1978 

National Cancer Institute 

CARCINOGENESIS 

Technical Report Series 

No. 131 

BIOASSAYS OF 

DDT, IDE, AND p,p'-DDE 

FOR POSSIBLE CARCINOGENICITY 

CAS No. 50-29-3 

72-54-8 

72-55-9 

NCI-CG-TR-131 

U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE 

Public Health Service 

National Institutes of Health 
BIOASSAYS OF
 

DDT, IDE, AND p,p'-DDE
 

FOR POSSIBLE CARCINOGENICITY
 

Carcinogenesis Testing Program
 

Division of Cancer Cause and Prevention
 

National Cancer Institute
 

National Institutes of Health
 

Bethesda, Maryland 20014
 

U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE
 

Public Health Service
 

National Institutes of Health
 

DHEW Publication No. (NIH) 78-1386
 

REPORT ON THE BIOASSAYS OF DDT, TDE, AND p,p'-DDE
 

FOR POSSIBLE CARCINOGENICITY
 

CARCINOGENESIS TESTING PROGRAM
 

DIVISION OF CANCER CAUSE AND PREVENTION
 

NATIONAL CANCER INSTITUTE, NATIONAL INSTITUTES OF HEALTH
 

FOREWORD: This report presents the results of the bioassays of DDT,
 

TDE, and p,p'-DDE conducted for the Careinogenesis Testing Program,
 

Division of Cancer Cause and Prevention, National Cancer Institute
 

(NCI), National Institutes of Health, Bethesda, Maryland. These
 

are three of a series of experiments designed to determine whether
 

selected chemicals have the capacity to produce cancer in animals.
 

Negative results, in which the test animals do not have a significantly greater incidence of cancer than control animals, do not
 

necessarily mean the test chemicals are not carcinogens because the
 

experiments are conducted under a limited set of circumstances.
 

Positive results demonstrate that the test chemicals are carcinogenic for animals under the conditions of the tests and indicate a
 

potential risk to man. The actual determination of the risk to man
 

from animal carcinogens requires a wider analysis.
 

CONTRIBUTORS: These bioassays of DDT, TDE, and p,p'-DDE were conducted by Hazleton Laboratories America, Inc., Vienna, Virginia,
 

initially under direct contract to the NCI and currently under a subcontract to Tracor Jitco, Inc., prime contractor for the NCI Carcinogenesis Testing Program.
 

The experimental designs were determined by the NCI Project Officers, Dr. J. H. Weisburger (1,2) and Dr. E. K. Weisburger (1). The
 

principal investigators for the contract were Dr. M. B. Powers (3),
 

Dr. R. W. Voelker (3), Dr. W. A. Olson (3,4) and Dr. W. M. Weatherholtz (3). Chemical analyses were performed by Dr. C. L. Guyton
 

(3,5) and the analytical results were reviewed by Dr. N. Zimmerman
 

(6); the technical supervisor of animal treatment and observation was
 

Ms. K. J. Petrovics (3).
 

Histopathologic examinations were performed by Dr. R. H. Habermann (3) and reviewed by Dr. R. W. Voelker (3) at the Hazleton Laboratories America, Inc. , and the diagnoses included in this report
 

represent the interpretation of these pathologists. Histopathology
 

findings and reports were reviewed by Dr. R. L. Schueler (7).
 

Compilation of individual animal survival, pathology, and summary tables was performed by EG&G Mason Research Institute (8); the
 

ill
 
statistical analyses were performed by Mr. W. W. Belew (6,9), using
 

methods selected for the Carcinogenesis Testing Program by Dr. J.
 

J. Gart (10).
 

This report was prepared at METREK, a Division of The MITRE Corporation (6) under the direction of the NCI. Those responsible for
 

this report at METREK are the project coordinator, Dr. L. W. Thomas
 

(6), task leader Dr. M. R. Kornreich (6,11), senior biologist Ms. P.
 

Walker (6), biochemist Dr. B. Fuller (6), and technical editor Ms.
 

P. A. Miller (6). The final report was reviewed by members of the
 

participating organizations.
 

The following other scientists at the National Cancer Institute
 

were responsible for evaluating the bioassay experiments, interpreting the results, and reporting the findings: Dr. K. C. Chu (1), Dr.
 

C. Cueto, Jr. (1), Dr. J. F. Douglas (1), Dr. D. G. Goodman (1,11),
 

Dr. R. A. Griesemer (1), Dr. M. H. Levitt (1), Dr. H. A. Milman (1),
 

Dr. T. W. Orme (l), Dr. R. A. Squire (1,12), Dr. S. F. Stinson (1),
 

Dr. J. M. Ward (l), and Dr. C. E. Whitmire (1).
 

1.	 Carcinogenesis Testing Program, Division of Cancer Cause and
 

Prevention, National Cancer Institute, National Institutes of
 

Health, Bethesda, Maryland.
 

2.	 Now with the Naylor Dana Institute for Disease Prevention, American Health Foundation, Hammon House Road, Valhalla, New York.
 

3.	 Hazleton Laboratories America, Inc., 9200 Leesburg Turnpike,
 

Vienna, Virginia.
 

4.	 Now with the Center for Regulatory Services, 2347 Paddock Lane,
 

Reston, Virginia.
 

5.	 No wit w h Rhodia, Inc., 23 Belmont Drive, Somerset, New Jersey.
 

6.	 The MITRE Corporation, METREK Division, 1820 Dolley Madison
 

Boulevard, McLean, Virginia.
 

7.	 Tracer Jitco, Inc., 1776 East Jefferson Street, Rockville,
 

Maryland.
 

8.	 EG&G Mason Research Institute, 1530 East Jefferson Street,
 

Rockville, Maryland.
 

9.	 No wit w h the Solar Energy Research Institute, Cole Boulevard,
 

Golden, Colorado.
 

iv
 
10.	 Mathematical Statistics and Applied Mathematics Section, Biometry
 

Branch, Field Studies and Statistics Program, Division of Cancer
 

Cause and Prevention, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
 

11.	 Now with Clement Associates, Inc., 1010 Wisconsin Avenue, N.W.,
 

Washington, B.C.
 

12.	 Now with the Division of Comparative Medicine, Johns Hopkins
 

University, School of Medicine, Traylor Building, Baltimore,
 

Maryland.
 

v
 

SUMMARY
 

Bioassays of technical-grade DDT, TDE, and p,p'-DDE for possible
 

carcinogenicity were conducted using Osborne-Mendel rats and B6C3F1
 

mice. Each compound was administered in the feed, at either of two
 

concentrations, to groups of 50 male and 50 female animals of each
 

species. Twenty animals of each species and sex were placed on test
 

as controls for the bioassay of each compound. The time-weighted
 

average high and low dietary concentrations of DDT were, respectively,
 

642 and 321 ppm for male rats, 420 and 210 ppm for female rats, 44
 

and 22 ppm for male mice, and 175 and 87 ppm for female mice. The
 

time-weighted average high and low dietary concentrations of TDE were,
 

respectively, 3294 and 1647 ppm for male rats, 1700 and 850 ppm for
 

female rats, and 822 and 411 ppm for male and female mice. The time-


weighted average high and low dietary concentrations of DDE were,
 

respectively, 839 and 437 ppm for male rats, 462 and 242 ppm for fe­ male rats, and 261 and 148 ppm for male and female mice. After the
 

78—week dosing period there was an additional observation period of
 

up to 35 weeks for rats and 15 weeks for mice.
 

There were significant positive associations between increased
 

chemical concentration and accelerated mortality in female mice
 

dosed with DDT and in both sexes of rats and in female mice dosed
 

with DDE. This association was not demonstrated in other groups.
 

There was, however, poor survival among control and dosed male mice
 

used in the bioassays of DDT and DDE. In all cases adequate numbers
 

of animals in all groups survived sufficiently long to be at risk from
 

late-developing tumors.
 

When those male rats receiving TDE and their controls were combined within each group so that the numerators of the tumor incidences
 

represented those animals with either a follicular-cell carcinoma or
 

a follicular-cell adenoma of the thyroid, the incidence in the low
 

dose group was significantly higher than that in the control. There
 

was a significant positive association between the concentration of
 

DDE administered and the incidences of hepatocellular carcinomas in
 

male and female mice. Among dosed rats and mice no other neoplasms
 

occurred in statistically significant incidences when compared to
 

their respective control groups.
 

Under the conditions of these bioassays there was no evidence
 

for the carcinogenicity of DDT in Osborne-Mendel rats or B6C3F1 mice,
 

of TDE in female Osborne-Mendel rats or B6C3F1 mice of either sex, or
 

of p.p'-DDE in Osborne-Mendel rats, although p,p'-DDE was hepatotoxic
 

in Osborne-Mendel rats. The findings suggest a possible carcinogenic
 

effect of TDE in male Osborne-Mendel rats, based on the induction of
 

vii
 
combined follicular-cell carcinomas and follicular-cell adenomas of
 

the thytoid. Because of the variation of these tumors in control male
 

rats in this study, the evidence does not permit a more conclusive
 

interpretation of these lesions. p,p^-DDE was carcinogenic in B6C3F1
 

mice, causing hepatocellular carcinomas in both sexes;
 

viii
 
TABLE OF CONTENTS
 

Page
 

I. INTRODUCTION 1
 

II. MATERIALS AND METHODS 13
 

A. Chemicals 13
 

B. Dietary Preparation 14
 

C. Animals 15
 

D. Animal Maintenance 15
 

E. Selection of Initial Concentrations 17
 

1. DDT 17
 

2. TDE 18
 

3. DDE 19
 

F. Experimental Design 20
 

1. DDT 20
 

2. TDE 28
 

3. DDE 29
 

G. Clinical and Histopathologic Examinations 31
 

H. Data Recording and Statistical Analyses 33
 

III. CHRONIC TESTING RESULTS: RATS 38
 

A. DDT 38
 

1. Body Weights and Clinical Observations 38
 

2. Survival 40
 

3. Pathology 42
 

4. Statistical Analyses of Results 43
 

B. TDE 52
 

1. Body Weights and Clinical Observations 52
 

2. Survival 54
 

3. Pathology 54
 

4. Statistical Analyses of Results 57
 

C. DDE 66
 

1. Body Weights and Clinical Observations 66
 

2. Survival 6?
 

3. Pathology 68
 

4. Statistical Analyses of Results 71
 

IV. CHRONIC TESTING RESULTS: MICE 80
 

A. DDT 80
 

1. Body Weights and Clinical Observations 80
 

2. Survival 80
 

3. Pathology 83
 

4. Statistical Analyses of Results 83
 

ix
 
TABLE OF CONTENTS (Continued)
 

Page
 

B. IDE . 87
 

1. Body Weights and Clinical Observations 87
 

2. Survival 87
 

3. Pathology 90
 

4. Statistical Analyses of Results 91
 

C. DDE 96
 

1. Body Weights and Clinical Observations 96
 

2. Survival 98
 

3. Pathology 98
 

4. Statistical Analyses of Results 100
 

V. DISCUSSION 107
 

VI. BIBLIOGRAPHY 112
 

APPENDIX A SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

RATS TREATED WITH DDT A-l
 

APPENDIX B SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

MICE TREATED WITH DDT B-l
 

APPENDIX C SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN RATS TREATED WITH DDT C-l
 

APPENDIX D SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN MICE TREATED WITH DDT D-l
 

APPENDIX E SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

RATS TREATED WITH TDE E-l
 

APPENDIX F SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

MICE TREATED WITH TDE F-l
 

APPENDIX G SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN RATS TREATED WITH TDE G-l
 

APPENDIX H SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN MICE TREATED WITH TDE H-l
 

APPENDIX I SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

RATS TREATED WITH DDE 1-1
 

APPENDIX J SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

MICE TREATED WITH DDE J-l
 

x
 
TABLE OF CONTENTS (Concluded)
 

Page 

APPENDIX K SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN RATS TREATED WITH DDE K-l 

APPENDIX L SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN MICE TREATED WITH DDE L-l 

XI
 
LIST OF ILLUSTRATIONS 

Figure Number Page 

1 CHEMICAL STRUCTURE OF p,p'-DDT 2 

2 CHEMICAL STRUCTURE OF p,p'-TDE 3 

3 CHEMICAL STRUCTURE OF p,p'-DDE 4 

4 GROWTH CURVES FOR DDT CHRONIC STUDY 

RATS 39 

5 SURVIVAL COMPARISONS OF DDT CHRONIC 

STUDY RATS 41 

6 GROWTH CURVES FOR TDE CHRONIC STUDY 

RATS 53 

7 SURVIVAL COMPARISONS OF TDE CHRONIC 

STUDY RATS 55 

8 GROWTH CURVES FOR DDE CHRONIC STUDY 

RATS 67 

9 SURVIVAL COMPARISONS OF DDE CHRONIC 

STUDY RATS 69 

10 GROWTH CURVES FOR DDT CHRONIC STUDY 

MICE 81 

11 SURVIVAL COMPARISONS OF DDT CHRONIC 

STUDY MICE 82 

12 GROWTH CURVES FOR TDE CHRONIC STUDY 

MICE 88 

13 SURVIVAL COMPARISONS OF TDE CHRONIC 

STUDY MICE 89 

14 GROWTH CURVES FOR DDE CHRONIC STUDY 

MICE 97 

15 SURVIVAL COMPARISONS OF DDE CHRONIC 

STUDY MICE 99 

xii
 
LIST OF TABLES
 

Table Number Page 

1 DESIGN SUMMARY FOR OSBORNE-MENDEL

DDT FEEDING EXPERIMENT

 RATS— 

 21 

2 DESIGN SUMMARY FOR

FEEDING EXPERIMENT

 B6C3F1 MICE—DDT 

 22 

3 DESIGN SUMMARY FOR OSBORNE-MENDEL

TDE FEEDING EXPERIMENT

 RATS— 

 23 

4 DESIGN SUMMARY FOR B6C3F1 MICE—TDE 

FEEDING EXPERIMENT 24 

5 DESIGN SUMMARY FOR OSBORNE-MENDEL RATSDDE FEEDING EXPERIMENT 25 

6 DESIGN SUMMARY FOR

FEEDING EXPERIMENT

 B6C3F1 MICE—DDE 

 26 

7 ANALYSES OF

AT SPECIFIC

DDT

 THE INCIDENCE

 SITES IN MALE

 OF PRIMARY TUMORS 

 RATS TREATED WITH 

 44 

8 ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN FEMALE RATS TREATED 

WITH DDT 47 

9 ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN MALE RATS TREATED WITH 

TDE 58 

10 ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN FEMALE RATS TREATED 

WITH TDE 61 

11 ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN MALE RATS TREATED WITH 

DDE 72 

12 ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN FEMALE RATS TREATED 

WITH DDE 74 

xiii
 
LIST OF TABLES (Continued) 

Table Number Page 

13 TIME-ADJUSTED ANALYSES OF THE INCIDENCE OF 

PRIMARY TUMORS AT SPECIFIC SITES IN FEMALE 

RATS TREATED WITH DDE 77 

14 ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN MALE MICE TREATED WITH 

DDT 84 

15 ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN FEMALE MICE TREATED 

WITH DDT 85 

16 ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN MALE MICE TREATED WITH 

TDE 92 

17 ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN FEMALE MICE TREATED 

WITH TDE 94 

18 ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN MALE MICE TREATED WITH 

DDE 101 

19 ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN FEMALE MICE TREATED 

WITH DDE 103 

20 TIME-ADJUSTED ANALYSES OF THE INCIDENCE OF 

HEPATOCELLULAR CARCINOMAS IN MALE MICE 

TREATED WITH DDE 105 

Al SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

MALE RATS TREATED WITH DDT A-3 

A2 SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

FEMALE RATS TREATED WITH DDT A-7 

Bl SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

MALE MICE TREATED WITH DDT B-3 

B2 SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

FEMALE MICE TREATED WITH DDT B-6 

xiv
 
LIST OF TABLES (Continued)
 

Table Number Page 

Cl SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN MALE RATS TREATED WITH DDT C-3 

C2 SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN FEMALE RATS TREATED WITH DDT c ~ 7 

Dl SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN MALE MICE TREATED WITH DDT D-3 

D2 SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESTIONS IN FEMALE MICE TREATED WITH DDT D-6 

El SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

MALE RATS TREATED WITH TDE E-3 

E2 SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

FEMALE RATS TREATED WITH TDE E-6 

Fl SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

MALE MICE TREATED WITH TDE F-3 

F2 SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

FEMALE MICE TREATED WITH TDE F-6 

Gl SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN MALE RATS TREATED WITH TDE G-3 

G2 SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN FEMALE RATS TREATED WITH TDE G-7 

HI SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN MALE MICE TREATED WITH TDE H-3 

H2 SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN FEMALE MICE TREATED WITH TDE H-6 

11 SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

MALE RATS TREATED WITH DDE 1-3 

12 SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

FEMALE RATS TREATED WITH DDE 1-6 

xv
 
LIST OF TABLES (Concluded) 

Table Number Page 

Jl SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

MALE MICE TREATED WITH DDE J-3 

J2 SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

FEMALE MICE TREATED WITH DDE J-6 

Kl SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN MALE RATS TREATED WITH DDE K-3 

K2 SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN FEMALE RATS TREATED WITH DDE K-8 

LI SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN MALE MICE TREATED WITH DDE L-3 

L2 SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN FEMALE MICE TREATED WITH DDE L-6 

xvi
 
I. INTRODUCTION
 

DDT (NCI No. C00464) is the common name for the technical product
 

of which p,p'-DDT (Figure 1) is the predominant component. The compound is a synthetic, chlorinated hydrocarbon insecticide which has
 

broad-spectrum insecticidal activity. After being used commercially
 

and in large quantities in the United States for more than two decades, its status as an insecticide began to fade in the mid-1960s
 

when environmentalists detected a possible link between DDT and various ecological disturbances including the decline of selected bird
 

populations and numerous instances of fish kills. The growing realization of its ubiquitous distribution throughout all compartments of
 

the biosphere, its persistence in the environment, and its accumulation
 

in tissues of living organisms eventually resulted in the establishment of stringent regulations governing its use.
 

Despite the imposition of use restrictions, the probability of
 

continued low-level chronic exposure to DDT among the general population remained substantial. The classification of DDT as tumorigenic
 

by the Secretary's Commission on Pesticides and their Relationship
 

to Environmental Health (U.S. Department of Health, Education, and
 

Welfare, 1969) heightened the need for additional chronic toxicity
 

studies and prompted the inclusion of DDT in the NCI Carcinogenesis
 

Testing Program. TDE (Figure 2) (also known as ODD; NCI No. C00475)
 

and DDE (Figure 3) (NCI No. C00555), structurally related to DDT
 

1 
FIGURE 1

 

CHEMICAL STRUCTURE OF p,p'-DDT 

2 
FIGURE 2

 

CHEMICAL STRUCTURE OF p,p'-TDE 

3 
FIGURES

 

CHEMICAL STRUCTURE OF p,p'-DDE 

4 
and present as contaminants of the technical-grade compound, were
 

also subjected to bioassay.
 

The Chemical Abstracts Service (CAS) Ninth Collective Index
 

(1977) name for these compounds are 1,1'-(2 ,2 ,2-trichloroethylidene)
 

&
 

bis(4-chloro)-benzene for DDT; 1,1'-(2,2-dichloroethylidene) bis
 

(4-chloro)-benzene^C for IDE; and 1,!'-( 2,2-dichloroethenylidine)
 

*
 

bis(4-chloro)-benzene for DDE. Synonyms include: 1,1,1-trichloro2,2-bis(p-ch1orophenyl)-ethane and p,p'-dichlorodiphenyltrichloroethane for DDT; 1,l-dichloro-2,2-bis(p-chlorophenyl)-ethane and
 

p,p'-dichlorodiphenyldichloroethane for TDE; and 1 ,l-dichloro-2,2-bis
 

(p-chlorophenyl)-ethylene and p , p1 -dichlorodipheny'ldichloroethylene
 

for DDE.
 

DDT has been effective in the past in controlling hundreds of
 

pests attacking vineyard and orchard crops, nursery and greenhouse
 

crops, field crops, vegetables, and forest and shade trees (Andrilenas,
 

1974; Brooks, 1974; International Agency for Research on Cancer [IARC],
 

1974). DDT has also profoundly impacted the field of public health
 

where it has played a major role in the control of a large number of
 

insect-borne diseases, most notably malaria. Complete control of
 

mosquito larvae over wide geographical areas as well as long-term
 

protection of dwellings have been achieved, the former through massive
 

aerial spraying programs and the latter through the residual action of
 

*
 

The CAS registry numbers are: DDT—50-29-3
 

TDE—72-54-8
 

DDE—72-55-9
 

5 
DDT applied as a spray to walls and other home surfaces (Brooks, 1974),
 

Other diseases controlled by DDT include typhus, sleeping sickness,
 

and yellow fever (Brooks, 1974; IARC, 1974). In addition to its
 

agricultural and disease-control applications, DDT has been used
 

against household pests such as houseflies and cockroaches, against
 

pests of livestock (particularly beef and dairy cattle), and as a
 

moth-proofing agent (Brooks, 1974; Andrilenas, 1974; IARC, 1974).
 

Domestic production of DDT amounted to 123 million pounds in 1969
 

and declined sharply thereafter (Fowler and Mahan, 1976). The development of widespread resistance to DDT among numerous insect species
 

(Dahlsten et al., 1970) and the corresponding reduction in demand for
 

the pesticide played a significant role in determining production
 

trends; however, the imposition of increasingly stringent use limitations by the U.S. Department of Agriculture (Frost & Sullivan, Inc.,
 

1977), was the major factor in the observed decline in production.
 

By 1972, estimates indicated that as much as 90 percent of DDT consumption in the United States was for use on cotton crops with the
 

remainder used primarily on peanut and soybean crops (IARC, 1974).
 

Following suspension of the pesticide by the U.S. Environmental Protection Agency in 1973, domestic consumption of DDT was restricted
 

to specific public health applications and other minor uses (IARC,
 

1974).
 

Although current production statistics are considered proprietary
 

and are therefore not available, it has been estimated that over 70
 

6 
percent of production in recent years has been for export purposes
 

(Brooks, 1974). Exports in 1975 amounted to 47 million pounds
 

(Fowler and Mahan, 1976). At present, worldwide use of DDT is primarily for prevention of disease, particularly for mosquito abatement in world malaria-control programs (IARC, 1974; Brooks, 1974).
 

IDE was introduced commercially in the United States in 1945
 

shortly after the introduction of DDT. Although lacking the broad-


spectrum insecticidal activity of DDT, TDE does possess equal or
 

greater potency against the larvae of some mosquitos and lepidoptera
 

(Brooks, 1974). TDE is no longer produced commercially in the United
 

States; however, it was used in the past in this country for protection of a variety of crops including many fruits and vegetables (Farm
 

Chemicals Handbook, 1976). In 1971, 244,000 pounds of TDE were used
 

by farmers in the United States, 67 percent of which were applied to
 

tobacco (Andrilenas, 1974).
 

The potential for exposure to DDT remains greatest to workers
 

engaged in its manufacture, formulation, or application. During the
 

peak years of DDT usage, estimates of occupational dermal exposure
 

ranged from 84 mg per hour (Hayes, 1959) to 1755 mg per hour (Wolfe
 

et al., 1959; 1967), the latter value experienced by those engaged in
 

indoor spraying operations. Estimates of respiratory exposure during
 

this same period ranged from 0.11 mg per hour (Wolfe et al., 1959) to
 

14.1 mg per hour (Wolfe and Armstrong, 1971) with formulating plant
 

7 
workers at highest risk via this route. The average daily intake of
 

DDT by 20 men with high occupational exposure was estimated in 1967
 

as 17.5 to 18 mg per person or 450 times that of the general population (Laws et al., 1967).
 

Exposure of the general population to DDT and its metabolites, DDE
 

and TDE, is virtually unavoidable and may occ. ir through inhalation,
 

ingestion, or dermal contact. Exposure via inhalation and dermal
 

contact was probably of greatest concern prior to 1972 in agricultural
 

communities where atmospheric concentrations ranging from 0.1 to 8.0
 

3
 

jig DDT/m were detected during pesticide applications (Tabor, 1966).
 

However, atmospheric transport of these compounds, adsorbed to airborne particulates or in the vapor phase, resulted in their dissemination throughout areas relatively remote from agricultural or other
 

spraying operations. Thus, residents of urban environments also
 

experienced significant levels of exposure. Concentrations of up to
 

3
 

1.14 (jig DDT/m air were, for example, noted in Pittsburgh in the early
 

1960s (Antommaria et al., 1965).
 

Dermal exposure occurs as a result of contact with contaminated
 

air or with surfaces upon which airborne DDT has alighted. The
 

extent of this type of exposure is illustrated by the fact that DDT,
 

TDE and DDE were all detected in tenths of a microgram quantities in
 

hexane rinses from the hands of several individuals with no history
 

of occupational exposure to DDT or TDE (Kazen et al., 1974).
 

8 
Although levels of DDT, IDE and DDE in the diet appear to be declining (total dietary intake decreased from 0.9 p.g/kg body weight in
 

1965 to 0.4 fig/kg body weight in 1970; Duggan and Corneliussen, 1972),
 

ingestion of contaminated food (as well as contaminated drinking
 

water) remains a major route of widespread exposure.
 

Over the years, DDT residues at concentrations of up to 0.51 ppm
 

(Corneliussen, 1972; IARC, 1974) have been detected in a wide variety
 

of fruits and vegetables and will probably continue to be present in
 

agricultural produce indefinitely as a consequence of the persistence
 

of DDT in the soil. Estimates indicate that agricultural soils in
 

2
 

the United States contain an average of almost 0.168g DDT/m (Woodwell et al. , 1971).
 

Since DDT is excreted in mammalian milk, ingestion of contaminated
 

feed by lactating cows results in contamination of dairy products.
 

The concentration of total DDT in U.S. dairy products has decreased,
 

however, from a maximum of 03*8, ppm in 1967 to a maximum of 0.3 ppm in
 

f
 

1972 (Duggan et al., 1967-; Corneliussen, 1972).
 

The highest levels of DDT in the diet undoubtedly occur in meat,
 

fish and poultry since DDT and its metabolites are concentrated and
 

stored in animal tissues, particularly in adipose tissues. Once
 

again, concentrations appear to be declining; the maximum value
 

observed in these commodities in 1967 was 3.2 ppm while that observed
 

in 1972 was only 0.9 ppm (Duggan et al., 1967; Corneliussen, 1972).
 

9 
Ingested DDT is slowly metabolized in humans to IDE and DDE. TDE
 

undergoes further degradation and is eventually excreted in the urine
 

as DDA [2,2-bis(p-chlorophenyl)acetic acid]; DDE, on the other hand,
 

is retained in the adipose tissue along with unmetabolized DDT (IARC,
 

1974). DDT residues are widely distributed in the adipose tissue of
 

the general population both at home and abroad. The average concentration of total DDT in human fat in the United States was 10.6 ppm
 

in 1966 (Fiserova-Bergerova et al., 1967); averages of 30.2 ppm were
 

reported in India in 1964 (Dale et al., 1965). As is the case for
 

other mammalian species, levels of stored DDT in humans appear to be
 

declining (Fiserova-Bergerova et al., 1967; Morgan and Roan, 1970).
 

DDT and its metabolites are also excreted in human milk (Curley and
 

Kimbrough, 1969; Quinby et al., 1965; Zavon et al., 1969) and may
 

be transported through the placenta (Curley et al., 1969; O'Leary et
 

al., 1970; Zavon et al., 1969).
 

DDT is generally thought to pose a relatively modest health
 

hazard to warm-blooded animals including man (Farm Chemicals Handbook,
 

1976; Gosselin et al., 1976). The single oral dose of DDT necessary
 

to produce adverse symptoms in man is 10 mg/kg (Gosselin et al., 1976;
 

Farm Chemicals Handbook, 1976). Human volunteers ingested 35 mg DDT
 

per day, a dose equivalent to 0.5 mg/kg/day, for 21 months without
 

suffering any apparent ill effects (Hayes et al., 1971) and levels of
 

DDT stored in adipose tissue or passed on to breast-fed infants have
 

not been associated with demonstrable toxicity (Gosselin et al.,
 

10
 
1976). IDE is usually considered to be less toxic than DDT (Sax,
 

1975).
 

When DDT poisoning does occur, the primary site of action is the
 

central nervous system, particularly the cerebellum and higher motor
 

cortex. Symptoms of acute ingestion include vomiting, malaise, headache, sore throat, fatigue, paresthesias, tremors, and convulsions.
 

Death due to DDT poisoning is extremely rare and is usually attributed to respiratory failure from medullary paralysis. Although no
 

syndrome related to chronic DDT exposure is recognized in humans,
 

evidence indicates that DDT may cause aplastic anemia and thrombocytopenia (Gosselin et al., 1976).
 

DDT and its metabolites have been tested for mutagenicity in a
 

variety of test systems. DDT and DDE failed to revert histidine-


requiring strains of Salmonella typhimurium to prototype (The Ames
 

Test using strains TA1535, 1536, 1537, and 1538; Marshall et al.,
 

1976) and, along with DDA (the principal urinary excretion product
 

of DDT in mammals), proved nonmutagenic in host mediated bioassays
 

in mice using S. typhimurium G46 His , Serratia marcescens a21 leu
 

and S. marcescens a31 His as indicator organisms (Buselmaier et al.,
 

1973). DDT and DDA were also negative when tested for mutagenicity
 

in dominant lethal assays in mice (Buselmaier et al., 1973). On the
 

other hand, highly significant increases in back mutation rates were
 

observed in both of the above mentioned strains of S. marcescens in
 

the host mediated bioassay with TDK, Spot tests were negative,
 

11
 
suggesting that IDE is activated to a mutagenic agent by the host
 

organism (Buselmaier et al., 1973).
 

DBA proved positive for mutagenicity in _D. melanogaster, inducing
 

sex-linked recessive lethal mutations in male germ cells of that
 

species. DDT itself may be a very weak mutagen in Drosophila (Vogel,
 

1972).
 

Lymphocyte cultures from agricultural workers engaged in pesticide
 

application and exposed to a number of insecticides including DDT
 

were examined for chromosomal abberrations during the peak spraying
 

season and again in the wintertime (Yoder et al., 1973). While no
 

appreciable difference in the number of chromatid breaks per person
 

per 25 cells examined was noted at either sampling period among non-


exposed controls, a fivefold increase in these lesions was observed
 

among insecticide applicators during the summer months giving rise to
 

the speculation that one or more of the insecticides may be mutagenic
 

in humans (Yoder et al., 1973).
 

No evidence for carcinogenicity of DDT or its metabolites in
 

humans is available to date. Although increased levels of total DDT
 

have been observed in the adipose tissue of patients with various
 

malignancies when compared to controls (Radomski et al., 1968) and,
 

in one study, concentrations of total DDT-derived materials were
 

higher in malignant breast tissue than in adjacent normal breast
 

tissue or adjacent adipose tissue (Wassermann et al., 1976), these
 

findings are inconclusive as to a causal relationship.
 

12
 
II. MATERIALS AND METHODS
 

A. Chemicals
 

Technical-grade DDT containing p,p'-DDT [1,1,l-trichloro-2,2-bis
 

(p-chlorophenyl) ethane] as the main component was purchased from
 

Montrose Chemical Corporation and chemical analysis was performed by
 

Hazleton Laboratories America, Inc., Vienna, Virginia. The wide
 

range of the experimentally determined melting point (78° to 102°C)
 

was consistent with the indefinite melting point of the technical
 

product. The major gas-liquid chromatography (GLC) peak represented
 

70 percent of the total area. This peak was assumed to be the
 

p,p'-DDT isomer. GLC and melting point range analyses performed 12
 

months later provided similar results and indicated stability of the
 

compound.
 

Throughout this report the term DDT is used to represent this
 

technical-grade material.
 

Technical-grade TDE containing p,p'-TDE [1,l-dichloro-2,2-bis
 

(p-chlorophenyl)-ethane] as the main component was purchased from
 

Rohm and Haas Chemical Company and chemical analysis was performed by
 

Hazleton Laboratories America, Inc. The wide range of the experimentally determined melting point (60° to 103°C) was consistent with
 

the indefinite melting point of the technical material. The major
 

GLC peak represented approximately 60 percent of the total area and
 

was assumed to be the p,p'-TDE isomer. GLC also indicated at least
 

19 impurities. GLC total-area analysis and melting point range
 

13
 
determination performed 12 months later provided close approximations
 

of the results previously obtained. Therefore, these analyses indicated stability of the compound.
 

Throughout this report the term TDE is used to represent this
 

technical-grade material.
 

Commercially available DDE (dichlorodiphenyl dichloroethylene)
 

was purchased from Aldrich Chemical Company and chemical analysis was
 

performed by Hazleton Laboratories America, Inc. The narrow range of
 

the experimentally determined melting point (87° to 89°C) is consistent
 

with the fact that the commercially available material is the relatively pure p,p'-DDE isomer. GLC utilizing both internal standard
 

and total-area analysis methodologies suggested a purity greater than
 

95 percent. This was assumed to be the p,p'-DDE isomer. One minor
 

impurity was found to be present.
 

Throughout this report the term DDE is used to represent the
 

relatively pure p,p'-DDE isomer.
 

B.	 Dietary Preparation
 

The basal laboratory diet for both dosed and control animals
 

(S)
 consisted of Wayne Lab-Blox (Allied Mills, Inc., Chicago, Illinois)
 

(R)
 plus 2 percent Duke'sw

corn oil (S. F. Sauer Company, Richmond,
 

Virginia) by weight. Fresh mixtures of each chemical in corn oil
 

were prepared weekly and stored in the dark. These mixtures of DDT,
 

TDE, or DDE in corn oil were each incorporated as often as necessary
 

into the appropriate amount of laboratory diet in a twin-shell
 

blender fitted with an accelerator bar.
 

14
 
C.	 Animals
 

Two animal species, rats and mice, were used in the carcinogenicity bioassays. The Osborne-Mendel rat was selected on the basis of
 

a comparative study of the tumorigenic responsiveness to carbon tetrachloride of five different strains of rats (Reuber and Glover, 1970).
 

The B6C3F1 mouse was selected because it has been used by the NCI for
 

carcinogenesis bioassays and has proved satisfactory in this capacity.
 

Rats and mice of both sexes were obtained through contracts with
 

the Division of Cancer Treatment, National Cancer Institute. The
 

Osborne-Mendel rats were procured from the Battelle Memorial Institute,
 

Columbus, Ohio, and the B6C3F1 mice were obtained from the Charles
 

River Breeding Laboratories, Inc., Wilmington, Massachusetts. Upon
 

receipt, animals were quarantined for at least 10 days, observed for
 

visible signs of disease or parasites, and assigned to the various
 

dosed and control groups.
 

D. Animal Maintenance
 

All animals were housed by species in temperature- and humidity-


controlled rooms. The temperature range was 20° to 24°C, and the
 

relative humidity was maintained between 45 and 55 percent. The air
 

conditioning system in the laboratory provided filtered air at a rate
 

of 12 to 15 complete changes of room air per hour. Fluorescent lighting was provided on a 12-hour-daily cycle. The rats were individually
 

housed in suspended galvanized-steel wire-mesh cages with perforated
 

15
 
floors. Mice were housed by sex in groups of 10 in solid-bottom polypropylene cages equipped with filter tops. Sanitized cages with fresh
 

bedding (Sanichips®, Pinewood Sawdust Company, Moonachie, New Jersey)
 

were provided once each week for mice. Rats received sanitized cages
 

with no bedding with the same frequency. Food hoppers were changed
 

and heat-sterilized once a week for the first 10 weeks and once a
 

month thereafter. Fresh heat-sterilized glass water bottles and
 

sipper tubes were provided three times a week. Food and water were
 

available ad libitum.
 

The rats dosed with DDT or TDE and their respective controls
 

*
 

were housed in a room with other rats receiving diets containing
 

chlorobenzilate (510-15-6) and sulfallate (95-06-7). The rats
 

dosed with DDE and their controls were housed in the same room with
 

rats receiving diets containing methoxychlor (72-43-5) and safrole
 

(94-59-7).
 

All dosed and control mice used in these bioassays were housed
 

in a room with other mice receiving diets containing chlorobenzilate
 

(510-15-6); dioxathion (78-34-2); sulfallate (95-06-7); mexacarbate
 

(315-18-4); methoxychlor (72-43-5); dicofol (115-32-2); pentachloronitrobenzene (82-68-8); clonitralid (1420-04-8); nitrofen (1836-75-5);
 

endosulfan (115-29-7); trifluralin (1582-09-8); amitrole (61-82-5);
 

acetylaminofluorene (53-96-3); and safrole (94-59-7).
 

*
 

CAS registry numbers are given in parentheses.
 

16
 
E. Selection of Initial Concentrations
 

In order to establish the maximum tolerated concentrations of
 

DDT, IDE, or DDE for addition to the diets of dosed animals in the
 

chronic studies, subchronic toxicity tests were conducted with both
 

rats and mice. For the subchronic study for each of the three chemicals, animals of each species were distributed among six groups,
 

each consisting of five males and five females. DDT, TDE, or DDE
 

was premixed with a small amount of corn oil. The mixture was then
 

incorporated into the laboratory diet and fed ad libitum to five of
 

the six rat groups and five of the six mouse groups, for each of
 

these chemicals. The sixth group of each species served as a control
 

group, receiving only the basal diet of corn oil and laboratory meal.
 

The dosed dietary preparations were administered for a period of 6
 

weeks, followed by a 2-week observation period during which all animals were fed the basal diet.
 

A concentration inducing no mortality and resulting in a depression in mean group body weight relative to controls was selected as
 

the high concentration for the chronic study. When weight gain
 

criteria were not applicable, mortality data alone were utilized.
 

1. DDT
 

Mixtures of DDT in corn oil were incorporated into the basal
 

laboratory diet and fed ad libitum to the dosed rat groups at concentrations of 178, 316, 562, 1000, and 1780 ppm. The dosed mouse
 

groups received concentrations of 18, 32, 56, 100, and 178 ppm.
 

17
 
In rats dosed with DDT at 562 ppm, the mean body weight depression relative to controls was 16 percent in male rats and 4 percent
 

in female rats. At a concentration of 1000 ppm the mean body weight
 

depression in male rats was 7 percent and in female rats 45 percent.
 

