National Cancer Institute 

CARCINOGENESIS 

Technical Report Series 

No. 156 

1979 

BIOASSAY OF 

p, p'-ETHYL-DDD 

FOR POSSIBLE CARCINOGENICITY 

CAS No. 72-56-0 

NCI-CG-TR-156 

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

Public Health Service 

National Institutes of Health 

BIOASSAY OF
 

p,p'-ETHYL-DDD
 

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) 79-1712 

BIOASSAY OF
 

p,p'-ETHYL-DDD
 

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 bioassay of
 

p,p'-ethyl-ODD conducted for the Carcinogenesis Testing Program,
 

Division of Cancer Cause and Prevention, National Cancer
 

Institute (NCI), National Institutes of Health, Bethesda,
 

Maryland. This is one of a series of experiments designed to
 

determine whether selected chemicals have the capacity to produce
 

cancer in animals. A negative result, in which the test animals
 

do not have a greater incidence of cancer than control animals,
 

does not necessarily mean that the test chemical is not a
 

carcinogen, inasmuch as the experiments are conducted under a
 

limited set of circumstances. A positive result demonstrates
 

that the test chemical is carcinogenic for animals under the
 

conditions of the test and indicates that exposure to the
 

chemical is a potential risk to man. The actual determination of
 

the risk to man from chemicals found to be carcinogenic in
 

animals requires a wider analysis.
 

CONTRIBUTORS; This bioassay of p,p'-ethyl-DDD was conducted by
 

the NCI Frederick Cancer Research Center (FCRC) (1), Frederick,
 

Maryland, operated for NCI (2) by Litton Bionetics, Inc.
 

The manager of the bioassay at FCRC was Dr. B. Ulland, the
 

toxicologist was Dr. E. Gordon, and Drs. R. Cardy and D. Creasia
 

compiled the data. Ms. S. Toms was responsible for management of
 

data, Mr. D. Cameron for management of histopathology, Mr. L.
 

Callahan for management of the computer branch, and Mr. R. Cypher
 

for management of the facilities. Mr. A. Butler performed the
 

computer services. Necropsies were performed by Drs. B. Ulland,
 

R. Schueler, R. Ball, and R. Cardy. The lesions of the rats and
 

mice were reviewed by Dr. W. C. Hall. The diagnoses included in
 

this report represent his interpretation.
 

Animal pathology tables and survival tables were compiled at EG&G
 

Mason Research Institute (3). Statistical analyses were
 

performed by Dr. J. R. Joiner (4) and Ms. P. L. Yong (4), using
 

methods selected for the bioassay program by Dr. J. J. Gart (5).
 

iii
 
The chemicals used in this bioassay were analyzed at FCRC by Dr.
 

W. Zielinsky (1). The chemical narrative and analyses were
 

reviewed and approved by Dr. W. Lijinsky (1).
 

This report was prepared at Tracor Jitco (4) under the direction
 

of NCI. Those responsible for the report at Tracor Jitco were
 

Dr. L. A. Campbell, Director of the Bioassay Program; Dr. S. S.
 

Olin, Deputy Director for Science; Dr. J. F. Robens,
 

toxicologist; Dr. R. L. Schueler, pathologist; Dr. G. L. Miller,
 

Ms. L. A. Waitz, Ms. M. S. King, and Mr. W. D. Reichardt,
 

bioscience writers; and Dr. E. W. Gunberg, technical editor,
 

assisted by Ms. Y. E. Presley and Ms. P. J. Graboske.
 

The following scientists at NCI were responsible for evaluating
 

the bioassay experiment, interpreting the results, and reporting
 

the findings: Dr. Kenneth C. Chu, Dr. Cipriano Cueto, Jr., Dr.
 

J. Fielding Douglas, Dr. Richard A. Griesemer, Dr. Thomas E.
 

Hamm, Dr. William V. Hartwell, Dr. Morton H. Levitt, Dr. Harry A.
 

Milman, Dr. Thomas W. Orme, Dr. A. R. Patel, Dr. Sherman F.
 

Stinson, Dr. Jerrold M. Ward, and Dr. Carrie E. Whitmire.
 

(1)	 Frederick Cancer Research Center, P.O. Box B, Frederick,
 

Maryland.
 

(2)	 Carcinogenesis Testing Program, Division of Cancer Cause and
 

Prevention, National Cancer Institute, National Institutes of
 

Health, Bethesda, Maryland.
 

(3)	 EG&G Mason Research Institute, 1530 East Jefferson Street,
 

Rockville, Maryland.
 

(4)	 Tracor Jitco, Inc., 1776 East Jefferson Street, Rockville,
 

Maryland.
 

(5)	 Mathematical Statistics and Applied Mathematics Section,
 

Biometry Branch, Field Studies and Statistics, Division of
 

Cancer Cause and Prevention, National Cancer Institute,
 

National Institutes of Health, Bethesda, Maryland.
 

iv
 
SUMMARY
 

A bioassay of p,p'-ethyl-DDD for possible carcinogenicity was
 

conducted by administering the test chemical in feed to F344 rats and
 

B6C3F1 mice.
 

Groups of 50 rats of each sex were administered p,p'-ethyl-DDD at one
 

of two doses, either 3,500 or 7,000 ppm, for 105 weeks. Matched
 

controls consisted of 20 untreated rats of each sex. All surviving
 

rats were killed at the end of administration of the test chemical.
 

Groups of 50 male mice were administered p,p'-ethyl-DDD at one of two
 

doses, either 2,500 or 5,000 ppm, for 105 weeks. Groups of 50 female
 

mice were administered the test chemical at one of two doses, initially either 5,000 or 10,000 ppm. Because of excessive lowered body
 

weights in the dosed groups of females, the doses for the females were
 

reduced after 48 weeks to 1,000 and 3,000 ppm, respectively, and
 

administration at the lowered doses was continued for 57 weeks. The
 

time-weighted average doses for the female mice were 2,828 and 6,200
 

ppm. Matched controls consisted of 20 untreated mice of each sex.
 

All surviving mice were killed at the end of administration of the
 

test chemical.
 

Mean body weights of dosed rats and mice of each sex were lower than
 

those of corresponding controls, and were dose related throughout the
 

bioassay. Survivals of the rats and mice were not, however, affected
 

by administration of the test chemical.
 

No tumors occurred in the male or female rats or in the male mice at
 

incidences that could clearly be related to administration of the test
 

chemical.
 

In the female mice, hepatocellular carcinomas or adenomas occurred at
 

incidences that were dose related (P = 0.011), but in direct comparisons the incidences in the individual dosed groups were not
 

significantly higher than that in the corresponding control group.
 

Although the occurrence of hepatocellular carcinomas or adenomas in
 

the dosed female mice are not clearly related to the administration of
 

the test chemical, the increased incidence of these tumors in the 

high-dose group suggests that the tumors may be related to the 

administration of p,p'-ethyl-DDD. 

It is concluded that under the conditions of this bioassay, p,p'­

ethyl-DDD was not carcinogenic for male or female F344 rats or male
 

B6C3F1 mice. However, the occurrence of hepatocellular carcinomas and
 

adenomas in female mice was suggestive of a carcinogenic effect.
 
