the

estimated exposure.

The evidence for DES’s carcinogenicity

points to a nongenotoxic mechanism, so an effect at low doses can be disputed (Weisburger, 1977). In addition, the response might be

Table 33. –Occurrence and Latent Period of Mammary Carcinoma in Mice Fed Varying Concentrations

of DES in the Diet (Gass et al., 1964)

C3H females C3H males Strain A castrate males

Percent Latent Percent Latent Percent Latent

DES /n diet with period m with period In with period In

ppba No, ofmlce tumors weeks No of mice tumors weeks No. ofmlce tumors weeks

o 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 6200

25 60 4 3 3 51.07 62 0 — 70 2 9 48,50

50 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 61.33

500 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 eStr09enlc

suppression 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 50/0

M/cc slfaln es(lmale cmfdeme lmufld

L *JH fem[iles 1 / 13,000 118000

C’3H males 1 8? 000 1 ’47 000

S[r d n A castf Ate mdles 1 ~ndes 59000 1 ‘.37 000

Table 35.–Estimates of Dosage (ppb) of DES Required To Effect

an 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 0000162

C’3H rTI+ e5 O 00164 0000944

Sfr.j(n A caslr,ite mal?s 0170117 0000748

I 1. [ 1,1, I ‘?

largely limited to females. However, in both

animal experiments and from what is known

about DES effects in humans: (1) cancer is

known to occur even in the absence of continuous DES stimulation, and (2) effects in

males have been observed, The rough estimates for the number of extra cases expected

in humans are for lifetime exposure risks. If

DES has a carcinogenic effect at low doses,

these estimates would n(Jt be overstating [he

ef feet.

Nitrofurans

In 1964, in the course of conducting toxicity studies, scientists at the University of

Wisconsin discovered that a substantial numIJ~I’ of mammary tumors had developed in

rats fed nitrofurazone. Subsequent studies in

1966 and 1967 sho~ted that animals fed nitrofurans had significantly higher incidence of

tumors, Sinre that time, Norwich Pharmacal

Company has conducted four chronic toxicity

studies to assess the tumorigenic and carcinogenic effects of one of these nitrofurans,

furazolidone. In all of these studies, the experiments were started when the animals

wer[~ about 2 months of age, and three of

these studies fed furazolidone for a limited

period, followed by a furazolidone-free diet

until the experiment was terminated. A more

pronounced carcinogenic effect might have

been observed if the doses had been continued throu~hout the experiment.

Brief descriptions of these experiments follow:

1.

2

3.

4.

The High-Dose Sprague-Dawley Ra t

Study .’’—Four hundred Sprague-Dawley rats approximately 2 months of age

were divided into four groups of 50 male

and 50 female rats each. The diet of the

four groups contained furazolidone in

the feed in the amounts of O ppm, 250

ppm, 500 ppm, and 1,000 ppm for approximately 18 months. All groups were

then maintained on a furazolidone-free

diet until mortality in each group

reached 90 percent, at which time the

remaining animals were sacrificed.

The Fischer Rat Study .’Z—This study

was performed identically to the HighDose Sprague-Dawley Rat Study except

that Fischer 344 rats were used instead

of Sprague-Dawley rats.

The Low-Dose Sprague-Dawley Ra t

Study .’3—Three hundred and twenty

Sprague-Dawley rats approximately 2

months old were divided into four groups

of 40 male and 40 female rats each. The

diet of the four groups contained furazolidone in the feed in the amounts of O

ppm, 17.6 ppm, 87,9 ppm, and 264.4

ppm. These are average amounts since

the concentrations of furazolidone in the

diet were increased as the animals continued to grow. The animals wer e

treated continuously until the experiment was terminated after 2 years.

The Mouse Study .’’—Four hundred

Swiss MBRIICR mice approximately 2

months of age were divided into four

groups of 50 male and 50 female mice

each. The diets of the four groups contained furazolidone in the feed in the

amounts of O ppm, 75 ppm, 150 ppm, and

300 ppm for approximately 13 months.

‘‘“Tumorigenesis Evaluation of Nh’- 180 in Spra~ueDawley and Fischer Rats, Part 1. S~~r:~~~lc-Il:]\\l[:\ Evaluation. ” Nov. 9, 1973, Projert No, 475.091),

‘“‘Tumorigenesis Evaluation of NF-180 in Spra~ueDawley and Fischer Rats, Part II, Fischer 344 Ev;~luation, ” 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, Project No. 475.09E.