One female rat receiving 1000 ppm died. The high concentrations of
 

DDT selected for administration in the chronic bioassay were 840 ppm
 

for the male rats and 630 ppm for the female rats.
 

In the mice dosed with DDT, mean body weight depression was
 

not dose-related in either sex. In the male mice the mean body
 

weight gain, expressed as a percentage of that gained by the controls,
 

was 121 percent at a level of 18 ppm and 147 percent at 32 ppm. One
 

male mouse receiving 32 ppm died during the study. In the female
 

mice, mean body weight gain was 152 percent at 56 ppm, 126 percent at
 

100 ppm, and 132 percent at 178 ppm. Four female mice receiving
 

178 ppm died by the end of the 8-week subchronic study. The high
 

concentrations of DDT selected for administration in the chronic
 

study were 20 ppm for the male mice and 100 ppm for the female
 

mice.
 

2. TDE
 

Mixtures of TDE in corn oil were incorporated into the basal
 

laboratory diet in concentrations of 562, 1000, 1780, 3160, and 5620
 

ppm for the dosed rats, and in concentrations of 251, 398, 631,
 

1000, and 1590 ppm for the dosed mice.
 

18
 
In male rats, at a concentration of 1780 ppm the depression in
 

mean body weight was 9 percent. At 3160 ppm the mean body weight
 

depression was 10 percent. For female rats, the depression in mean
 

body weight was 39 percent at 1000 ppm and 4 percent at 1780 ppm. No
 

deaths were observed at these dosages. The high concentrations of
 

IDE selected for administration in the chronic study were 2800 ppm
 

for the male rats, and 1700 ppm for the female rats.
 

In the mice, the mean body weight was not clearly affected
 

by compound administration. Mean body weight gain in males and
 

females receiving up to 631 ppm was greater than the mean body weight
 

gain in their respective control groups. Deaths occurred in all male
 

groups, except the controls and the group receiving 631 ppm, and in
 

the female groups receiving 1000 and 1590 ppm. The high concentratii
 

of TDE selected for administration in the chronic mouse bioassay was
 

630 ppm for both males and females.
 

3. DDE
 

Mixtures of DDE in corn oil were incorporated into the basal
 

laboratory diet and administered to the dosed rats in concentrations
 

of 316, 562, 1000, 1780, and 3160 ppm. The dosed mice received DDE
 

in concentrations of 139, 193, 269, 363, and 519 ppm.
 

In the male rats, mean body weight depression was observed in
 

all dosed groups. At 1000 ppm, the depression in mean group body
 

weight was 11 percent while at 1780 ppm the depression was 22 perce
 

No deaths occurred in the male rats dosed with 1780 ppm or less.
 

19
 
In the female rats, mean body weight depression was not associated
 

with compound administration. At a concentration of 1000 ppm one
 

female rat died and at 1780 and 3160 ppm all female rats were dead
 

by week 6. The high concentrations of DDE selected for administration in the chronic study were 1350 ppm for the male rats and 750 ppm
 

for the female rats.
 

In either male or female mice, DDE administration was not
 

related to mean body weight depression. One death was observed in
 

the male control group and in the male group receiving 269 ppm. Four
 

deaths in the males and two deaths in the females occurred in the
 

groups receiving 373 ppm of DDE. The high concentration of DDE
 

selected for administration in the chronic study was 250 ppm for both
 

male and female mice.
 

F. Experimental Design
 

The experimental design parameters for the chronic bioassays
 

(species, sex, group size, concentrations administered, duration of
 

treated and untreated observation periods, and the time-weighted
 

average concentrations) are summarized in Tables 1 and 2 for DDT,
 

Tables 3 and 4 for IDE, and Tables 5 and 6 for DDE. All concentrations given were administered to the dosed rats and mice during
 

a dosing period of 78 weeks, followed by observation periods of up
 

to 35 weeks for the rats and up to 15 weeks for the mice.
 

1. DDT
 

The experimental design parameters for the DDT chronic bioassay
 

are presented in Tables 1 and 2. At the initiation of the study all
 

20
 
TABLE 1
 

DESIGN SUMMARY FOR OSBORNE-MENDEL RATS
 

DDT FEEDING EXPERIMENT
 

INITIAL OBSERVAT ION PERIOD TIME-WEIGHTED 

GROUP DDT TREATED UNTREATED AVERAGE 

SIZE CONCENTRATION3 (WEEKS) (WEEKS) CONCENTRATION 

MALE 

CONTROL 20 0 111 0 

LOW DOSE 50	 420 12 321
 

500 14
 

250 52
 

0	 32
 

HIGH DOSE 50 840 12 642
 

1000 14
 

500 52
 

0 33
 

FEMALE
 

CONTROL 20 0	 111 0
 

LOW DOSE 50 315 26 210
 

158 52
 

0 33
 

HIGH DOSE 50 630 26 420
 

315 52
 

0 33
 

fl
 

Concentrations given in parts per million.
 

b .	 . 2(concentration X weeks received)
 Time-weighted average concentration = -=-7 ; "•—: T : 7\
 Z/(.weeks receiving chemical)
 

21
 
TABLE 2
 

INITIAL 

GROUP 

SIZE 

MALE 

CONTROL 20 

LOW DOSE 50 

HIGH DOSE 50 

FEMALE 

CONTROL 20 

LOW DOSE 50 

HIGH DOSE 50 

DESIGN SUMMARY FOR B6C3F1 MICE
 

DDT FEEDING EXPERIMENT
 

OBSERVAT ION PERIOD
 

DDT TREATED UNTREATED
 

CONCENTRATION3 (WEEKS) (WEEKS)
 

0 91
 

10 8
 

15 6
 

20 14
 

25 50
 

0 14
 

20 8
 

30 6
 

40 14
 

50 50
 

0 14
 

0 92
 

50 8
 

60 6
 

75 14
 

100 50
 

0 15
 

100 8
 

120 6
 

150 14
 

200 50
 

0 15
 

TIME-WEIGHTED
 

AVERAGE
 

CONCENTRATION
 

0
 

22
 

44
 

0
 

87
 

175
 

a
 

Concentrations given in parts per million.
 

h . . , , ,_ 2 (concentration X weeks received)
 Time-weighte 0 d average concentration = -=r? ; =—= r = r\
 2., (weeks receiving chemical;
 

22
 
TABLE 3
 

DESIGN SUMMARY FOR OSBORNE-MENDEL RATS
 

TDE FEEDING EXPERIMENT
 

INITIAL 

GROUP 

SIZE 

MALE 

CONTROL 20 

LOW DOSE 50 

HIGH DOSE 50 

FEMALE 

CONTROL 20 

LOW DOSE 50 

HIGH DOSE 50 

TDE
 

CONCENTRATION a


0
 

1400
 

1750
 

0
 

2800
 

3500
 

0
 

0
 

850
 

0
 

1700
 

0
 

OBSERVA1 'ION PERIOD
 

TREATED UNTREATED
 

 (WEEKS) (WEEKS)
 

111
 

23
 

55
 

34
 

23
 

55
 

35
 

111
 

78
 

35
 

78
 

35
 

TIME- WEIGHTED
 

AVERAGE
 

CONCENTRATION
 

0
 

1647
 

3294
 

0
 

850
 

1700
 

Concentrations given in parts per million.
 

b . 2(concentration X weeks received)
 Time-weighte 6 6 d average concentration = -=—? : :—: r :—r\
 S(weeks receiving chemical)
 

23
 
TABLE 4
 

DESIGN SUMMARY FOR B6C3F1 MICE
 

IDE FEEDING EXPERIMENT
 

INITIAL OBSERVAT ION PERIOD TIME-WEIGHTED 

GROUP TDE TREATED UNTREATED AVERAGE 

SIZE CONCENTRATION3 (WEEKS) (WEEKS) CONCENTRATION 

MALE
 

CONTROL 20 0	 90 0
 

LOW DOSE 50	 315 5 411
 

375 11
 

425 62
 

0	 13
 

HIGH DOSE 50	 630 5 822
 

750 11
 

850 62
 

0	 14
 

FEMALE
 

CONTROL 20 0	 90 0
 

LOW DOSE 50	 315 5 411
 

375 11
 

425 62
 

0	 14
 

HIGH DOSE 50	 630 5 822
 

750 11
 

850 62
 

0	 15
 

*l
 

Concentrations given in parts per million.
 

b ,	 . S(concentration X weeks received)
 Time-weighte 6	 d averag&	e concentration = -577 : :—: r :—^
 —
 S(weeks receiving chemical)
 

24
 
TABLE 5
 

DESIGN SUMMARY FOR OSBORNE-MENDEL

DDE FEEDING EXPERIMENT 

 RATS 

INITIAL 

GROUP 

SIZE 

DDE 

CONCENTRATION3 

OBSERVAT 

TREATED 

(WEEKS) 

'ION PERIOD 

UNTREATED 

(WEEKS) 

TIME-WEIGHTED 

AVERAGE 

CONCENTRATION 

OVER A 78-WEEK 

PERIOD5 

MALE 

CONTROL 20 0 111 0 

LOW DOSE 50 

675 

338 

0 

23 

55 

33 

437 

HIGH DOSE 50 1350 

675 

675° 

0 

23 

36 

15 4 

33 

839 

FEMALE 

CONTROL 20 0 111 0 

LOW DOSE 50 375 

187 

0 

23 

55 

34 

242 

HIGH DOSE 50 750 

375 

375° 

0 

23 

32 

18 5 

34 

462 

a
 

Concentrations given in parts per million.
 

bm. .. . • 2(concentration X weeks received)
 Time-weighted average concentration = jj; r '
 

These concentrations were cyclically administered with a pattern of 1
 

dosage-free week followed by 4 weeks of dosing at the level indicated.
 

25
 

c
TABLE 6 

DESIGN SUMMARY FOR B6C3F1 MICE 

DDE FEEDING EXPERIMENT 

TIME-WEIGHTED 

AVERAGE 

INITIAL OBSERVAT ION PERIOD CONCENTRATION 

GROUP DDE TREATED UNTREATED OVER A 78-WEEK 

SIZE CONCENTRATION3 (WEEKS) (WEEKS) PERIODb 

MALE 

CONTROL 20 0 92 0 

LOW DOSE 50 125 7 148 

150 71 

0 14 

HIGH DOSE 50 250 7 261 

300 29 

300° 33 9 

0 14 

FEMALE 

CONTROL 20 0 92 0 

LOW DOSE 50 125 7 148 

150 71 

0 15 

HIGH DOSE 50 250 7 261 

300 29 

300° 33 9 

0 15 

a
 

Concentrations given in parts per million.
 

b . .. . . S(concentration X weeks received)
 Time-weighted average concentration = r-r
 

£
 

These concentrations were cyclically administered with a pattern of 1
 

dosage-free week followed by 4 weeks of dosing at the level indicated.
 

26
 
rats were approximately 7 weeks old. The dietary concentrations of
 

DDT initially utilized for male rats were 840 and 420 ppm. Throughout this report those male rats initially receiving the former concentration are referred to as the high dose male rats, while those
 

initially receiving the latter concentration are referred to as the
 

low dose male rats. For female rats, the initial concentrations were
 

630 and 315 ppm. Throughout this report those female rats initially
 

receiving the former concentration are referred to as the high dose
 

female rats, while those initially receiving the latter concentration
 

are referred to as the low dose female rats. During week 13, the
 

high and low levels administered to the male rats were increased to
 

1000 and 500 ppm, respectively. During week 27, the administered
 

concentrations were decreased for all of the dosed rats as signs of
 

toxicity at the previous dosages had been observed. The concentrations administered to the high and low dose male rats were decreased
 

to 500 and 250 ppm, respectively, while those administered to the
 

female rats were decreased to 315 and 158 ppm, respectively. These
 

dosages were maintained for the remainder of the dosing period.
 

At the initiation of the study all mice were approximately 6
 

weeks old. The dietary concentrations of DDT initially administered
 

to the male mice were 20 and 10 ppm. The dietary concentrations initially administered to the female mice were 100 and 50 ppm. Throughout this report those male mice initially receiving 20 ppm and those
 

female mice initially receiving 100 ppm are referred to as the high
 

27
 
dose groups, while those male mice initially receiving 10 ppm and
 

those female mice initially receiving 50 ppm are referred to as the
 

low dose groups. The concentrations administered to all dosed mice
 

were increased on three separate occasions as tolerance to the previous dosage levels was observed. In week 9, the concentrations
 

administered to the high and low dose groups were increased, respectively, to 30 and 15 ppm for the male mice and to 120 and 60 ppm for
 

the female mice. During week 15, the high and low doses were again
 

increased, this time to 40 and 20 ppm for the high and low dose male
 

mice, respectively. The high and low doses administered to the
 

female mice were raised to 150 and 75 ppm, respectively. In week 29
 

the doses administered were again increased, to 50 and 25 ppm for the
 

high and low dose male mice, and to 200 and 100 ppm for the high and
 

low dose female mice, respectively. These dosage levels were maintained for the remainder of the dosing period.
 

2. TDE
 

The experimental design parameters for the TDE chronic bioassay
 

are presented in Tables 3 and 4. At the initiation of the study all
 

rats were approximately 7 weeks old. The dietary concentrations of
 

TDE initially utilized for male rats were 2800 and 1400 ppm. For female rats the initial dietary concentrations were 1700 and 850 ppm.
 

Throughout this report those male rats initially receiving 2800 ppm
 

and those female rats initially receiving 1700 ppm are referred to
 

as the high dose groups, while those males initially receiving 1400
 

28
 
ppm and those females initially receiving 850 ppm are referred to as
 

the low dose groups. In week 24, the high and low doses administered
 

to the male rats were increased to 3500 and 1750 ppm, respectively,
 

as tolerance to the previous doses was observed. These concentrations were maintained for the remainder of the dosing period.
 

At the initiation of the study all mice were approximately 6
 

weeks old. The dietary concentrations initially administered to the
 

male and female mice were 630 and 315 ppm. Throughout this report
 

those mice initially receiving the former concentration are referred
 

to as the high dose groups, while those initially receiving the
 

latter concentration are referred to as the low dose groups. The
 

dosages administered to the mice were increased twice, as tolerance
 

to the previous concentrations was observed. In week 6, the concentration administered to the high dose male and female mice was increased to 750 ppm, and the concentration administered to the low
 

dose male and female mice was increased to 375 ppm. The high and low
 

concentrations administered to the male and female mice were raised
 

again in week 17, to 850 and 425 ppm, respectively. These concentrations were maintained for the remainder of the dosing period.
 

3. DDE
 

The experimental design parameters for the DDE chronic bioassay
 

are presented in Tables 5 and 6.
 

At the initiation of the study all rats were approximately 7
 

weeks old. The dietary concentrations of DDE initially utilized for
 

29
 
male rats were 1350 and 675 ppm. For female rats, the initial concentrations were 750 and 375 ppm. Throughout this report those male
 

rats initially receiving 1350 ppm and those female rats initially receiving 750 ppm are referred to as the high dose groups, while those
 

male rats initially receiving 675 ppm and those female rats initially
 

receiving 375 ppm are referred to as the low dose groups. During
 

week 24, the concentrations administered to all of the dosed rats
 

were decreased as signs of toxicity were observed. The high and low
 

concentrations administered to the male rats were decreased to 675
 

and 338 ppm, respectively. The high and low concentrations administered to the female rats were decreased to 375 and 187 ppm, respectively. In week 56, administration of DDE to the high dose female
 

rats ceased for 1 week followed by 4 weeks of feeding at the previous
 

concentration of 375 ppm. This same method of total intake reduction
 

was employed for the high dose male rats beginning with week 60.
 

This pattern of cyclic administration continued for the remainder of
 

the dosing period at the concentrations indicated.
 

At the initiation of the study all mice were approximately 7
 

weeks old. The initial dietary concentrations administered to the
 

male and female mice were 250 and 125 ppm. Throughout this report
 

those mice initially receiving the former concentration are referred
 

to as the high dose groups, while those initially receiving the
 

latter concentration are referred to as the low dose groups. In week
 

8, the dosages administered to all dosed mice were increased as
 

30
 
tolerance to the previous dosages had been observed. The high dose
 

male and female mice received 300 ppm, and the low dose male and female mice received 150 ppm. Administration of DDE to the high dose
 

male and female mice ceased for 1 week in week 37 followed by 4 weeks
 

of feeding at the previous dosage of 300 ppm. This method of total
 

intake reduction was used for the remainder of the dosing period at
 

the concentrations indicated.
 

G. Clinical and Histopathologic Examinations
 

Animals were weighed immediately prior to initiation of the
 

experiment. Body weights, food consumption, and data concerning
 

appearance, behavior, signs of toxic effects, and incidence, size,
 

and location of tissue masses were recorded at weekly intervals for
 

the first 10 weeks and at monthly intervals thereafter. From the
 

first day, all animals were inspected daily for mortality. The presence of tissue masses was determined by observation and palpation of
 

each animal.
 

During the course of these bioassays several pathology protocols
 

were in effect, each for different periods of time. The minimum protocol required that tissues were to be taken and examined histopathologically from all control animals, from any animal in which a tumor
 

was observed during gross examination, and from at least 10 grossly
 

normal males and 10 grossly normal females from each dosed group.
 

Under later protocols, tissues were taken from additional dosed
 

animals. In addition, any tissue from any animal showing gross
 

31
 
abnormalities was to be taken and examined histopathologically.
 

The number of animals in each group from which a particular tissue
 

was examined is indicated in Appendices A through L.
 

A necropsy was performed on each animal regardless of whether it
 

died, was killed when moribund, or was sacrificed at the end of the
 

bioassay. The animals were euthanized by exsanguination under sodium
 

pentobarbital anesthesia, and were immediately necropsied. The histopathologic examination consisted of gross and microscopic examination
 

of major tissues, organs, and gross lesions taken from sacrificed
 

animals and, whenever possible, from animals found dead.
 

Tissues were preserved in 10 percent buffered formalin, embedded
 

in paraffin, sectioned, and stained with hematoxylin and eosin prior
 

to microscopic examination. An occasional section was subjected to
 

special staining techniques for more definitive diagnosis.
 

Slides were prepared from the following tissues from selected
 

animals: skin, subcutaneous tissue, lungs and bronchi, trachea, bone
 

marrow, spleen, lymph nodes, thymus, heart, salivary gland, liver,
 

gallbladder (mice), pancreas, esophagus, stomach, small intestine,
 

large intestine, kidney, urinary bladder, pituitary, adrenal, thyroid, parathyroid, testis, prostate, brain, muscle, tunica vaginalis,
 

uterus, mammary gland, and ovary. Bone samples were not examined in
 

animals dosed with DDE or TDE and the tunica vaginalis was not
 

examined in animals dosed with DDE.
 

32
 
A few tissues were not examined for some animals, particularly
 

for those that died early. Also, some animals were missing, cannibalized, or judged to be in such an advanced state of autolysis as to
 

preclude histopathologic interpretation. Thus, the number of animals
 

for which particular organs, tissues, or lesions were examined microscopically varies and does not necessarily represent the number of
 

animals that were placed on experiment in each group.
 

H. Data Recording and Statistical Analyses
 

Pertinent data on these experiments have been recorded in an
 

automatic data processing system, the Carcinogenesis Bioassay Data
 

System (Linhart et al., 1974). The data elements include descriptive
 

information on the chemicals, animals, experimental design, clinical
 

observations, survival, body weight, and individual pathologic
 

results, as recommended by the International Union Against Cancer
 

(Berenblum, 1969). Data tables were generated for verification of
 

data transcription and for statistical review.
 

These data were analyzed using the statistical techniques described in this section. Those analyses of the experimental results
 

that bear on the possibility of carcinogenicity are discussed in the
 

statistical narrative sections.
 

Probabilities of survival were estimated by the product-limit
 

procedure of Kaplan and Meier (1958) and are presented in this report
 

in the form of graphs. Animals were statistically censored as of the
 

time that they died of other than natural causes or were found to be
 

33
 
missing; animals dying from natural causes were not statistically
 

censored. Statistical analyses for a possible dose-related effect on
 

survival used the method of Cox (1972) when testing two groups for
 

equality and used Tarone's (1975) extensions of Cox's methods when
 

testing a dose-related trend. One-tailed P-values have been reported
 

for all tests except the departure from linearity test, which is only
 

reported when its two-tailed P-value is less than 0.05.
 

The incidence of neoplastic or nonneoplastic lesions has been
 

given as the ratio of the number of animals bearing such lesions at a
 

specific anatomic site (numerator) to the number of animals in which
 

that site was examined (denominator). In most instances, the denominators included only those animals for which that site was examined
 

histologically. However, when macroscopic examination was required
 

to detect lesions prior to histologic sampling (e.g., skin or mammary
 

tumors), or when lesions could have appeared at multiple sites (e.g.,
 

lymphomas), the denominators consist of the numbers of animals necropsied.
 

The purpose of the statistical analyses of tumor incidence is to
 

determine whether animals receiving the test chemical developed a significantly higher proportion of tumors than did the control animals.
 

As a part of these analyses, the onertailed Fisher exact test (Cox,
 

1970, pp. 48-52) was used to compare the tumor incidence of a control
 

group to that of a group of treated animals at each dose level. When
 

34
 
results for a number of treated groups, k, were compared simultaneously with those for a control group, a correction to ensure an
 

overall significance level of 0.05 may be made. The Bonferroni inequality (Miller, 1966, pp. 6-10) requires that the P-value for any
 

comparison be less than or equal to 0.05/k. In cases where this
 

correction was used, it is discussed in the narrative section. It
 

is not, however, presented in the tables, where the Fisher exact
 

P-values are shown.
 

The Cochran-Armitage test for linear trend in proportions, with
 

continuity correction (Armitage, 1971, pp. 362-365), was also used
 

when appropriate. Under the assumption of a linear trend, this test
 

determined if the slope of the dose-response curve is different from
 

zero at the one-tailed 0.05 level of significance. Unless otherwise
 

noted, the direction of the significant trend was a positive dose relationship. This method also provided a two-tailed test of departure
 

from linear trend.
 

A time-adjusted analysis was applied when numerous early deaths
 

resulted from causes that were not associated with the formation of
 

tumors. In this analysis, deaths that occurred before the first tumor was observed were excluded by basing the statistical tests on
 

animals that survived at least 52 weeks, unless a tumor was found at
 

the anatomic site of interest before week 52. When such an early
 

tumor was found, comparisons were based exclusively on animals that
 

survived at least as long as the animal in which the first tumor was
 

35
 
found. Once this reduced set of data was obtained, the standard procedures for analyses of the incidence of tumors (Fisher exact tests,
 

Cochran-Armitage tests, etc.) were followed.
 

When appropriate, life-table methods were used to analyze the
 

incidence of tumors. Curves of the proportions surviving without an
 

observed tumor were computed as in Saffiotti et al. (1972). The week
 

during which animals died naturally or were sacrificed were entered
 

as the time point of tumor observation. Cox's methods of comparing
 

these curves were used for two groups; Tarone's extension to testing
 

for linear trend was used for three groups. The statistical tests
 

for the incidence of tumors which used life-table methods were one-


tailed and, unless otherwise noted, in the direction of a positive
 

dose relationship. Significant departures from linearity « 0.05,
 

two-tailed test) were also noted.
 

The approximate 95 percent confidence interval for the relative
 

risk of each dosed group compared to its control was calculated from
 

the exact interval on the odds ratio (Gart, 1971). The relative risk
 

is defined as p /p where p is the true binomial probability of the
 

t c t
 

incidence of a specific type of tumor in a treated group of animals
 

and p is the true probability of the spontaneous incidence of the
 

c
 

same type of tumor in a control group. The hypothesis of equality
 

between the true proportion of a specific tumor in a treated group
 

and the proportion in a control group corresponds to a relative risk
 

36
 
of unity. Values in excess of unity represent the condition of a
 

larger proportion in the treated group than in the control.
 

The lower and upper limits of the confidence interval of the
 

relative risk have been included in the tables of statistical analyses. The interpretation of the limits is that in approximately 95
 

percent of a large number of identical experiments, the true ratio
 

of the risk in a treated group of animals to that in a control group
 

would be within the interval calculated from the experiment. When
 

the lower limit of the confidence interval is greater than one, it
 

can be inferred that a statistically significant result (a P < 0.025
 

one-tailed test when the control incidence is not zero, P < 0.050
 

when the control incidence is zero) has occurred. When the lower
 

limit is less, than unity but the upper limit is greater than unity,
 

the lower limit indicates the absence of a significant result while
 

the upper limit indicates that there is a theoretical possibility
 

of the induction of tumors by the test chemical which could not be
 

detected under the conditions of this test.
 

37
 
III. CHRONIC TESTING RESULTS: RATS
 

A. DDT
 

1. Body Weights and Clinical Observations
 

Compound-related mean body weight depression was observed in high
 

dose rats of both sexes (Figure 4).
 

Clinical signs characteristic of central nervous system stimulation were observed in the dosed female rats early in the study.
 

Beginning in week 5, a number of high dose females started to exhibit
 

hyperactivity, body tremors, and a hunched appearance. By the following week about 70 percent of the high dose females appeared hunched,
 

with 50 percent showing concomitant tremors. As the study progressed,
 

a few low dose females and some high dose males started to show tremors
 

and occasional hunched appearance. By week 26, tremors were evident
 

in about 8 percent of the low dose females, 40 percent of the high
 

dose males, and 90 percent of the high dose females. Because of
 

the observed neurotoxicity, the feeding levels of DDT were decreased.
 

Consequently, in week 30 only two high dose females exhibited tremors
 

and in the succeeding weeks (until week 58), none of the dosed rats
 

exhibited this obviously reversible neurotoxic effect. In the
 

following weeks, as compound intake continued with presumed DDT tissue
 

accumulation, tremors were again exhibited by an increasing number of
 

high dose females (30 to 50 percent) and a small number of high dose
 

males and low dose females. By termination of the study (week 111,
 

38
 
FIGURE 4

 

GROWTH CURVES FOR DDT CHRONIC STUDY RATS 

39 
including 14 to 15 weeks on compound-free diets) tremors had completely
 

subsided in all dosed groups.
 

Other clinical signs observed with slightly greater frequency in
 

the dosed groups than in the controls included a hunched appearance
 

and abdominal urine stains. Respiratory signs characterized by
 

labored respiration, wheezing and/or nasal discharge were observed
 

during the second year at a low incidence in all groups including
 

controls. The incidence of this condition increased slightly during
 

the last 4 months of the study.
 

Signs often associated with aging in Osborne-Mendel rats were observed at a comparable rate in dosed and control animals during the
 

last year. These signs included sores on the body and/or extremities,
 

localized alopecia, reddish crust or discharge around body orifices,
 

palpable tissue masses, and swollen areas of the body or nodules.
 

Isolated observations in one or two dosed rats included head tilt,
 

circling, ataxia, apparent hernia, bloating, and hind-limb paralysis.
 

2. Survival
 

The estimated probabilities of survival for male and female rats
 

in the control and DDT-dosed groups are shown in Figure 5. For both
 

male and female rats there was no significant positive association
 

between dosage and mortality.
 

Adequate numbers of males were at risk from late-developing
 

tumors, as 76 percent (38/50) of the high dose, 64 percent (32/50) of
 

the low dose, and 55 percent (11/20) of the control rats survived on
 

40
 
FIGURES

 

SURVIVAL COMPARISONS OF DDT CHRONIC STUDY RATS 

41 
test at least 100 weeks. For females the survival was also adequate
 

as 78 percent (39/50) of the high dose, 86 percent (43/50) of the low
 

dose, and 85 percent (17/20) of the control rats survived on test at
 

least 100 weeks.
 

3. Pathology
 

Histopathologic findings on neoplasms in rats are summarized in
 

Appendix A (Tables Al and A2); findings on nonneoplastic lesions are
 

summarized in Appendix C (Tables Cl and C2).
 

A variety of neoplasms was observed among both the dosed and control rats. Each of the types of tumors represented has been encountered previously as a spontaneous lesion in the Osborne-Mendel rat.
 

Neoplasms and hyperplasias of the thyroid gland occurred with a
 

moderate incidence in both dosed and control rats as shown in the
 

following tabulation:
 

MALES FE MALES 

Low High Low High 

Control Dose Dose Control Dose Dose 

Number of Animals with
 

Thyroids Examined
 

Histopathologically (19) (45) (49) (19) (45) (43)
 

Follicular-Cell Carcinoma 1 6 5 0 4 6
 

Follicular-Cell Adenoma 8 14 17 1 10 5
 

Follicular-Cell Hyperplasi. a 0 4 7 1 3 0
 

C-Cell Carcinoma 0 1 1 1 1 0
 

C-Cell Adenoma 1 4 2 3 2 0
 

C-Cell Hyperplasia 3 3 1 2 8 3
 

42
 
The morphology of the thyroid lesions was similar to that described
 

in TDK (pp. 56-57).
 

The inflammatory, degenerative, and proliferative lesions seen
 

in the control and dosed rats were similar in number and kind to
 

those lesions occurring naturally in aged Osborne-Mendel rats.
 

In this study, there was no pathologic evidence for the carcinogenicity of DDT in Osborne-Mendel rats.
 

4. Statistical Analyses of Results
 

The results of the statistical analyses of tumor incidence in
 

rats are summarized in Tables 7 and 8. The analysis is included for
 

every type of tumor in either sex where at least two such tumors were
 

observed in at least one of the control or DDT-dosed groups and where
 

such tumors were observed in at least 5 percent of the group. Due to
 

early deaths in the high dose group, additional time-adjusted analyses
 

were conducted for the female rats; no important differences were
 

observed in the statistical results.
 

For females the Cochran-Armitage test indicated a significant
 

(P = 0.031) positive association between dose and the incidence of
 

adrenal pheochromocytomas. The Fisher exact tests, however, were
 

not significant.
 

When incidences of follicular-cell adenomas and follicular-cel1
 

carcinomas of the thyroid were combined, the Fisher exact test comparing low dose to control had a probability level of P = 0.032, a
 

43
 
TABLE 7
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN MALE RATS TREATED WITH DDTa
 

TOPOGRAPHY : MORPHOLOGY
 

Subcutaneous Tissue: Fibroma
 

P Values
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Pituitary: Chromophobe Adenoma
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Thyroid: Follicular-Cell Carcinoma
 

P Values
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

LOW HIGH 

CONTROL DOSE DOSE 

0/20(0.00) 3/50(0.06) 3/50(0.06) 

N.S. N.S. N.S. 

Infinite Infinite 

0.250 0.250 

Infinite Infinite 

92 106 

3/19(0.16) 4/22(0.18) 3/21(0.14) 

N.S. N.S. N.S. 

1.152 0.905 

0.224 0.137 

6.957 5.993 

106 104 106 

1/19(0.05) 6/45(0.13) 5/49(0.10) 

N.S. N.S. N.S. ___ 

2.533 1.939 

0.346 0.243 

113.695 89.722 

Ill 110 102 
TOPOGRAPHY : MORPHOLOGY
 

Thyroid: Follicular-Cell Carcinoma or
 

Follicular-Cell Adenomab
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Thyroid: C-Cell Adenoma or C-Cell
 

Carcinoma"3
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Brain: Glioma NOS
 

P Values0
 

Departure from Linear Trend
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

TABLE 7 (CONTINUED) 

LOW HIGH 

CONTROL DOSE DOSE 

9/19(0.47) 19/45(0.42) 22/49(0.45) 

N.S. N.S. N.S. 

0.891 0.948 

0.497 0.542 

1.866 1.953 

81 62 94 

1/19(0.05) 5/45(0.11) 3/49(0.06) 

N.S. N.S. N.S. ___ 

2.111 1.163 

0.265 0.103 

97.475 59.809 

Ill 101 110 

0/19(0.00) 2/21(0.10) 0/21(0.00) 

N.S. N.S. N.S. 

P = 0.047 

Infinite 

0.278 

Infinite 

86 
TABLE 7 (CONCLUDED) 

n
 

Treated groups received time-weighted average doses of 321 or 642 ppm in feed.
 

Number of tumor-bearing animals/number of animals examined at site (proportion).
 Q
 

The probability level for the Cochran-Armitage test is given beneath the incidence of tumors
 

in the control group when P < 0.05; otherwise, not significant (N.S.) is indicated. The
 

probability level for the Fisher exact test for the comparison of a treated group with the
 

control group is given beneath the incidence of tumors in the treated group when P < 0.05;
 

otherwise, not significant (N.S.) is indicated. For both Cochran-Armitage and Fisher exact
 

tests a negative designation (N) indicates a lower incidence in the treated group(s) than
 

in the control group.
 

The 95% confidence interval on the relative risk of the treated group to the control group.
 e

The probability level of the test for departure from linear trend is given beneath the control
 

group when P < 0.05.
 
___ 

___ 

TABLE 8
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN FEMALE RATS TREATED WITH DDT*
 

LOW
 

TOPOGRAPHY : MORPHOLOGY CONTROL DOSE
 

Subcutaneous Tissue: Fibroma 0/20(0.00) 6/50(0.12)
 

P Values0 N.S. N.S.
 

Departure from Linear Trend P = 0.005
 

Relative Risk (Control) Infinite
 

Lower Limit 0.666
 

Upper Limit Infinite
 

Weeks to First Observed Tumor 76
 

Pituitary: Chromophobe Adenoma 13/19(0.68) 16/39(0.41)
 

P Values0 N.S. P = 0.046(N)
 

Relative Risk (Control) 0.600
 

Lower Limit 0.383
 

Upper Limit 1.080
 

Weeks to First Observed Tumor 104 71
 

Adrenal: Pheochromocytoma 0/19(0.00) 0/38(0.00)
 

P Values0 P = 0.031 N.S.
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

HIGH
 

DOSE
 

0/50(0.00)
 

N.S.
 

13/27(0.48)
 

N.S.
 

0.704
 

0.431
 

1.265
 

103
 

3/24(0.13)
 

N.S.
 

Infinite
 

0.498
 

Infinite
 

109
 
___ 

TABLE

TOPOGRAPHY: MORPHOLOGY
 

Thyroid: Follicular-Cell Carcinoma
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Thyroid: Follicular-Cell Carcinoma or
 

Follicular-Cell Adenoma^1
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Thyroid: C-Cell Adenoma or C-Cell
 

Carcinoma
 

P Values
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

8 (CONTINUED) 

CONTROL
 

0/19(0.00)
 

N.S.
 

1/19(0.05)
 

N.S.
 

Ill
 

4/19(0.21)
 

P = 0.004(N)
 

110
 

LOW
 

DOSE
 

4/45(0.09)
 

N.S.
 

Infinite
 

0.408
 

Infinite
 

111
 

13/45(0.29)
 

P = 0.032
 

5.489
 

0.942
 

226.304
 

111
 

3/45(0.07)
 

N.S.
 

0.317
 

0.053
 

1.722
 

111
 

HIGH
 

DOSE
 

6/43(0.14)
 

N.S.
 

Infinite
 

0.740
 

Infinite
 

109
 

10/43(0.23)
 

N.S.
 

4.419
 

0.714
 

186.157
 

84
 

0/43(0.00)
 

P = 0.007(N)
 

0.000
 

0.000
 

0.469
 
___ 

TOPOGRAPHY :MORPHOLOGY
 

Mammary Gland: Fibroadenoma
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Uterus: Endometrial Stromal Polyp
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Ovary: Granulosa-Cell Tumor
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

TABLE 8 (CONTINUED) 

CONTROL
 

8/20(0.40)
 

P = 0.008(N)
 

_—
 

75
 

0/19 CO. 00)
 

N.S.
 

0/19(0.00)
 

N.S.
 

LOW
 

DOSE
 

11/50(0.22)
 

N.S.
 

0.550
 

0.249
 

1.376
 

111
 

2/43(0.05)
 

N.S.
 

Infinite
 

0.137
 

Infinite
 

104
 

2/37(0.05)
 

N.S.
 

Infinite
 

0.158
 

Infinite
 

111
 

HIGH
 

DOSE
 

6/50(0.12)
 

P = 0.012(N)
 

0.300
 

0.104
 

0.871
 

103
 

4/31(0.13)
 

N.S.
 

Infinite
 

0.594
 

Infinite
 

103
 

0/24(0.00)
 

N.S.
 
TABLE 8 (CONCLUDED)
 

TOPOGRAPHY : MORPHOLOGY CONTROL 

LOW 

DOSE 

HIGH 

DOSE 

Kidney: Lipoma or Liposarcoma 

P Values0 

0/19(0.00) 

N.S. 

2/38(0.05) 

N.S. ­

1/25(0.04) 

N.S. 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

Infinite 

0.154 

Infinite 

Infinite 

0.042 

Infinite 

Weeks to First Observed Tumor 111 111 

Treated groups received time-weighted average doses of 210 or 420 ppm in feed.
 

Number of tumor-bearing animals/number of animals examined at site (proportion).
 

C

The probability level for the Cochran-Armitage test is given beneath the incidence of tumors
 

in the control group when P < 0.05; otherwise, not significant (N.S.) is indicated. The
 

probability level for the Fisher exact test for the comparison of a treated group with the
 

control group is given beneath the incidence of tumors in the treated group when P < 0.05;
 

otherwise, not significant (N.S.) is indicated. For both Cochran-Armitage and Fisher exact
 

tests a negative designation (N) indicates a lower incidence in the treated group(s) than
 

in the control group.
 

The 95% confidence interval on the relative risk of the treated group to the control group.
 0
 

The probability level of the test for departure from linear trend is given beneath the control
 

group when P < 0.05.
 
marginal result which was not significant under the Bonferroni criterion.
 

No other statistical tests for either males or females indicated
 

a positive association between chemical administration and incidence.
 

Based upon these statistical results there was no convincing evidence
 

of the carcinogenicity of DDT in rats.
 

For females a negative association between administration and
 

incidence was observed both for mammary fibroadenomas and for the
 

combined incidence of C-cell adenomas and C-cell carcinomas of the
 

thyroid. No other tests were significant under the Bonferroni criterion.
 

The incidence of thyroid follicular-cell neoplasms (9/19 or 47
 

percent) in control males was somewhat higher than commonly seen.
 

In historical control data collected by this laboratory for the NCI
 

Carcinogenesis Testing Program, these neoplasms were observed in
 

32/383 (8 percent) of the untreated male Osborne-Mendel rats. With
 

15 control groups included in this historical data, this DDT control
 

group had 9 of the total of 32 tumors. Excluding the DDT control
 

group, the incidences in the other 14 control groups ranged from 0/50
 

to 3/20 (15 percent).
 