vi

 
TABLE OF CONTENTS
 

I. Introduction 1
 

II. Materials and Methods 5
 

A. Chemical 5
 

B. Dietary Preparation 5
 

C. Animals 6
 

D. Animal Maintenance 7
 

E. Subchronic Studies 9
 

F. Chronic Studies 13
 

G. Clinical and Pathologic Examinations 13
 

H. Data Recording and Statistical Analyses 16
 

III. Results - Rats 23
 

A. Body Weights and Clinical Signs (Rats) 23
 

B. Survival (Rats) 23
 

C. Pathology (Rats) 26
 

D. Statistical Analyses of Results (Rats) 27
 

IV. Results -Mice 29
 

A. Body Weights and Clinical Signs (Mice) 29
 

B. Survival (Mice) 29
 

C. Pathology (Mice) 32
 

D. Statistical Analyses of Results (Mice) 35
 

V. Discussion 37
 

VI. Bibliography 41
 

APPENDIXES
 

Appendix A Summary of the Incidence of Neoplasms in
 

Rats Administered p,p'-Ethyl-DDD
 

in the Diet 45
 

Table Al Summary of the Incidence of Neoplasms in
 

Male Rats Administered p,p"-Ethyl-ODD
 

in the Diet 47
 

vii
 
Table A2 Summary of the Incidence of Neoplasms in 

Female Rats Administered p,p'-Ethyl-DDD 

in the Diet 51 

Appendix B Summary of the Incidence of Neoplasms in 

Mice Administered p,p'-Ethyl-ODD 

in the Diet 55 

Table Bl Summary of the Incidence of Neoplasms in 

Male Mice Administered p,p'-Ethyl-DDD 

in the Diet 57 

Table B2 Summary of the Incidence of Neoplasms in 

Female Mice Administered p,p'-Ethyl-DDD 

in the Diet 61 

Appendix C Summary of the Incidence of Nonneoplastic 

Lesions in Rats Administered p,p'-Ethyl-DDD 

in the Diet 65 

Table Cl Summary of the Incidence of Nonneoplastic 

Lesions in Male Rats Administered 

p,p'-Ethyl-DDD in the Diet 67 

Table C2 Summary of the Incidence of Nonneoplastic 

Lesions in Female Rats Administered 

p,p'-Ethyl-ODD in the Diet 74 

Appendix D Summary of the Incidence of Nonneoplastic 

Lesions in Mice Administered p,p'-Ethyl-ODD 

in the Diet 81 

Table Dl Summary of the Incidence of Nonneoplastic 

Lesions in Male Mice Administered 

p,p'-Ethyl-ODD in the Diet 83 

Table D2 Summary of the Incidence of Nonneoplastic 

Lesions in Female Mice Administered 

p,p'-Ethyl-DDD in the Diet 88 

Appendix E Analyses of the Incidence of Primary 

Tumors in Rats Administered p,p'-Ethyl-DDD 

in the Diet 93 

Table El Analyses of the Incidence of Primary Tumors 

in Male Rats Administered p,p*-Ethyl-ODD 

in the Diet 95 

viii
 
Table E2 Analyses of the Incidence of Primary Tumors 

in Female Rats Administered p,p'-Ethyl-DDD 

in the Diet 100 

Appendix F Analyses of the Incidence of Primary Tumors 

in Mice Administered p,p'-Ethyl-DDD 

in the Diet 105 

Table Fl Analyses of the Incidence of Primary Tumors 

in Male Mice Administered p,p'-Ethyl-DDD 

in the Diet 107 

Table F2 Analyses of the Incidence of Primary Tumors 

in Female Mice Administered p,p'-Ethyl-ODD 

in the Diet Ill 

TABLES 

Table 1 p,p'-Ethyl-ODD Subchronic Feeding Studies 

in Rats 10 

Table 2 p,p'-Ethyl-ODD Subchronic Feeding Studies 

in Mice 11 

Table 3 p,p'-Ethyl-DDD Chronic Feeding Studies 

in Rats 14 

Table 4 p,p"-Ethyl-DDD Chronic Feeding Studies 

in Mice 15 

FIGURES 

Figure 1 Growth Curves for Rats Administered 

p,p'-Ethyl-DDD in the Diet 24 

Figure 2 Survival Curves for Rats Administered 

p, p' -Ethy 1-DDD in the Diet 25 

Figure 3 Growth Curves for Mice Administered 

p,p'-Ethy 1-DDD in the Diet 30 

Figure 4 Survival Curves for Mice Administered 

p,p"-Ethy1-DDD in the Diet 31 

ix
 
X

 
I. INTRODUCTION
 

CH3CH2 CH2CH3
 

p,p'-Ethyl-DDD
 

p,p'-Ethyl-DDD. is 1»l~dichloro-2,2-bis(p-ethylphenyl)ethane (CAS
 

72-56-0; NCI C02868)i This organochlorine insecticide, which is
 

®
 marketed under the trade name Perthane , has a lower toxicity
 

to both insects and mammals than its structural analogs, DDT and
 

DDD (Brooks, 1975) and is of moderate persistence in the
 

environment (Martin and Worthing, 1977). First marketed in 1950
 

for use against houseflies and clothes moths, it has since been
 

used on vegetables, pears, and livestock (Finnegan et al., 1955;
 

Brooks, 1975; Meister, 1977). In the late 1950's, this compound
 

was one of several DDT analogs that were administered to patients
 

with breast or prostatic cancer for adrenocortical suppression
 
because of the selective toxicity of these compounds for the
 

adrenal cortex (Taliaferro and Leone, 1957).
 

Current production figures for p,p'-ethyl-DDD are withheld
 

(United States International Trade Commission, 1977); however, in
 

1974, approximately 200,000 pounds of this pesticide were used in
 

the United States (Ayers and Johnson, 1976). An analysis of use
 

patterns in that year showed that all applications were in
 

agriculture for the control of pests on fruits, nuts, and
 

various vegetable crops (Ayers and Johnson, 1976).
 

The oral LD,_0 of p,p'-ethyl-DDD has been reported as 8,170
 

rag/kg body weight in weanling albino rats (Finnegan et al., 1955)
 

and greater than 4,000 mg/kg body weight in adult Sherman rats
 

(Gaines, 1969). In weanling albino mice, the oral LD^ has
 

been reported as 9,340 mg/kg body weight (Finnegan et al., 1955)
 

and in mice of unspecified strain as 6,600 mg/kg body weight
 

(Brooks, 1975). p,p'-Ethyl-DDD causes atrophy of the adrenal
 

cortex in dogs, a property common to DDD, the
 

2,2-bis(p-chlorophenyl) analog (Larson et al., 1955; Bleiberg and
 

Larson, 1957). p,p'-Ethyl-DDD also inhibits adrenocortical
 

function in humans (Taliaferro and Leone, 1957), but the adrenal
 

cortex of the rat is unaffected by this or similar analogs
 

(Bleiberg and Larson, 1957).
 
p,p'-Ethyl-DDD was selected for testing in the Carcinogenesis
 

Testing Program because of its use as a pesticide and the
 

preliminary findings of Innes et al. (1969), which suggested that
 

further carcinogenicity testing was necessary.
 

II. MATERIALS AND METHODS
 

A. Chemical
 

Technical-grade Perthane was obtained from Rohm & Haas. This
 

material is a light-yellow, waxy semisolid at room temperature.
 

Its purity was determined by gas-liquid chromatography to be 93%,
 

with at least 40 contaminants ranging from 3.1% to less than
 

0.01%. It melting point was 38.9 C (literature value for pure
 

crystalline solid: 60 to 61 C) and its refractive index was
 

np 1.568 (literature value: n^ 1.561). Elemental analysis
 

showed an average of 69.2% carbon and 6.4% hydrogen (theoretical:
 

C 70.3%, and H 6.5%). Mass spectral analysis showed a molecular
 

ion at m/e 223. The infrared spectrum of the compound was
 

consistent with its chemical structure and identical with that of
 

an authentic standard.
 

B. Dietary Preparation
 

Test diets containing p,p'-ethyl-DDD were prepared every week in
 

6- to 12-kg batches at the appropriate doses. A known weight of
 

the chemical was first mixed with an equal weight of autoclaved
 
Wayne® Sterilizable Lab Meal (Allied Mills, Inc., Chicago,
 

111.) using a mortar and pestle. The mixing was continued with
 

second and third additions of feed, and the final mixing was
 

performed with the remaining quantity of feed for a minimum of 20
 

minutes in a Patterson-Kelly twin-shell blender with an
 

intensifier bar.
 

The diets were stored at 7°C until used.
 

C. Animals
 

Male and female F344 (Fischer) rats and B6C3F1 mice were obtained
 

as 4-week-old weanlings, all within 3 days of the same age, from
 

the Federick Cancer Research Center animal farm (Frederick, Md.),
 

monitored by the Division of Cancer Treatment, NCI. The animals
 

were housed within the test facility for 2 weeks and then were
 

assigned four rats to a cage and five mice to a cage on a weight
 

basis for each cage of animals of a given species and sex. For
 

use in the chronic study, male rats were required to weigh 90 to
 

105 g, averaging at least 100 g; female rats, 80 to 95 g,
 

averaging at least 90 g; male mice, 18 to 22 g, averaging at
 

least 19.5 g; and female mice, 17 to 21 g, averaging at least
 

18.5 g. Individual animals were identified by ear punch.
 
D. Animal Maintenance
 

The animals were housed in polycarbonate cages (Lab Products,
 

Inc., Garfield, N.J.), 19 x 10-1/2 x 8 inches for the rats and
 

11-1/2 x 7-1/2 x 5 inches for the mice, which were suspended from
 

aluminum racks (Scientific Cages, Inc., Bryan, Tex.) and were
 

covered by nonwoven polyester-fiber 12-mil-thick filter paper
 

(Hoeltge, Inc., Cincinnati, Ohio). The bedding used was
 

Absorb-dri hardwood chips (Northeastern Products, Inc.,
 

Warrenburg, N.Y.). The feed was presterilized Wayne
 

Sterilizable Lab Meal, provided ad libitum in suspended stainless
 

steel hoppers and replenished at least three times per week.
 

Water, acidified to pH 2.5, was supplied ad libitum from glass
 

bottles. Sipper tubes (Lab Products, Inc.) were suspended
 

through the tops of the cages.
 

The contaminated bedding was disposed of through an enclosed
 

vacuum line that led to a holding tank from which the bedding was
 

fed periodically into an incinerator. The cages were sanitized
 

twice per week and the feed hoppers twice per month at 82 to
 

88 C in a tunnel-type cagewasher (industrial Washing Machine
 

Corp., Mataway, N. J.), using the detergents, Clout® (Pharmacal
 

Research Laboratories, Greenwich, Conn.) or Oxford D'Chlor
 

(Oxford Chemicals, Atlanta, Ga.).
 