5 5
The four groups were then maintained

on a furazolidone-free diet for 10 additional months, at which time the experiment was terminated and the surviving

animals were sacrificed.

Table 36 summarizes the tumorigenic and

carcinogenic findings. There is a high rate of

spontaneous tumors in all four groups. The

mice results are the most sensitive. Although

exposed to the lowest concentrations of furazolidone, they developed the greatest percentages of tumors, particularly when malignant

tumors were separated from nonmalignant

ones.

The results of various statistical tests performed on the data are given in table 37. A

chi-square goodness-of-fit test of no carcinogenic-dose-related effect is significant at the

0.01 level of significance for four of the data

sets. More importantly, a test of no dose-related effect versus the alternative of a onestage effect (a multistage model) is significant

at the 0.01 level for six of the data sets including all four of the data sets for mice. Thus

furazolidone had a statistically significant effect in mice. A chi-square goodness-of-fit test

for compatibility with the one-stage model of

carcinogenesis was significant at the 0.05

level in only z of the 16 data sets. The two

data sets for which significance was found

Table 36.–Summary of Tumorigenic and Carcinogenic Results

From Four Experiments With Furazolidone (N F-180)

(Data is presented in the form “no. responders/no animals

tested”)

High-dose

SpragueDawley Rat

Study

Fischer 344

Rat Study

Low-dose

SpragueDawley Rat

Study

Mice Study

Dose

(ppm)

o

250

500

1,000

0

250

500

1,000

0

1 7 6

8 7 9

2644

0

75

150

300

SOURCE CrumD 1978

All neoplasms Malignant neoplasms

. . . . Males

29/50

33/49

35/50

40/49

48/49

49/50

45/50

44/49

21 /34

1 3/34

1 7/35

23/32

25/49

30148

36/50

46/51

females

44/99

46/50

48/50

45/50

39/49

46/50

50/50

45/50

26/34

24/35

29/33

33/35

35/50

35/50

40/47

42/48

Males

10/50

12/49

1 5/50

1 3/49

1 5/49

2/50

1 5/50

13/49

3/34

5/34

9/35

6/32

21 /49

26/48

32/50

43/51

~emales

11 /49

6/50

12/50

13/50

14/49

10/50

11 /50

16/50

7/34

11 /35

9/33

12/35

32/50

28/50

37/47

40/48

Table 37.–Levels of Significance of Various Goodness-of-Fit

Tests 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 alternative 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 rats

All neoplasms Males 31 < 01 92

Female s 64 49 47

Mallgnant neoplasms Males 73 .21 64

Females 38 .18 25

Fischer rats

All neoplasms Males 13 .50 06

Females. C 01 .05 01

Malignant neoplasms Males <0 1 28 <,0 1

Female s 48 ,26 37

All neoplasms Males ,

Females .

Malignant neoplasms Male s

Female s

All neoplasms Male s

Females

Mallgnant neoplasms Male s

Females

SOURCE Crump 1978

Low-dose Sprague -Dawley rats

03 .03 07

03 < 0 1 47

29 16 23

61 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 be

compatible with any dose-response function

for which the risk increases with increasing

dose.

Before using these data to estimate extra

risks for furazolidone residues, it is first

necessary to assess the level of furazolidone

residue likely to occur in food products from

animals exposed to furazolidone. In 1971 it

was announced by FDA that a method for

measuring residues of furazolidone would be

required that would reliably measure residues as low as 2 ppb. The FDA concluded in

1976 that there was at that time no method

available for reliably measuring residues of 2

ppb.15 Thus there currently is no way to know

if food products from animals treated with

furazolidone do not have at least 2 ppb in

them.

Table 38 presents estimates of extra risk at

a dose of 2 ppb based on the rodent data in

table 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 Per

Billion of Furazolidone Using the Data in Table 36

Most hkeiy Upper 97 5%

eslimate of confidence llmlLs

extra risk for exfra nsk

H(gh-dose Sprague -Dawley rats

All neoplasms Males 1/1 500000 1 /760 000

Females 1 /375 000,000 1/4 800000

Mallgnant neoplasms Males 1/6 900,000 1/1 900,000

Females 1/6 900000 1/2 100,000

Fischer rats

All neoplasms Males o 1/5 500,000

Malignanl neoplasms Females 1 /9,400 000 1 /2,200,000

Low-dose Sprague -Daw/ey rats

All neoplasms Males 1 /490,000 1 /21 0000

Females 1 /260,000 1 / 130,000

Mallgnant neoplasms Males 1 i 1 300000 1 /430,000

Females 1 /’1 30(J 000 I f39(3 ()()(J

SWISS MBR IIBR mme

All neoplasms Males 1 / 200,000 1 / 1 20,000”