To provide additional insight into the possible carcinogenicity
 

of this compound, 95 percent confidence intervals on the relative
 

risk have been estimated and entered in the tables based upon the
 

observed tumor incidence rates. In many of the intervals 'shown in
 

51
 
Tables 7 and 8, the value one is included; this indicates the absence
 

of statistically significant results. It should also be noted that
 

many of the confidence intervals have an upper limit greater than
 

one, indicating the theoretical possibility of tumor induction in
 

rats by DDT that could not be established under the conditions of
 

this test.
 

B. TDE
 

1. Body Weights and Clinical Observations
 

Distinct dose-related mean body weight depression was evident
 

among both male and female rats (Figure 6).
 

During the first 6 months of the study, the appearance and
 

behavior of the TDE-dosed rats was generally comparable to that of
 

the controls. From week 30 to cessation of dosing in week 78, clinical signs consisting of a hunched appearance and abdominal urine
 

stains were observed in a slightly greater number of dosed rats than
 

controls. The incidences of these signs were comparable in dosed and
 

control rats during the last 6 months of the study. Respiratory signs
 

were observed at a low incidence in all groups during the second year
 

of the study, increasing slightly during the last 6 months.
 

Clinical signs commonly associated with aging in the Osborne-


Mendel rat were observed at comparable rates in dosed and control
 

rats during the second year. These signs included sores on the body
 

and extremities, localized alopecia, rough or discolored fur, squinted
 

or reddened eyes (often with exudate in the conjunctival sac), palpable
 

52
 
FIGURES 

GROWTH CURVES FOR TDE CHRONIC STUDY RATS 

53 
nodules, and tissue masses or swollen areas of the body. Isolated,
 

apparently spontaneous observations in one or two dosed rats included
 

paralysis of hind limbs, salivation, circling, tremors, ataxia, and
 

testicular atrophy.
 

2. Survival
 

The estimated probabilities of survival for male and female
 

rats in the control and TDE-dosed groups are shown in Figure 7. No
 

significant positive association between dosage and mortality was
 

observed for either male or female rats.
 

Adequate numbers of males were at risk from late-developing tumors, as 84 percent (42/50) of the high dose, 86 percent (43/50) of
 

the low dose and 70 percent (14/20) of the control rats survived on
 

test for at least 100 weeks. Adequate numbers of females were also
 

at risk, as 84 percent (42/50) of the high dose, 86 percent (43/50)
 

of the low dose, and 75 percent (15/20) of the control rats survived
 

on test for at least 100 weeks.
 

3. Pathology
 

Histopathologic findings on neoplasms in rats are summarized in
 

Appendix E (Tables El and E2); findings on nonneoplastic lesions are
 

summarized in Appendix G (Tables Gl and G2).
 

Neoplasms and hyperplasias of the thyroid gland occurred in both
 

the dosed and control rats as shown in the following tabulation:
 

54
 
FIGURE 7 

SURVIVAL COMPARISONS OF TDE CHRONIC STUDY RATS 

55 
MALES FEMALES
 

Low High Low High 

Control Dose Dose Control Dose Dose 

Number of Animals with 

Thyroid Examined 

Histopathologically (19) (49) (49) (19) (48) (50) 

Follicular-Cell 

Carcinoma 1 6 3 2 5 1 

Follicular-Cell 

Adenoma 0 11 9 0 6 5 

Follicular-Cell 

Hyperplasia 2 5 6 1 2 3 

Follicular Cyst 0 2 4 0 0 1 

C-Cell Carcinoma 0 4 2 1 2 4 

C-Cell Adenoma 1 4 1 1 2 1 

C-Cell Hyperplasia 1 2 2 2 4 5 

The morphology of the follicular-cell carcinomas in this study
 

consisted of hyperchromatic anaplastic cuboidal epithelial cells
 

forming irregular-sized follicles, with a piling up of cells around
 

the follicles, papillary projections into the enlarged follicles, and
 

in some areas forming densely cellular sheets. Pale colloid material
 

was present in some of the follicles. The neoplastic cells had central nuclei which were variable and could be small or large, pale or
 

dark, round or bizarre. In some areas the follicular-cell carcinomas
 

approached the spindle-cell form. The neoplastic cells invaded the
 

capsule and adjacent normal tissue.
 

56
 
The follicular-cell adenomas were expansive growths composed of
 

follicles lined by single layers of large basophilic epithelial cells,
 

usually well-demarcated from the adjacent normal thyroid parenchyma.
 

Differentiation of the follicular-cell adenoma from hyperplasia was
 

based largely on compression of the normal thyroid tissue and encapsulation of the adenoma and the degree of differentiation of the
 

follicular cells.
 

The C-cell adenomas were composed of sheets and compact masses
 

of large pale, irregular cuboidal cells with central nuclei and pale
 

eosinophilic cytoplasm which resembled interfollicular thyroid cells.
 

The C-cell carcinomas were generally composed of less differentiated
 

cells with poor demarcation from the surrounding tissue. C-cell
 

hyperplasias of the thyroid were determined by their architecture,
 

size, and cellular differentiation.
 

Other proliferative, degenerative, and inflammatory lesions that
 

occurred in the control and dosed rats were similar in number and
 

kind to those lesions occurring naturally in aged Osborne-Mendel rats.
 

This pathologic evaluation indicated that under the conditions
 

of this bioassay, there was an increased incidence of thyroid
 

follicular-cell tumors in dosed rats of both sexes and a marginal
 

increased incidence of C-cell tumors in dosed males when compared
 

with controls.
 

4. Statistical Analyses of Results
 

The results of the statistical analyses of tumor incidence in
 

rats are summarized in Tables 9 and 10. The analysis is included for
 

57
 
T\3LE 9
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS
 

AT SPECIFIC SITES IN MALE RATS TREATED WITH TOE*
 

TOPOGRAPHY : MORPHOLOGY
 

b
 

Subcutaneous Tissue: Fibroma
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Pituitary: Chromophobe Adenoma 

P Values0 

d 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Thyroid: Follicular-Cell Carcinoma
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

CONTROL
 

4/20(0.20)
 

P = 0.002(N)
 

93
 

1/20(0.05)
 

N.S.
 

99
 

1/19(0.05)
 

N.S.
 

103
 

LOW
 

DOSE
 

2/50(0.04)
 

N.S.
 

0.200
 

0.020
 

1.297
 

111
 

7/26(0.27)
 

N.S.
 

5.385
 

0.786
 

230.300
 

84
 

6/49(0.12)
 

N.S.
 

2.327
 

0.316
 

104.667
 

99
 

HIGH
 

DOSE
 

0/50(0.00)
 

P = 0.005(N)
 

0.000
 

0.000
 

0.427
 

5/25(0.20)
 

N.S.
 

4.000
 

0.505
 

180.057
 

108
 

3/49(0.06)
 

N.S.
 

1.163
 

0.104
 

59.809
 

112
 
___ 

TOPOGRAPHY : MORPHOLOGY
 

Thyroid: Follicular-Cell Carcinoma
 

or Follicular-Cell Adenoma*3
 

P Values0
 

Departure from Linear Trend
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Thyroid: C-Cell Carcinoma
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Thyroid: C-Cell Adenoma or C-Cell
 

Carcinoma*3
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

TABLE 9 (CONTINUED)
 

CONTROL
 

1/19(0.05)
 

N.S.
 

P = 0.025
 

103
 

0/19(0.00)
 

N.S.
 

1/19(0.0:' ,
 

N.S.
 

Ill
 

LOW
 

DOSE
 

16/49(0.33)
 

P = 0.016
 

6.204
 

1.102
 

252.587
 

94
 

4/49(0.08)
 

N.S.
 

Infinite
 

0.374
 

Infinite
 

103
 

8/49(0.16)
 

N.S.
 

3.102
 

0.469
 

134.437
 

103
 

HIGH
 

DOSE
 

11/49(0.22)
 

N.S.
 

4.265
 

0.704
 

178.941
 

60
 

2/49(0.04)
 

N.S.
 

Infinite
 

0.120
 

Infinite
 

112
 

3/49(0.06)
 

N.S.
 

1.163
 

0.104
 

59 . 809
 

112 
TABLE 9 (CONCLUDED)
 

TOPOGRAPHY: MORPHOLOGY CONTROL 

LOW 

DOSE 

HIGH 

DOSE 

Liver: Hepatocellular Carcinoma 

P Values0 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

0/20(0.00) 

N.S. ___ 

1/27(0.04) 

N.S. 

Infinite 

0.041 

Infinite 

2/38(0.05) 

N.S. 

Infinite 

0.161 

Infinite 

Weeks to First Observed Tumor 108 112 

Spleen: Hemangiosarcoma 

P Values0 

0/20(0.00) 

N.S. 

4/20(0.21) 

N.S. 

0/20(0.00) 

N.S. 

Departure from Linear Trand P = 0.004 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

Infinite 

0.975 

Infinite 

Weeks to First Observed Tumor 109 

Treated groups received time-weighted average doses of 1647 or 3294 ppm in feed.
 

Number of tumor-bearing animals/number of animals examined at site (proportion) .
 C

The probability level for the Cochran-Armitage test is given beneath the incidence of tumors in
 

the control group when P < 0.05; otherwise, not significant (N.S.) is indicated. The probability
 

level for the Fisher exact test for the comparison of a treated group with the control group is
 

given beneath the incidence of tumors in the treated group when P < 0.05; otherwise, not signifi­ cant (N.S.) is indicated. For both Cochran-Armitage and Fisher exact tests a negative designa­ tion (N) indicates a lower incidence in the treated group(s) than in the control group.
 

The 95% confidence interval on the relative risk of the treated group to the control group,
 e

The probability level of the test for departure from linear trend is given beneath the control
 

group when P < 0.05.
 
TABLE 10
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS
 

AT SPECIFIC SITES IN FEMALE RATS TREATED WITH TDE£
 

TOPOGRAPHY : MORPHOLOGY
 

Subcutaneous Tissue: Fibroma
 

? Values0
 

Departure from Linear Trend
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Subcutaneous Tissue: Lipoma
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Hematopoietic System: Malignant
 

Lvmphoma
 

c


P Values
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

CONTROL
 

2/19(0.11)
 

P = 0.023(N)
 

P = 0.037
 

49
 

0/19(0.00)
 

N.S.
 

3/19(0.16)
 

N.S.
 

LOW
 

DOSE
 

0/49(0.00)
 

N.S.
 

0.000
 

0.000
 

1.303
 

0/49(0.00)
 

N.S.
 

1/49(0.02)
 

N.S.
 

0.129
 

0.003
 

1.516
 

HIGH
 

DOSE
 

0/49(0.00)
 

N.S.
 

0.000
 

0.000
 

1.303
 

3/49(0.06)
 

N.S.
 

Infinite
 

0.243
 

Infinite
 

113
 

2/49(0.04)
 

N.S.
 

0.259
 

0.024
 

2.120
 

Weeks to First Observed Tumor 29 113 113
 
TOPOGRAPHY : MORPHOLOGY
 

Pituitary: Chromophobe Adenoma
 

P Values
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

b
 Thyroid: Follicular-Cell Carcinoma
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Thyroid: Follicular-Cell Carcinoma
 

or Follicular-Cell Adenoma"
 

P Values0
 

Relative Risk (Control)
 

Lower limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

TABLE 10 (CONTINUED) 

CONTROL
 

4/19(0.21)
 

N.S.
 

Ill
 

2/19(0.11)
 

N.S.
 

105
 

2/19(0.11)
 

N.S.
 

105
 

LOW
 

DOSE
 

14/30(0.47)
 

N.S.
 

2.217
 

0.849
 

7.869
 

102
 

5/48(0.10)
 

N.S.
 

0.990
 

0.184
 

9.980
 

113
 

11/48(0.23)
 

N.S.
 

2.177
 

0.549
 

19 . 100
 

112
 

HIGH
 

DOSE
 

12/33(0.36)
 

N.S.
 

1.727
 

0.630
 

6.427
 

90
 

1/50(0.02)
 

N.S.
 

0.190
 

0.009
 

3.494
 

113
 

6/50(0.12)
 

N.S.
 

1.140
 

0.231
 

10.985
 

92
 
TOPOGRAPHY : MORPHOLOGY
 

Thyroid: C-Cell Carcinoma
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Thyroid: C-Cell Adenoma or C-Cell
 

Carcinoma^
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper limit
 

Weeks to First Observed Tumor
 

Liver: Hepatocellular Carcinoma
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

TABLE 10 (CONTINUED) 

CONTROL
 

1/19(0.05)
 

N.S.
 

70
 

2/19(0.11)
 

N.S.
 

70
 

1/19(0.05)
 

N.S.
 

Ill
 

LOW
 

DOSE
 

2/48(0.04)
 

N.S.
 

0.792
 

0.045
 

45.751
 

113
 

4/48(0.08)
 

N.S.
 

0.792
 

0.127
 

8.329
 

113
 

0/32(0.00)
 

N.S.
 

0.000
 

0.000
 

10.977
 

HIGH
 

DOSE
 

4/50(0.08)
 

N.S.
 

1.520
 

0.168
 

73.309
 

113
 

5/50(0.10)
 

N.S.
 

0.950
 

0.177
 

9.498
 

113
 

3/40(0.08)
 

N.S.
 

1.425
 

0.126
 

72.391
 

90 
___ 

___ 

TABLE 10 (CONCLUDED)
 

TOPOGRAPHY: MORPHOLOGY
 

Uterus: Endometrlal Stromal Polyp
 

P Values
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Mammary Gland: Fibroadenoma
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

CONTROL
 

1/19(0.05)
 

N.S.
 

Ill
 

7/19(0.37)
 

N.S.
 

84
 

LOW
 

DOSE
 

6/30(0.20)
 

N.S.
 

3.800
 

0.521
 

167.766
 

94
 

13/49(0.27)
 

N.S.
 

0.720
 

0.332
 

1.857
 

104
 

HIGH
 

DOSE
 

8/36(0.22)
 

N.S.
 

4.222
 

0.646
 

180.880
 

92
 

10/49(0.20)
 

N.S.
 

0.554
 

0.235
 

1.504
 

83
 

Treated groups received time-weighted average doses of 850 or 1700 ppm in feed.
 

Number of tumor-bearing animals/number of animals examined at site (proportion).
 ft
 

The probability level for the Cochran-Armitage test is given beneath the incidence of tumors in
 

the control group when P < 0.05; otherwise, not significant (N.S.) is indicated. The probability
 

level for the Fisher exact test for the comparison of a treated group with the control group is
 

given beneath the incidence of tumors in the treated group when P < 0.05; otherwise, not significant (N.S.) is indicated. For both Cochran-Armitage and Fisher exact tests a negative designation (N) indicates a lower incidence in the treated group(s) than in the control group.
 

The 95% confidence interval on the relative risk of the treated group to the control group.
 

6

The probability level of the test for departure from linear trend is given beneath the control
 

group when P < 0.05.
 
every type of tumor in either sex where at least two such tumors were
 

observed in at least one of the control or TDE-dosed groups and where
 

such tumors were observed in at least 5 percent of the group.
 

High incidences of follicular-cell thyroid neoplasms were noted
 

in dosed male rats. When incidences were combined so that the numerator represented males with either a follicular-cell adenoma or a
 

follicular-cell carcinoma of the thyroid, the Fisher exact test comparing the low dose to the control was significant (P = 0.016). The
 

first observed thyroid follicular-cell neoplasm was in week 60, 94,
 

and 103 for the high dose, low dose, and control group, respectively.
 

In the historical control data compiled by this laboratory for the
 

NCI Carcinogenesis Testing Program, 32/352 (9 percent) of the untreated male Osborne-Mendel rats had a follicular-cell adenoma or a
 

follicular-cell carcinoma of the thyroid—compared to 1/19 (5 percent), 16/49 (33 percent), or 11/49 (22 percent) for the control, low
 

dose, or high dose group, respectively, in this bioassay.
 

Based upon these results the statistical conclusion is that the
 

increased incidence of follicular-cell neoplasms of the thyroid in
 

male rats was associated with the administration of TDE. No such
 

association was shown for C-cell neoplasms of the thyroid.
 

For both male and female rats the incidence of fibromas of the
 

subcutaneous tissue had a significant negative association with the
 

administration of TDE. For the females, however, the Fisher exact
 

tests were not significant.
 

65
 
To provide additional insight into the possible carcinogenicity
 

of this compound, 95 percent confidence intervals on the relative
 

risk have been estimated and entered in the tables based upon the
 

observed tumor incidence rates. In many of the intervals shown in
 

Tables 9 and 10, the value one is included; this indicates the absence of statistically significant results. It should also be noted
 

that many of the confidence intervals have an upper limit greater
 

than one, indicating the theoretical possibility of tumor induction
 

in rats by TDE that could not be established under the conditions of
 

this test.
 

C. DDE
 

1. Body Weights and Clinical Observations
 

Compound-related mean body weight depression was observed in both
 

male and female rats (Figure 8).
 

No clinical signs were observed during the first 7 weeks of the
 

study. Beginning in week 8, a few dosed rats started to exhibit a
 

hunched or thin appearance which was observed in increasing numbers of
 

rats, particularly in the high dose males. Following a decrease in
 

dose level in week 24, the incidence of this sign decreased sharply in
 

the dosed groups; however, it was still noted with greater frequency
 

in these groups than in the controls for the duration of the dosing period. From week 78 to termination of the study, comparable numbers of
 

dosed and control rats showed a hunched appearance. Other signs
 

66
 
FIGURES 

GROWTH CURVES FOR DDE CHRONIC STUDY RATS 

67 
observed at similar frequency and at a low incidence in dosed and control rats included respiratory signs, abdominal urine stains, squinted
 

or reddened eyes, body sores, alopecia, bloated appearance, and palpable nodules and/or tissue masses. Isolated instances of tremors,
 

ataxia, loss of equilibrium, hyperactivity, and vaginal discharge were
 

observed in one or two dosed rats.
 

2. Survival
 

The estimated probabilities of survival for male and female rats
 

in the control and DDE-dosed groups are shown in Figure 9. For both
 

male and female rats the Tarone test indicated a significant (P <
 

0.015) positive association between dosage and mortality.
 

Adequate numbers of males were at risk from late-developing tumors, as 52 percent (26/50) of the high dose, 68 percent (34/50) of
 

the low dose, and 80 percent (16/20) of the control rats survived on
 

test at least 92 weeks. For females the survival was also adequate
 

as 72 percent (36/50) of the high dose, 84 percent (42/50) of the low
 

dose, and all 20 of the control rats survived on test at least 92
 

weeks. Of the 14 high dose females that died before week 92, 9 died
 

in weeks 21 through 24; 2 of the 9 were autolyzed.
 

3. Pathology
 

Histopathologic findings on neoplasms in rats are summarized in
 

Appendix I (Tables II and 12); findings on nonneoplastic lesions are
 

summarized in Appendix K (Tables Kl and K2).
 

68
 
FIGURE 9

 

SURVIVAL COMPARISONS OF DDE CHRONIC STUDY RATS 

69 
Neoplasms and hyperplasias of the thyroid gland occurred in both
 

dosed and control rats as shown in the following tabulation:
 

MALES 

Control 

Low 

Dose 

High 

Dose Control 

FEMALES 

Low 

Dose 

High 

Dose 

Number of Animals with 

Thyroid Examined 

Histopathologically (20) (49) (47) (19) (48) (48) 

Follicular-Cell 

Adenoma 2 8 8 1 6 8 

Follicular-Cell 

Carcinoma 1 5 2 1 3 4 

Follicular-cell 

Hyperplasia 2 2 4 0 7 4 

C-Cell Adenoma 2 1 1 0 5 1 

C-Cell Carcinoma 1 1 0 1 3 1 

C-Cell Hyperplasia 4 0 1 3 3 2 

The morphology of the thyroid lesions observed in this study was
 

similar to that described in TDE (pp. 56-57).
 

DDE caused a toxic hepatopathy which was manifested by centrilobular necrosis and fatty metamorphosis in the hepatocytes. Centrilobular necrosis occurred in 2/40 low dose males, 3/40 high dose
 

males, 1/20 control females, 7/34 low dose females, and 10/33 high
 

dose females. Fatty metamorphosis in hepatocytes occurred in 2/20
 

control males, 25/40 low dose males, 20/40 high dose males, 11/20
 

control females, 3/34 low dose females, and 10/33 high dose females.
 

The livers with centrilobular necrosis had lost many centrilobular
 

70
 
hepatocytes and the adjacent hepatocytes in the lobule contained
 

lipid droplets. In some livers there was an infiltration of lymphocytes.
 

The numbers and kinds of neoplasms that occurred in dosed rats
 

were similar in frequency to those occurring in the control rats.
 

In this study pathologic evidence was not provided for the carcinogenicity of DDE in Osborne-Mendel rats, but the compound was
 

toxic to the livers, causing a centrilobular necrosis and fatty metamorphosis in the dosed male and female rats.
 

4. Statistical Analyses of Results
 

The results of the statistical analyses of tumor incidence in
 

rats are summarized in Tables 11 and 12. The analysis is included
 

for every type of tumor in either sex where at least two such tumors
 

were observed in at least one of the control or DDE-dosed groups and
 

where such tumors were observed in at least 5 percent of the group.
 

Because of the early mortality in the high dose males and females,
 

additional, time-adjusted analyses were conducted based either upon
 

those rats which survived at least 52 weeks or, in the event that the
 

tumor of interest was observed earlier than 52 weeks, upon rats which
 

/
 

survived at least until the first tumor of that type was observed.
 

The results of interest for these additional analyses are given in
 

Table 13.
 

For the time-adjusted analysis, the Cochran-Armitage test indicated a significant (P = 0.041) positive association between dosage
 

71
 
TABLE 11
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN MALE RATS TREATED WITH DDE3
 

TOPOGRAPHY: MORPHOLOGY
 

Subcutaneous Tissue: Fibroma
 

P Values0
 

Departure from Linear Trend
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Pituitary: Chromophobe Adenoma
 

P Values0
 

Departure from Linear Trend
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Thyroid: Follicular-Cell Carcinoma
 

P Valuer0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

LOW HIGH 

CONTROL DOSE DOSE 

0/20(0.00) 4/50(0.08) 0/47(0.00) 

N.S. N.S. N.S. 

P = 0.023 ___ 

Infinite 

0.386 

Infinite 

29 

0/18(0.00) 4/18(0.22) 0/19(0.00) 

N.S. N.S. N.S. 

P = 0.003 

Infinite 

0.983 

Infinite 

101 

1/20(0.05) 5/49(0.10) 2/47(0.04) 

N.S. N.S. N.S. 

2.041 0.851 

0.254 0.048 

94.440 49.165 

Ill 85 111 
TABLE 11 (CONCLUDED) 

LOW HIGH 

TOPOGRAPHY : MORPHOLOGY CONTROL DOSE DOSE 

Thyroid: Follicular-Cell Adenoma or 

Follicular-Cell Carcinoma 3/20(0,15) 12/49(0.24) 10/47(0.21) 

P Values0 N.S. N.S. N.S. 

Relative Risk (Control) 1.633 1.418 

Lower Limit 0.512 0.424 

Upper Limit 8.342 7.425 

Weeks to First Observed Tumor 11] 77 57 

Thyroid: C-Ce21 Adenoma or C-Cell 

Carcinoma 3/20(0.15) 2/49(0.04) 1/47(0.02) 

P Values0 P = 0.047(N) N.S. N.S. 

Relative Risk (Control) 0.272 0.142 

Lower Limit 0.025 0.003 

Upper Limit 2.232 1.665 

Weeks to First Observed Tumor Ill 105 103 

Treated groups received time-weighted average doses cf 437 or 839 ppm in feed.
 

Number of tumor-bearing animals/number of animals examined at site (proportion).
 

"The probability level for the Coc.hran-Armitage test is given beneath the incidence of tumors
 

in the control group when P < 0.05; otherwise, not significant (N.S.) is indicated. The
 

probability level for the Fisher exact test for the comparision of a treated group with the
 

control group is given beneath the incidence of tumors in the treated group when P < 0.05;
 

otherwise, not significant (N.S.) is indicated. For both Cochran-Armitage and Fisher exact
 

tests a negative designation (N) indicates a lower incidence in the treated group(s) than
 

in the control group.
 

The 95% confidence interval on the relative risk of the treated group to the control group.
 

"The probability level of the test for departure from linear trend is given beneath the control group when P < 0.05.
 
TABLE 12
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN FEKALF RATS TREATED WITH DDE3
 

TOPOGRAPHY : MORPHOLOGY
 

Pituitary: Chromophobe Adenoma
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Thyroid: Follicular-Cell Carcinoma
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Thyroid: Follicular-Cell Adenoma or
 

Follicular-Cell Carcinoma^
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

CONTROL
 

9/18(0.50)
 

N.S.
 

96
 

1/19(0.05)
 

N.S.
 

Ill
 

2/19(0.11)
 

N.S.
 

Ill
 

LOW
 

DOSE
 

10/33(0.30)
 

N.S.
 

0.606
 

0.291
 

1.395
 

107
 

3/48(0.06)
 

N.S.
 

1.188
 

0.106
 

61.031
 

112
 

9/48(0.19)
 

N.S.
 

1.781
 

0.425
 

16.042
 

101
 

HIGH
 

DOSE
 

14/27(0.52)
 

N.S.
 

1.037
 

0.558
 

2.118
 

96
 

4/48(0.08)
 

N.S.
 

1.583
 

0.174
 

76.296
 

309
 

12/48(0.25)
 

N.S.
 

2.375
 

0.611
 

20.621
 

43
 
___ 

TOPOGRAPHY : MORPHOLOGY
 

Thyroid: C-Cell Carcinoma
 

c
 

P Values
 

d
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Thyroid: C Cell Adenoma or C-Cell
 

Carcinoma^
 

P Values0
 

Departure from Linear Trend
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Mammary Gland: Adenocarcinoma NOS^
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

TABLE 12 (CONTINUED) 

CONTROL
 

1/19(0.05)
 

N.S.
 

Ill
 

1/19(0.05)
 

N.S.
 

P = 0.040
 

Ill
 

1/20(0.05)
 

N.S.
 

Ill
 

LOW
 

DOSE
 

3/48(0.06)
 

N.S.
 

1.188
 

0.106
 

61.031
 

112
 

8/48(0.17)
 

N.S.
 

3.167
 

0.478
 

137.163
 

83
 

5/49(0.10)
 

N.S.
 

2.041
 

0.254
 

94.440
 

67
 

HIGH
 

DOSE
 

1/48(0.02)
 

N.S.
 

0.396
 

0.005
 

30.454
 

112
 

2/48(0.04)
 

N.S.
 

0.792
 

0.045
 

45.751
 

112
 

0/50(0.00)
 

N.S.
 

0.000
 

0.000
 

7.475
 
TABLE 12 (CONCLUDED)
 

TOPOGRAPHY: MORPHOLOGY CONTROL 

LOW 

DOSE 

HIGH 

DOSE 

Mammary Gland: Fibroadenoma 5/20(0.25) 5/49(0.10) 7/50(0.14) 

P Values N.S. N.S. N.S. 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

0.408 

0.110 

1.614 

0.560 

0.179 

2.028 

Weeks to First Observed Tumor 104 82 91 

Uterus: Endometrial Stromal Polyp 

P Values0 

0/19(0.00) 

N.S. 

3/33(0.09) 

N.S. 

0/23(0.00) 

N.S. 

Departure from Linear Trend 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

P = 0.046 

_—_ Infinite 

0.363 

Infinite 

___ 

Weeks to First Observed Tumor 111 

Treated groups received time-weighted average doses of 242 or 462 ppm in feed.
 

Number of tumor-bearing animals/number of animals examined at site (proportion).
 

°The probability level for the Cochran-Armitage test is given beneath the incidence of tumors
 

in the control group when P < 0.05; otherwise, not significant (N.S.) is indicated. The
 

probability level for the Fisher exact test for the comparison of a treated group with the
 

control group is given beneath the incidence of tumors in the treated group when P < 0.05;
 

otherwise, not significant (N.S.) is indicated. For both Cochran-Armitage and Fisher exact
 

tests a negative designation (N) indicates a lower incidence in the treated group(s) than
 

in the control group.
 

The 95% confidence interval on the relative risk of the treated group to the control group.
 

e

The probability level of the test for departure from linear trend is given beneath the control
 

group when P < 0.05.
 
TABLE 13
 

TIME-ADJUSTED ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT SPECIFIC
 

SITES IN FEMALE RATS TREATED WITH
 

TOPOGRAPHY : MORPHOLOGY CONTROL 

LOW 

DOSE 

HIGH 

DOSE 

Thyroid: Follicular-Cell Adenoma or 

Follicular-Cell Carcinoma13*6 2/19(0.11) 9/48(0.19) 12/38(0.32) 

P Values0 P = 0.041 N.S. N.S. 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

___ 1.781 

0.424 

16.042 

3.000 

0.778 

25.661 

Weeks to First Observed Tumor Ill 101 43 

Treated groups received time-weighted average doses of 242 or 462 ppm in feed.
 

Number of tumor-bearing animals/number of animals examined at site (proportion).
 Q
 

The probability level for the Cochran-Armitage test is given beneath the incidence of tumors
 

in the control group when P < 0.05; otherwise, not significant (N.S.) is indicated. The
 

probability level for the Fisher exact test for the comparison of a treated group with the
 

control group is given beneath the incidence of tumors in the treated group when P < 0.05;
 

otherwise, not significant (N.S.) is indicated. For both Cochran-Armitage and Fisher exact
 

tests a negative designation (N) indicates a lower incidence in the treated group(s) than
 

in the control group.
 

These analyses were based solely upon animals surviving at least 43 weeks.
 
and the combined incidence of follicular-cell adenomas and follicularcell carcinomas of the thyroid in females. The Fisher exact tests,
 

however, were not significant. The first observed follicular-cell
 

thyroid neoplasm was at week 43, 101, and 111 for the high dose, low
 

dose, and control group, respectively.
 

No other statistical tests for any site in rats of either sex
 

indicated a significant positive association between the administration of DDE and tumor incidence. Thus, at the dose levels used in
 

this experiment there was no convincing evidence that DDE was a
 

carcinogen in Osborne-Mendel rats.
 

In male rats the Cochran-Armitage test indicated a significant
 

negative association between dose and the combined incidence of
 

C-cell adenomas and C-cell carcinomas of the thyroid. The Fisher
 

exact tests, however, did not support this finding.
 

In female rats the incidence of pituitary chromophobe adenomas
 

in the control group (9/18 or 50 percent) was high compared to that
 

observed in the historical controls (130/350 or 37 percent).
 

To provide additional insight into the possible carcinogenicity
 

of this compound, 95 percent confidence intervals on the relative
 

risk have been estimated and entered in the tables based upon the
 

observed tumor incidence rates. In all of the intervals shown in
 

Tables 11, 12, and 13 the value one is included; this indicates the
 

absence of statistically significant results. It should also be
 

noted that all of the confidence intervals have an upper limit
 

78
 
greater than one, indicating the theoretical possibility of tumor
 

induction in rats by DDE that could not be established under the
 

conditions of this test.
 

79
 
IV. CHRONIC TESTING RESULTS: MICE
 

A. DDT
 

1. Body Weights and Clinical Observations
 

Distinct, dose-related mean body weight depression was not apparent in male or female mice (Figure 10).
 

Throughout the study, there was no evidence of compound effect
 

with regard to physical appearance and behavior among the mice at
 

any dosage. Clinical signs were observed at similar rates in dosed
 

and control mice. These signs included sores on the body or extremities (more prevalent in the males), localized alopecia, rough or
 

stained fur, external genital irritations with occasional anal prolapse, bloated appearance, palpable nodules, and tissue masses or
 

swollen areas.
 

2. Survival
 

The estimated probabilities of survival for male and female mice
 

in the control and DDT-dosed groups are shown in Figure 11. For
 

males no significant positive association between dose and mortality
 

was observed. For females the Tarone test indicated a significant
 

(P = 0.005) positive association between dosage and mortality.
 

There was high mortality among all male groups during the second
 

year of the study—possibly due to fighting. There were, however,
 

adequate numbers of male mice at risk from late developing tumors as
 

74 percent (37/50) of the high dose, 40 percent (20/50) of the low
 

80
 
FIGURE 10 

GROWTH CURVES FOR DDT CHRONIC STUDY MICE 

81 
FIGURE 11

 

SURVIVAL COMPARISONS OF DDT CHRONIC STUDY MICE 

82 
dose, and 60 percent (12/20) of the control mice survived on test at
 

least 70 weeks.
 

For females survival was adequate as 72 percent (36/50) of the
 

high dose, 90 percent (45/50) of the low dose, and all 20 of the
 

control mice survived on test until the end of the experiment.
 

3. Pathology
 

Histopathologic findings on neoplasms in mice are summarized in
 

Appendix B (Tables B.I and B2); findings on nonneoplastic lesions are
 

summarized in Appendix D (Tables Dl and D2).
 

Hepatocellular carcinomas occurred in 2/19 (11 percent) control
 

males, 1/49 (2 percent) low dose males, 1/48 (2 percent) high dose
 

males, 0/20 control females, 1/22 (5 percent) low dose females, and
 

3/27 (11 percent) high dose females. The incidence of these tumors
 

in the mice was not considered to have been increased by administration of the chemical.
 

Other neoplasms that occurred in this bioassay are presented in
 

Appendix B. The inflammatory, degenerative, and proliferative lesions (both neoplastic and nonneoplastic) seen in the control and
 

dosed animals were similar in number and kind to those lesions
 

occurring naturally in aged B6C3F1 mice.
 

In this study, pathologic evidence was not provided for the
 

carcinogenicity of DDT in B6C3F1 mice.
 

4. Statistical Analyses of Results
 

The results of the statistical analyses of tumor incidence in
 

mice are summarized in Tables 14 and 15. The analysis is included
 

83
 
_ __ 

TABLE 14
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS
 

AT SPECIFIC SITES IN MALE MICE TREATED WITH DDT*
 

TOPOGRAPHY : MORPHOLOGY
 

Hematopoietic System: Malignant Lymphoma
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Liver: Hepatocellular Carcinoma
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

CONTROL
 

0/19(0.00)
 

N.S.
 

2/19(0.11)
 

N.S.
 

91
 

LOW
 

DOSE
 

2/49(0.04)
 

N.S.
 

Infinite
 

0.119
 

Infinite
 

45
 

1/49(0.02)
 

N.S.
 

0.194
 

0.003
 

3.561
 

88
 

HIGH
 

DOSE
 

1/50(0.02)
 

N.S.
 

Infinite
 

0.021
 

Infinite
 

71
 

1/48(0.02)
 

N.S.
 

0.198
 

0.004
 

3.635
 

80
 

Treated groups received time-weighted average doses of 22 or 44 ppm in feed.
 

Number of tumor-bearing animals/number of animals examined at site (proportion).
 f\
 

The probability level for the Cochran-Armitage test is given beneath the incidence of tumors
 

in the control group when P < 0.05; otherwise, not significant (N.S.) is indicated. The
 

probability level for the Fisher exact test for the comparison of a treated group with the
 

control group is given beneath the incidence of tumors in the treated group when P < 0.05;
 

otherwise, not significant (N.S.) is indicated. For both Cochran-Armitage and Fisher exact
 

tests a negative designation (N) indicates a lower incidence in the treated group(s) than
 

in the control group.
 

The 95% confidence interval on the relative risk of the treated group to the control group.
 
TABLE 15
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS
 

AT SPECIFIC SITES IN FEMALE MICE TREATED WITH DDT£
 

TOPOGRAPHY :MORPHOLOGY CONTROL 

LOW 

DOSE 

HIGH 

DOSE 

Hematopoietic System: Malignant Lym

P Values0 

phoma 0/20

P =

(0.00) 

 0.026 

3/49(0.06) 

N.S. 

7^46(0.15) 

N.S. 

Relative Risk (Control) 

Lower Li-nit 

Upper Limit 

Infinite 

0.255 

Infinite 

Infinite 

0.880 

Infinite 

Weeks to First Observed Tumor 92 76 

Liver: Hepatocellular

P Values0 

 Carcinoma 0/20

N

(0.00) 

.S. 

1/22(0.05) 

N.S. 

3/27(0.11) 

N.S. 

Relative Risk (Control) 

Lower Liait 

Upper Limit 

Infinite 

0.050 

Infinite 

Infinite 

0.465 

Infinite 

Weeks to First Observed Tumor 93 93 

Treated groups received time-weighted average doses of 87 or 175 ppm in feed.
 

Number of tumor-bearing animals/number of animals examined at site (proportion).
 

"The probability level for the Cochran-Armitage test is given beneath the incidence of tumors
 

in the control group when P <0.05; otherwise, not significant (N.S.) is indicated. The
 

probability level for the Fisher exact test for the comparison of a treated group with the
 

control group is given beneath the incidence of tumors in the treated group when P <0.05;
 

otherwise, not significant (N.S.) is indicated. For both Cochran-Armitage and Fisher exact
 

tests a negative designation (N) indicates a lower incidence in the treated group(s) than
 

in the control group.
 

The 95% confidence interval on the relative risk of the treated group to the control group.
 
for every type of tumor in either sex where at least two such tumors
 

were observed in at least one of the control or DDT-dosed groups and
 

where such tumors were observed in at least 5 percent of the group.
 

Due to the poor survival, additional, time-adjusted analyses were
 

conducted; there were no important changes in the statistical results.
 

For female mice the Cochran-Armitage test indicated a significant
 

(P * 0.026) positive association between dosage and the incidence of
 

malignant lymphomas. The Fisher exact tests, however, were not significant.
 

No other statistical tests were significant for male or female
 

mice. Thus, based upon these statistical results there was no convincing evidence that DDT was a carcinogen in mice under the conditions of this experiment.
 

To provide additional insight into the possible carcinogenicity
 

of this compound, 95 percent confidence intervals on the relative
 

risk have been estimated and entered in the tables based upon the
 

observed tumor incidence rates. In many of the intervals shown in
 

Tables 14 and 15, the value one is included; this indicates the absence of statistically significant results. It should also be noted
 

that many of the confidence intervals have an upper limit greater
 

than one, indicating the theoretical possibility of tumor induction
 

in mice by DDT that could not be established under the conditions of
 

this test.
 