The glass bottles and sipper tubes were sanitized at 82 to 88 C
 

in a tunnel-type bottle washer (Consolidated Equipment Supply
 

Co., Mercersburg, Pa.) three times per week, using a Calgen
 

Commercial Division detergent (St. Louis, Mo.). The racks for
 

the cages were sanitized at or above 82 C in a rack washer
 

(Consolidated Equipment Supply Co.) once per month, using the
 

Calgen Commercial Division detergent, and the filter paper was
 

changed at the same time.
 

The air in the animal rooms was maintained at 22 to 24 C and 45
 

to 55% relative humidity. Fresh air was passed through a filter
 

of 65% efficiency and a bag filter of 95% efficiency at the
 

intake and through a "Z"-type roughing filter of 30% efficiency
 

and a bag system of 90 to 95% efficiency at the exhaust (American
 

Air Filters, Louisville, Ky.; Mine Safety Appliances, Pittsburgh,
 

Pa.) and was not recirculated. Room air was changed 15 times per
 

hour. The air pressure was maintained negative to a clean
 

hallway and positive to a return hallway. Fluorescent lighting
 

was provided automatically on a 12-hour-per-day cycle.
 

Rats administered p,p'-ethyl-DDD and their corresponding controls
 

were housed in the same room as rats on feeding studies of the
 

following chemicals:
 

(CAS 103-33-3) azobenzene
 

(CAS 51-03-6) piperonyl sulfoxide
 

8
 
Mice administered p,p'-ethyl-ODD and their corresponding controls
 

were housed in the same room as mice on feeding studies of the
 

following chemicals:
 

(CAS 103-33-3) azobenzene
 

(CAS 128-66-5) C.I. vat yellow 4
 

(CAS 20941-65-5) ethyl tellurac
 

(CAS 298-00-0) methyl parathion
 

(CAS 85-44-9) phthalic anhydride
 

E. Subchronic Studies
 

Subchronic feeding studies were conducted to estimate the maximum
 

tolerated doses (MTD's) of p,p'-ethyl-DDD, on the basis of which
 

two concentrations (referred to in this report as "low" and
 

"high" doses) were selected for administration in the chronic
 

studies. Groups of five rats and five mice of each sex were fed
 

diets containing ,p,p"-ethyl-DDD at one of several doses, and
 

groups of five control animals of each species and sex were
 

administered basal diet only. The period of administration of
 

the test chemical was 5 or 7 weeks; the 7-week groups were
 

observed for an additional week. Tables 1 and 2 show the number
 

of animals in each dosed group that Survived to the end of the
 

dosing period and the week on study when the last death occurred;
 

the tables also show the mean body weights of dosed animals at
 
Table 1. p,p'-Ethyl-DDD Subchronic Feeding Studies
 

In Rats
 

Male
 Female
 

Week on
 Mean Weight
 Week on
 Mean Weight
 

Study When
 at Week 5
 Study When
 at Week 5
 

Dose
 Surviv- Last Death
 as % of
 Surviv­ Last Death
 as % of
 

(ppm)
 al (a) Occurred
 Control
 al (a)
 Occurred
 Control
 

First
 Study
 

1,000
 5/5
 100
 5/5
 102
 

3,500 5/5
 92
 5/5
 96
 

5,000 5/5
 90
 5/5
 103
 

7,000 5/5
 92
 5/5
 93
 

9,000 5/5
 87
 5/5
 93
 

14,700 5/5
 85
 5/5
 92
 

20,000 5/5
 71
 5/5
 82
 

Mean Weight
 Mean Weight
 

at Week 7
 at Week 7
 

as % of
 as % of
 

Control
 Control
 

Second Study
 

6,800 5/5
 91
 5/5
 93
 

10,000 5/5
 65
 5/5
 90
 

14,700 5/5
 74
 5/5
 76
 

21,500 5/5
 42
 5/5
 62
 

31,500 3/5 4
 28
 1/5
 7
 33
 

(a) Number surviving/number in group.
 

10
 
Table 2. p,p'-Ethyl-DDD Subchronic Feeding Studies
 

In Mice
 

Male Female
 

Week on Mean Weight Week on Mean Weight
 

Study When at Week 7 Study When at Week 7
 

Dose Surviv- Last Death as % of Surviv- Last Death as % of
 

(ppm) al (a) Occurred Control al (a) Occurred Control
 

First Study
 

2,000 5/5 101 5/5 93
 

4,000 5/5 106 5/5 95
 

5,000 5/5 104 5/5 90
 

6,000 5/5 102 5/5 105
 

7,000 5/5 102 5/5 94
 

8,000 5/5 106 5/5 92
 

9,000 5/5 99 5/5 82
 

10,000 5/5 90 5/5 84
 

12,000 5/5 98 5/5 85
 

Second Study
 

10,000 5/5 89 5/5 105
 

14,700 4/5 2 92 4/5 3 93
 

21,500 5/5 77 4/5 4 93
 

31,500 2/5 4 83 4/5 2 84
 

46,500 1/5 4 73 2/5 3 73
 

(a) Number surviving/number in group.
 

11
 
week 5 or 7, expressed as percentages of mean body weights of
 

controls.
 

At the end of the subchronic studies, all animals were killed
 

using C0_ and necropsied. The lowest dose at which
 

histopathologic findings were observed for the male and female
 

rats was 21,500 ppm. At this dose, there was a marked increase
 

in splenic hematopoiesis and a generally slight decrease in bone
 

matrow cellularity. No clinical or histopathologic findings were
 

reported for the mice dosed at 31,500 ppm.
 

Ten percent depression in body weight was the major criterion for
 

estimation of MTD's. The doses required to produce this response
 

were determined by the following procedure: first, least squares
 

regressions of mean body weights versus days on study were used
 

to estimate mean body weights of each of the dosed groups at day
 

49. Next, probits of the percent weights of dosed groups at day
 

49 relative to weights of corresponding control groups were
 

plotted against the logarithms of the doses, and least squares
 

regressions fitted to the data were used to estimate the doses
 

required to induce 10% depression in weight.
 

Based on the data thus obtained, the low and high doses for
 

chronic studies using rats were set at 3,500 and 7,000 ppm; using
 

12
 
male mice, 2,500 and 5,000 ppm; and using female mice, 5,000 and
 

10,000 ppm.
 

F. Chronic Studies
 

The test groups, doses administered, and durations of the chronic
 

feeding studies are shown in tables 3 and 4. Due to excessive
 

depression in the amount of body weight gained in the dosed
 

female mice, doses for the low- and high-dose groups were reduced
 

to 1,000 and 3,000 ppm, respectively, after week 48.
 

G* Clinical and Pathologic Examinations
 

All animals were checked twice daily for deaths. Observations
 

for sick, tumor-bearing, and moribund animals were recorded
 

daily. Clinical examination and palpation for masses were
 

performed each month, and the animals were weighed at least once
 

per month. Moribund animals and animals that survived to the end
 

of the bioassay were killed using C0_ and then necropsied.
 

The pathologic evaluation consisted of gross and microscopic
 

examination of major tissues, major organs, and all gross
 

13
 
Table 3. p,p'-Ethyl-DDD Chronic Feeding Studies
 

in Rats
 

Sex and Initial p,p' -Ethyl -ODD Time on 

Test No. of in Diet (b) Study 

Group Animals (a) (ppm) (weeks) 

Male
 

Mat ched-Contro 1 20 0 105
 

Low-Dose 50 3,500 105
 

High-Dose 50 7,000 105
 

Female
 

Matched-Control 20 0 105
 

Low-Dose 50 3,500 105
 

High-Dose 50 7,000 105
 

(a)	 All animals were 6 weeks of age when placed on study.
 

(b)	 Test and control diets were provided a.d libitum 7 days
 

per week.
 

14
 
Table 4. p,p'-Ethyl-DDD Chronic Feeding
 

Studies in Mice
 

Sex 

and Test 

Group 

Initial 

No. of 

Animals (a) 

p,p'-EthylDDD 

in Diet (b) 

(ppm) 

Time on 

Study 

(weeks) 

Time-Weighted 

Average 

Dose (c) 

(ppm) 

Male 

MatchedControl 20 0 105 

Low-Dose 50 2,500 105 

High -Dose 50 5,000 105 

Female
 

Matched-


Control 20 0 105
 

Low-Dose 50	 5,000 48
 

1,000 57 2,828
 

High -Dose 50 10,000 48
 

3,000 57 6,200
 

(a)	 Al animal l s were 6 weeks of age when placed on study.
 

(b)	 Test and control diets were provided ad_ 1 ibi turn 7 days
 

per week.
 