Females 1 /470 000 I 1230,000

Maltgnant neoplasms Males 1 /220,000 1 / 130000

Females 1 /420,000 1 /21 0000

nearly linear with dose at risks below 1 percent, risk estimates for other doses can be

determined from the table by simply multiplying by the appropriate factor. For example, to

compute risks at zo ppb, multiply the results

in table 38 by 10.

The risk estimates in table 38 are based on

the statistical procedures of Crump et al.

(1977] associated with a multistage model. To

obtain the “most likely estimates, ” the particular multistage model was selected (Guess

and Crump, 1976) that maximized the likelihood of the data. Risk estimates are not given

for the Fischer rats for “females, all neoplasm,” nor for “males, malignant neoplasm, ” because these data are not consistent with the multistage model. For the most

sensitive result—namely, in the mice—the

extra risk at a dose of 2 ppb furazolidone exceeds the proposed regulatory “no residue”

risk level of 1/ 10h by two to five times.

It should be noted that the estimates of risk

are higher for the mice and low-dose rats

than for the high-dose rats because the highdose rats had lower or approximately equivalent tumor rates as rats and mice in the

other experiments. High-dose rats were fed

250 ppm, 500 ppm, or 1,000 ppm furazolidone. Low-dose rats were fed approximately

17.6 ppm, 87.9 ppm, or 264.4 ppm furazolidone; and the mice were fed 75 ppm, 150

ppm, or 300 ppm furazolidone. When extrapolated to extra risks from a dose of 2 ppb

furazolidone (table 38), the low-dose experiments result in higher incidence of tumors

than the high-dose experiments.

Two ppb may be the residue level in meat,

but it is not the dose to which humans are exposed. These risks can be translated at low

doses for mice into comparable risks for humans in the following way: Furazolidone is

used extensively in chickens and turkeys and

for limited periods in swine, In the estimates

of effects from banning selected antibacterial, banning nitrofurans (of which furazolidone is one) was estimated to have an effect

on chickens and turkeys but not on pork. (See

table 23.) Thus, human exposure from meat

consumption comes from chickens and turkeys.

For DES, Americans were assumed to consume an average of 2,3 lbs of beef a week and

24 lbs of food a week. Thus beef was assumed

to average about 0.2 ppb DES, for an average

dose of 0.02 ppb, Taking a population of approximately 200 million and a total beef supply in 1976 of 25,969 million lbs (see table 22),

the average amount of beef consumed by

Americans was approximately 2.3 Ibs a week

(25,969 million lbs of beef - 200 million people - 52 weeks). This correlates with the 2.3

lbs used in calculating the DES risk, where

average dose from DES residues was 0.02

ppb.

A comparable calculation for furazolidone

is as follows: Total chicken and turkey production in 1976 was 10,930 million Ibs (table

22). The average weekly consumption per

person was therefore:

I0,g30 million lbs 1.05 lbs — - 52 weeks = {l ~~,e[>k

200 million people .,

Using the same caluclation as used for

DES, the average dose of furazolidone per

person from residues in chicken and turkey

meat would he:

57
The estimates of extra risk in table 38 for a

dose of z ppb can be used to estimate the

risks for other doses by multiplying by the appropriate factor, 0.09/2, or approximately

I/ZO. Taking the most sensitive animal data,

that for Swiss MBRIIBR mice, and multiplying by I/20, these risks are approximately 1

- (4 x 10”); 1 - (9,4 x 10”); 1 - (4.4 x

1O[)); and 1 - (8.4 x 10’). Thus the risk to

humans from furazolicione in poultry is 4 to 10

times less than the target “no residue” risk of

1/10’. In contrast to expected extra cancers

of 200 for the “no residue” risk of l/l Ob, these

exposures to furazolidone are estimated to

produce 20 to 50 extra cases of cancer.

These estimates also can be illustrated by

contrasting the calculated exposure of humans to furazolidone with estimates of the

dose of furazolidone required to produce an

extra risk of 1/10” (table 39). The most sensitive mice data result in doses of 0.41 to 0.95

ppb, as contrasted to the 0.09 ppb dose calculated for human exposure.