86
 
B. IDE
 

1. Body Weights and Clinical Observations
 

Dose-related mean body weight depression was apparent in females
 

beginning in week 30 and continuing for the remainder of the bioassay.
 

Effect of chemical administration on mean body weight was not readily
 

evident for male mice (Figure 12).
 

Throughout the study there was no evidence that the compound affected physical appearance or behavior among the dosed mice. Signs
 

often observed in B6C3F1 mice were observed at comparable rates in
 

dosed and control animals. These common signs included body sores
 

(predominantly in the males and attributable to fighting), a hunched
 

appearance, localized alopecia, penile or vulvar irritation, occasional
 

anal prolapse, and rough or stained fur. Palpable nodules, tissue
 

masses, bloating and/or swollen areas on the body were observed at a
 

comparable rate in dosed and control mice, particularly in the females.
 

The incidence of these common signs increased gradually during the
 

last 6 months of the study as the age of the animals increased.
 

2. Survival
 

The estimated probabilities .of survival for male and female mice
 

in the control and TDE-dosed groups are shown in Figure 13. No significant positive association between dosage and mortality was observed for either sex.
 

There were adequate numbers of males at risk from late-developing
 

tumors, as 54 percent (27/50) of the high dose, 60 percent (30/50) of
 

87
 
FIGURE 12

 

GROWTH CURVES FOR TDE CHRONIC STUDY MICE 

88 
FIGURE 13

 

SURVIVAL COMPARISONS OF TDE CHRONIC STUDY MICE 

89 
the low dose, and 65 percent (13/20) of the control mice survived on
 

test until the end of the study. Survival was also adequate for the
 

females as 88 percent (44/50) of the high dose, 82 percent (41/50) of
 

the low dose, and 90 percent (18/20) of the control mice survived on
 

test until the end of the study.
 

3. Pathology
 

Histopathologic findings on neoplasms in mice are summarized in
 

Appendix F (Tables Fl and F2); findings on nonneoplastic lesions are
 

summarized in Appendix H (Tables HI and H2).
 

Hepatocellular carcinomas occurred in 2/18 (11 percent) control
 

male, 12/44 (27 percent) low dose male, 14/50 (28 percent) high dose
 

male, 0/20 control female, 2/48 (4 percent) low dose female, and 3/47
 

(6 percent) high dose female mice. One hepatocellular carcinoma in a
 

low dose male metastasized to the lung.
 

The hepatocellular carcinomas varied greatly in appearance. Some
 

lesions contained well-differentiated hepatocytes that had relatively
 

uniform arrangement of the cords, and others had very anaplastic liver
 

cells with large hyperchromatic nuclei, often with inclusion bodies
 

and with vacuolated pale cytoplasm. Arrangement of the neoplastic
 

hepatocytes varied from short stubby cords to nests of hepatic cells
 

and occasionally acinar formation. Mitotic figures were often present.
 

Some of the tumors were characterized by foci of anaplastic cells.
 

The inflammatory, degenerative, and proliferative lesions seen
 

in the control and dosed animals were similar in number and kind to
 

those lesions occurring naturally in aged B6C3F1 mice.
 

90
 
Although there was a higher incidence of hepatocellular carcinomas in TDE-dosed male mice (11 percent in the control group, 27 percent in the low dose group, and 28 percent in the high dose group),
 

these tumors have been observed in as many as 20 percent of the
 

control mice in other studies. Therefore, in the judgment of the
 

pathologist, TDE was not carcinogenic to B6C3F1 mice at the dosages
 

administered in this study.
 

4. Statistical Analyses of Results
 

The results of the statistical analyses of tumor incidence in
 

mice are summarized in Tables 16 and 17. The analysis is included
 

for every type of tumor in either sex where at least two such tumors
 

were observed in at least one of the control or TDE-dosed groups and
 

where such tumors were observed in at least 5 percent of the group.
 

No statistical tests for either males or females indicated a
 

significant positive association between chemical administration and
 

tumor incidence. Based upon these results there was no evidence that
 

TDE was a carcinogen in B6C3F1 mice.
 

A possible negative association between TDE administration and
 

incidence was observed for fibroma of the subcutaneous tissue in
 

males.
 

To provide additional insight into the possible carcinogenicity
 

of this compound, 95 percent confidence intervals on the relative
 

risk have been estimated and entered in the tables based upon the
 

observed tumor incidence rates. In many of the intervals shown in
 

91
 
___ 

TABLE 16
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS
 

AT SPECIFIC SITES IN MALE MICE TREATED WITH TDEe
 

TOPOGRAPHY: MORPHOLOGY
 

Subcutaneous Tissue: Fibroma
 

P Values
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Lung: Alveolar /Bronchiolar Adenoma or
 

Alveolar/Bronchiolar Carcinoma"
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Liver: Hepatocellular Carcinoma
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

CONTROL
 

3/18(0.17)
 

P = 0.007(N)
 

__—
 

90
 

1/18(0.06)
 

N.S.
 

90
 

2/18(0.11)
 

N.S.
 

90
 

LOW
 

DOSE
 

2/49(0.04)
 

N.S.
 

0.245
 

0.023
 

2.003
 

91
 

4/29(0.14)
 

N.S.
 

2.483
 

0.277
 

117.569
 

84
 

12/44(0.27)
 

N.S.
 

2.455
 

0.638
 

21.184
 

83
 

HIGH
 

DOSE
 

0/50(0.00)
 

P = 0.016(N)
 

0.000
 

0.000
 

0.592
 

2/35(0.06)
 

N.S.
 

1.029
 

0.058
 

58.934
 

92
 

14/50(0.28)
 

N.S.
 

2.520
 

0.675
 

21.536
 

67
 
TABLE 16 (CONCLUDED)
 

Treated groups received time-weighted average doses of 411 or 822 ppm in feed.
 

Number of tumor-bearing animals/number of animals examined at site (proportion).
 cThe probability level for the Cochran-Armitage test is given beneath the incidence of tumors
 

in the control group when P < 0.05; otherwise, not significant (N.S.) is indicated. The proba­ bility level for the Fisher exact test for the comparison of a treated group with the control
 

group is given beneath the incidence of tumors in the treated group when P < 0.05; otherwise,
 not significant (N.S.) is indicated. For both Cochran-Armitage and Fisher exact tests a nega­ tive designation (N) indicates a lower incidence in the treated group(s) than in the control
 

group.
 

The 95% confidence interval on the relative risk of the treated group to the control group.
 
___ 

___ 

__ _ 

TABLE 17
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS
 

AT SPECIFIC SITES IN FEMALE MICE TREATED WITH TDE*
 

TOPOGRAPHY: MORPHOLOGY
 

Lung: Alveolar/Bronchiolar


or Alveolar/Bronchiolar


P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

 Adenoma
 

 Carcinoma
 

Weeks to First Observed Tumor
 

Liver: Hepatocellular Carcinoma
 

P Values
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Liver: Hepatocellular Adenoma or
 

Hepatocellular Carcinoma"
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

CONTROL
 

0/20(0.00)
 

N.S.
 

0/20(0.00)
 

N.S.
 

0/20(0.00)
 

N.S.
 

LOW
 

DOSE
 

4/27(0.15)
 

N.S.
 

Infinite
 

0.718
 

Infinite
 

91
 

2/48(0.04)
 

N.S.
 

Infinite
 

0.128
 

Infinite
 

91
 

2/48(0.04)
 

N.S.
 

Infinite
 

0.128
 

Infinite
 

91
 

HIGH
 

DOSE
 

1/15(0.07)
 

N.S.
 

Infinite
 

0,073
 

Infinite
 

90
 

3/47(0.06)
 

N.S.
 

Infinite
 

0.267
 

Infinite
 

92
 

4/47(0.09)
 

N.S.
 

Infinite
 

0.412
 

Infinite
 

92
 
TABLE 17 (CONCLUDED)
 

TOPOGRAPHY : MORPHOLOGY CONTROL 

LOW 

DOSE 

HIGH 

DOSE 

Hematopoietic System: Malignant Lymphoma 

P Values0 

1/20(0.05) 

N.S. 

7/49(0.14) 

N.S. 

1/47(0.02) 

N.S. 

Departure from Linear Trend 

Relative Risk (Control) 

Lower Limit 

Upper Limit 

P = 0.040(N) 

2.857 

0.411 

125.834 

0.426 

0.006 

32.720 

Weeks to First Observed Tumor 90 86 93 

rt 

Treated groups received time-weighted average doses of 411 or 822 ppm in feed,
 k
 

Number of tumor-bearing animals/number of animals examined at site (proportion).
 

The probability level for the Cochran-Armitage test is given beneath the incidence of tumors in
 

the control group when P < 0.05; otherwise, not significant (N.S.) is indicated. The probabili
 

level for the Fisher exact test for the comparison of a treated group with the control group is
 

given beneath the incidence of tumors in the treated group when P < 0.05; otherwise, not signif:
 

cant (N.S.) is indicated. For both Cochran-Armitage and Fisher exact tests a negative designation (N) indicates a lower incidence in the treated group(s) than in the control group.
 

The 95% confidence interval on the relative risk of the treated group to the control group.
 

6

The probability level of the test for departure from linear trend is given beneath the control
 

group when P < 0.05.
 
Tables 16 and 17, the value one is included; this indicates the
 

absence of statistically significant results. It should also be
 

noted that many of the confidence intervals have an upper limit
 

greater than one, indicating the theoretical possibility of tumor
 

induction in mice by IDE that could not be established under the conditions of this test.
 

C. DDE
 

1. Body Weights and Clinical Observations
 

Dose-related mean body weight depression was evident in female
 

mice as early as week 10. Administration of DDE had no apparent
 

effect on growth of male mice (Figure 14).
 

During the first 20 weeks of the study, the dosed and control
 

mice exhibited essentially comparable appearance and behavior. Signs
 

often observed in B6C3F1 mice were observed at similar frequencies in
 

all groups. These signs included body sores with localized alopecia,
 

external genital irritation, and abdominal urine stains.
 

From week 22 to week 34 of the study, 60 to 85 percent of the
 

dosed male mice exhibited a hunched appearance. The incidence of
 

this sign alternately decreased and then increased from week 38 to
 

cessation of dosing in week 78, presumably reflecting the cyclic
 

regimen of compound administration during this period. During the
 

last 12 weeks of the study the signs mentioned above, including
 

palpable tissue masses, were observed at a comparable rate in the
 

surviving dosed and control mice.
 

96
 
FIGURE 14 

GROWTH CURVES FOR DDE CHRONIC STUDY MICE 

97 
2. Survival
 

The estimated probabilities of survival for male and female mice
 

in the control and DDE-dosed groups are shown in Figure 15. For males
 

the Tarone test did not indicate a significant positive association
 

between dosage and mortality. For females a significant (P < 0.001)
 

positive association between dosage and mortality was observed.
 

For males the survival of the control mice was quite low, as
 

7/20 (35 percent) died in week 40 and only 25 percent (5/20) survived
 

on test at least 70 weeks. Survival was somewhat better in the dosed
 

males as 62 percent (31/50) of the high dose and 70 percent (35/50)
 

of the low dose mice survived on test at least 70 weeks. Amyloidosis
 

of the spleen, kidney, and liver were quite common among the control
 

males and among those low dose males that survived less than 85
 

weeks.
 

For females there were adequate numbers of mice at risk from
 

late-developing tumors as 56 percent (28/50) of the high dose,
 

94 percent (47/50) of the low dose, and 95 percent (19/20) of the
 

control mice survived on test at least 75 weeks.
 

3. Pathology
 

Histopathologic findings on neoplasms in mice are summarized in
 

Appendix J (Tables Jl and J2); findings on nonneoplastic lesions are
 

summarized in Appendix L (Tables Ll and L2).
 

Hepatocellular carcinomas occurred in 7/41 (17 percent) low dose
 

male, 17/47 (36 percent) high dose male, 19/47 (40 percent) low dose
 

98
 
FIGURE 15

 

SURVIVAL COMPARISONS OF DDE CHRONIC STUDY MICE 

99 
female, and 34/48 (71 percent) high dose female mice. None of the
 

male or female controls developed hepatocellular c-arcinotnas. One of
 

the liver tumors in the high dose females metastasized to the lung.
 

The hepatocellular carcinomas varied greatly in appearance.
 

Some lesions contained well-differentiated hepatocytes that had a relatively uniform arrangement of the cords, and others had anaplastic
 

hepatocytes with large hyperchromatic nuclei, often with inclusion
 

bodies and with vacuolated, pale cytoplasm. Arrangement of the neoplastic hepatocytes varied from short stubby cords to nests of hepatocytes and occasionally acinar formation. Mitotic figures were
 

often present. Some of the tumors were characterized by foci of
 

anaplastic cells.
 

The number and kind of other neoplasms that occurred in this
 

study were not appreciably different in the control and dosed mice.
 

Inflammatory, degenerative, and proliferative lesions seen in the
 

control and dosed animals were similar in number and kind to those
 

lesions occurring naturally in aged B6C3F1 mice.
 

In this study pathologic evidence was provided for the carcinogenicity of DDE in B6C3F1 mice, with a dose-related increase in hepatocellular carcinomas.
 

4. Statistical Analyses of Results
 

The results of the statistical analyses of tumor incidence in
 

mice are summarized in Tables 18 and 19. The analysis is included
 

for every type of tumor in either sex where at least two such tumors
 

100
 
___ 

___ 

TABLE 18
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN MALE MICE TREATED WITH DDE3
 

LOW HIGH
 

TOPOGRAPHY: MORPHOLOGY CONTROL DOSE DOSE
 

Subcutaneous Tissue: Fibrosarcoma 0/18(0.00) 1/41(0.02) 4/47(0.09)
 

P Values0 N.S. N.S. N.S.
 

Relative Risk (Control) —_ Infinite Infinite
 

Lower Limit 0.024 0.373
 

Upper Limit Infinite Infinite
 

Weeks to First Observed Tumor 92 69
 

Hematopoietic System: Malignant
 

Lymphoma° 0/18(0.00) 4/41(0.10) 4/47(0.09)
 

P Values0 N.S. N.S. N.S.
 

Relative Risk (Control) Infinite Infinite
 

Lower Limit 0.449 0.391
 

Upper Limit Infinite Infinite
 

Weeks to First Observed Tumor 70 39
 

Liver: Hepatocellular Carcinoma 0/19(0.00) 7/41(0.17) 17/47(0.36)
 

P Values0 P = 0.001 N.S. P = 0.001
 

Relative Risk (Control) Infinite Infinite
 

Lower Limit 0.941 2.288
 

Upper Limit Infinite Infinite
 

Keeks to First Observed Tumor 71
 71
 
TABLE 18 (CONCLUDED)

 

LOW HIGH 

TOPOGRAPHY: MORPHOLOGY CONTROL DOSE DOSE 

Liver : Hemangioma or 

Hemangiosarcoma0 0/19(0.00) 2/41(0.05) 0/47(0.00) 

P Values0 N.S. N.S. N.S. ___ 

Relative Risk (Control) Infinite 

Lower Limit 0.143 

Upper Limit Infinite 

Weeks to First Observed Tumor 62 

Treated groups received time-weighted average doses of 148 or 261 ppm in feed.
 

Number of tumor-bearing animals/number of animals examined at site (proportion).
 

c
The probability level for the Cochran-Armitage test is given beneath the incidence of tumors in
 

the control group when P < 0.05; otherwise, not significant (N.S.) is indicated. The probability
 

level for the Fisher exact test for the comparison of a treated group with the control group is
 

given beneath the incidence of tumors in the treated group when P < 0.05; otherwise, not signifi­ cant (N.S.) is indicated. For both Cochran-Armitage and Fisher exact tests a negative designation (N) indicates a lower incidence in the treated group(s) than in the control group.
 

The 95% confidence interval on the relative risk of the treated group to the control group.
 
___ 

TABLE 19
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN FEMALE MICE TREATED WITH DDE3
 

TOPOGRAPHY: MORPHOLOGY
 

Hematopoietic System: Malignant Lymphoma
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Liver: Hepatocellular Carcinoma
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Circulatory System: Hemangioma or
 

Hemangiosarcoma°
 

P Values0
 

Relative Risk (Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

CONTROL
 

2/19(0.11)
 

N.S.
 

92
 

0/19(0.00)
 

P < 0.001
 

1/19(0.05)
 

N.S.
 

84
 

LOW
 

DOSE
 

4/48(0.08)
 

N.S.
 

0.792
 

0.127
 

8.329
 

66
 

19/47(0.40)
 

P < 0.001
 

Infinite
 

2.585
 

Infinite
 

87
 

2/43(0.04)
 

N.S.
 

0.792
 

0.045
 

45.751
 

87
 

HIGH
 

DOSE
 

2/49(0.04)
 

N.S.
 

0.388
 

0.031
 

5.109
 

34/48(0.71)
 

P < 0.001
 

Infinite
 

4.773
 

Infinite
 

61
 

0/49(0.00)
 

N.S.
 

0.000
 

0.000
 

7.244
 

68 
TABLE 19 (CONCLUDED)
 

created groups received time-weighted average doses of 148 or 261 ppm in feed.
 

Number of tumor-bearing animals/number of animals examined at site (proportion).
 

C

The probability level for the Cochran-Armitage test is given beneath the incidence of tumors
 

in the control group when P < 0.05; otherwise, not significant (N.S.) is indicated. The
 

probability level for the Fisher exact test for the comparison of a treated group with the
 

control group is given beneath the incidence of tumors in the treated group when P < 0.05;
 

otherwise, not significant (N.S.) is indicated. For both Cochran-Armitage and Fisher exact
 

tests a negative designation (N) indicates a lower incidence in the treated group(s) than
 

in the control group.
 

The 95% confidence interval on the relative risk of the treated group to the control group.
 
TABLE 20
 

TIME-ADJUSTED ANALYSES OF THE INCIDENCE OF HEPATOCELLULAR CARCINOMAS
 

IN MALE MICE TREATED WITH DDEa'e
 

LOW HIGH 

TOPOGRAPHY: MORPHOLOGY CONTROL DOSE DOSE 

Liver: Hepatocellular Carcinoma 0/8(0.00) 7/38(0.18) 17/36(0.47) 

P Values P = 0.002 N.S. P = 0.013 ___ 

Relative Risk (Control) Infinite Infinite 

Lower Limit 0.473 1.398 

Upper Limit Infinite Infinite 

Weeks to First Observed Tumor 71 71 

Treated groups received time-weighted average doses of 148 or 261 ppm in feed.
 

Number of tumor-bearing animals/number of animals examined at site (proportion).
 £
 

The probability level for the Cochran-Armitage test is given beneath the incidence of tumors
 

in the control group when P < 0.05; otherwise, not significant (N.S.) is indicated. The
 

probability level for the Fisher exact test for the comparison of a treated group with the
 

control group is given beneath the incidence of tumors in the treated group when P < 0.05;
 

otherwise, not significant (N.S.) is indicated. For both Cochran-Armitage and Fisher exact
 

tests a negative designation (N) indicates a lower incidence in the treated group(s) than
 

in the control group.
 

The 95% confidence interval on the relative risk of the treated group to the control group.
 

e

These analyses were based solely upon animals surviving at least 52 weeks, except for sites
 

where the first tumor of interest was observed earlier than 52 weeks, where the analyses were
 

based upon all animals that survived until or past the date that the first tumor was observed.
 
were observed in at least one of the control or DDE-dosed groups and
 

where such tumors were observed in at least 5 percent of the group.
 

In both male and female dosed mice significant numbers of
 

hepatocellular carcinomas were observed. For both sexes the Cochran-


Armitage test indicated a significant (P _<_ 0.001) positive association between dosage and incidence. For the males the Fisher exact
 

test comparing high dose to control was significant (P = 0.001); for
 

the females both the high dose and the low dose comparisons were
 

significant (P < 0.001). In the historical controls for untreated
 

B6C3F1 mice, 68/389 (18 percent) of the males and 8/411 (2 percent)
 

of the females had hepatocellular carcinomas or hepatocellular adenomas, compared to the 17/47 (36 percent) and 34/48 (71 percent)
 

observed in the high dose males and high dose females, respectively.
 

Because of the unexpectedly low survival in the male control mice
 

an additional, time-adjusted analysis of the incidence of hepatocellular carcinomas was performed (Table 20). This analysis considered
 

only those mice that survived on test for at least 52 weeks. Once
 

again both the Cochran-Armitage test (P = 0.002) and the Fisher exact
 

test comparing high dose to control (P = 0.013) were significant.
 

Based upon these results the statistical conclusion is that the
 

administration of DDE was associated with an increased incidence of
 

hepatocellular carcinomas in both male and female B6C3F1 mice.
 

106
 
V. DISCUSSION
 

Under the conditions of these bioassays there were statistically
 

significant associations between increased concentration and accelerated mortality in female mice dosed with DDT and in both sexes of
 

rats and female mice dosed with DDE. This association was not demonstrated in other groups. There was,however, poor survival among control and dosed male mice used in the bioassays of DDT and DDE. In all
 

cases adequate numbers of animals in all groups survived sufficiently
 

long to be at risk from late-developing tumors.
 

Hyperplasias and neoplasms of the thyroid were observed in rats
 

dosed with each of the three compounds; however, only for TDE did
 

the pathologists consider that the tumors were related to chemical
 

administration. The percentage of rats in each group having either
 

follicular-cell adenoma or follicular-cell carcinoma of the thyroid
 

is shown in the following table. The percentage of rats with
 

follicular-cell carcinoma is shown in parentheses.
 

Control 

MALES 

Low 

Dose 

High 

Dose Control 

FEMALES 

Low 

Dose 

High 

Dose 

DDT 

IDE 

DDE 

47(5) 

5(5) 

15(5) 

42(13) 

33(12) 

24(10) 

45(10) 

22(6) 

21(4) 

5(0) 

11(11) 

11(5) 

29(9) 

23(10) 

19(6) 

23(14) 

12(2) 

25(8) 

When those male rats receiving TDE and their controls were combined
 

within each group so that the numerators of the tumor incidences
 

represented those animals with either a follicular-cell carcinoma or
 

a follicular-cell adenoma of the thyroid the Fisher exact comparison
 

107
 
of the low dose to the control was significant. In historical control data compiled by the laboratory performing these bioassays for
 

the NCI Carcinogenesis Testing Program, 32/352 (9 percent) of the
 

untreated Osborne-Mendel male rats had either a follicular-cell adenoma or a follicular-cell carcinoma of the thyroid. However, because
 

of the high variation (5 to 47 percent) of these lesions in control
 

male rats in these studies, the findings must be considered only as
 

suggestive of a chemical-related effect.
 

Among dosed rats no other neoplasms occurred in statistically
 

significant incidences when compared to controls.
 

In mice the only neoplasms occurring in statistically significant
 

incidences were hepatocellular carcinomas among groups receiving DDE.
 

The incidences of hepatocellular carcinoma in DDE-dosed mice were 0/19,
 

7/41 (17 percent), and 17/47 (36 percent) in control, low dose, and
 

high dose males, respectively, and 0/19, 19/47 (40 percent), and 34/48
 

(71 percent) in control, low dose, and high dose females, respectively. The Cochran-Armitage tests indicated a significant positive association between dosage and incidence in both sexes. Both
 

Fisher exact comparisons for the females supported the finding as
 

did the high dose to control Fisher exact comparison for the males.
 

Although administration of DDE did not result in significant incidences of liver tumors in rats, the compound was indicated to be
 

hepatotoxic, inducing centrilobular necrosis and fatty metamorphosis.
 

Long-term ingestion of p,p'-DDT or technical-grade DDT has been
 

found to induce liver tumors in several strains of mice (IARC, 1974).
 

108
 
Administration of technical-grade DDT in the diet at a concentration
 

of 2 ppm resulted in a significant increase in the incidence of tumors
 

observed in male CF-1 mice surviving for more than 60 weeks (Tomatis
 

et al. , 1972); a concentration of 250 ppm was, however, necessary to
 

induce a significant number of tumors in BALB/c mice. At this concentration 59 percent of the females and 48 percent of the males
 

developed liver tumors as compared to none of the female controls and
 

2 percent of the male controls (Terracini et al. , 1973). Dietary administration of p,p'-DDT at a concentration of 100 ppm for 110 weeks
 

induced liver tumors in 79 percent of male and 96 percent of female
 

CF-1 mice. Tumors were observed in 24 percent of the male and 23
 

percent of the female controls, respectively. The ratio of benign
 

tumors to those possessing characteristics associated with malignancy
 

was 1:1 in the dosed mice (Thorpe and Walker, 1973).
 

Other tumors reported in the literature to have occurred at
 

elevated frequencies in various strains of dosed mice included
 

maligant lymphorna (innes et al., 1969); lymphoma, carcinoma of the
 

lung, and leukemia (Tarjan and Kemeny, 1969); and adenoma of the lung
 

(Shabad et al., 1973).
 

Ingestion of technical-grade DDT at a concentration of 500 ppm
 

produced liver cell tumors in 56 percent of surviving female outbred
 

Wistar rats and in 35 percent of surviving males. These tumors were
 

not, however, classified by the authors as hepatocellular carcinomas.
 

No liver cell tumors were observed in controls and no other compound-


related tumors were detected (Rossi et al., 1977).
 

109
 
DDT by the oral route did not produce tumors in Syrian golden
 

hamsters in excess of those observed in controls, and feeding studies
 

in dogs, monkeys and rainbow trout were considered inconclusive by
 

the IARC Working Group (lARC, 1974).
 

Tumor induction has been observed in CF-1 mice following dietary
 

administration of either p,p'-TDE or p,p'-DDE at a concentration of
 

250 ppm for their lifespan (Tomatis et al., 1974). TDE produced an
 

elevated incidence of hepatomas in males (52 percent versus 34 percent in controls) and lung tumors in males and females (86 percent
 

in males versus 54 percent in controls; 73 percent in females versus
 

41 percent in controls). DDE produced an elevated incidence of
 

hepatomas in both sexes (74 percent in males versus 34 percent in
 

controls; 98 percent in females versus 1 percent in controls).
 

The concentration of DDT to male mice may have been set too low
 

because of undue emphasis on a single death during the subchronic
 

test. During the chronic bioassay, no growth retardation or other
 

adverse clinical signs appeared to be associated with administration
 

of DDT to male mice. Survival of DDT-dosed male mice was better
 

than that of controls. No tumors were induced by DDT in male mice
 

although tumor induction by DDT in male mice has been reported in
 

the literature.
 

Under the conditions of these bioassays there was no evidence
 

for the carcinogenicity of DDT in Osborne-Mendel rats or B6C3F1 mice,
 

of TDE in female Osborne-Mendel rats or B6C3F1 mice of either sex, or
 

110
 
of p,p'-DDE in Osborne-Mende1 rats, although p,p'-DDE was hepatotoxic
 

in Osborne-Mende1 rats. The findings suggest a possible carcinogenic
 

effect of TDE in male Osborne-Mende1 rats, based on the induction of
 

combined follicular-cell carcinomas and follicular-cell adenomas of
 

the thyroid. Because of the variation of these tumors in control male
 

rats in this study, the evidence does not permit a more conclusive
 

interpretation of these lesions. p,p'-DDE was carcinogenic in B6C3F1
 

mice, causing hepatocellular carcinomas in both sexes.
 

Ill
 
VI. BIBLIOGRAPHY
 

Andrilenas, P.A., Farmers' Use of Pesticides in 1971—Quantities.
 

Agricultural Economic Report No. 252. Economic Research Service,
 

U.S. Department of Agriculture, 1974.
 

Antommariaj P., M. Corn, and L. DeMaio, "Airborne Particulates in
 

Pittsburgh: Association with p,p'-DDT." Science 150:1476, 1965
 

as cited in IARC, 1974.
 

Armitage, P., Statistical Methods in Medical Research, Chapter 14.
 

J. Wiley & Sons, New York, 1971.
 

Berenblum, I., editor, Carcinogenicity Testing. International Union
 

Against Cancer, Technical Report Series, Vol. 2. International
 

Union Against Cancer, Geneva, 1969.
 

Brooks, G.T., Chlorinated Insecticides: Vol. I. Technology and
 

Application. CRC Press, Inc., Cleveland, Ohio, 1974.
 

Buselmaier, W., G. Roehrborn, and P. Propping, "Comparative Investigations of the Mutagenicity of Pesticides in Mammalian Test
 

Systems." Mutation Research 21:25-26. 1973.
 

Chemical Abstracts Service. The Chemical Abstracts Service (CAS)
 

Ninth Collective Index, Volumes 76-85, 1972-1976. American
 

Chemical Society, Washington, B.C., 1977.
 

Corneliussen, P.E., "Pesticide Residues in Total Diet Samples (VI)."
 

Pesticides Monitoring Journal 5:313, 1972 as cited in IARC,
 

1974.
 

Cox, D.R., Analysis of Binary Data, Chapters 4 and 5. Methuen and
 

Co., Ltd., London, 1970.
 

Cox, D.R., "Regression Models and Life-Tables." Journal of the Royal
 

Statistical Society, Series "B" 34:187-220, 1972.
 

Curley, A., and R.D. Kimbrough, "Chlorinated Hydrocarbon Insecticides
 

in Plasma and Milk of Pregnant and Lactating Women." Archives
 

of Environmental Health 18:156, 1969 as cited in IARC, 1974.
 

Curley, A., M.F. Copeland, and R.D. Kimbrough, "Chlorinated Hydrocarbon Insecticides in Organs of Stillborn and Blood of Newborn Babies." Archives of Environmental Health 19:628, 1969
 

as cited in IARC, 1974.
 

112
 
Dahlsten, D.L., R. Garcia, J.E. Laing, and R. van den Bosch, Pesticides. Scientists' Institute for Public Information, New York,
 

New York, 1970.
 

Dale, W.E., M.F. Copeland, and W.J. Hayes, Jr., "Chlorinated Insecticides in the Body Fat of People in India." Bulletin of the
 

World Health Organization 33:471, 1965.
 

Duggan, R.E., and P.E. Corneliussen, "Dietary Intake of Pesticide
 

Chemicals in the United States (ill)." Pesticides Monitoring
 

Journal 5:331, June 1968-April 1970 as cited in IARC, 1974.
 

Duggan, R.E., H.C. Barry, and L.Y. Johnson, "Pesticide Residues
 

in Total Diet Samples (II)." Pesticides Monitoring Journal
 

J_(ii):2, 1967 as cited in IARC, 1974.
 

Farm Chemicals Handbook. Meister Publishing Company, Willoughby,
 

Ohio, 1976.
 

Fiserova-Bergerova, V., J.L. Radomski, J.E. Davies, and J.H. Davis,
 

"Levels of Chlorinated Hydrocarbon Pesticides in Human Tissues."
 

Industrial Medicine and Surgery 36:65, 1967 as cited in IARC,
 

1974.
 

Fowler, D.L. , and J.N. Mahan, The Pesticide Review, 1975. Agricultural Stabilization and Conservation Service, U.S. Department
 

of Agriculture, 1976.
 

Frost & Sullivan, Inc., Pesticide Industry Economic Forecast. New
 

York, New York, 1977.
 

Gart, J.J., "The Comparison of Proportions: A Review of Significance
 

Tests, Confidence Limits, and Adjustments for Stratification."
 

International Statistical Institute Review 39:148-169, 1971.
 

Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason, Clinical
 

Toxicology of Commercial Products, Acute Poisoning, 4th edition.
 

The Williams and Wilkins Company, Baltimore, Maryland, 1976.
 

Hayes, W.J., Jr., "Pharmacology and Toxicology of DDT." DDT: The
 

Insecticide Dichlorodiphenyltrichloroethane and Its Significance, P. Muller, editor. Volume 2. Basel, Birkhauser Verlog,
 

p. 2, 1959 as cited in IARC, 1974.
 

Hayes, W.J., Jr., W.E. Dale, and C.I. Pirkle, "Evidence of Safety
 

of Long-term, High, Oral Doses of DDT for Man." Archives of
 

Environmental Health 22:119, 1971 as cited in IARC, 1974.
 

113
 
Innes, J.R.M., B.M. Ulland, M.G. Valerio, L. Petrucelli, L. Fishbein,
 E.R. Hart, A.J. Pallatta, R.R* Bates, H.L. Falk, J.J. Gart,
 M. Klein, I. Mitchell, and J. Peters, "Bioassay of Pesticides
 

and Industrial Chemicals for Tumorigenicity in Mice. A Prelim­ inary Note." Journal of the National Cancer Institute 42:1101,
 1969 as cited in IARC, 1974.
 

International Agency for Research on Cancer (IARC), IARC Monographs
 

on the Evaluation of Carcinogenic Risk of Chemicals to Man.
 Volume 5, Some Organochlorine Pesticides. World Health Organi­ zation, IARC, Lyon, France, 1974.
 

Kaplan, E.L., and P. Meier, "Nonparametric Estimation from Incomplete
 

Observations." Journal of the American Statistical Association
 

13:457-481, 1958.
 

Kazen, C., A. Bloomer, R. Welch, A. Oudbier, and H. Price, "Persis­ tence of Pesticides on the Hands of Some Occupationally Exposed
 

People." Archives of Environmental Health 29:315-318, 1974.
 

Laws, E.R., Jr., A. Curley, and F.J. Biros, "Men with Intensive Occu­ pational Exposure to DDT. A Clinical and Chemical Study."
 

Archives of Environmental Health 15:766, 1967 as cited in IARC,
 1974.
 

Linhart, M.S., J.A. Cooper, R.L. Martin, N.P. Page, and J.A. Peters,
 "Carcinogenesis Bioassay Data System." Computers and Biomedical
 

Research 7:230-248, 1974.
 

Marshall, T.C., H.W. Dorough, and H.E. Swim, "Screening of Pesticides
 

for Mutagenic Potential Using Salmonella typhimurium Mutants."
 

Journal of Agricultural and Food Chemistry 24:560-563, 1976.
 

Miller, R.G., Simultaneous Statistical Inference. McGraw-Hill Book
 

Co., New York, 1966.
 

Morgan, D.P., and C.C. Roan, "Chlorinated Hydrocarbon Pesticide
 

Residues in Human Tissues." Archives of Environmental Health
 

^0_:452^ 1970 as cited in IARC, 1974.
 t
 

O'Leary, J.A., J.E. Davies, W.F. Edmundspn, and G.A. Reich, "Trans­ placental Passage of Pesticides." American Journal of Obstetrics
 

and Gynecology 107:65, 1970 as cited in IARC, 1974.
 

Quinby, G.E., J.F. Armstrong, and W.F. Durham, "DDT in Humans' Milk."
 

Nature 207:726, 1965 as cited in IARC, 1974.
 

114
 
Radomski, J.L., W.B. Deichmann, and E.E. Glider, "Pesticide Concentrations in the Liver, Brain and Adipose Tissue of Terminal
 

Hospital Patients." Food and Cosmetics Toxicology 6:209, 1968
 

as cited in IARC, 1974.
 

Reuber, M.D., and E.L. Glover, "Cirrhosis and Carcinoma of the Liver
 

in Male Rats Given Subcutaneous Carbon Tetrachloride." Journal
 

of the National Cancer Institute 44:419-423, 1970.
 

Rossi, L. , M. Ravera, F. Repetti, and L. Santi, "Long-term Administration of DDT or Phenobarbital-Na in Wistar Rats." International Journal of Cancer 19; 179-185, 1977.
 

Saffiotti, U., R. Montesano, A.R. Sellakumar, F. Cefis, and D.G.
 

Kaufman, "Respiratory Tract Carcinogenesis in Hamsters Induced
 

by Different Numbers of Administration of Benzo (a) Pyrene and
 

Ferric Oxide." Cancer Research 32:1073-1079, 1972.
 

Sax, N.I., Dangerous Properties of Industrial Materials, 4th edition.
 

Van Nostrand Reinhold Company, New York, 1975.
 

Shabad, L.M., T.S. Kolesnichenko, and T.V. Nikonova, "Transplacental
 

and Combined Long-term Effect of DDT in Five Generations of
 

A-Strain Mice." International Journal of Cancer 11:688, 1973 as
 

cited in IARC, 1974.
 

Tabor, E.G., "Contamination of Urban Air Through the Use of Insecticides." Annals of the New York Academy of Sciences 28:569, 1966
 

as cited in IARC, 1974.
 

Tarjan, R., and T. Kemeny, "Multi-generation Studies on DDT in
 

Mice." Food and Cosmetics Toxicology 7:215, 1969 as cited in
 

IARC, 1974.
 

Tarone, R.E., "Tests for Trend in Life-Table Analysis." Biometrika
 

6^:679-682, 1975.
 

Terracini, B., R.J. Cabral, and M.C. Testa, "A Multi-generation
 

Study on the Effects of Continuous Administration of DDT to
 

BALB/C Mice." In: Proceedings of the 8th Inter-American
 

Conference on Toxicology: Pesticides and the Environment,.A
 

Continuing Controversy. Miami, Florida, 1973, W.B. Deichmann,
 

editor. Intercontinental Medical Book Corporation, New York,
 

p. 77, 1973 as cited in IARC, 1974.
 

115
 
Thorpe, E., and A.I.T. Walker, "The Toxicology of Dieldrin (HEOO):
 

II. Comparative Long-term Oral Toxicology Studies in Mice with
 

Dieldrin, DDT, Phenobarbitone, (3-BHC and Y-BHC. Food and
 

Cosmetics Toxicology 11:433. 1973 as cited in IARC, 1974.
 

Tomatis, L., V. Turusov, R.T. Charles, and M. Boiocchi, "The Effect
 

of Long-term Exposure to 1,l-dichloro-2,2-bis(p-chlorophenyl)
 

ethylene (p,p'-DDE), to 1,l-dichloro-2,2-bis(p-chlorophenyl)
 

ethane (p,p'-DDD) and to the Two Chemicals Combined, on CF1
 

Mice." Journal of the National Cancer Institute 52:(in press),
 

1974 as cited in IARC, 1974.
 

Tomatis, L., V. Turusov, N. Day, and R.T. Charles, "The Effect of
 

Long-term Exposure to DDT on CF1 Mice." International Journal
 

of Cancer 10:489, 1972 as cited in IARC, 1974.
 

U.S.	 Department of Health, Education, and Welfare, Report of the
 

Secretary's Commission on Pesticides and their Relationship
 

to Environmental Health. U.S. Government Printing Office,
 

Washington, D.C., 1969.
 