(c)	 Time-weighted average dose =£(dose in ppm x no. of weeks at that dose)
 

£(no.of weeksreceiving eachdose)
 

15
 
lesions. The tissues were preserved in 10% neutral formalin,
 

embedded in paraffin, sectioned, and stained with hematoxylin and
 

eosin. The following tissues were examined microscopically:
 

skin, lungs and bronchi, trachea, bone marrow (femur), spleen,
 

lymph nodes (mesenteric and submandibular), thymus, heart,
 

salivary glands (parotid, sublingual, and submaxillary), liver,
 

pancreas, esophagus, stomach (glandular and nonglandular), small
 

and large intestines, kidney, urinary bladder, pituitary,
 

adrenal, thyroid, parathyroid, mammary gland, testis, prostate,
 

uterus, ovary, brain (cerebrum and cerebellum), and all tissue
 

masses. Peripheral blood smears also were made for all animals,
 

whenever possible.
 

Necropsies were also performed on all animals found dead, unless
 

precluded in whole or part by autolyis or cannibalization. Thus,
 

the number of animals from which particular organs or tissues
 

were examined microscopically varies and does not necessarily
 

represent the number of animals that were placed on study in each
 

group.
 

H. Data Recording and Statistical Analyses
 

Pertinent data on this experiment have been recorded in an
 

16
 
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 appropriate 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 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) for testing two groups for equality and Tarone's (1975)
 

extensions of Cox methods for testing for a dose-related trend.
 

17
 
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 is 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 one-tailed Fisher
 

exact test (Cox, 1970) was used to compare the tumor incidence of
 

a control group with that of a group of dosed animals at each
 

dose level. When results for a number of dosed groups (k) are
 

compared simultaneously with those for a control group, a
 

correction to ensure an overall significance level of 0.05 may be
 

made. The Bonferrotii inequality (Miller, 1966) requires that the
 

18
 
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), was also used. Under the
 

assumption of a linear trend, this test determines 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 is a positive dose
 

relationship. This method also provides 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 found. Once this reduced set of data was
 

obtained, the standard procedures for analyses of the incidence
 

19
 
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 an animal died naturally or was sacrificed
 

was 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 (P less than 0.05,
 

two-tailed test) were also noted.
 

The approximate 95 percent confidence interval for the relative
 

risk of each dosed group compared with 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 incidence of a specific type of tumor
 

in a dosed group of animals and p is the true probability of
 

the spontaneous incidence of the same type of tumor in a control
 

group. The hypothesis of equality between the true proportion of
 

20
 
a specific tumor in a dosed group and the proportion in a control
 

group corresponds to a relative risk of unity. Values in excess
 

of unity represent the condition of a larger proportion in the
 

dosed 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% of a large number of identical experiments, the
 

true ratio of the risk in a dosed 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 (P less than 0.025 one-tailed test when the
 

control incidence is not zero, P less than 0.050 when the control
 

incidence is zero) has occurred. When the lower limit is less
 

than unity, but the upper limit is a 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.
 

21
 
22

 
III. RESULTS - RATS
 

A. Body Weights and Clinical Signs (Rats)
 

Mean body weights of dosed male and female rats were lower than
 

those of corresponding matched controls, and depressions in the
 

amount of body weight gained were dose related throughout the
 

bioassay (figure 1). Other clinical signs, such as corneal
 

opacity and tissue masses, were common to both the dosed and the
 

control groups.
 

B. Survival (Rats)
 

The Kaplan and Meier curves estimating the probabilities of
 

survival for male and female rats administered p,p"-ethyl-ODD in
 

the diet at the doses of this bioassay, together with those of
 

the matched controls, are shown in figure 2. The result of the
 

Tarone test for dose-related trend in mortality is not
 

significant in either sex.
 

In male rats, 35/50 (70%) of the high-dose group, 34/50 (68%) of
 

the low-dose group, and 11/20 (55%) of the matched-control group
 

23
 
TIME ON STUDY (WEEKS) 

Figure 1. Growth Curves for Rats Administered p, p'-Ethyl-DDD in the Diet 

24 
MALE RATS 

D MATCHED CONTROL 

O LOW DOSE 

A HIGH DOSE 

TIME ON STUDY (WEEKS) 

Figure 2. Survival Curves for Rats Administered p, p'-Ethyl-DDD in the Diet 

25 
lived to the end of the bioassay. In females, 42/50 (84%) of the
 

high-dose group, 42/50 (84%) of the low-dose group, and 15/20
 

(75%) of the matched-control group lived to the end of the
 

bioassay.
 

Sufficient numbers of rats of each sex were at risk for the
 

development of late-appearing tumors.
 

C. Pathology (Rats)
 

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 were found in dosed and control animals.
 

The neoplasms were of a type, incidence, and distribution known
 

to occur in aged F344 rats and are therefore not considered to be
 

related to compound administration.
 

A variety of nonneoplastic lesions were encountered among both
 

control and dosed rats. Such lesions have been encountered
 

previously in aged laboratory rats and did not appear to be
 

related to the chemical under study. Sialoadenitis, typical of
 

26
 
the disease induced by a coronavirus (Jacoby et al., 1975) was
 

commonly encountered.
 

Nonneoplastic proliferative lesions, found only in dosed rats,
 

were basophilic foci or areas of the liver (1/50 low-dose males,
 

6/50 high-dose males; 1/50 low-dose females, 3/50 high-dose
 

females), stromal polyps of the uterus (5/50 low-dose and 3/50
 

high-dose females), and an adenomatous polyp of the uterus (1/50
 

high-dose females). These may be compound related, but the
 

incidence is too low for conclusions to be formed.
 

Based on the histopathologic examination, there was no evidence
 

for the carcinogenicity of p,p'-ethyl-DDD in F344 rats under the
 

conditions of this bioassay.
 

D. Statistical Analyses of Results (Rats)
 

Tables El and E2 in Appendix E contain the statistical analyses
 

of the incidences of those primary tumors that occurred in at
 

least two animals of one group and at an incidence of at least 5%
 

in one or more than one group.
 

27
 
In each sex of rats, the results of the Cochran-Armitage test for
 

positive dose-related trend in the incidence of tumors and the
 

results of the Fisher exact test comparing the incidence of
 

tumors in the control group with that in each dosed group in the
 

positive direction are not significant. In female rats,
 

significant results in the negative direction are observed in the
 

incidence of squamous-cell carcinoma in the integumentary system
 

and in the incidence of cortical adenoma of the adrenal, in which
 

the incidences of the tumors in the control group are 2/20 (10%)
 

and 3/20 (15%), respectively, but no such tumors are observed in
 

the dosed groups.
 

In each of the 95% confidence intervals for relative risk, shown
 

in the tables, the value of one or less than one is included;
 

this indicates the absence of significant positive results. It
 

should also be noted that each of the intervals (except that for
 

the incidence of cortical adenoma of the adrenal in female rats)
 

has an upper limit greater than one, indicating the theoretical
 

possibility of the induction of tumors by p,p'-ethyl-DDD, which
 

could not be detected under the conditions of this test.
 

28
 
IV. RESULTS - MICE
 

A. Body Weights and Clinical Signs (Mice)
 

Mean body weights of dosed male and female mice were lower than
 

those of corresponding controls, and depressions in the amount of
 

body weight gained were dose related throughout the bioassay
 

(figure 3). Other clinical signs, such as corneal opacity and
 

tissue masses, were common to both dosed and control groups.
 

Some fluctuations in the growth curves may be due to mortality;
 

as the size of a group diminishes, the mean body weight may be
 

subject to variation.
 

B. Survival (Mice)
 

The Kaplan and Meier curves estimating the probabilities of
 

survival for male and female mice administered p,p'-ethyl-DDD in
 

the diet at the doses of this bioassay, together with those of
 

the matched controls, are shown in figure 4. The result of the
 

Tarone test for dose-related trend in mortality is not
 

significant in either sex.
 

29
 
TIME ON STUDY (WEEKS) 

Figure 3. Growth Curves for Mice Administered p, p'-Ethyl-DDD in the Diet 

30 
TIME ON STUDY (WEEKS) 

Figure 4. Survival Curves for Mice Administered p, p'-Ethyl-DDD in the Diet 
In male mice, 38/50 (76%) of the high-dose group, 35/50 (70%) of
 

the low-dose group, and 14/20 (70%) of the matched-control group
 

lived to the end of the bioassay. In females, 41/50 (82%) of the
 

high-dose group, 39/50 (78%) of the low-dose group, and 17/20
 

(85%) of the matched-control group lived to the end of the
 

bioassay.
 

Sufficient numbers of mice of each sex were at risk for the
 

development of late-appearing tumors.
 

C. Pathology (Mice)
 

Histopathologic findings on neoplasms in mice are summarized in
 

Appendix B, tables Bl and B2; findings on nonneoplastic lesions
 

are summarized in Appendix D, tables Dl and D2.
 

A variety of neoplasms were found in both dosed and control
 

animals. With the exception of hepatic lesions, the neoplasms
 

were of a type, incidence, and distribution known to occur in
 

aged B6C3F1 mice and are therefore not considered to be related
 

to compound administration.
 