The mice and rat strains used in these experiments all had rather high spontaneous

rates of both tumors and malignancies, Mantel (1977) has not recommended using the

Table 39.–Estimates of Dose in Parts Per Billion of Furazolidone

Required 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 5

Females 750 9 5

Mallqnant neoplasms Males 137 39

Females 139 41

F/scher rd(s

Ali neoplasrns Males — 402 ppm

Maltgnant neoplasms Females 189 4 3

Low-dose Sprague l)dwley rdis

A I neoplasms Males O 988 0429

Females O 527 0253

M,]llgndnl neoplasms Mdles ? 58 0862

Females ? 56 0783

SIt/ss MBR 1 /t?f7 mice

All neoplasms Males 0410 0247

Fcmales O 946 0454

Mallgndnt neophsms Males 0431 0265

Females O 836 0424

Mantel-Bryan procedure for data with high

spontaneous rates, In his analysis of the experiments described here,lfi Mantel selected a

“cut off” time and only considered tumors detected prior to this time. This modification of

the data used by Mantel was applied to the

mice data and was found to have relatively

little effect, the maximum change in the upper confidence bounds on risk being less than

a factor or two (Crump, 1978). Therefore, the

risk estimates in table 38 would not have

been significantly different if the test animals

had had a lower spontaneous rate of tumor

production or if the data had been modified

so as to discount tumors that occur late in

life.

There should be neither statistical nor

theoretical grounds for rejecting the risk

estimates in table 38 as unreasonable estimates of rodent risk at 2 ppb. Each of the 14

nitrofurans tested with the Salmonella/Ames

test were mutagenic (McCann et al., 1975).

Consequently, furazolidone should be considered to be a genotoxic carcinogen with the

property of being linear at low dose. The upper confidence bounds on risk computed from

the multistage model also have this property.

(See figure 1.) Moreover, as is shown in table

37, the multistage model cannot be ruled out

on the basis of a chi-square goodness-of-fit

test for those data sets for which risk estimates are listed in table 38,

Since the carcinogenic effect of furazolidone in man has not been measured directly,

data such as in table 36 constitute the currently available dose-response information

for estimating the carcinogenic risk to man.

The assumptions underlying the kinds of

risk estimates as calculated for DES and

furazolidone are not unanimously accepted,

and calculations based on different assumptions could lead to different estimates. The

point of the foregoing quantitative exercise

was to test the usefulness of a target risk approach to the definition of “no residue” and

whether that approach would avoid the problem caused by using actual physical presence

of residues for the definition. As discussed

earlier, technical improvements in measuring

I F [ 1! [, ‘ ~ ‘OIbid.

58
very minute quantities of residue have led to

problems in continuing to use the physical

presence approach.

Present tI’DA regulatory authority is riskoriented. A regulated substance must be

shown to have its intended effect, but more

importantly for this discussion, risks must be

estimated because safety as well as effectiveness is a regulatory criterion. Thus, even if

there were agreement that the 1/10’) adde d

lifetime exposure risk of (~ancer was an appropriate definition of “no residue, ” determining the amount of drug that corresponds

to that risk level remains a problem.

Similar differences exist among researchers in quantifying the benefits of using animal

drugs. The estimates summarized in the previous chapter on benefits of thf~ use of certain

antibacterial and DES produced different

quantitative results, even though the USDA

and Headley analyses began with the same

model,

In contrast to risk assessment, FDA’s regulatory decisionmaking basis does not include

a quantification of benefits. Furthcrrnore,

FDA will not make an official estimate of

relative effectiveness of the different drugs

they approve for similar uses, FDA’s position

is that the Agency does not deal in relative effectiveness and that any product with the

same claims may be used interchangeably as

a substitute for the others (FDA, 1979). The

USDA and Headley analyses on benefits lead

to different results, although starting from

the same model. If FDA had to quan!ify benefits, it most likely would have reached ctifferent quantitative results.

FDA does have to estimate risks. In contrast to the estimate of cancer risks from DES

and furazolidone included in this report, FDA

has indicated that, according to the estimates

they have made, present DES and furazolidone uses would lead to cancer risks in excess of the proposed target risk of 1/10’) (FDA,

1979). The difference in results comes primarily from two different assumptions. FDA

uses the ninth decile for consumption distribution rather than average per capita consumption “to provide protection for the vast

majority of the population. But use of average per capita consumption does Ilot necessarily underestimate the risk to humans. The

estimates used here assumed all beef contained at least 2 ppb of DES, when in fact DES

or other weight-promoting chemicals are

given to about 80 percent of fed cattle. and

FDA itself reports that DES has dropped considerably in the dollar-volume s;iles list.