Vogel, E., "Mutagenicity of DDT and the DDT Metabolites DDE, ODD,
 

DOOM, and DDA in Drosophila melanogaster." Mutation Research
 

_16_:157-164, 1972.
 

Wassermann, M., D.P. Nogueira, L. Tomatis, A.P. Mirra, H. Shibata,
 

G. Arie, S. Cucos, and D. Wassermann, "Organochlorine Compounds
 

in Neoplastic and Adjacent Apparently Normal Breast Tissue."
 

Bulletin of Environmental Contamination and Toxicology 15:
 

478-484, 1976.
 

Wolfe, H.R., and J.F. Armstrong, "Exposure of Formulating Plant
 

Workers to DDT." Archives of Environmental Health 23:169, 1971
 

as cited in IARC, 1974.
 

Wolfe, H.R., W.F. Durham, and J.F. Armstrong, "Exposure of Workers
 

to Pesticides." Archives of Environmental Health 14:622, 1967
 

as cited in IARC, 1974.
 

Wolfe, H.R., K.C. Walker, J.W. Elliott, and W.F. Durham, "Evaluation
 

of the Health Hazards Involved in House-Spraying with DDT."
 

Bulletin of the World Health Organization 20:1, 1959 as cited in
 

IARC, 1974.
 

Woodwell, G.M., P.P. Craig, and H.A. Johnson, "DDT in the Biosphere:
 

Where Does It Go?" Science 174:1101, 1971 as cited in IARC,
 

1974.
 

116
 
Yoder, J., M. Watson, and V.V. Benson, "Lymphocyte Chromosome Analysis
 

of Agricultural Workers During Extensive Occupational Exposure to
 

Pesticides." Mutation Research 21:335-340, 1973.
 

Zavon, M.R., R. Tye, and L. Latorre, "Chlorinated Hydrocarbon Insecticide Content of the Neonate." Annals of the New York Academy of
 

Sciences 160:196, 1969 as cited in IARC, 1974.
 

117
 

APPENDIX A
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS
 

IN RATS TREATED WITH DDT
 

TABLE Al

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE RATS TREATED WITHBDT 

1CONTBOL(VEH) 

01-H018 

LOR DOSE 

01-S019 

ANIflALS INITIALLY IN STODY 

ANIMALS NECHOFSIED 

ANIMALS EXAMINED HISTOPATHOLOGICALLY ** 

20 

20 

19 

50 

50 

46 

INTEGUMENTARY SISTER
 

*SUBCDT TISSUI (20) (50)
 PAPILLOHA, NOS 1 (2%)
 

SQUAHOOS CELL CARCINOMA
 

FIBBOHA 3 (6%)
 FIBROSARCOHA 1 <2»)
 LI POMA 1 (2«)
 HBMANGIOSARCOMA 1 (5«)
 

RESPIBATORT SISTER
 

tLONS (19) (21)
 ADENOCARCINORA. NOS, METASTATIC 1 (5»)
 

HEMATOPOIETIC SYSTEM
 

NONE
 

CIRCDLATOBI SYSTEM
 

NONJi
 

DIGESTIVE SYSTEM
 

tSALIYABY GLAND (D
 SQUAHOUS CELL CABCINOHA
 

tLIVER (19) («»)
 PIBBOSA8COHA. HETASTATIC
 

tteoas 1..JI2S1
 

t NDHB.EH OF ANIMALS WITH TISSUE EX1HIIED HICROSCOPICALLY 

* NUMBER OF ASIHALS NECROPSIED 

** EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

HIGH DOSE
 

01-M020
 

50
 

50
 

19
 

(50)
 

1 (2*)
 

3 (6%)
 

1 (2%)
 

1 <2X)
 

(23)
 

(1)
 

1 (100X)
 

(HI)
 

1 (2X)
 

A-3 
TABLE Al (CONTINUED)

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE RATS TREATED WITH DDT 

CONTROL (VEH) LOU DOSE
 01-N018 01-M019
 

URINARY SYSTEI"
 

IKIDNEY (19) (28)
 LIPOSABCCMA 1 (1«)
 

ENDOCBIHE SYSTEM
 

IPITOITARY (19) (22)
 CHRONOPHOBE ADENOMA 3 (16X) 1 (18*)
 

*ADBENAL (19) (23)
 PHEOCHBOMCCYTOMA 1 (M)
 

ITHYBOID (19) (15)
 

FOL1ICULAB-CELL ADENOMA 8 (i*2X) 1« (31X)
 

FdLLICULAH-CELL CARCINOMA 1 (5X) 6 (13%)
 C-CELL ADENOMA 1 (5X) a (9*)
 C-CELL CARCINOMA 1 (2X)
 

tPANCREATIC ISLETS (18) (21)
 ISLET-CELt ADENOMA 1 (5X)
 

BEPRODOCTIVE SYSTEM
 

*NARMARY GLANE (20) (50)
 ADENOCABCINOMA, NOS 1 (S%)
 PIBBOADENOMA 1 (2«)
 

•EPIDIDYMIS	 (20) (50)
 LIPOMA
 

NHRVOUS SYSTEM
 

* BRAIN (19) (21)
 GLIOSA, NOS 2 (10X)
 

SPECIAL SENSE ORGANS
 

KULS _- _ _ - _ .
 

t HUMBER OP ANIMAL S WITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBER OF ANIMAL S NEC BOPSIED 

HIGH DOSE
 01-M020
 

(26)
 

(21)


3 (1UX)
 

(21)
 

<H9)


17 (35X)
 

5 (10X)
 

2 (UX)
 

1 (2X)
 

(22)
 

(50)
 

(50)
 

1 (2X)
 

(21)
 

A-4 
TABLE Al (CONTINUED) 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE RATS TREATED WITH DDT 

—•"""*~———•—• — — ————•————•———


HOSCULOSKELETAL SYSTEM
 

•MUSCLE OF BACK
 

FIBROSARCCMA
 

BODT CAVITIES
 

*ABDOHINAL CAVITY
 

LIPOHA
 

*TUNICA VAGINALIS
 

MKSOTHELIOHA, MOS
 

ALL OTHER SYSTEMS
 

THOBACIC CAVITY
 

FIBROSABCOMA
 

JNIMAL DISPOSI1IOS SDHHAEY
 

— — —————
 

ANIUALS INITIALLY IN STUDY
 

NATURAL DEATHS
 

HOBIBUND SACRIFICE
 

SCHEDULED SACRIFICE
 

ACCIDENTALLY KILLED
 

TERMINAL SACRIFICE
 

ANIMAL MISSING
 

9 HLCJ.iiP.E5 AMc.iIZEe_MIfl&i.S_
 

CONTROL (VEH)
 

01-M018
 

(20)
 

(2C)
 

(20)
 

20
 

11
 

9
 

LOR DOSE
 01-S019
 

(50)
 

(50)
 

(50)
 

50
 

24
 

3
 

23
 

HIGH DOSE
 

01-M020
 

(50)
 

1 (2%)
 

(50)
 

1 <2X)
 

(50)
 

2 («%)
 

1
 

50
 

22
 

28
 

I NUMBER OF ANIMALS KITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

A-5
 
TABLE A1 (CONCLUDED) 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE RATS TREATED WITH DDT 

_-_ TM^—~ TTH-ini — L —«.—— ~'"""~~
 

CONTROL (VEH) LOH DOSE HIGH DOSE
 01-M018 01-H019 01-8020
 

TUHOR SUMMARY
 

TOTAL ANIHALS HITH PBIHABY TDHOBS* 10 29 32
 TOTAL PBIRABY TONOBS 15 U2 V1
 

TOTAL AMIHALS WITH BENIGN TOHORS 9 21 24
 TOTAL BENIGN TOHORS 12 31 28
 

TOTAL ANIRALS HITH HALIGNANT TUBORS 3 10 10
 TOTAL HALIGNANT TOHORS 3 11 11
 

TOTAL ANIHALS HITH SECONDARY TUMORS* 1 1
 

TOTAL SGCCIDABT TOHORS 1 1
 

TOTAL ANIHALS HITH TUI1OBS UNCEETAINBENIGN OB RALIGNANT 2
 TOTAL UNCERTAIN TDHORS 2
 

TOTAL ANIHALS HITH TUMORS ONCEBTAINPRIAABY OB HETASTATIC
 TOTAL UNCERTAIN TUBORS
 

* PRIHABY TDHORS: ALL TUMORS EXCEPT SE CONDARY TDMORS
 

* SECONDARY TUMORS: HETASTATIC TDHORS OB TDHORS INVA SIVE INTO AN ADJACENT ORGAN
 

A-6
 
TABLE A2

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS TREATED WITH DDT 

ANIMALS INITIAILY IN STODY
 

ANIMALS NECROPSIED
 

ANIMALS EXAMINEE HISTOPATHOLOGICALLY


INTEGUHENTiRY SYSTEM
 

»SUBCUT TISSUE
 

FIBBOMA
 

FIBROS&HCCHA
 

LIPOHA
 

RESPIRATORY SYSTEM
 

»LUNG
 

CARCINOMA, NOS, METASTATIC
 

HEMATOPOIETIC SYSTEM
 

tSPLfiEN
 

CARCINOMA. NOS, HETASTATIC
 

CI8CULATOBY SYSTEH
 

NONE
 

DIGESTIVE SYSTHM
 

«LIV£H
 

CABCINOBA, NOS, METASTATIC
 

*BILE DUCT
 

BILE DUC1 CARCINOMA
 

*P»NCHEAS
 

_ C4RCINQNAXJ!OS _ __
 

CONTROL (VEH)
 

01-F018
 

20
 

20
 

 ** 19 

(20)
 

(19)
 

(19)
 

(19)
 

(20)
 

(19)
 

LOW DOSE HIGH DOSE
 01-F021 01-F022
 

50 50
 

50 50
 «6 41
 

(50)	 (50)
 

6 (12X)
 

1 (2«) 1 (2X)
 

1 (2X)
 

(37)	 (29)
 

1 (3X)
 

(37)	 (23)
 

1 (IX)
 

C*2) (38)
 

1 (3X)
 

(50)	 (50)
 

1 (2X)
 

(38)	 (21)
 

J_I«Si
 

t NUMBER OF ANIMAL S HITH TISSUE EXAMINE D MICROSCOPICALL Y 

* NUMBER OF ANIMALS NECROPSIED 

** EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

A-7 
TABLE A2 (CONTINUED) 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS TREATED WITH DDT 

" CONTROL (VEH) LOW DOSE HIGH DOSE 

01-F018 01-F021 01-F022 

FIBROSABCCMA, NETASTATIC 1 (3%) 

tSTOSACH 

CARCINOMA, NOS, HETASTATIC (19) (38) (29) 

1 (3X) 

DBIHABY SYSTEM 

•KIDNEY (19) (38) (25) LIPOHA 2 <5X) LIPOSARCCNA 1 (tX) 

•URETER (20) (50) (50) CARCINOMA, NOS, METASTATIC 1 (2X) 

IHDOCBINE SISTIM 

*PITUITARY (19) (39) (27) 

CHROMOPHOBE ADENOMA 11 (68%) 16 (UU) 13 (H6%) 

•ADRENAL (19) (38) (2<l) COETICAL ADENOMA 

PHEOCHBOMCCYTOHA 

1 (3X> 3 (13X) 

tTHYBOID 

FOLLICOLAR-CELL ADENOMA 

POLLICULAR-CELI. CABCINOHA 

C-CELL ADENOMA 

(19) 

1 <5X> 

3 (16X) 

(15) 

10 (22%) 

U (9X) 

2 (UX) 

(13)

5 (12X) 

6 (14X) 

C-CELL CARCINOMA 1 (5X) 1 (2X) 

IPANCHEATIC ISLETS (19) (38) (2U) ISLET-CELL ADENOMA 1 (5X) 

8EPBODOCTIVE SYSTBM 

*HAHHABY GLAND (20) (50) (50) ADENOMA, NOS 

ADENOCARCINOMA, NOS 

FIBROADENCMA 8 (HO*) 

1 (2X) 

1 (2X) 

11 (22X) 

1 UX) 

6 (12X) 

•VAGINA 

FIBROSABCCMA 

(20) (50) 

1 <2X) 

(50)

i l (2X) 

•UTEfiUS 

_JSB2BBT£IA1 Slfi2Bli_£2I,IE _. (19) -­

(13) 

_ 2 J5Sl_ 

(31) . ­1

* J11J1-

* NUHBEB OF ANIMALS WITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBER OF ANIMAL S NECROPSIED 

A-8 
TABLE A2 (CONTINUED)

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS TREATED WITH DDT 

CONTROL (VEH) LOR DOSE HIGH DOSE
 01-F018 01-F021 01-F022
 

tOVAHY (19) (37) (2U)
 

CYSTiDENOMA, NOS 1 <5X) 1 (»«)
 GRANULOSA-CELl TUMOR 2 (5X)
 

NERVOUS SYSTEM
 

NONE
 

SPECIAL SENSE ORGANS
 

NONE
 

MUSCULOSKELETAL SYSTEM
 

*RIB (20) (50) (50)
 CdONDROMA 1 (2X)
 

BODY CAVITIES
 

•ABDOMINAL	 VISCERA (20) (50) (50)
 PIBROSABCCMA 1 (2X)
 

ALL OTHER SYSTEMS
 

OMENTDM
 

CARCINOMA, NOS, HETASTATIC 1
 

ANIMAL DISPOSITION SUNHABY
 

ANIMALS INITIALLY IN STODY 20 50 50
 NATURAL DEATHS it 9 12
 MORIBUND SACRIFICE 1 2 it
 

SCHEDULED SACRIFICE
 

ACCIDENTALLY KILLED
 

TERMINAL SACRIFICE 15 39 3t
 ANIMAL MISSING
 

2_i!!£ijiDES_4J!3ei.iZEa ifilfiilS
 

I NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

A-9
 
TABLE A2 (CONCLUDED)
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS TREATED WITH DDT
 

CONTBOL(VEH) LOB DOSE
 

01-F018 .•>« P021
 

TONOB SOIIHART
 

TOTAL AMIHALS 8ITH PBIHABT TUMORS* 16 38
 

TOTAL PRIMARY TOMOBS 28 63
 

TOTAL ANIMALS KITH BENIGN THROBS 16 35
 TOTAL BENIGN TUMORS 27 52
 

TOTAL ANIMALS KITH MALIGNANT TO MOBS 1 8
 TOTAL MALIGNANT TUMORS 1 9
 

TOTAL ANIMALS WITH SECONDARY TUMORS* 1
 

TOTAL SECONDARY TUMORS 1
 

TOTAL ANIMALS WITH TUMORS UNCERTAINBENIGN OR MALIGNANT 2
 

TOTAL UNCERTAIN TUHOBS 2
 

TOTAL ANIMALS KITH TUROBS UNCERTAINPRIMARY OR HETASTATIC
 

TOTAL UNCERTAIN TUMOBS
 

* PRIMARY TUMORS: ALL TUMORS EXCEPT SE CONDARY TUMORS
 

t SECONDARY TUMORS: NETASTATIC TUMORS OB TUMORS INVAi 3IVE INTO AN
 

A-IO
 

HIGH DOSE
 01-F022
 

27
 

U5
 

22
 

33
 

9
 

12
 

1
 

6
 

ADJACENT ORGAN
 
APPENDIX B
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS
 

IN MICE TREATED WITH DDT
 

TABLE Bl

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE MICE TREATED WITH DDT 

CONTROL (VEH) LOU DOSE HIGH DOSE
 

02-MO<42 02-BOU3 02-R044
 

ANIMALS INITIAILY IN STUDY 20 50 50
 ANIMALS NECSOPSIED	 19 49 50
 ANIMALS EXAMINED HISTOPATHOLOGICALLY** 19 49 50
 

INTEGUMENTARY SYSTEM
 

*SKIN (19) (49) (50)
 

FIBROMA 1 <5X) 1 (2%) 1 (2X)
 FIBBOSAECOI1A 1 (2*)
 

RESPIRATORY SYSTEM
 

ILUNG (19) (19) (48)
 

ALVEOLAR/BRONCHIOLAR ADENOMA 1 (5*) 1 (2*)
 

HEMATOPOIETIC SYSTEM
 

*MOLTIPLE ORGANS (19) (49) (50)
 HALIG.LYNPHOBA, LYMPHOCYTIC TYPE 1 (2%)
 MALIG.LYMPHOMA, HISTIOCYTIC TYPE 1 (2*)
 

•KIDNEY	 (19) (49) (48)
 

HALIG.LYHPHOMA, LYMPHOCYTIC TYPE 1 (2%)
 

CIRCULATORY SYSTEM
 

NONE
 

EIGESIIVE SYSTIH
 

OLIVER (19) (49) (48)
 

HEPATOCELLULAR CARCINOMA 2 (11X) 1 (2%) 1 (2«)
 

URINARY SYSTEM
 

fiOfifi _
 

« NUMBER OF ANIMAL S WIT H TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

** EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

B-3 
TABLE Bl (CONTINUED) 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE MICE TREATED WITH DDT 

" "
 CONTROL (VEH) 

02-M01I2 

LOS DOSE 

02-B003 

HIGH DOSE 

02-MOUt 

ENDOCRINE SYSTEM 

ITHY80ID 

FOLLICULAR-CELL ADENOMA 

(17) (U1) («5) 

1 (2X) 

REPRODUCTIVE SYSTEM 

NONE 

NERVOUS SYSTEM 

•BRAIN 

EPENDYMCMA 

(19) (U9) (US) 

1 (2») 

SPECIAL SENSE ORGANS 

NONE 

BUSCULOSKELETAL SYSTEM 

NONE 

BODY CAVITIES 

NONE 

AIL OTHER SYSTEMS 

NONE 

ANIHAL DISPOSITION SUMMARY 

ANIMALS INITIALLY IN STUDY 

NATURAL DEATHS 

MORIBUND SACRIFICE 

SCHEDULED SACRIFICE 

ACCIDENTALLY KILLED 

TERHINAL SACBIFICE 

ANIMAL MISSING 

20 

1<l 

6 

50 

as 

2 

3 

50 

12 

8 

9 INCLUDES AUTCLIZED ANIMALS 

* NUMBER OF ANIMALS WITH TISSUE EXAMINE D

* NUBBEB OF ANIMAL S NECROPSIED 

 MICROSCOPICALLY 

B-4 
TABLE Bl (CONCLUDED)
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE MICE TREATED WITH DDT
 

CONTROL (VEH) LOR DOSE HIGH DOSE
 

02-H042 02-H043 02-H044
 

TUDOR SUMMARY
 

TOTAL ANIMALS HITH PRIMARY TOHOBS» 4 6 4
 TOTAL PBIMABY TUMORS 4 6 5
 

TOTAL ANIMALS HITH BENIGN TUMORS 2 2 2
 TOTAL BENIGN TUMORS 2 2 2
 

TOTAL ANIMALS KITH MALIGNANT TUMORS 2 4 3
 TOTAL MALIGNANT TUMORS 2 4 3
 

TOTAL ANIMALS HITH SECONDARY TUMORS*
 

TOTAL SECONDARY TUMORS
 

TOTAL ANIMALS HITH TUMORS UNCERTAINBENIGN OB MAIIGNANT
 

TOTAL UNCERTAIN TUMORS
 

TOTAL ANIMALS HITH TUMORS UNCERTAIN­ PRIMARY OR METASTATIC
 

TOTAL UNCERTAIN TUMORS
 

* PRIMARY TUHOBS: kit TUMORS EXCEPT SECONDARY TUMORS
 * SECONDARY TUMORS: NETASTATIC TUMORS OR TUMORS INVASIVE INTO ill ADJACENT ORGAN
 

B-5
 
TABLE B2

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE MICE TREATED WITH DDT 

1

CONTROL (VEH) LOW DOSE 

02-FOM2 02-F045 

ANIMALS INITIALLY IN STUDY 20 50 

ANIMAL S HISSING ANIMALS NECHOPSIED 20 19 

ANIMALS EXAMINE D HISTOPATHOLOGICALLY ** 20 22 

INTEGUMENTARY SYSTEM 

NONE 

SESPIBATOHY SYSTEM 

*LUNG (20) (21) 

ALVEOLAH/ESONCHIOLA R ADENOM A 1 (5*) 

HEMATOPOIETIC SYSTEM 

*MULTIPLE ORGAN S (20) («9) 

MALIG.LYMPHOMA, HISTIOCYTIC TYPE 2 (U*) 

*SPLEEN (20) (22) 

MALIG.LYflPHOMA , LYMPHOCYTIC TYPE 

*MESENTERIC L. NODE (20) (20) MALIG.LYMPHOMA , HISTIOCYTIC TYPE 1 (5%) 

CIRCULATORY SYSTEM 

NONE 

DIGESTIVE SYSTIN 

*LIVER (20) (22) HEPATOCELLULA R CARCINOM A 1 (5%) HEMANGIOSARCOMA 1 (5«) 

URINAR Y SYSTEM 

NOB£ 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMAL S NECROPSIED 

** EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

HIGH DOSE 

02-F046 

50 

1 

146 

27 

(27) 

<«6) 

5 (11*) 

(26) 

1 (i»X) 

(21)

1 (US) 

(27) 

3 (11*) 

B-6 
TABLE B2 (CONTINUED) 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE MICE TREATED WITH DDT 

HIG H DOSE 

02-F046 

(25) 

(27) 

1 (4X ) 

1 (KX ) 

(46) 

<27) 

FNDOCBINE SYSTE M 

tPITUITARY 

CHHOMOPHOBE ADENOH i 

ITHYBOID 

FOLLICULAR-CEL L ADENOM A 

FOLLICB1AE-CELL CARCINOM A 

C-CELL iDENOM A 

REPRODUCTIV E SYSTE M 

*MAMMAR Y GLAN D 

ADENOCARCINCMA , NOS 

HOVAiiY 

CYSTADENCHA , NOS 

NERVOU S SYSTEM 

NONE 

SPECIAL SENS E ORGAN S 

NON E 

MUSCULOSKELETA L SYSTEM 

NONE 

BODY CAVITIES 

NON£ 

A LL OTHER SYSTEMS 

NONE 

CONTROL (VEH ) 

02-FOU2 

(19) 

1 <5X ) 

(20) 

(20) 

1 <5X ) 

(20) 

1 (518) 

LOU DOSE 

02-FOU5 

(15) 

1 (7S) 

(22) 

1 (5*) 

(H9 > 

(21) 

» NOS3ER OF ANIHULS WITH TISSUE EXAHINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS HECROPSIED
 

B-7 
TABLE B2 (CONCLUDED)
 

SUMMARY OF THE INaDENCE OF NEOPLASMS IN FEMALE MICE TREATED WITH DDT
 

CONTROL (VEH) LOU DOSE HIGH DOSE
 

02-FOH2 02-FOU5 02-FOU6
 

ANIMAL DISPOSITION SUMMARY
 

ANIMALS INITIALLY IN STUDY 20 50
 NATURAL DEATHS 5
 

HORIBDHD SACRIFICE
 

SCHEDULED SACRIFICE
 

ACCIDENTALLY KILLED
 

TERMINAL SACRIFICE 20 l»5
 

ANIMAL HISSING
 

9 INCLUDES AUTCLYZED ANIMALS
 

TUMO8 SUMMARY
 

TOTAL ANIMALS WITH PRIMABY TUMORS* 2 8
 TOTAL PRIMARY TUMORS 3 8
 

TOTAL ANIMALS WITH BENIGN TUMORS 2 2
 TOTAL BENIGN TUMORS 2 2
 

TOTAL ANIMALS HITH MALIGNANT TDMOgS 1 6
 TOTAL MALIGNANT TUMORS 1 6
 

TOTAL ANIMALS KITH SECONDARY TUMORS*
 

TOTAL SECONDARY TUMORS
 

TOTAL ANIMALS WITH TUMORS UNCERTAINBENIGN OR MALIGNANT
 TOTAL UNCERTAIN TUMORS
 

TOTAL ANIMALS ilTH TUMORS UNCERTAIN­ PRIUARY OR NETASTATIC
 

TOTAL UNCERTAIN TUMORS
 

50
 

13
 

36
 

1
 

10
 

12
 

2
 

2
 

9
 

10
 

* PBIMABI T-OHOBS: ALL TUHORS EXCEPT SECONDAEY TOflORS
 * SECONDARY TUROBS: HETASTA1IC TUBORS OB TOHOBS INVASIVE INTO AN ADJACENT ORGAN
 

B-8
 
APPENDIX C
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN RATS TREATED WITH DDT
 

TABLE Cl

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE RATS TREATED WITH,DDT 

CONTROL (VEH) LOU DOSE
 01-M018 01-M019
 

ANIMALS INITIALLY IN STUDY 20 50
 ANIMALS NECBOPSIED 20 50
 ANIMALS EXAHINED HISTOPATHOLOGICALLY ** 19 146
 

INTEGUMENTARY SYSTEM
 

*SKIN (20) (50)
 EPIDERMAL INCLUSION CYST 1 (2X)
 INFLAMMATION, NOS 1 (5X)
 

*SUBCUT TISSUE (20) (50)
 EPIDERMAL INCLUSION CYST 1 (5X)
 ULCER, NOS
 

ABSCESS, NCS 1 <5X>
 

BESPIBATOHY SYSTEM
 

iLUN3 (19) (2U)
 

PNEUMONIA, CHRONIC HURINE 2 (11X) 5 (21X)
 CALCIUM DEPOSIT 1 (5X)
 

HEMATOPOIETIC SYSTEM
 

ISPL£EN (19) (22)
 HEMORRHAGE 1 (5X)
 ABSCESS, NOS 1 (5X)
 ANGIECTASIS 1 (5X)
 HEMATOPOIISIS 1 <5X) 1 (5X)
 

IMESENTERIC I. NODE (16) (21)
 CONGESTION, NOS 1 (5X)
 HEMORRHAGE 2 (10X)
 

CIRCULATORY SYSTEM
 

tHEABT (19) <2<»)
 

lUH5BA.iIZAlIo.fi ... 3.JSS1
 

« NUMBER OF ANIMALS WITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBER OF ANIMAL S NECROPSIED 

** EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

C-3 

HIGH DOSE
 

01-H020
 

50
 

50
 

49
 

(50)
 

3 16%)
 

(50)
 

2 («*)
 

1 (2X)
 

2 (»X)
 

(23)
 

H (17X)
 

(22)
 

« (18X)
 

(19)
 

(22)
 

... ,
 
TABLE Cl (CONTINUED) 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE RATS TREATED WITH DDT 

CONTROL (VEH) LOW DOSE
 

01-M018 01-B019
 

ABTEBIOSCLEBOSIS, NOS 1 (5*)
 CALCIUH DBEOSIT 2 (11X) 1 («*)
 

CALCIFICATION, NOS 1 (**)
 

•MYOCARDIUM	 (19) (2U)
 

INFLAMMATION, NOS 7 (37X)
 DEGENERATION, NOS 2 (11X) t (17X)
 

•ENDOCARDIUM	 (19) (2U)
 

HYPERPLASIA, NOS 2 (11X) 1 (M)
 

•AORTA	 (20) (50)
 

ARTERIOSCLEROSIS, NOS 3 (15X) 9 (18X)
 

CALCIUM DEPOSIT 1 (2%)
 

DIGESTIVE SYSTEM
 

•SALIVARY	 GLAND (1)
 INFLAMMATION, NOS 1 (100X)
 

FIBROSIS 1 (100X)
 

*LIVER (19) (<*«)
 CIST, NOS 1 (2X)
 INFLAMMATION, NOS 2 (11X) 11 (25X)
 

METAMORPHOSIS FATTY 1 (5X) 20 (USX)
 

HYPE8PLASIA, NOS 1 {2X)
 

•BILE DDCT (20) (50)
 

HIPERPLASIA. NOS 3 (6X)
 

•PANCREAS	 (18) (21)
 

THROMBOSIS, NOS 1 (6X)
 

PilRIARTEBIlIS 3 (17X) 1 (5X)
 

AfiTERIOSCLEPOSIS, NOS 1 (6X)
 

CALCIUM DEPOSIT 1 (5X)
 

•STOMACH	 (19) (25)
 INFLAMMATION, NOS 1 («X)
 

ULCER, FOCAL 2 (8X)
 

CALCIUM DIEOSIT 5 (26X) 3 (12X)
 

•DUODENUM	 (19) (22)
 

INFLAMMATICN, NOS 1 <5X)
 

•COLON	 (19) (20)
 

-EABASJTISM __ __ _ _ 2 J10SI. _
 

i NUMBE B OF ANIMAL S KITH TISSUE EXAMINE D MICBOSCOPICALLY 

* NUMBER OF ANIMAL S NECBOPSIED 

._


HIGH DOSE
 

01-M020
 

1 (5X)
 

(22)
 

5 (23X)
 

(22)
 

1 <5X)
 

(50)
 

2 (»X)
 

(D
 

(U1)
 

1 (2X)
 7 (17X)
 

16	 (39X)
 

(50)
 

1 <2X)
 

(22)
 

2 (9X)
 

(26)
 

2 (8X)
 

3 (12X)
 

(22)
 

<2C)
 

^ _
 

C-4 
TABLE Cl (CONTINUED)

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE RATS TREATED WITH DDT 

HIGH DOSE
 01-M020
 

(26)
 

1 <"»*>
 1 (i»X)
 

18 (69X)
 

1 (»X)
 

(21)
 

(21)
 

(21)
 

(19)
 

5 (10X)
 

1 (2X)
 

7 (11X)
 

(t9)
 

5 (10X)
 

(50)
 

1 <2X)
 

(50)
 

1 (2%)
 

1 (2X)
 

(23)
 

9	 (39X)
 

(50)
 

7 J118I_
 

URINARY SYSTEM
 

•KIDNEY
 CYST. NOS
 PYELONEPHRITIS, NOS
 

INFLAMMATION, CHRONIC
 

CALCIUM DEPOSIT
 

•URINARY	 BL8DDEB
 

INFLAMMATION, NOS
 

ESDOCEINE SYS1IM
 

•PITUITARY
 

CYST, NOS
 

HYPERPLASU, NOS
 

• ADRjSNAL
 ANGIECTASIS
 

•THYROID
 FOLLICDLAR CYST, NOS
 

HIPERPLASIA, C-CBLL
 

HYPEEPLASIA, FOLLICULAR-CELL
 

•PARATHYROID
 

HYPEBPLASIA, NOS
 

REPRODUCTIVE SYSTEM
 

•MAMHARY GLAND
 

GALACTOCE1E
 

*SEMINAL VESICLE
 

DILATATION, NOS
 INFLAMMATION, NOS
 ABSCESS, NOS
 

•TESTIS
 

CALCIUM DEPOSIT
 

ATROPHY, NOS
 

*EPIDIDYMIS
 

4IBQBHY,. BQ5__ _ .
 

CONTROL (VEH)
 

01-M018
 

(19)
 

17 (89X)
 

1 (21%)
 

(19)
 

(19)
 

1 (5X)
 

(19)
 

(19)
 

1 <5X)
 

3 (16X)
 

(19)
 

5 (26X)
 

(20)
 

(20)
 

1 (5)1)
 

(19)
 

2 (11X)
 

6 (32%)
 

(20)
 

3. J15S1__.
 

LOW DOSE
 01-M019
 

(28)
 

1 (KX)
 

17 (61X)
 

4 (It*)
 

(22)
 

1 (5X)
 

(22)
 

2 (9X)
 

(23)
 

3 (13X)
 

(15)
 

U (9X)
 

3 (7X)
 

t (9X)
 

(HO)
 

8 (20X)
 

(50)
 

(50)
 

1 (2X)
 

(20)
 

1 (5X)
 

8 (U0«)
 

(50)
 

5 J12SI
 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

C-5
 
TABLE Cl (CONCLUDED) 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE RATS TREATED WITH DDT 

CONTROL (VEH) LOW DOSE HIG H DOSE 

01-H018 01-M019 01-M020 

NERVOUS SYSTEM 

NONE 

SPECIAL SENSE CBGAN S 

*EYE (20) (50) (50)

 

PANNUS 2 (10») 

SYNECHIA, ANTERIOR 1 <5«)

 

MOSCUIOSKELETAL SYSTEM 

MONK 

BODY CAVITIES 

*PERITONE0M (20) (50) (50)

 

IHFLAMMATICN, DOS 1 (2%)

 

*PE8ICABDIUH (20) (50) (50)

 

INFLAMMATION , NOS 2 (10*) 

•MESENTERY (20) (50) (50) 

ARTERIOSCLEROSIS, NOS 2 (10«)

 

ALL OTHEB SYSTEMS 

NONE 

SPECIAL MORPHOLOGY SUMMARY 

NO LESION REPORTED 1 5 

NECROPSY PERF/NO HISTO PERFORMED 3 1 

AUTO/NECROPSY/NO HISTO 1 1 

t NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBEB OF ANIMALS NECROPSIED
 

C-6 
TABLE C2

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE RATS TREATED WITHtoDT 

' "~ """"* ——— —I— -J-— -r~ —— ——— •-• —— — P—.—I 

CONTROL (VEH) LOW DOSE 

01-F018 01-F021 

ANIHALS INITIAILY IN STUDY 20 50 ANIMALS NECROPSIED 20 50 ANIHALS EXAMINED HI STOPATHOLOGICALLY ** 19 146 

INTEGUMENTARY SYSTEM
 

• SKIN (20) (50)
 INFLAMMATION, NOS
 

HYPE8KERATOSIS
 

•SOBCOT TISSUE (20) (50)
 ABSCESS, NOS
 

RESPIBATOBY SYSTEM
 

ILUNS (19) (37)
 PNEUHONIA, CHRONIC BURINE 3 (16*) U (11*)
 

HEHATOPOIETIC SYSTEB
 

tSPLEEB (19) (37)
 

INFLAHHATICN, NOS 1 (3X)
 HEHATOPOIESIS 2 (11X)
 

CIRCULATORY SYSTEM
 

•MYOCARDIUM	 (19) (37)
 INFLAMMATION, NOS 1 (3%)
 DEGENERATION, NOS 3 (16X) 5 (14X)
 

•INDOCARDIDM	 (19) (37)
 HYPERPLASIA, NOS
 

DIGESTIVE SYS1IH
 

•LIVER	 (19) (12)
 

CISIx-HSS 2_15J)
 

« NUMBER OF ANIMALS WITH TISSDE EXAMINE D MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

** EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

HIGH DOSE
 

01-F022
 

50
 

50
 

Ml)
 

(50)
 

2 («*)
 

1 12%)
 

(50)


1 (21)
 

(29)
 

4 (14X)
 

(23)
 

1 («*)
 

(23)
 

2 (9X)
 

(23)
 

1 (4X)
 

(38)
 

7_Q8X)
 

C-7 
TABLE C2 (CONTINUED) 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE RATS TREATED WITH DDT 

CONTROL (VEH) LOB DOSE HIGH DOSE
 

01-F018 01-F021 01-F022
 

INFLAMMATION, DOS 1 (5X) U (10*) 2 (5X)
 METAMORPHOSIS PATTY U (11X)
 

HYPERPLASIA. NOS 2 (5X)
 

*BILE DUCT (20) (50) (EC)
 DILATATION. NOS 1 (5X> 1 (2X)
 HYPERPLASIA. NOS 1 (2X)
 

(PANCREAS (19) (38) <2t)
 PERIARTERI1IS 1 dX)
 

tSTOMACH (19) (38) (29)
 ULCER. FOCAL 2 <5X) a (1«X)
 

•COLON	 (19) (37) (23)
 

PABASlilSH 1 (5%) 1 (3X) 1 («*)
 

ORINAHY SYSTHM
 

• KIDNEY (19) (38) (25)
 INFLAMMATION. CHRONIC 5 (26X) 6 (16X) 6 (2<tX)
 

ENDOCBINE SYSTIM
 

#ADRENAL (19) (38) (2U)
 INFLAMMATION, NOS 1 («)
 ANGIECTASIS 1 (5«)
 

*THYROID (19) (15) («3)
 FOLLICOLAR CYST, NOS 2 (tX) 1 <9X)
 HYPEBPLASIA, C-CELL 2 (11*) 8 (18X) 3 (7X)
 HYPERPLASIA, FOLLICOLAH-CELL 1 (5*) 3 (7*)
 

tPARATHYROID (19) (45) (» 3)
 HYPERPLASIA, NOS 1 (5X)
 

REPRODUCTIVE SYSTEM
 

*MAMHARY GLANE (20) (50) (50)
 GALACTOCEIE 1 (5X) 1 (2X) 1 (2X)
 

•VAGINA (20) (50) (50)
 

_ P21IE 1 1211
 

• NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECHOPSIED
 

C-8
 
TABLE C2 (CONCLUDED) 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE RATS TREATED WITH DDT 

HIG H DOSE 

01-F022 

(3D 

3 (10«) 

(31)

5 (16«) 

(21) 

8 

4 

2 

•UTERUS 

HYDROMETR A 

INFLAMMATION , NOS 

*UTEKUS/ENDOMITRIUM 

HYPERPLASIA , CYSTIC 

*OVASY 

CYST. NOS 

FOLLICULAR CYST, NOS 

ISFLAHMATION , NOS 

NERVOU S SYSTEM 

NONE 

SPECIAL SENSE ORGANS 

NON E 

MUSCOLOSKELETAt SYSTEI1 

NONE 

BODY CAVITIES 

NONE 

ALL OTHER SYSTEMS 

NONE 

SPECIAL MOBPHOIOGY SOMMAB Y 

NO LESION REPORTED 

NECROPSY PERF/NO HISTO PERFORMED 

AUTO/NECROPSY/NO HISTO 

CONTROL (VEH ) 

01-F018 

(19) 

3 (16X) 

(19) 

(19) 

2 (11X) 

1 (5<) 

1 

LOU DOSE 

01-F021 

<t3) 

» (9%) 1 (2%) 

C»3) 

5 (12X) 

(37) 

1 (3X) 

3 

t 

I NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OP ANIMALS NECROPSIED
 

C-9
 

APPENDIX D
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN MICE TREATED WITH DDT
 

TABLE Dl

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE MICE TREATED WITH DDT 

HIGH DOSE
 

C2-M044
 

50
 

50
 

50
 

(50)
 

1 (2X)
 

(50)


1 (2X)
 

1 <2X)
 