There was an increased incidence of hepatocellular neoplasms in
 

32
 
the female mice. Adenomas occurred in 1/47 (2%) of the low-dose
 

and 1/47 (2%) of the high-dose groups, but were absent in control
 

animals. Carcinomas were found in 1/19 (5%) of the controls,
 

2/47 (2%) of the low-dose, and 10/47 (21%) of the high-dose
 

female mice. The hepatocellular adenomas were characterized by
 

compression of adjacent parenchyma, single or multiple nodules,
 

occasional encapsulation, absence of nuclear atypia, and rare or
 

no mitotic figures.
 

Hepatocellular carcinomas with pulmonary metastasis had the
 

following characteristics: generally, they were relatively large
 

masses with multiple anaplastic nodules throughout, which varied
 

in appearance from nodule to nodule. The surrounding parenchyma
 

was compressed. The tissue between the nodules was often
 

compressed and occasionally necrotic and fibrotic. Cytoplasmic
 

tinctorial characteristics also varied from nodule to nodule. In
 

some areas it was basophilic while in other areas it was more
 

eosinophilic than normal hepatocytes. Large vacuoles were seen
 

in some cells while in other areas the cells had a foamy
 

appearance. Councilman-like bodies were frequently found in the
 

cytoplasm. Nuclei varied from relatively normal to large,
 

irregularly shaped nuclei containing cytoplasmic invaginations,
 

coarse clumped chromatin, and prominent nucleoli. Mitotic
 

figures in the most atypical portion of the tumors ranged from
 

33
 
2/10 high power fields (hpf) to 36/10 hpf, with a mean of 9.5 and
 

median of 5.5 mitoses/10 hpf. Three types of cell patterns were
 

observed in the tumors: solid, where hepatocytes formed solid
 

masses without apparent cord formation, nodular, where cords were
 

formed but were oriented without regard to portal-central
 

architecture, and trabecular, where broad hepatic cords usually
 

two cells thick and often containing a central canal or space
 

between them (bile canaliculus) traversed large vascular spaces
 

in a haphazard fashion. Areas of coagulation necrosis were
 

frequent and were occasionally observed in adjacent, uninvolved
 

hepatic parenchyma. Bile ducts were found irregularly throughout
 

some of the tumors but were largely absent from the more
 

anaplastic portions of the neoplasm.
 

Criteria for diagnosing hepatocellular carcinoma metastasis were
 

not demonstrated based on the above features. Those essential to
 

a positive diagnosis were: 1) compression of adjacent
 

parenchyma, 2) nuclear atypia, and 3) a minimum of 2 mitoses/10
 

hpf. Sixty-three percent of the hepatocellular carcinomas
 

without metastatic lesions had all three patterns as described
 

above (solid, nodular, trabecular). Multiple hepatocellular
 

tumors were found in these mice, especially in the males.
 

However, a difference in incidences in dosed and control groups
 

of male mice was not observed for hepatocellular carcinoma.
 

34
 
A variety of nonneoplastic lesions were encountered among both
 

control and dosed mice. Such lesions have been encountered
 

previously in aged laboratory mice, and most did not appear to be
 

related to the chemical. Of possible significance, however, was
 

the finding of nonsuppurative meningitis, choroiditis, and in one
 

mouse, encephalitis. This was observed in three high-dose and
 

seven low-dose female mice but not in controls. The lesions were
 

mild.
 

Based on the histopathologic examination, there was no conclusive
 

evidence for the carcinogenicity of p,p'-ethyl-DDD in B6C3F1 mice
 

under the conditions of this bioassay.
 

D. Statistical Analyses of Results (Mice)
 

Tables Fl and F2 in Appendix F contain the statistical analyses
 

of the incidences of those primary tumors that occurred in at
 

least two animals of one group and at an incidence of at least 5%
 

in one or more than one group.
 

In male mice, the result of the Fisher exact comparison of the
 

incidences of alveolar/bronchiolar carcinomas in the control and
 

high-dose groups is not significant, but the incidence in the
 

35
 
control group is significantly higher (P = 0.018) than that in
 

the low-dose group. When statistical analyses are performed on
 

the incidence of animals with alveolar/bronchiolar adenoma or
 

carcinoma, the results are not significant.
 

In female mice, the results of the Cochran-Armitage test for the
 

incidence of hepatocellular carcinoma and for the combined
 

incidence of hepatocellular adenoma and carcinoma are significant
 

(P = 0.013 and P = 0.011, respectively); however, the results of
 

the Fisher exact tests are not significant. In historical-


control groups of mice compiled to date at this laboratory, the
 

incidence of hepatocellular carcinomas or adenomas ranges from
 

0/20 to 2/19 (11%), with an overall incidence of 14/324 (4.3%).
 

In each of the 95% confidence intervals for relative risk, shown
 

in the tables, the value of one or less than one is included;
 

this indicates the absence of significant positive results. It
 

should also be noted that each of the intervals (except that for
 

the incidence of alveoler/bronchiolar carcinoma in low-dose male
 

mice) has an upper limit greater than one, indicating the
 

theoretical possibility of the induction of tumors by p,p'-ethyl-


DDD, which could not be detected under the conditions of this
 

test.
 

36
 
V. DISCUSSION
 

Mean body weights of the dosed rats and mice of each sex were
 

lower than those of corresponding controls, and were dose related
 

throughout the bioassay. However, survivals of the dosed rats
 

and mice were unaffected, and no other clinical signs could be
 

related to administration of the test chemical. Since the
 

lowered body weights in the dosed groups may have resulted from
 

the test diets being unpalatable to the animals, there was no
 

conclusive evidence of toxicity of p,p'-ethyl-DDD at the doses
 

tested.
 

In the male and female rats and the male mice, no tumors occurred
 

in the dosed groups at incidences that were significantly higher
 

than those in the corresponding control groups.
 

In the female mice, hepatocellular carcinomas or adenomas
 

occurred at incidences that were dose related (P = 0.011), but in
 

direct comparisons the incidences in the individual dosed groups
 

were not significantly higher than that in the corresponding
 

control group (controls 1/19 (5%), low-dose 3/47 (6%), high-dose
 

11/47 (23%). The incidence of hepatocellular carcinomas or
 

adenomas in historical-control female B6C3F1 mice at this
 

37
 
laboratory was only 14/324 (4.3%). Thus, even though the
 

occurrence of hepatocellular carcinomas or adenomas in the dosed
 

female mice cannot clearly be related statistically to
 

administration of the test chemical, the increased incidence of
 

these tumors in the high-dose group in relation to that in the
 

matched or historical controls suggests that the tumors may be
 

related to the administration of p,p'-ethyl-DDD.
 

In previous tests for tumorigenicity (NTIS, 1968; Innes et al.,
 

1969), it was reported that when p,p'-ethyl-DDD, called
 

Perthane" in these reports, was administered at 215 mg/kg body
 

weight by stomach tube for 3 weeks, then in the diet at 815 ppm
 

for 18 months, to hybrid mice (C57BL/6 x C3H/Anf and C57BL/6 x
 

AKR), an elevated incidence of hepatomas (P = 0.01) was
 

observed. The dichlorodiphenyl-tri-chloroethane analog,
 

p,p'-DDT, has also been reported to induce hepatomas in various
 

strains of mice (international Agency for Research on Cancer,
 

1974), and the p,p'-dichlorodiphenyl-dichloro-ethylene analog,
 

DDE, has been reported to induce hepatomas in CF-1 mice (Tomatis
 

et al., 1974). Thus, tumors of the same cell type, i.e.,
 

hepatocytes of the liver, have been observed previously with
 

p,p"-ethyl-ODD and related compounds.
 

38
 
It is concluded that under the conditions of this bioassay,
 

p,p'-ethyl-DDD was not carcinogenic for male or female F344 rats
 

or male B6C3F1 mice. However, the occurrence of hepatocellular 

carcinomas and adenomas in female mice was suggestive of s 

carcinogenic effect. 

39
 
40

 
VI. BIBLIOGRAPHY
 

Armitage, P., Statistical Methods rn Medical Research, John Wiley
 

& Sons, Inc., New York, 1971, pp. 362-365.
 

Ayers, J. H. and Johnson, 0. H., Insecticides In: Chemical
 

Economics Handbook, Stanford Research Institute, Menlo Park,
 

Calif., 1976, sec. 573.3007 E-F.
 

Berenblum, I., ed., Carcinogenicity Testing: A Report o£ the
 

Panel on Carcinogenicity £f the Cancer Research Commission of the
 

UICC, Vol. :2. International Union Against Cancer, Geneva, 1969.
 

Bleiberg, M. J. and Larson, P. S., Studies on derivatives of
 

2,2-bis-(p-chlorophenyl)-l,1-dichloroethane (DDD, IDE) with
 

special reference to their effects on the adrenal cortex. J.
 

Pharmacol. Exp. Ther. 121, 421-431, 2957.
 