Second, FDA is also concerned that risks

occur from both the parent drugs and their

metabolizes and that for both DES and furozolidone, the parent drug represents only :)

small percentage of the total residue, which

has not been well-characterized or shown to

be safe. FDA states that: “VVithout identification and testing of the compounds which comprise the residue, no estimates of risk are of

much value in judgin~ the safety of thp drug

use. At best it may be said that the information available gives rise to the possibility that

residue exposure may greatly exceed an accepta ble level of risk from cancer’ (FDA,

1979). The estimates used here were based

on residue levels that were at the limits of

detection by methods presently approved by

FDA, whereas FDA’s estimates ~re based on

newer methods not yet approved. In addition,

if FDA’s use of the target-risk approach leads

to no practical difference on how regulatory

decisions are made, the FDA statement that

no estimates of risk are of much value without identification and testing of the metabolizes raises the question of whether a targetrisk approach is any improvement over physical presence criteria. Furthermore+ this

would be a contradiction to the previously

quoted statement by FDA’s Director of the

Bureau of Veterinary Medicine that the new

method would “provide a mechanism

whereby a reasonably safe level ma~ be established and then, irrespective of further

analytical developments, there will be that

expectation that the originally set level will

remain until toxicological evidence rather

than analytical evidence [demonstrates that to

be an incorrect tolerance” (FCKJd Chemical

News, oct. 16,1978).

59
APPENDIX

Commissioned Papers

References
COMMISSIONED PAPERS

Chapters III and IV, which summarize the evidence on the benefits ancl risks of the use of

drugs in livestock feeding, were based on reviews commissioned by the office of Technology

Assessment and on a paper originally prepared for the Council for Agricultural Science and

Technology’s Task Force on Antibiotics in Animal Feeds. The authors and their reviews are as

follows: -

W. M. Beeson

Professor Emeritus, Animal Nutrition

Department of Animal Science

Purdue University

Kenny S, Crump

Professor of Mathematics and Statistics

Louisiana Technical University

George K. Davis, Professor of Animal Science

Institute of Food and Agricultural Sciences

University of Florida

L.C. Grumbles, Head

Department of Veterinary Microbiology and

Parasitology

College of Veterinary Medicine

Texas A&M University

Virgil W. Hays

Professor and Chairman

Depar~ment of Animal Sciences

University of Kentucky

J.C. Headley

Professor of Production Economics

Univcrsit y of Missouri

Richard P. Novick, Chief

Department of Plasmid Biology

Public Health Research Institute

City of New York

}. H, ~’eisburger, Vice-President

Research

American Health Foundation

Valhalla, New York

“Use of Drugs and Chemicals as Feed

Additives to Increase the Productivity of

Cattle and Sheep”

“Estimating Human Risks From Drug Feed

Additives”

“Drugs and Chemicals as Feed Additives for

the Protection of the Health of Cattle, Sheep,

and Goats’

“Protection of the Health and Performance of

Poultry and Swine by the Use of Drugs and

Chemicals as Feed Additives”

“Effectiveness of Feed Additive Usage of

Antibacterial Agents in Swine and Poultry

Production”

“Economic Aspects of Drug and Chemical

Feed Additives”

“Transmission of Bacterial Pathogens From

Animals to Man With Special Reference to

Antibiotic Resistance” (originally prepared

for the Council for Agricultural Science and

Technology’s Task Force on Antibiotics in

Animal Feeds, Ames, Iowa)

“Comments on the Physiological and

Pathological Effects of Diethylstilbestrol

(DES)”

These papers are available from OTA on request.

63
REFERENCES

Anderson, E. S. (1977). In: The Problems of Infectious Diseases, Springer-Verlag,

Anderson, E. S., G. 0, Humphreys, and G. A, Willshaw (1975). “Molecular Relatedness of RFactors in Enterobacteria of Human and Animal Origin,” J. Gen. A4icrobiol,, 91:376.

Anderson, G, W., J. D. Cunningham, and S. J. Slinger (1952). “Effect of Protein Level and Penicillin on Growth and Intestinal Flora of Chickens,” j. Nutr., 47:175,

Beeson, W. M., V. M. Thomas, T. W. Perry, and M.

T, Mohler (1977). “Effect of Withdrawal of

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