1 (2X)
 

(48)
 

36 (79X)
 

(45)
 

(45)
 

4 (9X)
 

(45)
 

(18)
 _ J_I2S1
 

ANIMALS INITIALLY IN STUDY
 

ANIHALS NECROPSIED
 

ANIMALS EXAMINED HISTOPATHOLOGICALLY**
 

INTEGUMENTARY SYSTEM
 

*SKIN
 

INFLAMMATION, NOS
 

CALCIUM DEPOSIT
 

*SUBCUT TISSUE
 

EPIDERMAL INCLUSION CYST
 

ULCER, NOS
 

ABSCESS. NCS
 

HESPIfiATORY SYSTEM
 

NONE
 

HEHATOPOIETIC SYSTEM
 

ISPLBEN
 

AHYLOIDOSIS
 

tCEBVICAL LYMPH NODE
 

EDEMA, NOS
 

IHFLAHMATICN, NOS
 

*MESENTE8IC L. NODE
 

INFLAMHATICN, NOS
 

•INGUINAL	 LYHPH NODE
 

EDEMA, NOS
 

INFLAMHATICN, NOS
 

CIRCULATORY SYSTEH
 

•HEART
 

_AflYLOIEQSIS_
 

CONTROL (VEH)
 

02-M042
 

20
 

19
 

19
 

{19)
 

(19)
 

1 (5*)
 

(18)


11	 (61X)
 

(16)


1 (6J)
 

1 (6«)
 

(16)
 

6 (38%)
 

(16)


1 (6X)
 

1 (6«)
 

(19)
 

LOW DOSE
 

02-HO<43
 

50
 

49
 

49
 

(49)
 

1 (2X)
 

(49)
 

(47)
 

42 (89X)
 

(43)
 

(43)
 

(43)
 

(49)
 

t NUHBEB OF ANIMALS KITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBER OF ANIMAL S NECROPSIED 

** EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

D-3
 
TABLE Dl (CONTINUED)

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE MICE TREATED WITH DDT 

" CONTROL (VBH) 

02-HOU2 

LOR DOSE 

02-8013 

CALCIOH DEPOSIT 3 (6X) 

*HYOCAHDIUH 

INFLAHHATICN, NOS 

(19) (49) 

tENDOCARDIDPI 

INFLAHHATICN, NOS 

(19) (U9) 

DIGESTIVE SYS1EB 

*LI7ER (19) («9) 

INFLAHHATICN, NOS 1 (2*) 

AHYLOIDOSIS 3 (16*) 20 (41*) 

HYPEBPLASIA, NODULAB 2 (11*) 

•STOMACH (19) (49) 

CALCIOH DEPOSIT 2 (11*) 3 (6X) 

» COLON (19) (49) 

INFLABHATICN, DOS 1 (5*) 

PABASITISH 

*RECTDH (19) (49) 

PHOLAPSE 1 (5X> 

URINAR Y SYSTIH 

• KIDNEY (19) (49) 

HYDBONEPHBOSIS 2 (11X) 

CYST. NOS 1 (2*) 

PYELONEPHRITIS. NOS 2 («*) 

INFLAHHATICN, CHRONIC 11 (58X) 28 (57X) 

AtlYLOIDOSIS 11 (58X) 37 (76*) 

•URINARY BLADDER (19) (47) 

INFLAHHATICN, NOS 1 (2*) 

ENDOCRINE SYSTIH 

NONE 

REPRODUCTIVE SYSTEH 

•PROSTATE (18) (46) 

I!iEtiafiAJ-I££*_fiS§ . _- 2_-UJ*jL 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUBBER OF AKIBALS NECROPSIED
 

D-4
 

HIGH DOSE 

02-H044 

(48) 

1 <2X) 

(48) 

1 (2X) 

(48) 

25 (52X) 

(5C) 

1 (2X> 

(47) 

1 (2X) 

(50) 

(48) 

3 (SX) 

35 (73X) 

37 (77X) 

(48) 

(47) 
TABLE Dl (CONCLUDED) 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE MICE TREATED WITH DDT 

" • CONTROL (VEH) LOW DOSE HIG H DOSE 

02-HOI»2 02-MOU3 02-H04U 

ITESIIS (19) (19) (17) 

ATROPHY, NOS 1 (2X) 

*EPIDIDYMIS (19) (»9) (50) 

GRANULOHA , SPERMATIC 1 (2X) 

NERVOUS SYSTEH 

NONE 

SPECIAL SEHSE CBGANS 

NONE 

fflJSCULOSKELETAL SYSTEM 

NONE 

BODY CAVITIES 

NOUS 

ALL OIHES SYSTEMS 

NONE 

SPECIAL NORPHOIOG Y SUMMAR Y 

NO LESION REPORTED 3 3 3 

AUTO/NECROESY/HISTO PERF 1 1 4 

AUTOLYSIS/NO NECROPSY 1 1 

» NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

» DUMBER OF ANIMALS NECROPSIED
 

D-5 
TABLE D2
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE MICE TREATED WITH DDT
 

CONTROL (VEH) LOW DOSE HIGH DOSE
 

02-F042 02-FOItS 02-FOU6
 

ANIMALS INITIALLY IN STUDY 20 50 50
 

ANIMALS HISSING 1
 ANIMALS NECBOPSIED 20 49 U6
 ANIMALS EXAMINED HISTOPATHOLOGICALLY** ' 20 22 27
 

INTEGUMENTARY SYSTEM
 

NONE
 

BESPIHATOBY SYSTEM
 

NONE
 

HEMATOPOIETIC SYSTEM
 

ISPLEEN (20) (22) (26)
 

HYPBRPLASIA, RETICULUM CELL 1 (t*>
 HJSHATOPOIESIS 1 ("»*)
 

CIRCHLATOBY SYSTEM
 

NONE
 

DIGESTIVE SYSTBM
 

•LIVES	 (20) (22) (27)
 

HYPEBPLASIA, NODULAR 1 (5X) 1 (1*)
 ANGIECTASIS 2 (9«)
 

*PANCBEAS (19) (22) (26)
 

ATROPHY, NCS 1 (5%)
 

•PANCREATIC DUCT (19) (22) (26)
 CYST, SOS 1 (5*)
 

•STOMACH	 (20) (22) (26)
 

ai£Efii_I2£AL_ 1_I5S1_ ,.
 

* NUMBER OF ANIMAL S HITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

** EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

D-6 
TABLE D2 (CONTINUED) 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE MICE TREATED WITH DDT 

———————— ———«"«————"•"— •«• 

CONTROL (VEH) LOR DOSE 02-FOU2 02-FO»5 

URINAHY SISTER
 

HONE
 

ENDOCRINE SYSTIH
 

»THYBOID (20) (22)
 KYPERPLASIA, FOLLICULAR -CELL
 

REPRODUCTIVE SJSTEH
 

•NAB HA BY GLAND (20) C»9)
 GALACTOCELE 1 (5*)
 

tUTEBUS (20) (22)
 HYDROBETRA 1* (20X) 2 (9*)
 IHFLAHHATION, NOS 6 (30«) 2 (9*)
 

lUTEiUS/ENDCBITRIDM (20) (22)
 HYPERPLASIA, CYSTIC 3 (15*) 5 (23*)
 

iOVAHY/OVIDUCI (20) (22)
 IMFLAHHATICN, DOS
 

tOVABY (20) (21)
 CYST, NOS 3 (15X) 3 (!<»*)
 IHPLAMHATICH, NOS 2 (10*) 2 (10*)
 

NERVOUS SYSTEM
 

NOME
 

SPECIAL SENS; ORGANS
 

NONB
 

BUSCULOSKELE1AI SYSTEH
 

PQHfe -,-­

I MOHBER OF ANIMALS KITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

HIGH DOSE
 C2-FOK6
 

(27)
 

1 (1*)
 

(U6)
 

(27)
 

1 (<•*)
 

3 (11*1
 

(27)
 

6 (22X)
 

(27)
 

1 (<**)
 

(27)
 

3 (11*)
 

2 (7*)
 

D-7
 
TABLE D2 (CONCLUDED)

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE MICE TREATED WITH DDT 

CONTROL (VEH) LOW DOSE HIG H DOSE 

02-F042 02-FOU5 02-FOU6 

BODY CAVITIES 

*PERITOHEUH (20) <t9) (46) 

INFLAMMATION , NOS 1 (5*)

 

AIL OTHER SYS1EHS 

NON E 

SPECIAL MORPHOLOG Y SUMMAR Y 

NO LESION 5EPORTED U 6 6 

ANIMA L MISSING/NO NECROPSY 1

 

NECROPSY PERF/NO HISTO PERFORMS! ) 27 19 

AUTO/NECHOPSY/HISTO PERF 1 1

 

AUTOLYSIS/NO NECROPSY 1 3 

I NUHBER OF AHIMAIS WITH TISSUE EXAHINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECBOPSIFD
 

D-8 
APPENDIX E
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS
 

IN RATS TREATED WITH TDE
 

TABLE El

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE RATS TREATED WITH TDE 

1CONTRO L (VEH) 

01-H033 

ANIMAL S INITIALLY I N STUDY 20 

ANIMAL S NECPOPSIED 20 

ANIMAL S EXAMINE D HISTOPATHOLOGICALLY* * 20 

INTEGUMENTAP Y SYSTE M 

*SUBCU T TISSUE (20) 

FIBROM A U (2 0", ) 

RESPIRATOR Y SYSTE M 

tLUN G (20) 

ALVECLAF/BSONCHIOLA P ADENOM A 1 (5%) 

HEMATOPOIBTIC SYSTEM 

*MULTIPLF OH3AN S (20) 

HALIG. I.YMPHOMA, LYMPHOCYTIC TYPE 

MALIG.I.YMPH3MA , HISTIOCYTIC TYPE 

*SPL£EN (20) HEMANGTCSAKCOM A 

CIBCDLATCB Y SYSTE M 

NON E 

DIGESTIV E SYSTEM 

tLIVFB (20) 

HEPATOCFLLULA H ADFNOK A 1 (5«) 

HEPATOCELLOLA B CARCINOM A 

UHINAE Y SYSTEM 

tKIDNE Y (20) 

MIXE D TUHQBi MALIGNANT. 

L OW DOS E 

01-M03U 

50 

50 

50 

HIGH DOSE 

01-^035 

50 

50 

a? 

(50) 

2 (4%) 

(50) 

(19) (20) 

(50) 

1

1

(20) 

«

 (2%) 

 (2%) 

 (20%) 

(50) 

(20) 

(27) 

1 («») 

(38) 

2 (5%) 

(20) 

.__

(20 ) 

.1 J5*l 

* NUMBE R O F ANIMAL S WIT H TISSUE FXAHINE D MICROSCOPICALL Y 

* NUHBFR OF ANIMAL S NECBOPSIED 

•"EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

E-3 
TABLE El (CONTINUED)

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE RATS TREATED WITH TDE 

HABAFTOKA 

IURINAB Y BLADDER 

PAPILLOHA, SOS 

ENDOCRIN E 5YSTEH 

fPITUITAR Y 

CHBOHOPHOBE ADENOH A 

GLIOHA, NOS 

1ADRENAL 

PHFOCHFCMOCYTOMA 

•THYHCID 

ADFNCMA , NOS 

FOLLICUI.A8-CELL ADENOH A 

FOLLICHLAR-CELL CARCINOMA 

C-CSLL ADENDN A 

C-CELL CARCINDK A 

*PANCFFATIC ISLETS 

ISLET-CFLL ADENOM A 

REPRODUCTIV E SYSTEB 

*«AHHAR Y GLAN D 

FIBROADENOH A 

NEKVOO S SYSTEH 

IBPAIN 

GLIONA, NOS 

SPECIAL SFNSE ORGAN S 

NONE 

HOSCOLOSKELETAL SYSTEd 

HONE 

» NOBBER OF ANIMAL S HITH TISSUE

* NUMBE R OF ANIRAL S NECROPSIED 

CONTROL (VEH) L0» DOSE 

01-M033 01-H034 

2 (10X) 

(19) (20) 

(20) (26)

1 (5») 7 (27%) 

(20) (19) 

1 (5X) 

(19) (49) 

11 (22X) 

1 <5X) 6 (12X) 

1 (5X) t (8*) «

 (8«) 

(20) (19) 

(20) (50) 

(20) (19) 

1 (5») 

 EXAMINE D SICROSCOPICALLY 

E-4 

HIGH DOSE 

01 -HO 35 

(23) 

1 (UK ) 

(25) 

5 <20X) 

1 («*) 

(20) 

1 <5X) 

(D9 ) 

1 (2X) 

9 (18X) 

3 (6X) 

1 (2X) 

2 (»X) 

(22) 

1 (5X) 

(50) 

1 <2X> 

(20) 
TABLE El (CONCLUDED) 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE RATS TREATED WITH TDE 

CONTROL(VFH ) LOW DOSE HIGH DOSE 

01-M033 01-M034 01-M035 

BODY CAVITIF S 

•TUNICA VAGINALI S (20) (50) (50) 

MESOTHEIIOMA, DOS 1 (2X) 

A LL OTHER SYSTEH S 

NONF 

ANIMAL DISPOSITION SUMMAR Y 

ANIMAL S INITIALL Y I N STUDY 20 50 50 

NATURA L DEATHS 12 23 19

 

MORIBUND SACRIFICE 

SCHEDULED SACBIFICE 

ACCIDENTALLY KILLED 

TERMINA L SACRIFICE 8 27 31

 

ANIMA L BISSIN3 

i INCLUDES AUTOLYZE D ANIMAL S 

TUMOR SUMMAR Y 

TOTAL ANIBALS WIT H PPIMRY TUMORS* 7 33 25

 

TOTAL PRIMAR Y TUKOH S 10 t5 30

 

TOTAL ANIFAL S KIT H BENIGN TUMORS 7 22 19 

TOTAL BENIGN TOKORS 9 27 20 

TOTAL ANIMAL S WIT H MALIGNAN T TUHORS 1 14 9 

TOTAI BALI3NAN T TUMORS 1 18 9 

TOTA L ANIMAL S KIT H SECONDAR Y TUMORSI 

TOTAL SECONDAR Y TUMORS

 

TOTAL ANIBALS WIT H TUBORS UNCERTAIN ­

BENIG N OP MALIGNAN T 1 

TOTAL UNCERTAI N TUMORS 1 

TOTAL ANIBAL S WIT H TUMORS UNCERTAIN ­

PRIMAR Y OE METASTATIC 

TOTAI UNCERTAI N TUMORS 

* PRKIABY TUMOBS: ALL TUMOR S EXCEPT SECONDARY TUMORS 

t SECONDARY TUMORS : METASTATIC TUMORS OE TUMORS INVASIV E INTO AN ADJACENT ORGA N 

E-5 
TABLE E2

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS TREATED WITH TDE 

CONTROL (VEH) LOU DOSE HIGH DOSE 

01-F033 01-F036 01-F037 

ANIMAL S INITIALLY I M STUDY 20 j? 50 

ANIMAL S SECROPSIED 19 i»9 «9 

ANIMAL S EXAMINE D HI STOPATHOLOGICALL Y»* 19 148 1(9 

INTEGUMENTAR Y SYSTEM 

*SUBCUT TISSUE (19) (i»9) <t9) 

SQUAMOUS CELL CARCINOM A 1 (2X ) 

SARCOMA, NDS 1 (2X) 

FI BRON A 2 (11*) 

FIBBOSAHCOM A 2 (11*) 

LIPOMA 3 (6X) 

LIPOSASCOMA 1 (2*) 

H8SPIRAIORY SYSTEM 

NONE 

HEMATOPOIETIC SYSTEM 

*MULTIPLF OH3ANS (19) (K9 ) C*9) 

MALIG. LYMPHOMA . LYMPHOCYTIC TYPE 1 (5*) 

MALIG.LYMPH3MA , HISTIOCYTIC TYP? 1 <5X) 1 (2X) 

*SUBCOT TISSUE/AXILLA (19) («9) («9) 

MALIG. LYMPHOHA , HISTIOCYTIC TYPE 1 (5%) 

• PANCREA S (19) (25) (30)

 

MALIGNAN T LYMP H OPIA, NOS 1 (««>

 

IKIDNIY (19) (25) (29) 

MALIG.LYBPHOMA . HISTIOCYTIC TYPE 1 <3X) 

CIRCULATORY SYSTEM 

HON E 

f NUMBE R OF ANIMAL S HITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBE R OF ANIMAL S NECROPSIED 

••EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

E-6 
TABLE E2 (CONTINUED) 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS TREATED WITH TDE 

CONTROL(VF.H) LOW DOSE 

01-F033 01-F036 

DIGESTIVE SYSTEM 

#LIVER (19) (32)

 HIPATOCELLOLAR CARCINOMA 1 (5»)

 

tPANCREA S (19) (25) SQUAMODS ;ELL CARCINOMA , KSTASTA

 1 <«) 

DRINAP Y SYSTEM 

NON E 

ENDOCRIN E SYSTEM 

iPITUITAPY (19) (30) CHSOMOPHOBE ADENOM A » (21%) It (17*) 

tADRENA L (19) (27) CORTICAL ADENOMA 

CORTICAL CARCINOM A 

PHEOCHPCBOCYTOM A 1 («X) 

#THYROI D (19) (U8) FOLLICCIAB-;ELL ADFNOM A 6 (13*) FOLLICOIAB-CELL CAPCINONA 2 (11X) 5 (10X) C-CELL ADENOM A 1 (5*) 2 <«X ) C-CELL CARCINDM A 1 <5X) 2 («X) 

#PAHATHYROI D (D (D

 ADENOMA , NO S 1 (100X)

 

#PANCPEATIC ISLETS (19) (25)

 ISLFT-CELL ADENOM A 2 (11%)

 

REPRODUCTIV E SYSTE M 

• MAMMAR Y CHAN D (19) <U9) ADENOCARCINOMA , NO S 1 (2X) 

FIEROADFNOM A 7 (37%) 13 (27X) 

tUTERUS (19) (30)

 

SQUANOIIS 3EL1 CAgCINOflA __ 1.J1S1 

» NUMBE R OF ANIMAL S WITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBE R OF ANIMAL S NFCROPSIE D 

HIGH DOSE 

01-P037 

(»0) 

3 (8X) 

(30) 

(33) 

12 (36*) 

(29) 

1 (3X) 

1 (3%) 

(50) 

5 (10X) 

1 <2X) 

1 (2X) a (8X) 

(D 

(30) 

(«9) 

1 (2X) 

10 (20X) 

(36) 

- -1-JQS1 

E-7 
TABLE E2 (CONTINUED) 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS TREATED WITH TDE 

CONTROL(VEH ) LOW DOSE HIGH DOSE 

01-F033 01-F036 01-F037 

LEIOMYOSABCOH A 

ENDOMFTRIA L STROMA L POLYP 

1

1

 (5*) 

 (5*) 6 (20X) 8 (22%) 

*OVAR Y (19) (26) (30) GRANULOSA-CELL THROB 1 <3X) 

NERVOOS SYSTEH 

*BBAIN (19) (26) (28) ASTROCYTOMA 1 (IX) 

SPECIAL SENSE ORGAN S 

NON E 

MUSCULOSKELFTAL SYSTEM 

NOSE 

BODY CAVITIFS 

*ABDOMINAL VISCER A (19) («9) (19) FIBROSARCOM A 1 (2X) 

ALL OTHER SYSTEMS 

NON E 

ANIMA L DISPOSITION SU«HAR Y 

ANIMAL S INITIALL Y I N STUDY 20 50 50 

NATURAL DEATHS 8 12 16 

MORIBUN D SACRIFICE 1 1 

SCHEDULED SACPIFICF 

ACCIDENTALLY KILLED 

TERMINAL SACRIflCF 11 38 33 ANIMAL MISSIN3 

$ INCLUDES ADTOLYZE D ANIMAL S 

* NUWBFB OF ANIMALS HITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER 0? ANIMALS NEC80PSIED
 

E-8 
TABLE E2 (CONCLUDED) 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS TREATED WITH TDE 

CONTROL (V?H) LOW DOSE HIGH DOSE 

01-K033 01-F036 01-F037 

TUMO R SUMMAR Y 

TOTAL ANIMAL S KITH PRIMAR Y TUMORS* 17 35 36 

TOTAL PRIMAR Y TUMORS 28 54 57 

TOTAL ANIKAL S WIT H BENIG N TUMORS 13 30 30

 

TOTAL BFNIG N TUMOR S 18 42 40

 

TOTAL ANIMAL S WIT H MALIGNAN T TUMORS 10 12 15

 

TOTAL MALIGNAN T TUMOP S 10 12 16 

TOTAL ANIMALS WITH SECONDARY TUMOPS* 1

 

TOTAL SECONDAR Y TUMOR S 1

 

TOTAL ANIMAL S WIT H TUMORS UNCERTAIN ­

BENIG N OP. MALIGNAN T 1 

TOTAL UNCERTAI N TUMOP S 1 

TOTAL ANIMAL S BITH TUMOBS UNCEPTATN ­

PEIBAR Y OP METASTATIC 

TOTAL UNCERTAI N TUMOF S 

* PRIMARY T'JHOFS: ALL TUMORS EXCEPT SECONDARY TUMORS
 

» SECONDARY TUMORS: HETASTATIC TDHORS OR TUNORS INVASIVE INTO »N ADJACENT ORGAN
 

E-9 

APPENDIX F
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS
 

IN MICE TREATED WITH TDE
 

TABLE Fl

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE MICE TREATED WITH TDE 

(:ONTROL (VEH ) 

02-M029 

L OB DOSE 

02-M030 

ANIMAL S

ANIMAL S

ANIMAL S

ANIMAL S

 INITIALL Y I N STUD Y 

 MISSIN G 

 NECPOPSIED 

 EXAMINE D HISTOPATHOLOGICALL Y *¥ 

20 

1 

18 

18 

50 

1 

49 

49 

INTEGUMENTAR Y SYSTE M 

*SKIN (18) (49) SEBACEOUS ADENOM A 

FIBEOM A 

FIEEOSAPCOM A 1 (2%) 

*SUBCUT TISSUE (18) (49) SEBACEOUS ADENOM A 

FIEEOM A 3 (17%) 2 (it%) FIBEOSAPCOM A 1 (6X) 2 (4X) 

RESPIRATOR Y SYSTE M 

#LUN G (18) (29) HEPATOCFLLOLA E CAECISOMA , METAS T 1 (3«) ALVEOLAP/BEONCHIOLA P ADENOM A 1 (6X) 4 (14*) 

ALVEOLAP/B80NCHIOLA E CARCINOM A 1 (3%) 

HEMATOPOIETIC SYSTE M 

*MULTIPLE ORGAN S (18) (49) 

MALIG.LYMPH3MA , HISTIOCYTIC TYPE 1 (2X) 

IKIDNFY (18) (35) MAIIG. I YMPHOMA , HISTIOCYTIC TYPE 

CIRCULATOP Y SYSTE M 

NON E 

DIGESTIV E SYSTEM 

OLIVE R (18) (44) 

HEPATOCFLLULA R CABCIN01 A . 2 imi 12 J27JJ. 

* NUMBE P OF ANIMAL S KIT K "ISSUf EXAMINE D MICROSCOPICALLY 

* NUMBE R OF ANIMAL S NECPOPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

HIGH DOSE 

02-M031 

50 

50 

49 

(50) 

1 <2X ) 

1 (2X ) 

(50) 

1 (2X) 

1 (2%) 

(35) 

1 (3X > 1 (3X) 

(50) 

1 (2X) 

(40) 

1 (31) 

(50) 

. _ 14 128X1.. 

F-3 
TABLE Fl (CONTINUED)

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE MICE TREATED WITH TDE 

URINAR Y SYSTEM 

*URINAP Y RUDDER 

PAPILLOMA , NOS 

ENDOCRINE SYSTEM 

NOME 

REPRODUCTIVE SYSTEM 

*EPIDIDYHIS 

LIPOHA 

NERVOU S SYSTEM 

NON E 

SPECIAL SENSE ORGAN S 

NONE 

MUSCULO SUBTOTAL SYSTEM 

•SKELETAL RUSCLE 

FIBROSAPCOKA 

30BY CAVITIFS 

HONE 

ALL OT HEP SYSTEMS 

_N.QHE ___ 

I NUMBE R OP ANI.1ALS WITH TISSUE

* NUMBT F OF A8IHAIS NFCFOPSTED 

CONTROL (V EH) 

02-H029 

(18) 

1 (6») 

(18) 

1 <6X) 

,(18) 

LOR DOSE HIGH DOSE 

02-M030 02- HO 31 

(2«) (22) 

1 (»%) 

(49) (50) 

(»9) (50) 

1 (2X) 

 EXAMINE D MICROSCOPICALLY 

F-4 
TABLE Fl (CONCLUDED) 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE MICE TREATED WITH TDE 

ANIMA L DISPOSITION SUMMAR Y 

ANIMAL S INITIALLY IN STUDY 

NATURA L DEATHS 

MORIBUN D SACRIFICE 

SCHEDULED SACRIFICE 

ACCIDENTALLY KILLED 

TERMINA L SACRIFICE 

ANIMA L MISSIN3 

S INCLUDES AUTOLYZE D ANIMAL S 

TUMCS SUMAE Y 

TOTAL ANIMALS WIT H PRIMAR Y TUMORS* 

TOTAL PRIMAR Y TUMORS 

TOTAL ANIMAL S KITH BENIG N TUMORS 

TOTAL BENIG N TUMORS 

TOTAL ANIMAL S WIT H MALIGNAN T TDHORS 

TOTAL MALIGNAN T TUMORS 

TOTAL ANIMALS KIT H SECONDARY TUMORS* 

TOTAL SECONDARY THMORS 

TOTAL ANIMALS WIT H TUMORS UNCERTAIN ­

BENIG N OR MALIGNAN T 

TOTAL UNCERTAI N TUMORS 

TOTAL ANIMALS WIT H TUMORS UNCERTAINPRIMAR Y OR METASTATIC 

TOTAL UNCERTAIN TUMORS 

COHTROL(VEH) 

02-H029 

20 

6 

13 

1 

8 

9 

6 

6 

3 

3 

LOW DOSE 

02-M030 

50 

19 

30 

1 

19 

25 

7 

7 

17 

18 

1 

1 

HIGH DOSE 

02-M031 

50 

22 

1 

27 

19 

22 

4 

4 

17 

18 

* PRIMARY TUBOBS: ALL TOHOBS EXCEPT SECONDARY TDHORS
 

I SECONDARY TUMORS: MET*STATIC TUMORS OR TUMORS INVASIVE INTO AN ADJACENT ORGAN
 

F-5 
TABLE F2

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE MICE TREATED WITH TDE 

1

CONTROL (VEH ) L OW DOSE 

02-F029 02-F030 

ANIMAL S INITIALL Y I N STDDY 20 50 

ANIMAL S MISSIN G 1 

ANIMAL S NFCEOPSIE D 20 49 

ANIMAL S EXAMINE D HI STOPA THOLOGICALLY* * 20 i»9 

INTEGUMENTAR Y SYSTE M 

NONE 

8ESPIRATOR Y SYSTE M 

iLUN G (20) (27) 

ALVEOLAP/BRONCHIOLA R ADENOM A 3 (11*) ALVFOLAR/BBONCHIOLA R CARCINOM A 1 («) 

H E M ATOPOIETIC SYSTE M 

*MDLTIPL E ORGAN S (20) (49) MAL1G.LYMPH3MA , LYMPHOCYTIC TYP F 1 (2«) MALIC. LYMPH3MA , HISTIOCYTIC TYPF 1 (59!) 2 (IX) MALIGNAN T LYMPHOMA , MIXE D TYPE 1 <2X ) 

iLUN G (20) (27) MAI.IG . LYMPHOMA , LYMPHOCYTIC TYPF, 1 (US) 

HLIVF.R (20) (48) 

MALIG.IYMPHOMA , LYMPHOCYTI C TYP? 2 («*) 

CIRCULATOR Y SYSTEM 

NON E 

DIGESTIV E SYSTEM 

tLIVE R (20) (48) 

HEPATOCELLULA R ADEN0.1S 

HEPATOCFLLULA R CARCINOM A 2 (i»X) 

URINAR Y SYSTEM 

NON E 

* NUMBE R OF ANIMAL S WITH TISSUE EXAMINE D MICROSCOPICALL Y 

* NUMBE R O F ANIMAL S NECROPSIE D 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

HIGH DOSE 

02-F031 

50 

3 

47 

47 

(15) 

1 (7X) 

(47) 

1 (2*) 

(15) 

(47) 

(47) 

1 (2*) 

3 (6«) 

F-6 
TABLE F2 (CONTINUED) 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE MICE TREATED WITH TOE 

CONTROL (VBH) LOW DOSE HIGH DOSE 

02-P029 02-F030 02-F031 

ENDOCRINE SYSTEM 

NON E 

REPRODUCTIVE SYSTEM 

• MAMMAR Y GLAND (20) (09) (»7) ADENOCAFCINOMA , NOS 1 (5*)

 

tBTERUS (19) (31) (23)

 ENCOMETKA L STHOHAL POLYP 1 (3*)

 

NERVOUS SYSTEM 

NON E 

SPECIAL SENSE OR3AN S 

NON E 

MUSCULOSKELFTAL SYSTEM 

NON E 

BODY CAVITIES 

NON E 

A LL OTHER SYSTEMS 

NONE _ __ __ 

* NUMBE R OF ANIHAL S WITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUBBER OF ANIMAL S NFCROPSIED 

F-7 
TABLE F2 (CONCLUDED) 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE MICE TREATED WITH TDE 

CCSTROL(VEH) 

02-F029 

LOS DOSE 

02-F030 

HIGH DOSE 

02-F031 

ANIMA L DISPOSITION SUMMAR Y 

ANIMAL S INITIALL Y I N STUDY 

NATURA L DEATHS 

MORIBUN D SACRIFICE 

SCHEDULED SACRIFICE 

ACCIDENTALL Y KILLED 

TERMINA L SACRIFICE 

ANII-A L MISSIN3 

20 

1 

1 

18 

50 

8 

U1 

1 

50 

3 

4U 

3 

d INCLUDES AUTOLYZED ANIMAL S 

TBMC8 SUMMAR Y 

TOTAL ANIMALS WITH PRIMAR Y

TOTAL PRIMAR Y TUMOR S 

 TUMORS* 2 

2 

13 

1U 

6 

6 

TOTAL ANIMAL S WIT H BENIG N

TOTAL BENIG N TUMOR S 

 TUMORS u 

u 

1 

1 

TOTAL ANIMAL S HII H MALIGNAN T TUMORS 2 10 5 

TOTAL MALIGNAN T TUMORS 2 10 5 

TOTAL ANIMALS WIT H SECONDARY TUMORS* 1

 

TOTA L SECONDAR Y TUMOP.S 

TOTAL ANIMAL S WIT H TUMOR S UNCERTAIN ­

BENIG N O P MALIGNAN T 

TOTAI UNCERTAI N TUMOPS 

TOTAL ANIMAL S WIT H TUKORS UNCERTAIN ­

PRIMAR Y OP METASTATIC 

TOTA L UNCERTAI N TUMOR S

 

* PRIMAR Y TUMORS : ALL TUMOR S EXCEPT SECONDAR Y TUSORS 

* SECONDARY TUMORS: KETASTATIC TUMORS OR TUB08S INVASIVE INTO AN ADJACENT ORGAN 

F-8 
APPENDIX G
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN RATS TREATED WITH TDE
 

TABLE Gl

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE RATS TREATED WITH TDE 

1CONTROL (VEH) LOW DOSE HIGH DOSE 

01-M033 01-M03U 01-M035 

ANIMALS INITIALLY IN STODY 20 50 50 

ANIMALS SECROPSIED 20 50 50 

ANIHALS EXAMINE D HISTOPATHOLOGICALLY** 20 50 i»7 

INIEGUMEN1ABY SYSTEM 

*SKIN (20) (50) (50) 

EPIDERMAL INCLUSION CYST 1 <2X) 

INFLAMMATION, NOS 1 (5X) 2 (tX) 

GBANOLOKA , NO S 1 (2%) 

CALCIUM DEPOSIT 1 (2%) 

HYPERKIRATOSIS 2 (IX) 

ACANTHOSIS 2 («%) 

VEBEDCA 1 (2X) 

*SOBCUT TISSUE (20) (50) (50) 

ABSCESS, NOS 1 (2X) 

RESPIRATORY SYSTEM 

• NASAL CAVITY (20) (50) (50)

 

INFLAMMATION , NOS 1 (2X) 

•TRACHEA (20) (19) (20) 

INFLAMMATION, NOS 1 (5*) 

ILUNG (20) (19) (20) PNEDMOSIA, CHRONIC numN E 5 (25%) 6 (32X) 7 (35*) 

HBMATOEOIETIC SYSTEM 

tSPLEEN (20) (20) (20) 

ATROPHY, NOS 1 (5X) 

HEMATOPOIESIS 1 (5«) 

CIECOLATOEY SYSTEM 

•HEART (20) (2U) (22)

 

CAL£!OH._P.EE2SIT. 1 iSSL 2 (8X)

 

* NOHBEE OF ANIHALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NDHBEE OF ANIHAL S NECROPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

G-3 
TABLE Gl (CONTINUED) 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE RATS TREATED WITH TDE 

*MYOCARDIUB 

DEGENERATION, NOS 

*ENDOCABDIUM 

INFLAMMATION, NOS 

HYPERPLASIA, NOS 

*AOBTA 

INFLAMMATION. NOS 

ARTERIOSCLEROSIS, NOS 

DIGESTIVE SYSTEM 

ILIVER 

CYST, NOS 

INFLAMMATION, NOS 

METAHOPPHOSIS FATTY 

*BILE DUCT 

HYPERPLASIA, NOS 

• PANCREA S 

PEKIARTEBITIS 

*STOHACH 

INFLAMMATION, NOS 

ULCER, FOCAL 

CALCIUM DEPOSIT 

UEINA8 Y SYSTEM 

»KIDNEY 

CYST, NOS 

PYELONEPH8ITIS, NOS 

INFLAMMATION , CHRONIC 

CALCIUM DEP3SIT 

ENDOCRINE SYSTEM 

*PITOITARY 

CYST, NOS 

*ADRENAL 

_ AJiSJECTASlS _ . 