Brooks, G. T., Chlorinate Insecticides, Vol 1, CRC Press, Inc.,
 

Cleveland, Ohio, 1975, pp. 16-17, 34, 58-59.
 

Cox, D. R., Regression models and life tables. J. R._ Statist.
 

Soc. B 34(2);187-220, 1972.
 

Cox, D. R., Analysis of Binary Data, Methuen and Co., Ltd.,
 

London, 1970, pp.48-52.
 

Finnegan, J. K., Hennigar, G. R., Smith, R. B., Jr., Larson, P.
 

S. and Haag, H. B., Acute and chronic toxicity studies on
 

2,2-bis-(p-ethylphenyl)-l,1-dichloroethane (Perthane). Arch.
 

Internet. Pharmacodyn. Ther. 103:404-418, 1955.
 

Gaines, T. B., Acute toxicity of pesticides. Toxicol. Appl.
 

Pharmacol. 14:515-534, 1969.
 

Gart, J. J., The comparison of proportions: a review of
 

significance tests, confidence limits and adjustments of
 

stratification. Rev. Int. Statis. Inst. 39 (2);148-149, 1971.
 

Innes, J. R. M., Ulland, B. M., Valeric, M. G., Petrucelli, L.,
 

Fishbein, L., Hart, E. R., Pallotta, A. J., Bates, R. R., Falk,
 

H. L., Gart, J. J., Klein, M., Mitchell, I., and Peters, J.,
 

Bioassay of pesticides and industrial chemicals for 

tumorigenicity in mice: a preliminary note. J. Natl Cancer 

Inst. 42:1101-1114, 1969. 

41
 
International Agency for Research on Cancer, DDT and associated 

substances. In: IARC Monographs on the Evaluation of 

Carcinogenic Risk £f Chemical _t£ Man ­ Some Organochlorine 

Pesticides, Vol. 5_,_ International Agency for Research on Cancer,
 

Lyon, France, 1974, pp. 83-124.
 

Jacoby, R. 0., Bhatt, P. N., and Jonas, A. M., Pathogenesis of
 

sialodacryoadenitis in gnotobiotic rats. Vet. Pathol. 12:196,
 

1975.
 

Kaplan, E. L. and Meier, P., Nonparametic estimation from
 

incomplete observations. J. Amer. Statist. Assoc. 53:457-481,
 

1958. ~~
 

Larson, P. S., Hennigar, G. R., Finnegan, J. K., Smith, R. B.,
 

Jr., and Haag, H. B., Observations of the relation of chemical
 

structure to the production of adrenal cortical atrophy or
 

hypertrophy in the dog by derivatives of 2,2-bis-(p-chlorophenyl)
 

-1,1-dichloroethane (ODD, IDE). £._ Pharmacol. Exp. Ther.
 

115:408-412, 1955.
 

Linhart, M. S., Cooper, J. A., Martin, R. L., Page, N. P., and
 

Peters, J. A., Carcinogenesis bioassay data system. Comp. and
 

Biomed. Res. 7:230-248, 1974.
 

Martin, H. and Worthing, C. R., eds., 1,l-Dichloro-2,2­

di-(4-ethylphenyl)ethane. In: Pesticide Manual, British Crop
 

Protection Council, London, 1977, p.171.
 

Meister, R. T., ed., Perthane. In: 1977 Farm Chemicals
 

Handbook, Meister Publishing Co., Willoughby, Ohio, 1977, p. D202
 

Miller, R. G., Jr., Simultaneous Statistical Inference,
 

McGraw-Hill Book Co., New York, 1966, pp. 6-10.
 

National Technical Information Service, Evaluation £f
 

Carcinogenic, Teratogenic, and Mutagenic Activities of Selected
 

Pesticides and Industrial Chemicals, Vol. _1, National Technical
 

Information Service,Springfield, Va., 1968, p. 64.
 

Saffiotti. U., Montesano, R., Sellakumar, A. R., Cefis, F., and
 

Kaufman, D. G., Respiratory tract carcinogenesis in hamsters induced by different numbers of administrations of benzo(a) pyrene
 

and ferric oxide. Cancer Res. 32:1073-1081, 1972.
 

42
 
Taliaferro, I. and Leone, L., Inhibitory effect of Perthane
 

(2,2-bis- para-ethylphenyl -1,1-dichloroethane) on adenocortical
 

function in human subjects. NN_ Engl. J_._ Med. 257:855-860.
 

Tarone, R. E., Tests for trend in life table analysis.
 

Biometrika 62(3):679-682, 1975.
 

Tomatis, L., Turusov, V., Day, N., and Charles, R. T., The effect
 

of long-term exposure to DDT on CF-1 mice. Int. J^ Cancer
 

K):489, 1972.
 

United States International Trade Commission, Synthetic Organic
 

Chemicals - United States Production and Sales, 1976,USITC
 

Publication 833, United States International Trade Commission,
 

Washington, D. C., 1977.
 

43
 
44

 
APPENDIX A
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

RATS ADMINISTERED p,p'-ETHYL-DDD IN THE DIET
 

45
 
46

 
TABLE A1. 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE RATS 

ADMINISTERED p, p'-ETHYL-DDD IN THE DIET 

MATCHED
 

CONTROL LOW DOSE
 

ANIMALS INITIALLY IN STUDY 20 50
 

ANIMALS MISSING 1
 

ANIMALS NECROPSIED 19 50
 ANIMALS EXAMINED HISTOPATHOLOGICALL Y 19 50
 

INTEGUMENTARY SYSTEM
 

*SKIN (19) (50)
 

CARCINOMA, NOS
 

SQUAMOUS CELL CARCINOMA 1 (2%)
 

KERATOACANTHOMA 1 (2%)
 

LEIOMYOSARCOMA
 

*SUBCU1' TISSUE (19) (50)
 

FIBROSARCOMA 1 (2%)
 

RESPIRATORY SYSTEM 

#LUNG 

ADENOCARCINOMA, NOS, METASTATIC 

ALVFOLAR/BRONCHIOLAS ADENOMA 

ALVEOLAR/3PONCHIOLAR CAFCINOMA 

FIBROSARCOMA, METASTATIC 

OSTEOSARCOMA, METASTATIC 

(16) 

1 (6%) 

(47) 

2 (!»%) 

1 (215) 

1 (2%) 

HEMATOPOIETIC SYSTEM
 

tBPAIN (19) (48)
 

MALIGNANT PETICULOSIS 1 (2%)
 

*MULTIPLE ORGANS (19) (50)
 

MALIGNANT LYMPHOMA, NOS 1 (5<«)
 

*HEMATOPOIETIC SYSTEM (19) (50)
 

NEOPLASM, NOS 4 (21X) 11 (22%)
 

tSPLEEN (19) __ (50)
 

SiB££Bi«_S2S__ 1.12ZL
 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

HIGH DOSE
 

50
 

50
 

50
 

(50)
 

1 (2%)
 

3 (6%)
 

1 (2%)
 

(50)
 

1 (2%)
 

(48)
 

1 (2%)
 

2 (4%)
 

(50)
 

C^O)
 

1 (2%)
 

(50)
 

10 (20%)
 

(48)
 

47
 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

tTHYMHS (14 ) (H3) (43) 

FIBROSARCOMA , METASTATIC 1 (2%) HWlalkM_iB_K _«A.»««B«H«1BMB> V U«—W W »—-.— -. — —• _«•«•••»•»—«•••«•»««•. •»»•»•»••• •»0>ll»AHB«IBIB«flBflBK»W>»<*l>W 

CIRCUL.ATOPY SYSTEM 

*HEAHm (19) (49) (49) 

FIBFOSAPCOIH, METASTATIC 1 (2%) 

DIGESTIVE SYSTEM
 

tLIVEF (19) (50) (50)
 

NEOPLASTIC NODULE 1 (2%)
 

HEPATOCELLULAR CARCINOMA 1 (2%)
 

*S.INTESTINE/MUCOSA (19) (50) (49)
 

PAPILLARY ?DENOCARCINOMA 1 (2%)
 

URINARY SYSTEM
 

*KIDNEY (19) (50) (49)
 

TUBULAR-CELL ADENOMA 1 (2%)
 

f NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 * NUMBER OF ANIMALS NECROPSIED
 

48
 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

ISLET-CELL CARCINOM A 

REPRODUCTIV E SYSTEM 

*MAMMAP. Y GLAN D 

ADENOCARCINOMA , NO S 

FIBROADENOMA 

•TESTIS 

INTERSTITIAL-CELL TUMO R 

#TUNIC A ALBUGINE A 

MESOTHELIOMA , NOS 

NERVOU S SYSTE M 

NONE 

SPECIAL SENS E ORGAN S 

NON E 

MUSCULOSKELETA L SYSTEM 

NON E 

BODY CSVITIES 

*BODY CAVITIE S 

MESOTHELIOMA , NOS 

*ABDOMINA L CAVIT Y 

MESOTHELIOMA , NOS 

*PERITONEUM 

PAPILLAR Y ADENOCAPCINOMA , METAST 

^MESENTER Y 

ADENOMA , NO S 

iiPQSA 

MATCHED 

CONTROL 

(19) 

1 (5X) 

(19) 

17 (89%) 

(19) 

(19) 

(19) 

(19) 

(19) 

HIGH DOSE 

(50) 

1 (2*) 

(<*9) 

35 (7K) 

(«9) 

1 12*) 

(50) 

(50) 

<5Q) 

1 (2*) 

(50) 

1 (2«) ,„,.„— .wm. 

LOW DOSE 

1 (2*) 

(50) 

(50) 35 (70*) 

(50) 

(50) 

1 (2%) 

(50) 

T (2%) 

(50) 

(50) 

t NUMBER OF ANIMALS HITH TISSUE EXAMINED MICPOSCO'PICAllY
 

* NUMBER OF ANIMALS NECROPSIED
 

49
 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

*TUNICA VAGINALIS
 

PAPILLARY ADENOCARCINOMA, METAST
 

MESOTHELIOMA, NOS
 

ALL OTH"P SYSTEMS
 

AXILLA
 

SARCOMA, NOS
 

ANIMAL DISPOSITION SUMMARY
 

ANIMALS INITIALLY IN STUDY


NATURAL DEATHS
 

HOPIBUND SACRIFICE
 

SCHEDULED SACPIFICE
 

ACCIDENTALLY KILLED
 

TERMINAL SACPIFICE
 

ANIMAL MISSING
 

9 INCLUDES AHTOLYZED ANIMAL?
 

TOBOF. SUMMARY
 

TOTAL ANIMALS WITH PRIMARY TOMOP.S*
 

TOTAL PRIMARY TUMORS
 

TOTAL ANIHBLS WITH BENIGN TUMORS
 

TOTAL BENIGN TUMOPS
 

"OTAL ANIMA.LS WITH MALIGNANT TUMOPS
 

TOTAL MALIGNANT TUMOPS
 

TOTAL ANIMPL S WITH SECONDAP? TUWOFS*
 

TOTAL SECONDARY TUMOFS
 

TOTAL ANIMAL S WITH ""tTMOPS UNCERTAIN­ BENIGN OP MALIGNANT
 

TOTAL UNCERTAIN TUMOPS
 

TOTAL ANIMAI S WITH TUMORS UNCERTAIN­ PRIMARY OP METASTATIC
 

TOTAL UNCERTAIN TUMOFS
 

MATCHED 

CONTROL LOW DOSE 

(19) (50) 

1 (2%) 

1 

!20 SO 

5 1 1 

3 5 

1 1 3U 

1 

18 U6 

33 86 

17 39 

27 ^9 

2 11 

2 1 1 

2 

U 

U 16 

U 16 

HIGH DOSE
 

(50)
 

1 (2%)
 

50
 

8
 

7
 

3^
 

U2
 

77
 

36
 

50
 

12
 

12
 

2
 

3
 

1 1
 

11
 

* PRIMfPY TUMOPS: ALL TUMORS EXCEPT SECONDARY TUMOPS
 

# SECONDARY ^UMOPS: METASTATIC TUMOPS OR TUMOPS INVASIVE INTO AN ADJACENT OR3AN
 

50
 
TABLE A2.

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS 

ADMINISTERED p, p'-ETHYL-DDD IN THE DIET 

MATCHED
 

CONTROL LOW DOSE HIGH DOSE
 

ANIMALS INITIALLY IN STUDY 20 SO 50
 

ANIMALS NECROPSIED 20 50 50
 

ANIMALS EXAMINED HISTOPATHOLOGICALL Y 20 SO SO
 

INTEGUMENTARY SYSTEM
 

*SKIN (20) (SO) (50)
 

SQUAMOUS CELL CAPCINOMA 2 (10%)
 

RESPIRATORY SYSTEM
 

fLUNG (20) (50) (50)
 

ALVEOLAR/BPONCHIOLAP CAPCINOMA 1 (5%) 1 (21)
 

HEMATOPOIETIC SYSTEM
 

*«HLTIPLE ORGANS (20) ("0) (SO)
 

MALI'S. LYMPHOMA, UNDIFFEP-TYPF 1 (2%)
 

MONOCYTIC LEUKEMIA 1 (2%)
 

*HEMATOPOIFrnIC SYSTFM (20) (50) (50)
 

NEOPLASM, NOS 3 (15%) a (16«> 6 (12%)
 

*BONE MARRO W (20) (SO) (50)
 

GRANULOCYTIC SARCOMA 1 (5%)
 

CIRCULATORY SYSTEM
 

NONE
 

DIGESTIVE SYSTEM
 

*ORAL CAVITY (20) (50) (SO)
 

SQUAMOUS CELL CARCINOMA 1 (2%)
 

illVE* (20) (49) (50)
 

NEOPLASTIC NODULE 1 12*1
 

# NU"IBFP OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 * NUMBEP OF ANIMALS NECPOPSIFD
 

51
 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED) 

MATCHED
 

CONTROL LOW DOSE HIGH DOSE
 

HEPATOCELLULAR CARCINOMA 2 {«)
 

URINARY SYSTEM
 

NOTE
 

ENDCTRINE SYSTE1
 

SPI^UITARY (20) (50) (U9)
 

ADENOMA, NOS 1
 (*«)


CHFON3PHOBE ADFNOUt U (20«) 13 (26%) 6 (12S)
 

ACIDOPHIL ADENOMA 1 (?*)
 

t ADRENAL (20) (50) (48)
 

CORTICAL ADSNOMA 3 (1SX)
 

PHEOCHROMOCYTOMA 1 (2%)
 

#THYEOID (19) C*9) (49)
 

PAPILLARY ADFNOMA 1 (2%)
 

FOLLICULAR-CELL CAFCINOMA 1 (5%)
 

C-CELL ADENOMA 2 (11%) U (8%) 4 (3X)
 

REPRODUCTIVE SYSTEM
 

*MRMH?"Y GLAND (?0) (50) (50)
 

ADENOMA , NOS 1 (5%)
 

FIBROMA 1 (5%)
 

FIBROADENOMA 1 (*?) 1 (2%)
 

*VAGINA (20) ("50) (SO)
 

SQUAMOUS CELL CAFCINOHA 1 (2%)
 

tUTERUS (19) (50) (49)
 

PAPILLARY ADENOMA 1 (2%)
 

ENDOMETRIAL STROMAL POLYP (10«) 3 (6*)
 c,
 

NEPVOUS SYSTEM
 

SPRAIN (20) (H9) (50)
 

EPENDYMOMA
 J_J58I
 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 * NUMBER OF ANIMALS NECROPSIED
 

52 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED) 

SPECIAL SENSE ORGANS
 

*EAR C'NAL
 

ADENOCARCINOMA, NOS
 

MUSCDLOSKELETAI SYSTEM
 

NONE
 

BODY CAVITI2S
 

NONE
 

ALL OTHER SYSTEMS
 

NONE
 

ANIMAL DISPOSITION SUMMARY
 

ANIMAIS INITIALLY IN STUDY
 

NATURAL DEATHS
 

MORIBUND SACRIFICE
 

SCHEDULED SACRIFICE
 

ACCIDENTALLY KILLED
 

TERMINAL SACRIFICE
 

ANIMAL MISSING
 

9 INCL.UD.ES AUTCiYZED ANIMALS
 

MATCHED
 

CONTROL LOW DOSE HIGH DOSE
 

(20)	 (50) (SO)
 

1 (2%)
 

20 50 50
 

2 f 6
 

3 2 2
 

15	 42 42
 

t NOMBEP OF ANIHAtS HITH TISSUE EXAMINED MICPOSCOPICALLY
 * NUMBFP OF ANIMALS NECROPSIED
 

53
 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED) 

MATCHED
 

CONTROL LOW DOSE HIGH DOSE
 

TUMOR SUMMARY
 

TOTAL ANIMALS WITH PRIMARY TUMORS* 15 32 21
 

TOTAL PRIMARY TUMORS 23 38 2U
 

TOTAL ANIMALS WITH BENIGN TUMORS 10 22 12
 

TOTAL BENIGN TUMORS m 26 13
 

TOTAL ANIMALS WITH MALIGNANT TUMORS U 4
 ^
 TOTAL MALIGNANT TUMOR? 6 it 4
 

TOTAL ANIMALS WITH SECONDARY TUMORS*
 

TOTAL SECONDARY TUMORS
 

TOTAL ANIMALS WITH TUMORS UNCERTAINBENIGN OR MALIGNANT 3 8 1
 

TOTAL UNCERTAIN TUMORS 3 8 1
 

TOTAL ANIMALS WITH TUMORS UNCERTAINPRIMARY OF METASTATIC
 

TOTAL UNCERTAIN TUMORS
 

* PRIMARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 

# SECONDARY TUMORS: METASTATIC TUMORS OR TUMORS INVASIVE INTO AN ADJACENT OP3AN
 

54
 
APPENDIX B
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

MICE ADMINISTERED p,p'-ETHYL-ODD IN THE DIET
 

55
 
56

 
TABLE B1.