* NUMBER OF ANIMAL S IITH TISSUE

* NUMBER OF ANIMAL S NECROPSIED 

CONTROL(VEH) LOW DOSE 

01-H033 01- HO 31 

(20) (21) 

9 (<45X) 3 (13%) 

(20) (24) 

1 <«X) 

(20) (50) 

U (20%) 6 (12%) 

(20) (27) 

2 (10*) 

1 (5X) 5 (19%) 

(20) (50) 

1 (5%) 1 (2«) 

(20) (19) 

2 (10*) 

(20) (27) 

2 (7%) 

1 (5%) 2 (7%) 

3 (15X) 5 (19X) 

(20) (20) 

1 (5») 

12 (60%) 11 (55%) 

2 (10%) 

(20) (26) 

1 (l»X) 

(20) (19) 

 EXAMINE D MICHOSCOPICALLY 

G-4 

HIGH DOSE 

01-H035 

(22) 

6 (27%) 

(22) 

1 (5%) 

(50) 

1 (2%) 

(38) 

2 (5%) 

U (11%) 

(50) 

1 (2%) 

(22) 

3 (1U%) 

(2<0 

1 <U%) 

(20) 

1 (5%) 

12 (60%) 

(25) 

(20) 

._ _ _1 -15%.! . 
TABLE Gl (CONTINUED) 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE RATS TREATED WITH TDE 

tTHYROID 

FOILICULAR :YST, HOS 

HYPERPLASIA, C-CELL 

HYPERPLASIA , F3LLICULAR-CELI 

tPARATHYROI D 

HYPERPLASIA, NOS 

REPRODUCTIVE SYSTEM 

JPROSTATE 

HEB08RHAG E 

INFLAMMATION , NOS 

*SEBINAL VESICLE 

HEBORRHAG E 

iTESTIS 

INFIABMATION, NOS 

CALCIOK DEPOSIT 

ATROPHY, N3S 

*EPIDIDYBIS 

INFLAMMATION , NO S 

CALCIUM DEPOSIT 

ATROPHY, NO S 

NERVOU S SYSTEM 

*BRAIN 

HEMORRHAGE 

SPECIAL SENSE ORGAN S 

*EYE 

PANNU S 

SYNECHIA , AHTEBIO B 

CATARACT 

BUSCULOSKELETAL SYSTEM 

NONE 

# NUBBER OF ANIMALS WITH TISSUE

* NUMBE R OF ANIBAt S NECROPSIE D 

COST SOL (V EH) 

01-H033 

(19) 

1 (5») 

2 (11X) 

(7) 

» (57X) 

(19) 

1 (5*) 

(20) 

(19) 

2 (11X) tt (21X) 

(20) 

1 (5X| 

1 (5X1 

1 (5X1 

(20) 

(20) 

1 (5X) 

1 (5*) 

1 (5X) 

LOU DOSE 

01-H03U 

(U9) 

2 («X) 

2 (tX) 

5 (10X) 

(7) 

7 (100X) 

(17) 

(50) 

(19) 

7 (37X) 

(50) 

1 (2X) 

(19) 

(50) 

2 (UX) 

 EXAMINED MICROSCOPICALLY 

G-5 

HIGH DOSE 

01-H035 

(49) 

« (8X) 

2 <UX) 

6 (12X) 

(2) 

1 (50X) 

(20) 

1 (5X) 

1 (5X) 

(50) 

1 (2X) 

(23) 

1 («X) 

2 (9X) 

(50) 

1 (2X) 

(20) 

1 (5X) 

(50) 
TABLE Gl (CONCLUDED) 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE RATS TREATED WITH TDE 

CONTBOL(TEH) LOW DOSE 

01-H033 01-M034 

BODY CAVITIES 

*ABDOHINA L CAVIT Y (20) (50)

 

HEMORBHAG E 

*HESENTEBY (20) (50) 

ABTEEIOSCLEBOSIS, NOS U (20%)

 

ALL OTHEB SYSTEMS 

NOME 

SPECIAL MORPHOLOGY SUMMAR Y 

NO LFSION BEPOBTED 4 

HECBOPSY PEBF/NO HISTO PERFORMED 

AOTO/NECBOPSY/HISTO PEBF 1 

ADTO/NECROPSY/NO HISTO 

* NUSBEB OF ANIMAL S HITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBER OF ANIMAL S NECBOPSIED 

HIGH DOSE 

01-H035 

(50) 

1 (2X) 

(50) 

6 

1 

2 

G-6 
•TABLE G2 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE RATS TREATED WITH TDE 

CONTROL (VEH) L OW DOSE 

01-P033 01-F036 

ANIMALS INITIALLY IN STUDY 20 50 

ANIMALS NECROPSIED 19 49 

ANIHAL S EXAMINE D HI STOPATKOLOGICALl Y ** 19 18 

INTEGUMENTAR Y SYSTEM 

NON E 

RESPIBAICBY SYSTEH 

tLONG (19) (26) 

PNEUMONIA, :HEONIC MUHIN F 1 (5%) 1 C*«) 

HEMATOPOIETTC SYSTEH 

IBONE MARROi (19) (25) 

HETAHOBPHOSIS FATTY 1 <5X)

 

ISPLEEN (19) (27) 

HEMORBHA3E 

HEMATOPOIESIS 3 (16*) 1 <«X) 

tCEBVICAL 1YMPH NODE (17) (26) 

INFLAMMATION, NOS 1 (UX) 

tBESENTERIC L. NODE (") (26)

 

HEHOBBHASE 1 (6«)

 

CIRCULATORY SYSTEM 

*HEABT (19) (25) 

THROMBOSIS, NOS 1 (««> 

(MYOCARDIUM (19) (25) 

INFLAMMATION, NOS 1 (t*) 

DEGENERATION, NOS 1 (KX) 

• ENDOCARDIA (19) (25) 

HYPERPLASIA. NOS ^- _. m 

I NDHBER OF ANIMAL S WITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUHBFR OF ANIMALS NECROPSIED 

••EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

G-7 

HIGH DOSE 

01-F037 

50 

09 

49 

(28) 

» (1UX) 

(28) 

(30) 

1 (3X) 

« (13X) 

(27) 

(27) 

(29) 

1 (3X) 

(29) 

(29)

1.J3JU 
TABLE G2 (CONTINUED) 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE RATS TREATED WITH TDE 

CONTBOL(VBH ) LOW DOSE HIGH DOSE 

01-F033 01-F036 01-F037 

DIGESTIVE SYSTEM 

tLIVER (19) (32) (i*0) 

CYST, NOS 2 (6%) 1 <3X) 

MULTILOCULAR IYST 1 (5*) 2 (5*) 

INFLAMMATION , NO S 2 (6S) 

METAMORPHOSI S FATTY 1 (3*) 

#LIVEE/CENTRILOBDLAR (19) (32) (40) 

DEGENERATION , NOS 1 <3X ) 

*BILE DUCT (19) (1(9) (i»9) 

DILATATION, NOS 1 (2X) 

HYPEPPLASIA, NO S 1 (2*) 2 <UX ) 

*PANCREA S 

INFLAMMATION ,

PERIARTERITIS 

 NOS 

(19) 

1 (5X) 

(25) (30) 

1 (3X) 

tSTOHACH 

ULCER, FO=AL (19) 

2 (11*) 

(30) 

3 (10*) 

(33) 

2 (6X) 

*LARG E INTESTINE (19) (25) (27) 

INFLAMMATION , NOS 1 (**) 

#COLON (19) (25) (27) 

PARASITISM 3 (12*) 

URINAR Y SYSTEM 

#KIDNE Y (19) (25) (29) 

HYDRONEPH80SIS 1 (M) 

CYST, NOS 

INFLAMMATION, CHRONIC 

1 (5X) 

H (21%) 10 (U0%) 13 (USX) 

CALCIUM DEPOSII 1 (5%) 1 («X) 

ENDOCRIN E SYSTEM 

•ADRENAL (19) (27) (29) 

ANGIECTASIS 2 (11*) 3 (11X) 

tTHYROIB (19) (U8) (50) 

_F_OLLICULAg. -YST,. NOS ^ „ _ -1-J221 

# NUMBER OF ANIMAL S WITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBER OF ANIMALS NECBOPSIED 

G-8 
TABLE G2 (CONTINUED) 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE RATS TREATED WITH TDE 

HYPEBPLASIA, C-CELL 

HYPEBPLASIA, F3LLICOLAR-CELL 

*PAHATHY8OID 

HYPEBPLASIA, NOS 

BEPRODUCTIVE SYSTEH 

*MAHMABY GLAND 

GALACTOCELE 

*VAGINA 

INFLAMMATION . NOS 

POLYP 

tOTEBUS 

HYCFOSETBA 

CYST. NOS 

INFLAMMATION. NOS 

IUTEBUS/ENDOMETRIUN 

HYPEPPLASIA. NOS 

HYPEBPLASIA. CYSTIC 

*OVABY 

CYST. NOS 

NEBVOUS SYSTEM 

NONE 

SPECIAL SENSE ORGANS 

NONE 

MOSCULOSKELFTAL SYSTEM 

NON E 

BODY CAVITIES 

NONE. 

I NUMBE B OF ANIMAL S KITH TISSUE

* NUMBFB OF ANIMALS NECBOPSIED 

CONTROL (V EH) 

01-F033 

2 (11*) 

1 (5%) 

(1) 

(19) 

(19) 

(19) 

5 (26%) 

1 <5X) 

(19) 

(19) 

LOS DOSE HIGH DOSE 

01-F036 01-F037 

1 <8X) 5 (10X) 

2 (US) 3 (6X) 

(D dl 

1 (100X) 

(<»9) (U9) 

1 (2X) 

(»9) (49) 

2 (4X) 2 (IX) 

2 (tX) 

(30) (36) 

1 (3X) 5 (1«X) 

1 (3X) 

2 (7X) 1 (3X) 

(30) (36) 

1 (3%) 

3 (10X) » (11X) 

(26) (30) 

1 (3X) 

 EXAMINE D HICBOSCOPICALLY 

G-9 
TABLE G2 (CONCLUDED) 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE RATS TREATED WITH TDE 

CONTBOL(VEH) LOS DOSE HIGH DOSE 

01-F033 01-F036 01-F037 

ALL OTHER SYSTEMS 

NOME 

SPECIAL (IOBPHOL03Y SUMMAR Y 

MO LESION REPORTED 7 14

 

AUTO/NECROPSY/NO HISTO 1

 

ADTOLYSIS/NO NECROPSY 1 1 1

 

G-IO 
APPENDIX H
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN MICE TREATED WITH TDE
 

TABLE HI

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE MICE TREATED WITH TDE 

" " CONTBOL (»EH) LOI DOSE HIGH DOSE 

02-H029 02-H030 02-H031 

ANIMAL S INITIALLY IN STODT 20 50 50 

ANIMAL S BIS SINS 1 1 

ANIMALS NECROPSIBD 18 «9 50 

AH I HALS EXAMINED HISTOPATHOLOGICALLT** 18 49 49 

INTEGDMENTARY SYSTEM 

• SKIN (18) («9) (50) 

INFLAMMATION , NOS 2 (11*) 7 (1W) 3 (6«) 

CALCIFICATION, NOS 1 (2«) 

HYPEBKEBATOSIS 1 (6*) 

ACANTBOSIS 1 (6X) 

BESPIBA10BY SYSTEH 

•ACCESSORY SINUS (18) (49) (50)

 

INFLAMMATION, NOS 1 (6*)

 

ILUNG (18) (29) (35) 

PNEUMONIA , CHRONIC HUBINF 1 (3*)

 

HEHATOPOIETIC SYSTEH 

tSPLEF.N (18) (27) (26) 

AMYLOIDOSIS 1 (««) 3 (12« 

HEMATOPCIBSIS 3 (11*) 2 (8«) 

» 11 ES ENTER 1C L. NODE (") (25) (23) 

INFLAMMATION , NOS 2 (9*) 

CIRCULATORY SYSTEM 

tMYOCABDION (18) (2») (22)

 

DEGENERATION. NOS 1 <6«)

 

DIGESTIVE SYSTEH 

ILIVEB (18) («4) (50)

 

P.IGSSERA.TIOH, NOS 1.16X1

 

* NDNBEB OF ANIMAL S HITR TISSDE EXAMINED HICBOSCOPICALLY 

* NUNBEB OF ANIMALS NECBOPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

H-3 
TABLE HI (CONTINUED)

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE MICE TREATED WITH TDE 

INFARCT , NOS 

AMYLOIDOSIS 

CALCIUM DEPOSIT 

HYPERPLASIA , N3DDLA R 

*RECTU M 

PROLAPS E 

URINAR Y SYSTEM 

iKIDNE Y 

HYCSON5PHBOSI S 

CYST, NOS 

POLYCYSTIC KIDNE Y 

PYELONEPHRITIS , NOS 

INFLAMMATION , CHRONI C 

AHYLOIDOSIS 

CALCIU M DEP3SI1 

ENDOCRIN E SYSTEM 

IADRENAL 

INFLAMMATION , NOS 

REPRODUCTIV E SYSTE M 

*MAMMAR Y GLAN D 

GALACTOCELE 

*PREPUCF 

INFLAMMATION , NO S 

*PBEPUTIA L SLAN D 

INFLAMMATION , NOS 

ITESTIS 

ATROPHY , NOS 

*EPIDIDYflI S 

GRANULOMA , SPERMATI C 

NEBVOUS SYSTEM 

NONE 

* NUMBE R OF ANIMAL S WITH TISSUE

* NUMBE R OF ANIMAL S NECROPSIED 

CONTROL (VEH ) L OW DOSE 

02-M029 02-S030 

1 (2*) 

1 (2*) 

1 (6X) 

1 (6X) 2 (5X) 

(18) (19)

1 (6*) 11 (29X) 

(18) (35) 

2 <6X ) 

1 (6%) 

1 <3X) 

2 (11*) 12 (314%} 

6 (17S) 

(17) <2«) 

(18) (19) 

1 (2%) 

(18) (K9 ) 

1 (2«) 

(18) (i»9) 

1 (6*) 

(18) (25) 

(18) («9) 

1 <6X ) 

 EXAMINE D HICBOSCOPICALLY 

H-4 

HIGH DOSE 

02-M031 

1 (2%) 

1 (2X) 

(50) 

H (8«) 

(HO) 

1 OX) 

6 (15X) 

1 (3*) 

(23) 

1 <«» > 

(50) 

(50) 

(50) 

(25) 

2 (8X) 

(50) 

2 (IX) 
TABLE HI (CONCLUDED) 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE MICE TREATED WITH TDE 

CONTROL(VEH) L OR DOSE HIGH DOSE 

02-H029 02-H030 02-H031 

SPECIAL SENSE ORGAN S 

NON E 

HUSCULOSKELFTAL SYSTEM 

• MUSCLE HIP/THIGH (18) (i«9) (50) 

PABASITISM 1 <6X)

 

BODY CAVITIFS 

NONE 

A LL OTHER SYSTEMS 

NONE 

SPECIAL MOPPHDL3G Y SOBMAR Y 

NO LESION REPORTED 1 7 19 

ANIMAL HISSING/NO NECROPSY 1 1 

AUTO/NECBOPSY/HISTO PEBF 1 1 

AUTC/NSCROPSY/NO HISTO 1 

AUT01YSIS/NO NECROPSY 1 

I NUMBER OF ASIMALS WITH TISSUE EXAMINED MICBOSCOPICALLT
 

* NOMBEB OF ANIHALS NECFOPSIED
 

H-5
 
TABLE H2 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE MICE TREATED WITH TDE 

CONTROL (VFH) LOW DOSE HIGH DOSE 

02-F029 02-F030 02-F031 

AVI HALS INITIALLY IN STUDY 20 50 50 

ANIMALS HISSING 1 3 

ANIMAL S NECROPSIED 20 49 47 

ANIMALS FXAMINED HI STOPATHOLOGICALLY ** 20 49 47 

INTEGUMENTAP Y SYSTEM 

NONE 

tESPIRAIORY SYSTEM 

NONE 

HEMATOPOIETIC SYSTEM 

•SPLEEN (19) (21) (16) 

AMYLOIDOSIS 1 (5X) 

HEMATOPOIESIS 3 (19X) 

CI8COLATOSY SYSTEM 

NONE 

DIGESTIVE SYSTEM 

tSMALL INTFSTINE (20) (16) (13) 

INFLAMMATION , NOS 1 (8X) 

URINAR Y SYSTEM 

IKIDNEY (20) (22) (14) 

HYDRONEPHROSIS 1 (5*)

 

ABYLOIDOSIS 11 (50%) 

ENDOCRINE SYSTEM 

NON E _ _ 

t NUMBE R OF ANIMAL S WITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

"EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

H-6 
TABLE H2 (CONCLUDED) 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE MICE TREATED WITH TDE 

REPRODUCTIVE SYSTEM 

*UTEBUS 

HYDHOMETRA 

#UTERUS/£SDOMET8IUK 

INFLAMMATION , NO S 

HYPEPPLASIA , CYSTIC 

t O V A Rt O V A R Y

CYST. NONOS

INFLAMMATION. . NOS

S

NERVOUS SYSTEM 

N O N E 

SPECIAL SENSE ORGANB3ANS

N O N E 

MUSCULOSKELFTA L SYSTEM 

N O N E 

B O D Y CAVITIE CAVITIES

*ABDOMINAT . CAVIT Y

NECROSIS, FATT

A L L O T H E R SYSTEMS 

N O N E 

SPECIAL MORPHOLOG MORPHOLOGY SUMMARBA Y

NO LF.SION REPORTE REPORTE D

A N I H AA N I H A L MISSIN3/N MISSIN3/NO NECROPS NECROPS YY

I NUMBER OF ANIMALS WITH TISSUE

* NUMBER OF ANIMALS NECROPSIED 

CONTROL (VEH ) LOW DOSE 

02-F029 02-F030 

(19) (31) 

11 (58%) 16 (52S) 

(19) (31) 

1 (5*) U (13%) 

1 (5%) « (13%) 

(19))

(22 ) )

U

 (21% (21%) ) 5 (23% (23%))

3 (1K% (1W))

(20)(U9)

1 (5%(5%) ) 1 (2%(2) )

6 10

11

 EXAMINED MICROSCOPICALLY 

H-7 

HIGH DOSE 

02-F031 

(23) 

7 (30%) 

(23) 

4 (17%) 

2 (9*) 

(16 (16))

U (25% (25%)) 

2 (13* (13%)) 

(U747)

2233

 

3

 

APPENDIX I
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS
 

IN RATS TREATED WITH DDE
 

TABLE 111

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE RATS TREATED WITH DDE 

CONTROL (VBH) 

01-B028 LOi DOSE 01-M029 

HI3H DOSI 

01-M030 

MlI MLS INITIALLY IN STODT 

ANIMALS NBCROPSIED 

ANIMALS EXAMINED HISTOPATHOLOGICALLT** 

20 

29 

20 

50 

50 

19 

SO 

07 

«5 

INTEGUMENTARY SYSTEM
 

•SKIN	 (20) (50) («7)
 

FIBROHA 1 (2»)
 

•SOBCUT TISSUE (20) (50) (»7)
 

PAPILLOHA, DOS 1 (2*) 1 (2S|
 FIBROMA t (81)
 FIBROSARCOMA 1 (2X)
 

RESPIRATORY SYSTEM
 

HONE
 

HEMATOPOIETIC SYSTEH
 

*SPLEEN (19) (21) (19)
 

HENAMGIOSARCOHA 1 (5«)
 

CIRCDLATORY SYSTEH
 

iEHDOCARDIOl! (20) (2») (25)
 

SARCOMA, NOS 1 (5«)
 

DIGESTIVE SYSTEH
 

•BILE DOCT	 (20) (50) («7)
 

CYSTADENOMA, NOS	 1 (2X)
 

URINARY SYSTEM
 

*KIDNEY (20) (20) (20)
 

lIESSi 2_.{1JII
 

1-3 
TABLE II (CONTINUED) 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE RATS TREATED WITH DDE 

LIPOSARCOMA
 

ENDOCRINE SYSTEM
 

tPITUITARY
 CARCINOMA, NOS
 

CHROMOPHOBE ADENOMA
 

*THYROID
 

FOL1ICULAR-CELL ADENOMA
 

FOLLICDLAR-CELL CARCINOMA
 

C-CELL ADENOMA
 

C-CELL CARCINOMA
 

•PANCREATIC	 ISLETS
 

ISLET-CELL ADENOMA
 

REPRODUCTIVE SYSTEM
 

•MAMMARY GLAND
 

ADENOMA, NOS
 

PIBROADENOMA
 

•PROSTATE
 

SARCOMA, NOS
 

iTESTIS
 

INTERSTITIAL-CELL TUMOR
 

*EPIDIDYMIS
 

LIPOMA
 

NERVOUS SYSTEM
 

tBRAIN
 

6LIONA, NOS
 

SPECIAL SENSE ORGANS
 

NONE
 

MDSCOLOSKELETAl SYSTEM
 

— BQHE
 

CONTROL (VEH)
 

01-H028
 

(18)
 

(20)
 

2 (10X)
 

1 (5«)
 

2 (10X)
 

1 (5X)
 

(20)
 

(20)
 

1 (5X)
 

(16)
 

(18)
 

(20)
 

1 <5X)
 

(19)
 

LOW DOSE HI3H DOSR
 

01-H029 01-HC30
 

1	 (5t)
 

(18) (19)
 

1 (5X)
 

1 (22«)
 

(49) (U7)


8 (16K) 1

 8 (17X)
 

5 (10*) 2 (IX)
 

1 (2t| 1 <2X)
 

1 (2X)
 

(20)	 (21)
 

1 (5X)
 

(50) (K7)
 

1	 (2X)
 

(13)	 (16)
 

1 (6X|
 

(19)	 (18)


1 (6X)
 

(SO) (47)
 

(19)	 (18)
 

1 (5X)
 

*	 NDHBER OF ANIMALS KITH TISSDE EXAMINED MICROSCOPICALLY
 *	 NUMBER OF ANIMALS NECBOPSIED
 

I-4
 
TABLE II (CONCLUDED)

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE RATS TREATED WITH DDE 

" " "
 

BOOT CAVITIES
 

*ABDOHIHAL CAVITY
 

FIBROSARCONA
 

•MESENTERY
 

HEMANGIOHA
 

ALL OTBER StSTEHS
 

NONE
 

ANIMAL DISPOSITION SUMMARY
 

ANIMALS INITIALLY IN STUDY
 

NATURAL DEATH*
 

MORIBUND SACRIFICE
 

SCHEDULED SACRIFICE
 

ACCIDENTALLY KILLED
 

TERMINAL SACRIFICE
 

ANIMAL HISSING
 

9 INCLUDES AUTOLYZED ANIMALS
 

TUMOR SUMMARY
 

TOTAL ANIHALS SITB PRIMARY TUMORS*
 

TOTAL PRIMARY TUMORS
 

TOTAL ANIHALS KITH BENIGN TUMORS
 

TOTAL BENIGN TUMORS
 

TOTAL ANIMALS WITH MALIGNANT TUMORS
 

TOTAL MALIGNANT TUMORS
 

TOTAL ANIMALS WITH SECONDARY TUMORSt
 

TOTAL SECONDARY TUMORS
 

TOTAL ANIHALS IITH TUHORS UNCERTAINBENIGN OR MALIGNANT
 

TOTAL UNCERTAIN TUMORS
 

TOTAL ANIMALS ilTH TUMORS UNCERTAINPRIMARY OR HETASTAPIC
 

TOTAL UNCERTAIN TUMORS
 

CONTROL (VEH)
 

01-M028
 

(20)
 

(20)
 

1 <5X)
 

23
 

7
 

13
 

9
 

11
 

5
 

7
 

4
 

«
 

LOR DOSE
 01-M029
 

(50)
 

1 (2»)
 

(50)
 

50
 

32
 

18
 

21
 

29
 

15
 

20
 

9
 

9
 

HISH DOSE
 

01-H030
 

<«7)
 

(«7)
 

50
 

3D
 

1
 

15
 

20
 

20
 

15
 

15
 

5
 

5
 

* PRIMARY TUMORS: ALL TUHORS EXCEPT SECONDARY TDHORS
 

t SECONDARY TUMORS: BETASTATIC TUHORS OR TUMORS INVASIVE INTO AN ADJACENT ORGAN
 

1-5 
TABLE 12

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS TREATED WITH DDE 

HIGH DOSE
 

01-F032
 

50
 

50
 

46
 

(50)
 

1 (2X)
 

(50)
 

(50)


1 (2X)
 

(22)
 

(22)
 

(50)
 

ANIMALS INITIALLY IK STUDY
 

ANIMALS NECROPSIED
 

ANIMALS EXAMINED HISrOP ATHOLOGICALLY**
 

INTEGUMENTARY SYSTEM
 

*SUBCOT TISSUE
 SQOAMOUS CELL CARCINOMA
 

SARCOMA, NOS
 

FIBROSARCONA, METASTATIC
 HEHANGIOSARCOMA
 

RESPIRATORY SYSTEM
 

NONE
 

HEMATOPOIETIC SYSTEM
 

*MULTIPLE OBSANS
 MALIG.LYMPHOMA, HISTIOCYTIC TYPE
 

•SUBCOT TISSUE/BACK
 

MALIG.LYMPHOMA, HISTIOCYTIC TYPE
 

#SPLEEN
 

HEMANGIOHA
 

CI8COLATORY SYSTEM
 

tHEART
 

FIBROSARCOMA
 

*AORTA
 FIBROSARCOHA, METASTATIC
 

DIGESTIVE SYSTEM
 

HONE
 

t NUMBER OF ANIMAL S HIT H TISSUE

* NUMBER OF ANIMAL S NECROPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

CONTROL (VEH)
 

01-F028
 

20
 

20
 

20
 

(20)


1 (5X)
 

(20)
 

2 (10JS)
 

(20)
 

(20)
 

(20)
 

(20)
 

LOB DOSE
 

01-F031
 

50
 

19
 

47
 

(49)
 

1 (2*)
 

1 (2X)
 

1 (2*)
 

(U9)
 

1 (2X)
 

(K9)
 

(30)
 

1 (3%)
 

(29)
 

1 (3X)
 

(19)
 

1 (2X)
 

 EXAMINE D MICROSCOPICALLY 

1-6 
TABLE 12 (CONTINUED) 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS TREATED WITH DDE 

HIGH DOSE
 

01-F032
 

(23)
 

1 («*)
 

(27)
 

14 (52S)
 

(2«)
 

1 ("»*)
 

(«8)
 

8 (17X)
 » (8X)
 

1 (2*)
 

1 (2X)
 

(50)
 

1 (2X)
 

7 (1UX)
 

(50)
 

(23)
 

1 (««)
 

1 (««)
 

(21)
 

URINARY SYSTEH
 

tKIDNEY
 

PAPILLOMA, MOS
 

TUBULAR-CELL ADEHDHA
 

ENDOCRINE SYSTEM
 

IPITDITARY
 

CHROMOPHOBE ADENOMA
 

tADRENAL
 

CORTICAL ADENOMA
 

tTHYROID
 

FOLLICOLAR-CELL ADENOMA
 

FOLLICULAR-CELL CARCINOMA
 

C-CELL ADENOMA
 

C-CELL CARCINOMA
 

REPRODUCTIVE SYSTEH
 

*NAMHARY GLAND
 

ADENOMA. NOS
 

ADENOCARCINONA, NDS
 

FIBRO ADENOMA
 

*VA6INA
 

LEIOBYOSARCOHA
 

*UTERDS
 

SARCOMA, NOS
 

LEIOMYOSARCOBA
 

ENDOBETRIAL STROBAL POLYP
 

tOVARY
 

CYSTADENOBA, NOS
 

NERVOUS SYSTEH
 

NONE
 

SPECIAL SENSE ORGANS
 

—H2O
 

t NUMBER OF ANIMALS HITH TISSUE

* NUHBER OF ANIHALS NECBOPSIED 

CONTROL (VEH)
 

01-F028
 

(20)
 

1 (5*)
 

(18)


9 (50*)
 

(19)
 

(19)


1 (5X)
 

1 <5X)
 

1 (5X)
 

(20)
 

1 (5X)
 

5 (25*)
 

(20)
 

1 (5*)
 

(19)
 

(19)
 

 EXAHINED MICROSCOPICALLY 

LOfi DOSE
 

01-P031
 

(30)
 

(33)
 

10 (301)
 

(30)
 

1 (3X)
 

(l»8)
 

6 (13*)
 

3 (6*)
 

5 (10X|
 

3 <6X)
 

<«9)
 

2 (<»*)
 

5 (10«)
 

5 (10«)
 

(l»9)
 

(33)
 

3 (9X)
 

(30)
 

1 (3X)
 

I-7 
TABLE 12 (CONTINUED)

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS TREATED WITH DDE 

NDSCOLOSKELETAL SYSTEM
 

•SKULL
 

OSTEOHA
 

•SKELETAL MUSCLE
 

FIBSOSARCOMA
 

BOOT CAVITIES
 

•ABDOMINAL CAVITY
 PIBSOSARCOMA
 

ALL OTHER SYSTEMS
 

NONE
 

ANIMAL DISPOSITION SUMMARY
 

ANIMALS INITIALLY IH STODY
 

NATURAL OEATRi
 

NORIBDND SACRIFICE
 

SCHEDULED SACRIFICE
 ACCIDENTALLY KILLED
 

TERMINAL SACRIFICE
 

ANIMAL MISSING
 

i-IfiSmEES_4S12tYJED.4NlflH5
 

CONTROL (VEH)
 

01-F028
 

(20)
 

(20)
 

(20)
 

20
 

2
 

2
 

16
 

LOW DOSE HIGH DOSE
 

01-F031 01-F032
 

(19)	 (50)
 

1 (2»)
 

(«9) (50)
 

1 (2*)
 

(49)	 (50)
 

1 (2*)
 

50 50
 

11 24
 

2 3
 

37 23
 

* NUMBER OF ANIMALS KITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

i-8
 
TABLE 12 (CONCLUDED)

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS TREATED WITH DDE 

TUMOR SUMMARY
 

TOTAL ANIMALS WITH PRIMARY TUMORS*
 

TOTAL PRIMARY TUMORS
 

TOTAL ANIMALS WITH BENIGN TUMORS
 

TOTAL BENIGN TUMORS
 

TOTAL ANIMALS WITH MALIGNANT TUMORS
 

TOTAL MALIGNANT TUMORS
 

TOTAL ANIMALS WITH SECONDARY TUMORS*
 

TOTAL SECONDARY TUMORS
 

TOTAL ANIMALS WITH TUMORS UNCERTAIN­ BENIGN OR MALIGNANT
 

TOTAL UNCERTAIN TUMORS
 

TOTAL ANIMALS WITH TUMORS UNCERTAIN­ PRIMARY OR METASTATIC
 

TOTAL UNCERTAIN TUMORS
 

CONTROL (VEH)
 

01-F028
 

16
 

23
 

11
 

16
 

6
 

7
 

LOW DOSE HIGH DOSE 

01-F031 01-F032 

36 29 

49 U5 

27 25 

31 3« 

1U 10 

15 11 

1 

2 

* PRIMARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 

t SECONDARY TDHOHS: NETASTATIC TUMORS OR TUMORS INVASIVE INTO AN ADJACENT ORGAN
 

I-9
 

APPENDIX J
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS
 

IN MICE TREATED WITH DDE
 

TABLE Jl

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE MICE TREATED WITH DDE 

ANIMALS IRITIALLY II STDDI 

ANIMALS HISSING 

ANIMALS MECROPSIBD 

AIIHALS EXAHIIIED HISTOPATHOLOGICALLT* 

IRTEGOMBRTARY SYSTEM 

•SKIM 

SQOAHOOS CELL CARCINOMA 

FIBROMA 

PIBROSARCOMA 

* SOB COT TISSDE 

PIBROSARCOHA 

RESPIRATORY SYSTEM 

• LONG 

ALVEOLAR/BROBCHIOLAR ADENOBA 

HBHATOPOIBTIC SYSTEM 

•MULTIPLE ORGANS 

RALIG.LYHPHONA.

HALIG.LYNPHONA,

tMESENTERIC L. RODE 

NALIG.LYHPHOHA.

•LITER 

HALIG.LYRPHORA,

CIRCDLATORY SYSTEM 

ROIE 

DIGESTIVE SYSTEM 

tLI?ER 

 LYNPHOCYTIC TYPE 

 BISTIOCYTIC TYPE 

 HISTIOCIIIC TYPE 

 HISTIOCITIC TYPE 

BBEiietBHttliB.CiBCIJRBi .. 

CONTROL (TEH) 

02-H047 

20 

18 * 18 

(18) 

(18) 

(18) 

(18) 

(12) 

(19) 

(19) 

LOU DOSE HIGH DOSE 

02-M048 02-HOH9 

50 50 

1 

«1 »7 «1 *7

 

(«1) C»7) 

1 (2X) 

1 (2X) 

1 (2») 

(»1) (l»7) 

1 (2*1 » (9*) 

(»1) (US) 

1 (2X) 2 («*) 

(l»1) (17) 

1 (2«» 2 (5X) 1 (2«) 

(37) (39) 

2 (5») 

(«1) (l»7) 

1 <2») 1 (2») 

(«D (»7) 

2_£1ZIL 1Z.J368L 

t ROHBER OF AIIHALS IITH TISSOE EZAHIIZD MICROSCOPICALLY 

* IOMBER OF AIIMALS IBCROPSIBD 

••EXCLUDES PARTIALLY ADTOLYZED ANIMALS 

J-3
 
TABLE Jl (CONTINUED)

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE MICE TREATED WITH DDE 

CONTBOL(VEH) LOW DOSE HIGH DOSE 

02-HOH7 02-H048 02-M049 

HEMANGIOMA 1 (2*) 

HBHANGIOSARCOHA 1 (2X) 

URINAR Y SYSTEM 

KONF 

ENDOCRINE SYSTEM 

NONE 

REPRODUCTIVE SYSTEM 

tTESTIS O7) (HI) (4 HI 

INTERSTITIAL-CELL TOHOS 1 (2*) 

NERVOO S SYSTEM 

NONE 

SPECIAL SENSE ORGANS 

NONE 

MDSCOLOSKELETAL SYSTEM 

NONE 

BODY CAVITIES 

NONE 

ALL OTHER SYSTEMS 

__SONE ___ 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

J-4
 
TABLE Jl (CONCLUDED)
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE MICE TREATED WITH DDE
 

~ CONTROL (VEH) LOB DOSE HIGH DOSE 

02-HO<»7 02-H048 02-M049 

MURAL DISPOSITION SUHHARY
 

ANIMALS IHITIALLY IH STODY 20 50 50
 

NATURAL DEATH* 18 38 34
 MORIBUND SACRIFICE
 

SCHEDULED SACRIFICE
 

ACCIDENTALLY KILLED
 

TERHINAL SACRIFICE 2 11 16
 

ARIHAL HISSING 1
 

i INCLUDES ADTOLYZED AMI HALS
 

TDHOR SUHRARY
 

TOTAL ANIHALS ilTH PPIHARY TUMORS* 15 22
 

TOTAL PRIMARY TDBORS 18 28
 

TOTAL ANIHALS HITH BENIGN TUHORS tt 2
 

TOTAL BENIGN TUMORS 4 2
 

TOTAL ANIHALS HITH HALIGNANT TUMORS 13 22
 

TOTAL MALIGNANT TUMORS 14 26
 

TOTAL ANIMALS WITH SECONDARY TUMOHSt
 

TOTAL SECONDARY TUHORS
 

TOTAL ANIHALS RITH TUHORS UNCERTAINBENIGN OR HALIGNANT
 

TOTAL UNCERTAIN TUHORS
 

TOTAL ANIHALS MITH TUHORS UNCERTAINPRIHARY OR HETASTATIC
 

TOTAL UNCERTAIN TUMORS
 

* PBIKART TUMORS: ALL TUHORS EXCEPT SECONDARY TUMORS
 

I SECOND*8Y TDMORS: HETASTATIC TUMORS OB TUMORS INVASIVE INTO AN ADJACENT ORGAN
 

J-5
 
TABLE J2

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE MICE TREATED WITH DDE 

1
CONTROL (VEH) LOB DOSE HISH DOSE
 

02-P047 02-P050 02-F051
 

ANIMALS INITIALLY IK STUD! 20 50 50
 

ANIMALS HISSING 1
 

ANIMALS HECROPSIED 19 48 49
 ANIMALS EXAMINED HISTOPATHOLOGICALLY** 19 48 47
 

INTEGUMENTARY SYSTEM
 

•SKIN	 (19) (48) (49)
 SEBACEOUS ADENOHA 1 <5«)
 

•SDBCOT TISSBE (19) (48) (»9)
 HEMANGIOSARCORA 1 (2*)
 

RESPIRATORY SYSTEM
 

ILONG	 (19) (33) (44)
 HEPATOCELLDLAR CARCINOMA, NETAST	 1 (2*)
 

HEMATOPOIETIC SYSTEM
 

•HOLTIPLE ORGANS (19) (t8) (49)
 MALIG.LYMPHOMA, LYMPHOCYTIC TYPE 1 <S») 2 (41)
 NALIG.LYNPHOHA, HISTIOCYTIC TYPE 1 (2*) 1 (2*1
 

tSPLEEN (19) (33) (45)
 HEHANGIONA 1 (5*)
 BENANGIOSARCOHA 1 (3*1
 MALIG.LYHPHOMA. BISTIOCYTIC TYPE 1 (2*)
 

tLYMPH RODE (19) (32) (43)
 MALIG.LYNPHOMA. HISTIOCYTIC TYPE 1 <3X)
 

f UTERUS (18) (33) (44)
 HALIG.LYHPHONA, HISTIOCYTIC TYPE 1 (6%)
 

CIRCULATORY SYSTEH
 

--fiONI	 _
 

t NUMBER OF ANIMALS KITH TISSUE EXAMINE D MICROSCOPICALLY * NUMBER OF ANIMAL S HECBOPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

J-6 
TABLE J2 (CONTINUED)

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE MICE TREATED WITH DDE 

. ...
 

DIGESTIVE SISTER
 

*LIVER
 

HEPATOCELLOLAR CARCINOHA
 

HEHANGIOSARCOHA
 

ORINARY SYSTEM
 

NONE
 

ENDOCRINE STSTEH
 

tTHTBOID
 

FOLLICOLAR-CBLL CARCINOHA
 

*PANCREATIC ISLETS
 

ISLET-CELL ADENOHA
 

REPRODDCTIVE SISTEH
 

*RAHHART GLAND
 

ADENOCARCINOHA, N3S
 

FIBRO ADENOHA
 

tOTEROS
 

ADENOCARCINOHA, NOS
 

ENDOHETRIAL STROHAL POLYP
 

HEHAMGIOHA
 

NEBVODS STSTEH
 

NONE
 

SPECIAL SENSE ORGANS
 

NONE
 

HOSC0LOSKELETAL STSTEH
 

TONE
 

t NOHBER OF ANIMALS HITH TISSUE

* NDHBER OF ANIHALS NECROPSIED 

CONTROL (VEH) LOB DOSE
 

02-FOU7 02-F050
 

(19) (U7)


19 (40X)
 

1 12%}
 

(19) (33)
 

(19)	 (33)
 

1 <3X)
 

(19) (i»8)
 

2 (<•*)
 

1 (5«)
 

(18) (33)
 

1 (6*)
 

 EXAMINED HICROSCOPI^ALLT 

J-7
 

HIGH DOSE
 

02-F051
 

(48)
 

3U (71*)
 

(36)
 

1 (3XI
 

(45)
 

(i»9)
 

(« 11)
 

1 (2X)
 

1 (2X)
 
TABLE J2 (CONCLUDED) 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE MICE TREATED WITH DDE 

BODY CAVITIBS
 

NONE
 

ALL OTHER SYSTEMS
 

NONE
 

ANIMAL DISPOSITION SUMMARY
 

ANIMALS INITIALLY IS STUDY
 

NATURAL DEATHS
 MORIBUND SACRIFICE
 

SCHEDULED SACRIFICE
 

ACCIDENTALLY KILLED
 TERMINAL SACRIFICE
 ANIMAL HISSING
 

» INCLUDES AUTOLYZED ANIMALS
 

TDHOR SUMMARY
 

CONTROL (VEH)
 

02 -F 047
 

20
 

2
 

1
 

16
 

1
 

TOTAL ANIMALS RITE PRIMARY TUMORS* 

TOTAL PRIMARY TUMORS 

5 

6 

TOTAL ANIMALS KITH BENIGN TUMORS 

TOTAL. EENIGN TUMORS 

3 

4 

TOTAL ANIMALS HITH MALIGNANT TUMORS 

TOTAL MALIGNANT TUMORS 

2 

2 

TOTAL ANIMALS RITR SECONDARY TUHORSt 

TOTAL SECONDARY TUMORS 

TOTAL ANIMALS WITH TUMORS UNCERTAINBENIGN OR MALIGNANT TOTAL UNCERTAIN TUMORS 

TOTAL ANIMALS KITH TUMORS UNCERTAINPRIMARY OR HETASTATIC 

TOTAL UNCERTAIN TUMORS
 

* PRIMARY T080R3: ALL TDHOBS EXCEPT SECOHDART TOHORS
 

LOW DOSE 

02-F050 

HIGH DOSE 

02-F051 

50 

11 

1 

50 

27 

38 23 

25 

29 

1 

1 

2<» 

28 

35 

39 

1 

1 

35 

38 

1 

1 

I SECONDARY TO HOES: HETASTAIIC TOHORS Qfi TOHORS INVASIVE INTO AN ADJACENT ORGAN
 

J-8
 
APPENDIX K
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN RATS TREATED WITH DDE
 

TABLE Kl 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE RATS TREATED WITH DDE 

w_~w«<»~ ___»»««»— ~««~— ——»««~—
 

COMTROL(VIB) L0« DOSE HIGH DOSE
 01-H028 01-B029 01-H030
 

AfllHALS INITIALLY IM STUDY
 AIIHALS MECROPSIED
 AIIHALS EXAHIMED HIST3PATHOLOGICALLY**
 

IMTEGOHEMTABY SISTEH
 

• SKIM
 SEBACEOUS CIST
 

•SOBCOT TISSOE
 

HEHATOHA, NOS
 ULCER, NOS
 

RESPIRATOR! SYSTEM
 

tLOMG
 

CONGESTION, NOS
 

EDERA, ItOS
 

HEHORRRAGE
 PHEDHORIK, CHROMIC HORIHE
 

CALCIOH DEPOSIT
 HIPEFPLASIA, EPITHELIAL
 

HEBATOPOIETIC SYSTEM
 

IBORE HABROV
 HETAHOBPHOSIS FATTY
 

ISPLEEM
 COMGESTIOR, MOS
 PERIARTERITIS
 HEHATOPOIBSIS
 HYPOPLASIA, LIHPH3ID
 

*LYHPH MODE
 HYPFBPLASIA, MOS
 

•BESEHTERIC L. MODE
 

aiEEEEI.6,514^-1125 .
 

20 50
 

20 50
 

20 49
 

(20)	 (50)
 

1 (2»)
 

(20) (50)
 

3 (6*>
 

(20) (21)
 

1 (5*)
 

3 (1«»)
 3 (15*) 7 (33*)
 

1 (5») 1 (SX)
 

(19) (19)
 

3 (16X)
 

(19) (21)
 

1 (5X)
 

1 (5*) 5 (2l»X)
 

(19)	 (19)
 

1 (5X)
 

(19) (19)
 

50
 

U7
 

US
 

(17)
 

(47)
 

1 (2X)
 

(23)
 

t (17*)
 

6 (26X)
 

8 (35*)
 

1 (»X)
 

(18)
 

(19)
 

1 (5X)
 

6 (32X)
 

1 (5X)
 

(20)
 

(20)
 

J.I12IL
 

t MDHBEB OF AVIHALS WITH TISSOE EXAHIRED MICROSCOPICALLY * MUHBER OF ANIMALS MECROPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIHALS 

K-3 
TABLE Kl (CONTINUED) 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE RATS TREATED WITH DDE 

HISH DOSE
 

01-M030
 

(25)
 

1 (aX)
 

3 (12X)
 

(25)
 

1 (KX)
 

21 (841)
 

(25)
 

2 (8X)
 

(47)
 

6 (13X)
 

1 (2X)
 

(47)
 

(40)
 

5 (13X)
 

1 (3X)
 

3 <8X)
 

20 (50X)
 

5 (13X)
 

(40)
 

1 (3X)
 

(47)


4 (9X)
 

1 (2X)
 

1 (2*)
 

9 (19X)
 

(21)
 

CIRCULATORY SYSTEM
 

tHEART
 

ARTERIOSCLEROSIS, NOS
 

CALCIUM DEPOSIT
 

CALCIFICATION, NOS
 

tMYOCARDIUM
 

INFLAMMATION, NOS
 

DEGENERATION, NOS
 

CALCIUM DEPOSIT
 

IENDOCARDIOM
 

HYPERPLASIA, NOS
 

*AORTA
 ARTERIOSCLEROSIS, NOS
 

CALCIFICATION, NOS
 

*PULMONARY ARTERY
 HYPERTROPHY, NOS
 

DIGESTIVE SYSTEM
 

ILIVER
 CONGESTION, NOS
 

HEMATOMA, ORGANIZED
 

FIBROSIS
 

NECROSIS, NOS
 METAMORPHOSIS FATTY
 

ANGIECTASIS
 

tLIVER/CENTHILOBULAR
 

NECROSIS, COAGULATIVE
 

*BILE DOCT
 

DILATATION, NOS
 

CYST, NOS
 

INFLAMMATION, NOS
 FIBROSIS
 

HYPERPLASIA, NOS
 

tPANCREAS
 

CONTROL (VEH)
 

01-M028
 

(20)
 

1 <5X)
 

1 (5X)
 

(20)
 

10 (SOX)
 

1 <5X)
 

(20)
 

2 (10X)
 

(20)
 

3 (15X)
 

(20)
 

(20)
 

2 (10X)
 

(20)
 

(20)
 

2 (10X)
 

(20)
 

LOR DOSE
 

01-M029
 

(21)
 

2 (8X)
 

1 (4X)
 

(21)


1 (4X)
 

18 (75X)
 

(21)


1 (4X)­

(50)
 

10 (20*)
 

(50)
 

1 <2X)
 

(HO)
 

3 <8X)
 

1 <3X)
 

2 (5X|
 

25 (63X)
 

7 (18X)
 

(10)
 

(50)
 

1 <2X)
 

14 (28*)
 

(20)
 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMAL S NECROPSIED 

K-4 
TABLE Kl (CONTINUED)

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE RATS TREATED WITH DDE 

CONTROL (TEH) 

01-H028 

LOW DOSE 01-M029 

PERIARTEHITIS 

ARTERIOSCLEROSIS, HOS 

NECROSIS, FOCAL 

1

2

 (5X) 

 (19X) 

1 (20X) 

1 (5X1 

tSTOMACH 

ULCER. NOS 

ULCER, FOCAL 

CALCIDH DEPOSIT 

CALCIFICATION, HDS 

HYPERKERATOSIS 

(19) 

1

3

 (5X) 

 (16X) 

(25) 

5 (20X1 

6 (2UX) 

1 (i»X) 

IGASTRIC MUCOSA 

ULCER, NOS 

(19) (25) 

tPEYEHS PATCH 

HIPERPLASIA, HOS 

(19) (19) 

ICOLOH 

HEMATODIASIS 

PARASITISM 

(19) (18) 

1 (6X) 

URINARY SYSTEM
 

tKIONEY (20) (20)
 HYDRONBPHROSIS
 

CONGESTIOH. HOS 1 (5X)
 INFLAHMATIOH, CHR3NIC 15 (75X) 18 (901)
 

FIBROSIS
 

CALCIUM DEPOSIT 3 (15X) 1 (5X)
 

iKIDNEY/PELVIS (20) (20)
 

INFLAHMATION, NOS 1 (5X)
 

*ORETER (20) (50)
 

CALCIUM DEPOSIT 1 <2X)
 

fURINARY BLADDER (19) (25)
 

CYST, HOS 2 <8X)
 

IHPLAHHATIOH, NOS 3 (12X)
 tJLCER, FOCAL
 

HYPERTROPHY, NOS 3 (12*)
 

RYPERPLASIA, EPITHELIAL 1 (I»X)
 

ENDOCRINE SYSTEM
 

tPITDITARY (18) (18)
 

£I_It fl2£_ __ J_l__l


t NDHBER OF AHIRALS WITH TISSUE EXAMINED HICHOSCOPICALLY 

* NUHBER OF ANIHALS NECROPSIED 

K-5 

HISH DOSE
 01-H030
 

1 (5X)
 

1 <5X)
 

2 (10X)
 

(21)
 

2 (10X)
 

2 (10X)
 

2 (10X)
 

1 (5X)
 

1 (5X)
 

(21)
 

1 (5X)
 

(19)
 

1 (5X1
 

(1V)
 

1 (6X)
 

(20)
 

1 (5X1
 

18 (90S)
 

1 <5X)
 

2 (10X)
 

(20)
 

1 (5X)
 

(47)
 

(21)
 

1 (5X)
 

3 (UX)
 

(19)
 

 l-ilJI
 
TABLE Kl (CONTINUED)

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE RATS TREATED WITH DDE 

CONGESTION, NOS
 

•ADRENAL
 CONGESTION, HOS
 INFLAMMATION, FOCAL
 

DEGENERATION, NOS
 

HYPERTROPHY, HOS
 

HYPERPLASIA. HOS
 ANGIECTASIS
 

IADRFHAL CORTEX
 

CYTOPLASHIC VACOOLI ZATION
 

HYPERTROPHY, HOS
 

HYPERPLASIA, HOS
 

*THYROID
 CYST, HOS
 

POLLICULAB CYST, HOS
 

INFLAMMATION, NOS
 

ATROPHY, ROS
 

HYPERPLASIA, C-CELL
 

HYPERPLASIA, FOLLICDLAR-CELL
 

(PARATHYROID
 FIBROSIS
 

HYPERPLASIA, HOS
 

REPRODUCTIVE SYSTEM
 

»PROSTATE
 

CYST, HOS
 

IHFLAHNATIOH, HOS
 

ATROPHY, HOS
 

•SEMINAL VESICLE
 INFLAMMATION, HOS
 

INFLAMMATION, CHROHIC
 

tTESTIS
 INFLAMMATION, HOS
 

CALCIDH DEPOSIT
 CALCIFICATION, HOS
 

ATROPHY, HOS
 

•EPIDIDYMIS
 

&IE2EBJC...B25
 

COHTROL(VEH)
 

01-N028
 

(19)
 

(19)
 

(20)
 

4 (20*)
 

2 (10*)
 

(2)
 

2 (100X)
 

(16)
 

1 (6*)
 

(20)
 

(18)
 

1 (6«)
 

6 (33*)
 

(20)
 

2-.U2SI


LOR DOSE
 

01-H029
 

1 (6*)
 

(19)
 

1 (5*1
 

1 (SX)
 

1 <5X)
 

1 (5*1
 

(19)
 

1 (5»)
 

2 (111)
 

1 (5*)
 

(49)
 

1 (2()
 

3 (6»)
 

1 (2»)
 .
 

2 (»*>
 

(14)
 

1 (7*1
 14 (190*)
 

(13)
 

5 (38*)
 

2 (15X)
 

1 (8»)
 

(50)
 

1 (2X)
 

1 (2*)
 

(19)
 

1 (5*1
 

10 (531)
 

(50)
 

* HDHBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* ROBBER OF ANIMALS HECROPSIED 

K-6 

HI8H DOSE
 

01-H030
 

(19)
 

1 (5*1
 

1 (5X)
 

3 (16X)
 

(19)
 

(47)
 

6 (13*)
 

1 (2*)
 

1 (2«)
 » (9»)
 

(13)
 

12 (92*1
 

(16)
 

2 (13X)
 

(47)
 

2 (4*)
 

(18)
 

1 (6«)
 

» (22*)
 

(»7)
 

1-Ml
 
TABLE Kl (CONCLUDED) 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE RATS TREATED WITH DDE 

CONTROL (VEH) LOH DOSE 

01-H028 01-B029 

NERVOUS SYSTEH 

tBRAIN (19) (19)

 

HYDROCEPHALBS, NOS 

SPECIAL SENSE ORGANS 

*EYE (20) (50) 

PANNOS 2 (10X) 1 (2») 

CATARACT 1 (5%) 

*EYE/CORNEA (20) (50)

 

OLCEH, NOS 

HUSCOLOSKELETAL SYSTEH 

HONE 

BODY CAVITIES 

*ABDOHINAL CAVITY (20) (50) 

HFHORRHAGE 1 (2X) 

PIBROSIS 1 (2*) 

NECROSIS, FAT 1 (2X) 

*PERITONEOB (20) (50)

 

INFLAHHATION, NOS 

•MESENTERY (20) (50)

 

PERIARTERITIS 

ARTERIOSCLEROSIS, NOS 1 (5X)

 

ALL OTHER SYSTEHS 

NONE 

SPECIAL MORPHOLOGY SOHBABY 

NO LESION REPORTED 1 

NECROPSY PERF/NO HISTO PERPORflED 1 

AOTO/NECROPSY/NO HISTO 

4UIQI,XSI5^HQ-fiECE2ESI 

I NUBBER OP ANIBALS »ITH TISSUE EXABINED BICROSCOPICALLY
 

* NUBBER OP ANIBALS NECROPSIED
 

K-7
 

HIGH DOSE 

01-H030 

(18) 

1 (6») 

(47) 

(47) 

1 (2X) 

(47) 

(47) 

1 (2») 

(47) 

1 <2X) 

2 

2 
TABLE K2

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE RATS TREATED WITH DDE 

CONTROL (VEH) LOR DOSE 

01-F028 01-F031 

ANIMALS INITIALLY IN STUDY 20 50 

ANIMALS NECROPSIED 20 49 ANIMALS EXAMINED HISTDP ATHOLOGICA LLY ** 20 47
 

INTEGUMENTARY SYSTEM
 

•SOBCUT TISSUE (20) (49)
 ULCER, NOS
 

RESPIRATORY SYSTEM
 

ILUNG (20) (29)
 

MINERALIZATION
 

CONGESTION, NOS
 

EDEMA, NOS 6 (21*)
 HEMORRHAGE 5 (25X) 11 (381)
 ABSCESS, NOS
 

PNEUMONIA, CHRONIC HURINE 4 (20X) 1 (3X)
 GRANOL08A, NOS
 

CALCIFICATION, NOS
 

RYPERPLASIA, EPITHELIAL 2 (10X) 1 (3X|
 

• ALVEOLAR MALL (20) (29)
 CALCIFICATION, NOS 1 (3X)
 

HEHATOPOIETIC SYSTEM
 

•BONE MARROW (20) (29)
 METAMORPHOSIS FATTY 4 (20X) 1 (3X)
 

•SPLEEN	 (20) (30)
 THROMBOSIS, NOS
 

CONGESTION, NOS 1 <3X)
 GRANULOHA, NOS
 

PIGMENTATION, NOS 5 (25X)
 HYPERPLASIA. RETICULDM CELL 2 (10X)
 HERATOPOIESIS 4 (20X) 5 (17X)
 

tnESENTEBIC L. NODE	 (18) (27)
 

* NUHBER OF ANIMALS RITH TISSUE EXAHINBD MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

HIGH DOSE
 

01-F032
 

50
 

50
 

46
 

(50)
 

1 (2X)
 

(28)
 

1 (4X)
 

1 («*)
 

16	 (57X)
 

5 (18X)
 

1 (IX)
 

7 (25X)
 

1 (»»)
 

1 (««)
 

4	 (1»X)
 

(28)
 

(21)
 

(22)
 

1 <5X)
 

1 (5X)
 

1 (SX)
 

(18)
 

K-8 
TABLE K2 (CONTINUED)

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE RATS TREATED WITH DDE 

•TM»— ••»"••"•~«~""—TMTM"»«»—— *•••«••••»!••_•••
 

COMTROL(TEB) LOM DOSE
 

01-F028 01-F031
 

ARTERIOSCLEROSIS, NOS
 

HYPERPLASIA, MOS 1 (1»)
 

CIRCULATORY STSTEB
 

»HBART (20) (29)
 THROHBOSIS, MOS
 

CONGESTION, HOS 1 (5*)
 PIBROSIS 1 (5»)
 ARTERIOSCLEROSIS, HOS 1 (3X)
 

INYOCARDIOH (20) (29)
 IMFLAHBATIOM, HOS 2 (10%) 6 (21*)
 INFLABBATION, FOCAL
 

DEGENERATION, HOS 11 (55») 12 («1()
 

tENDOCAROiaH (20) (29)
 HTPERPLASIA, MOS 1 (3»)
 HYPERPLASIA. FOCAL
 

• AORTA (20) (»9)
 ARTERIOSCLEROSIS, HOS 2 (4S)
 

•POLHONARY VEIN (20) (19)
 PIBROSIS 1 (2<)
 

DIGESTIVE SYSTBH 

ILIVER 

THRORBOSIS, MOS 

COM6ESTIOM, MOS 

(20) (3») 

1 (3*1 

6RAMOLORA, BOS 

NECROSIS, MOS 

1 (5*) 

6 (181) MECROSIS, FOCAL 

MECROSIS. COAGOLATIVE 

BETARORPHOSIS FATTI 

1 (5%) 

11 (55*) 

1 (3«) 

3 (9«) 

ATROPHY, MOS HYPERTROPHY, MOS 2 (6X) HYPERTROPHY. FOCAL 

AMGIECTASIS 2 (6«) 3 (9*) 

•BILE DUCT 

DILATATION, BOS 

(20) («9) 

3 (6») 

IltU0JUXI°.l«-I&S 1.1511 , S-iBSL 

t IDMBER OP AIIHALS IITH TISSUE EXftRIIED ilCROSCOPICALLT
 

* iOHBER OF ARIHM.S HECBOPSIED
 

RICH DOSE
 

01-F032
 

1 (6X)
 

1 (6*)
 

(22)
 

1 (5X)
 

(22)
 

1 (18*)
 

1 (5X)
 

8 (361)
 

(22)
 

3 (1»»)
 

1 (5*)
 

(50)
 

2 («*)
 

(50)
 

(33)
 

1 (3*)
 « (12*)
 

1 (3*)
 

9 (27*)
 

1 (3*1
 

10 (30*)
 

1 (3*)
 

2 (6S)
 

(50)
 

3 <6«)
 

K-9 
TABLE K2(CONTINUED)

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE RATS TREATED WITH DDE 

FIBROSIS 

DEGENERATION, NOS 

HYPERPLASIA, NOS 

tPANCREAS 

PERIARTEHITIS 

ARTERIOSCLEROSIS, NOS 

CALCIFICATION, NOS 

•STOMACH 

OLCER, FOCAL OLCER, ACOTE 

GRANDLORA, NOS 

CALCIOH DEPOSIT HYPERKEHATOSIS 

ACANTROSIS 

*GASTRIC HOCOSA 

OLCER, FOCAL 

tSHALL INTESTINE 

HYPERPLASIA, NOS 

ILARGE INTESTINE 

IHPACTION, NOS 

URINARY SYSTEH 

tKIDNBY 

HINESALIZATION HYDRONEPHROSIS 

CONGESTION, NOS 

INFLAHHATION, CHR3NIC GRANOLOBA, NOS 

CALCIFICATION, NOS 

RYPERPLASIA, NOS 

HYPERPLASIA, EPITHELIAL 

tKIDHEY/PEHriS 

HINERALIZATION INFLABBATION, NOS 

IORIIARY BLADDER 

.- BIEMIB2EBI*.I25 _ .._

CONTROL (VEH)
 

01-F028
 

1 <5X)
 

9 (45X)
 

(20)
 

1 <5X)
 

(20)
 

(20)
 

2 (10X)
 

(20)
 

(20)
 

1 (5X)
 

(20)
 

3 (15X)
 

1 (5X)
 

2 (10X)
 

12 (60X)
 

1 (5X)
 

(20)
 

2 (10X)
 

1 (5X)
 

(20)
 

 1_J5SL
 

LOW DOSE
 01-F031
 

20 (41X)
 

(28)
 

1 (4X)
 

(30)
 

2 (7X)
 

1 (3X)
 

1 (3X)
 

(30)
 

(29)
 

1 (3X)
 

(29)
 

(3«)
 

11 (37X)
 

1 (3X)
 

17 (57X)
 

1 (3X)
 

3 (10X)
 

(30)
 

(28)
 

I KOHBER OF AIIHALS HITB TISSUE EXABINED HICROSCOPIZALLY * BOBBER OF ANIBALS NECROPSIED 

K-IO 

HISH DOSE
 

01-F032
 

1 (2X)
 

12 (2UX)
 

(21)
 

1 <5X)
 

1 (5X)
 

(30)
 

6 (20X)
 

1 (3X)
 

1 (3X)
 

1 (3X)
 

1 (3X)
 

(30)
 

(20)
 

(21)
 

(23)
 

6 (26X)
 

12 (S2X)
 

1 (»X)
 

1 C*X)
 

» (17X)
 

(23)
 

(21)
 
TABLE K2 (CONTINUED)

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE RATS TREATED WITH DDE 

ENDOCRINE SYSTEM 

•PITUITARY 

CYST, NOS 

HYPERTROPHY, HOS 

HYPERPLASIA, HOS 

HYPERPLASIA, CHROMOPHOBE-CELL 

•ADRERAL 

THROMBOSIS, HOS 

CONGESTION, MOS 

HEMORRHAGE 

DEGENERATION, NOS 

CYTOLOGIC DEGENERATION 

HYPERTROPHY, NOS 

ANGIECTASIS 

•ADREHAL CORTEX 

HYPERTROPHY, NOS

 

•THYROID 

FOLLICDLAR CYST, HOS 

DEGENERATION,

HYPERPIASIA,

HYPERPLASIA,

•PARATHYROID 

HYPERPLASIA,

 CYSTIC 

 C-CELL 

 FOLLICOLAR-CELL 

 NOS 

REPRODUCTIVE SYSTEM 

•VAGINA 

INFLAMMATION, MOS 

•UTERUS 

HYDROHETRA 

GRANULOHA, NOS 

• UTERUS/EHDOHETRIUM CIST, NOS 

INFLAMMATION, MOS 

HYPERPLASIA, NOS 

HYPERPLASIA, CYSTIC 

•OVARY 

CXSI* HQS .

* NUMBER OF ANIMALS KITH

 _

 TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

K-ll 

CONTROL (VEH) 

01-F028 

(18) 

1 (6*) 

(19) 

15 (79X) 

(19) 

(19) 

2 (11X) 

1 (5X) 

3 (16*) 

(20) 

(19) 

3 (16*) 

(19) 

1 <5X) 

1 (5*) 

(19) 

- ­

LOR DOSE 

01-F031 

(33) 

1 (3X) 

1 (3X) 

1 (3*) 

(30) 

1 (3X) 

1 (3X) 

2 (7X) 

1 (3X) 

8 (27X) 

(30) 

7 (23X) 

(U8) 

3 (6X) 

1 (2X) 

3 (6X) 

7 (15X) 

(2) 

2 (100*) 

(U9) 

1 (2X) 

(33) 

13 (39X) 

(33) 

2 (6X) 

3 (9X) 

(30) 

 2-JZSL

HIGH DOSE 

01-F032 

(27) 

1 («X) 

1 (»X) 

(2t) 

1 <«*) 

1 (»X) 

K (17X) 

(2<0 

» (17X) 

<t8) 

2 (tX) 

2 (UX) 

4 (8«) 

(3) 

3 (100X) 

(50) 

1 (2X) 

(23) 

6 (26X) 

1 C»X) 

(23) 

2 (9X) 

2 <9X) 

1 (4X) 

(21) 

 l.iSii 
TABLE K2 (CONCLUDED)

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE RATS TREATED WITH DDE 

HIGH DOSE
 

01-F032
 

1 (5X)
 

(20)
 

1 (5*)
 

(50)
 

(50)
 

1 (2X)
 

(50)
 

1 (2X)
 

1 <2X)
 

(50)
 

1 <2X)
 

2
 

2
 

FOLLICOLAR CIST, NOS
 

NERVOUS STSTEH
 

» BRUIN
 CYTOPLASMIC VACUOLIZATION
 

SPECIAL SENSE ORGAHS
 

*EY2
 

CONGENITAL MALFORMATION, SOS
 

EDEMA, NOS
 

CALCIFICATION, NOS
 

•EYE/CORNEA
 INFLAMMATION, NOS
 

MOSCULOSKELETAL SYSTEM
 

*NUSCLE HIP/THIGH
 

INFLAMMATION, NOS
 

INFLAMMATION, FOCAL
 

ARTERIOSCLEROSIS, NOS
 

BODY CAVITIES
 

*EPICARDIUH
 

INFLAMMATION, NOS
 

ALL OTHER SYSTEMS
 

NOME
 

SPECIAL MOBPHOLOGY SUMMARY
 

NECROPSY PEBF/NO HISTO PERFORMED
 

ADTO/NECROPSY/HISTO PERF
 

AUTO/HECROPSY/NO HISTO
 

AOTOLYSIS/NO KECR3PSY
 

CONTROL (VEH)
 

01-F028
 

(20)
 

(20)
 

(20)
 

1 <5X)
 

(20)
 

(20)
 

L0» DOSE
 

01-F031
 

(29)
 

(19)
 

1 (2X)
 

1 <2X)
 

1 (2X)
 

(19)
 

1 (2*)
 

(19)
 

1 (2X)
 

(19)
 

2
 

1
 

1
 

* HOHBEF OF AHIBALS KITH TISSUE EXASIHED MICROSCOPICALLY
 

* NOHBE8 OF ANIMALS NECROPSIED
 

K-I2
 
APPENDIX L
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN MICE TREATED WITH DDE
 

TABLE LI
 SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE MICE TREATED WITH DDE
 

CONTROL (VEH) LOW DOSE
 

P2-H047 02-H018
 

ANIHALS INITIALLY IN STUDY 20 50
 ANIHALS HISSING 1
 

ANIMALS NECROPSIED 18 <I1
 ANIHALS EXAHINED HISTOPATHOLOGICALLY** 18 »1
 

INTEGDHENTARY SYSTEH
 

*SKIN (18) (41)
 

EPIDERHAL INCLUSION CYST 1 (2*)
 

•SUBCUT TISSUE (18) (11)
 ABSCESS, NOS 1 (2X)
 

RESPIRATOR! SYSTEH
 

ILUNG (18) (»1)
 

PNEUHONIA, CHRONIC HDBINE 1 (2»)
 

HEMATOPOIETIC SYSTEM
 

•SPLEEN	 (19) (K1)
 INFLAHHATION, NOS 1 (5X)
 AHYLOIDOSIS 17 (89*) 25 (611}
 

HEHATOPOIESIS 2 <5X)
 

tHES ENTERIC L. NODE (12) (37)
 

INFLAHHATION, NOS 1 (8X) 1 (3X)
 

CIRCOLATOHY SYSTEH
 

•HEART	 (19) (»1)
 

THROHBOSIS, NOS 1 (2X)
 

tHYOCARDIDH (19) (41)
 INFLAHHATION, NOS 2 (5X)
 

tENDOCARDIUH (19) (41)
 

IBEUBBiII2B*-B25 _. 1-J2SL
 

* NUHBER OF ANIHALS WITH TISSUE EXAMINE D HICROSCOPICM.LY 

* NUMBER OF ANIMAL S NECHOPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

L-3 

HIGH DOSE
 

02-H049
 

50
 

47
 

47
 

(47)
 

(47)
 

(45)
 

(44)
 

13 (30X)
 

1 <2X)
 

(39)
 

(45)
 

(45)
 

1 (2X)
 

(45)
 
TABLE LI (CONTINUED) 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE MICE TREATED WITH DDE 

HIGH DOSE
 

02-BOa9
 

<»7)
 

1 (2X)
 

(US)
 

1 (2X)
 

(US)
 

1 (2X)
 

1 <2X)
 

16 (36*)
 

12 (27*)
 

(»«)
 

2 (5X)
 

(i»2)
 

1 (2»)
 

(«7)
 

DIGESTIVE STSTEB
 

tLIVER
 

THROMBOSIS, NOS
 

AHTLOIDOSIS
 

HYPERPLASIA. NODDLAR
 

tCOtON
 

PARASITISM
 

URINARY STSTEB
 

tKIDNEY
 POLICISTIC KIDHET
 

PYELONEPHRITIS, NDS
 INFLAMMATION, CHRONIC
 

AHYLOIDOSIS
 

IURINARY BLADDER
 

INFLAMMATION, BOS
 

ENDOCRINE SYSTEM
 

NONE
 

REPRODDCTITE SISTER
 

*PROSTATB
 

IRFLARHATIOI, HOS
 

•SEMINAL	 VESICLE
 INFLARHATION, IDS
 

NERVOUS SYSTEM
 

NONE
 

SPECIAL SENSE ORGANS
 

None
 

HUSCDLOSKELETAL SYSTEM
 

__BfiBE
 

CONTROL (VEH)
 

02-MOU7
 

(19)
 

8 («2»)
 

1 (5«)
 

(17)
 

(19)
 

2 (11X)
 

10 (53*)
 

(15)
 

(17)
 

(18)
 

1 (6X)
 

LOR DOSE
 

02-HO<(8
 

(1.1)
 

1 <2X)
 

2 (5J)
 

(«1)
 

1 (2X)
 

(»1)
 

1 (2X)
 

11 (27*)
 

26 (63*)
 

(40)
 

(39)
 

(41)
 

t NUMBER OF ANIMAL S KITH TISSUE EXAMINED MICROSCOPICAL!.?
 

* NUMBER OF ANIMALS HECBOPSIZD
 

L-4
 
TABLE LI (CONCLUDED) 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE MICE TREATED WITH DDE 

CONTROL (VEH) LOU DOSE HIGH DOSE 

02-B047 02-H008 02-BOU9 

BODY CAVITIES 

•PERICARDIUM (18) (»1) (U7)

 

INFLAMMATION , NOS 2 (5%}

 

ALL OTHER SYSTEHS 

NONE 

SPECIAL MORPHOLOGY SUMMAR Y 

NO LESION REPORTED 2 14 

ANIMA L HISSING/NO NECROPSY 1 

AUTOLYSIS/NO NECROPSY 2 8 3 

t NUHBER OF ANIHALS KITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

L-5
 
TABLE L2

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE MICE TREATED WITH DDE 

HIGH DOSE
 

02-F051
 

50
 

49
 

47
 

(49)
 

(44)
 

1 (2*1
 

(45)
 

1 (2X)
 

(44)
 

(48)
 

4 (8X)
 

1 (2*)
 

(49)
 

(45)
 

2.I2IL-...
 

ANIMALS INITIALLY IN ST0DY
 

ANIMALS HISSING
 

ANIMALS NFCROPSIED
 

ANIMALS EXAMINED HISTOPATHOLOGICALLY*¥
 

INTEGUMENTARY SYSTEM
 

*SOBCHT TISSUE
 

CYST, NOS
 

ABSCESS, NOS
 

RESPIRATORY SYSTEM
 

*LDNG
 

PNEUMONIA, CHRONIC MORINE
 

HEHATOPOIETIC SYSTEM
 

*SPLEEN
 AHYLOIDOSIS
 

HEMATOPOIESIS
 

CIRCULATORY SYSTEM
 

tHYOCAHDIOM
 

INFLAMMATION, NOS
 

DIGESTIVE SYSTEM
 

tLIVER
 

THHOHBOS, ORGANIZED
 HYPERPLASIA, NODULAR
 

•GALLBLADDER
 INFLAMMATION, NOS
 

•PANCREAS
 

£IST» NOS
 

t HOHBEfi OF ANIMAL S WITH TISSUE

* SOHBER OF ANIHAIS NECROPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

CONTROL (VEH)
 

02-POI»7
 

20
 

1
 

19
 

19
 

(19)
 

(19)
 

(19)
 

(19)
 

(19)
 

(19)
 

(19)
 

LOW DOSE
 

02-F050
 

50
 

48
 

US
 

<t8)
 

1 (2X)
 

1 (2X)
 

(33)
 

(33)
 

1 <3X)
 

1 (3X|
 

(33)
 

1 (3*1
 

(K7)
 

(«8)
 

1 (2X)
 

(33)
 

 EXAMIHED MICROSCOPICALLY 

L-6 
TABLE L2 (CONTINUED)

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE MICE TREATED WITH DDE 

HIGH DOSE
 02-F051
 

2 (»*)
 

(45)
 

(«»)
 

1 (2X)
 

(««)


6 (1«l)
 

(1»)
 

(UU)
 

3 (7X)
 

ATROPHY, NOS
 

URINARY STSTEN
 

IKIDNEY
 INFLAMMATION, CHROMIC
 

AMYLOIDOSIS
 

ENDOCRINE SYSTEM
 

MOKE
 

REPRODUCTIVE SYSTEM
 

IOTEROS
 

HYDROHETRA
 INFLAMMATION, NOS
 

•UTBRUS/ENDONETRIOH
 HYPERPLASIA, CYSTIC
 

»OVARY/OVIDDCT
 INFLAMMATION, DOS
 

•OVARY
 CYST, HOS
 

INFLAMMATION, HOS
 

HERVODS SYSTEM
 

MOME
 

SPECIAL SEMSE ORGANS
 

NOMB
 

MOSCOLOSKELETAL SYSTEM
 

-_B2HS ­

CONTROL (VEH)
 

02-POU7
 

(19)
 

(18)
 

1 (6*)
 

1 (6*>
 

(18)


3 (17X)
 

(18)
 

1 (6%)
 

(19)
 

6 (32*)
 

1 (5*)
 

LOU DOSE
 02-P050
 

(33)
 

2 (6X)
 

1 (3*)
 

(33)
 

1 (3*)
 

6 <2«)
 

(33)
 

8 (2UU)
 

(33)
 

(33)
 

» (12X)
 « (12X)
 

I NUMBER OP ANIMALS IITH TISSUE EXAMINED MICROSCOPICALLY
 * NUMBER OP ANIMALS NECROPSIED
 

L-7
 
TABLE L2 (CONCLUDED) 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE MICE TREATED WITH DDE 

CONTROL (VEH) LOU DOSE HIGH DOSE 

02-FOIt? 02-F050 02-F051 

BODY CAVITIES 

•PERITONEUM (19) <«8 ) (U9) 

INFLAMMATION , NOS 1 <5») 1 (2*)

 

•PERICARDIUM (19) (18) (49) 

INFLAMMATION , NOS 1 (2X)

 

ALL OTHER SYSTEHS 

NONE 

SPECIAL MORPHOLOGY SUMMAR Y 

NO LESION REPORTED 7 1tt 9 

ANIMA L MISSING/NO NECROPSY 1 

NECROPSY PERF/NO HISTO PERFORMED 1 

AOTO/NECBOPSY/HISTO PERF 2 

AUTO/NECROPSY/SO HISTO 1 

AOTOLYSIS/NO NECROPSY 2 1 

* NDMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

L-8
 
Review of the Bioassay of DDT, TDE, and p^p'-DDE*
 

for Carcinogenicity
 

by the Data Evaluation/Risk Assessment Subgroup
 

of the Clearinghouse on Environmental Carcinogens
 

June 29, 1978
 

The Clearinghouse on Environmental Carcinogens was
 

established in May, 1976, in compliance with DREW Committee
 

Regulations and the Provisions of the Federal Advisory
 

Committee Act. The purpose of the Clearinghouse is to
 

advise the Director of the National Cancer Institute (NCI)
 

on its bioassay program to identify and to evaluate chemical
 

carcinogens in the environment to which humans may be exposed.
 The members of the Clearinghouse have been drawn from
 

academia, industry, organized labor, public interest groups,
 State health officials, and quasi-public health and research
 

organizations. Members have been selected on the basis of
 

their experience in carcinogenesis or related fields and,
 collectively, provide expertise in chemistry, biochemistry,
 biostatistics, toxicology, pathology, and epidemiology.
 Representatives of various Governmental agencies participate
 

as ad hoc members. The Data Evaluation/Risk Assessment
 

Subgroup of the Clearinghouse is charged with the responsi­ bility of providing a peer review of reports prepared on
 

NCI-sponsored bioassays of chemicals studied for carcinogenic­ ity. It is in this context that the below critique is given
 

on the bioassay of DDT, TDE, and p^p'-DDE for carcinogenicity.
 

The reviewer agreed that the study did not provide firm
 

evidence for the carcinogenicity of DDT in rats or mice;
 

that TDE may be carcinogenic in the treated rats, as evid­ enced by an increased incidence of thyroid tumors; and that
 

p,p '-DDE was not carcinogenic in treated rats but did appear
 

to be a hepatocarcinogen in mice. The reviewer said that
 

caution should be exercised in interpreting the results in
 

view of the studies' shortcomings. Among the experimental
 

limitations, he noted the small matched control groups, the
 

fact that the study was conducted in a room in which other
 

chemicals were under test, the numerous dosage changes
 

during the course of the chronic study, and the variations
 

in the pathology protocol. The reviewer said that it was
 

not possible to assess human risk based on the results of
 

the study.
 

119
 
A Program staff member noted that other studies have
 

demonstrated the carcinogenicity of some of the test com­ pounds in mice. He said that the data from this study were
 

probably not ambiguous but rather reflected a difference in
 

response that exists between species and strains. It was
 

noted that any consideration to retesting the compounds
 

would be based, in part, on a review of all published studies,
 The reviewer moved that the report on the bioassay of DDT,
 TDE, and p,p'-DDE be accented as written. The motion was
 

approved without objection.
 

Clearinghouse Members present:
 

Arnold L. Brown (Chairman). Mavo Clinic
 

Paul Nettesheim. National Institute of Environmental
 

Health Sciences
 

Verne Rav. Pfizer Medical Research Laboratorv
 

Verald K. Rowe. Dow Chemical U.S.A.
 Michael B. Shimkin. Universitv of California at San Diego
 

Louise Strong. Universitv of Texas Health Sciences Center
 

*	 Subsequent to this review, changes may have been made
 

in the bioassay report either as a result of the review
 

or other reasons. Thus, certain comments and criticisms
 

reflected in the review may no longer be appropriate.
 

120
 

«OA GOVERNMENT PRINTING OFFICE: 1978 260-899/3197 1-3 


DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE
 

National Institutes of Health
 

i
 

REPORT ON BIOASSAY OF DDT,TDE AND P,P'-DDE FOR POSSIBLE CARCINOGENICITY
 

Availability
 

DDT, TDE and p,p'-DDE (CAS 50-29-3) have been tested for cancer-


causing activity with rats and mice in the Bioassay Program, Division of
 

Cancer Cause and Prevention, National Cancer Institute'. A report is
 

available to the public.
 

Summary: Bioassays of technical-grade DDT, TDE, and p,p'-DDE for
 

possible carcinogenicity were conducted using Osborne-Mendel rats and
 

B6C3F1 mice. TDE and p,p'-DDE are chemicals related to the insecticide
 

DDT. Each compound was administered in the feed, at either of two
 

concentrations, to groups of SO male and 50 female animals of each
 

species.
 

Under the conditions of these bioassays there was no evidence for
 

the carcinogenicity of DDT in.Osborne-Mendel rats or B6C3F1 mice, of TDE
 

in female Osborne-Mendel rats or B6C3F1 mice of either sex, or of p,p'­

DDE in Osborne-Mendel rats, although p,p'-DDE was hepatotoxic in Osborne-


Mendel rats. The findings suggest a possible carcinogenic effect of TDE
 

in male Osborne-Mendel rats, based on the induction of combined follicularcell carcinomas and follicular-cell adenomas of the thyroid. Because of
 

the variation of these tumors in control male rats in this study, the
 

evidence does not permit a more conclusive interpretation of/these
 
- 2 ­

lesions[ p,p'-DDE was carcinogenic in B6C3F1 mice, causing hepatocellulat carcinomas in both sexes.
 

Single copies of the report are available from the Office of Cancer
 

Communications, National Cancer Institute, Building 31, Room 10A21,
 

Nationa|. Institutes of Health, Bethesda, Maryland 20014.
 

Dated:
 

Octoberl 10, 1978 Director
 

National Institutes of Health
 

(Catalogue of Federal Domestic Assistance"Program Number 13.393, Cancer
 

Cause aijid Prevention Research)
 
DHEW Publication No. (NIH) 78-1386