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE MICE 

ADMINISTERED p, p'-ETHYL-DDD IN THE DIET 

MATCHED
 

CONTROL LOW DOSE
 

C

0
 

ANIMALS MISSING 1
 

ANIMAL? NECROPSIED 19 50
 

ANIMALS EXAMINED HIS^OPATHOLOGICALLY 19 50
 

ANIMALS INITIALLY IN STTTDY 20
 

INTEGUMENTARY SYSTEM
 

*SUBCOT TISSHF (19) (50)
 

FIBROSARCOMA 1 (5%)
 

HEMANGIOSARCOMA, METASTATIC
 

^ESPIRATOPY SYSTEM 

#LONG 

UNDIFFERENTIATED CARCINOMA «ETAS 

HEPATOCEILULAR CARCINOMA, METAST 

ALVEOLAR/BRONCHIOLAR ADENOMA 

ALVEOLAR/BRONCHIOLAR CAPCINOMA 

RHABDOMYOSARCOMA, METASTATIC 

(19) 

2

U

 (11%) 

 (21%) 

(50) 

2 (««) 

" (8%) 

1 (2%) 

1 (2%) 

HEMATOPOIETIC SYSTEM
 

*MULTIPLE OFGANS (19) (50)
 

MALIGNANT LYMPHOMA, NOS 2 (11%) 2 (4%)
 

MALIG. LYMPHOMA, ONDIFFEP-TYPE 1 (2%)
 

MALIG. LYMPHOMA, HISTIOCYTIC "*YPE 3 (6%)
 

MALIGNANT LYMPHOMA, MIXED TYPE 3 (6X)
 

IBONE MA5POW (18) (50)
 

MAST-CELL TUMOR 1 (2%)
 

tSPLEEN (19) (48)
 

HEMANGIOSARCOMA 1 (2%)
 

*LYMPH NODE (18) (45)
 

ALVEOLAP./BRONCHIOLAR CA , METASTA 1 (2X)
 

RHABDOMYOSARCOMA, METASTATIC 1 (2%)
 

#LUNG (19) (50)
 

XBXBSBi«_UIASX&XIC
 

t NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 * NUMBER OF ANIMALS NECROPSIED
 

HIGH DOSE
 

50
 

50
 

50
 

(50)
 

1 (2%)
 

(49)
 

1 (2%)
 

6 (12%)
 

9 (18%)
 

3 (6%)
 

(50)
 

1 (2%)
 

(49)
 

(47)
 

1 (2%)
 

(47)
 

(49)
 

_J_J251.
 

57
 
TABLE B1. MALE MICE: NEOPLASMS (CONTINUED) 

fTHYMUS
 

THYMOMA, MALIGNANT
 

MALIGNAN^ IYMPHOMA, NOS
 

CIRCULATORY SYSTEM
 

tHEABT
 

RHABDOMYOSARCOMA
 

DIGESTIVE SYSTEM
 

iLIVEP
 

BILE DUCT CARCINOMA
 

HEPATOCELLULAR ADENOMA
 

NEOPLASTIC NODtTLE
 

HEPATOCELLULAR CARCINOMA
 

HEMANGIOSARCOMA
 

ANGIOSAPCOBA
 

UPINARY SYSTEM
 

NONE
 

ENDOCRINE SYSTEM
 

t^HYROID
 

FOLIICDLAP-CELL ADENOMA
 

REPRODUCTIVE SYSTEH
 

NOPE
 

N5PVOUS SYSTEM
 

NONE
 

SPECIAL SENSF CRGANS
 

*EYE/LACPIM«L GLAND
 _ AfiENOMAj NOS _
 

MATCHED
 

CONTROL
 

(16)
 

(19)
 

(19)
 

1 (5%)
 

7 (37%)
 

(18)
 

(19)
 

1-15ZL
 

LOW DOSE
 

(39)
 

(47)
 

1 (2%)
 

(U9)
 

7 (1U%)
 

1 (2%)
 

19 (39%)
 

1 (2%)
 

(U7)
 

1 (2%)
 

(-50)
 

HIGH DOSE
 

(HO)
 

1 (3%)
 

1 (3S)
 

(50)
 

(50)
 

1 (2%)
 

5 (10%)
 

20 (H0%)
 

1 (2*)
 

1 (2%)
 

(50)
 

(50)
 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPIC^ILY
 * NUPBEP OF »NIMALS NECPOPSIED
 

58
 
TABLE B1. MALE MICE: NEOPLASMS (CONTINUED) 

*HARDERIAN GLAND
 

PAPILLARY CYSTADENOMA, NOS
 

*EAR
 

HEMANGIOSARCOMA
 

MUSCULOSKELETAL SYSTEM
 

NONE
 

BODY CAVITIES
 

*PERITONEUM
 

BItE DUCT CARCINOMA, METASTATIC
 

*PIEUFA
 

RHABDOMYOSARCOMA, METASTATIC
 

ALL OTHER SYSTEMS
 

DIAPHRAGM
 

ALVEOLAR/BRONCHIOLAP CA, METASTA
 

SITE UNKNOWN
 

UNDIFFERENTIATED CARCINOMA
 

ANIMAL DISPOSITION SUMMAR Y
 

ANIMALS INITIALLY IN STUDY
 

NATURAL DEATHS
 

MORIBUND SACRIFICE
 

SCHEDULED SACRIFICE
 

ACCIDENTALLY KILLED
 

TERMINAL SACRIFICE
 

ANIMAL MISSING
 

@includes autolyzed animals,
 

MATCHED
 

CONTROL
 

(19)
 

(19)
 

(19)
 

(19)
 

20
 

5
 

11*
 

1
 

LOW DOSE HIGH DOSE
 

(50)	 (50)
 

1 (2%)
 

(50)	 (50)
 

1 (2«)
 

(50)	 (50)
 

1 (2%)
 

(50)	 (50)
 

1 (2«)
 

1
 

1
 

50 50
 

15 9
 

1
 

2
 

35 38
 

*	 NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

59
 
TABLE B1. MALE MICE: NEOPLASMS (CONTINUED)

 

MATCHED
 

CONTROL LOW DOSE HIGH DOSE
 

TUMOP SUMMARY
 

TO^AL ANIMALS WITH PRIMAPY TUMORS* 11 38 33
 

TOTAL PRIHARY TUMOPS 16 43 U5
 

TOTAL ANIMALS WITH BENIGN TUMORS 2 11 1 1
 

TOTAL BENIGN TUMORS 2 13 It
 

TOT4L ANIMALS WITH MALIGNANT TUBTRS 10 27 27
 

TOTAL MALIGNANT TUMOR? 1H 33 31
 

TOTAL ANIMALS WITH SECONDARY TUMORS* 2 U 8
 

•^OTAL SECONDARY TtlwOPS 2 7 10
 

TOTAL ANIMALS WITH TUMORS UNCERTJINBENIGN OP. MALIGNANT 2
 

TOTAL UNCEPTAIN TUMOFS 2
 

TOTAL ANIMALS WITH TUMORS UNCERTAINPRIMARY OP METASTATIC
 

TOTAL UNCERTAIN TUMORS
 

* PRIMARY TUMORS: ALL TUMORS EXCEPT SECONDLY TUMORS
 

# SECONDARY TUMORS: METASTATIC TUMOPS 0* TUMOPS INVASIVE INTO AN ADJACENT OFGAN
 

60
 
TABLE B2.

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE MICE 

ADMINISTERED p, p'-ETHYL-DDD IN THE DIET 

MATCHED
 

CONTROL LOW DOSE HIGH DOSE
 

ANIMALS INITIALLY IN STUDY 20 50 50
 

ANIMALS MISSING 3 1
 

ANIMAL? NECROPSIED 20 HI U9
 

ANIMALS EXAMINED HISTOPA THOLOGICALLY 20 47 48
 

INTEGUMENTARY SYSTEM
 

*SKIN (20) («7) (49)
 

HEMANGIOMA 1 (2%)
 

*S(JBCUT TISSUE (20) (U7) (49)
 

SARCOMA, NOS 1 (2%) 2 (4%)
 

FIBROSARCOMA 1 (5%) 1 <2X) 1 (2%)
 

PESPIRATOPY SYSTEM
 

tLMNG (18) (U7) (47)
 

HEPATOCELLULAR CAPCINOBA, METAST 2 (4%)
 

ALV50LAP/BPONCHIOLAR ADENOMA 2 (H%) 1 (2*)
 

ALVEOLAR/BSONCHIOLAP CARCINOMA 1 (2%)
 

HEMATOPOIETIC SYSTEM
 

*MDLTIPLE ORGANS (20) (HI) (49)
 

MALIGNANT LYMPHOMA, NOS 1 (5X) 5 (11%) 4 (8%)
 

MALIG. LYMPHOMA, HISTIOCYTIC TYPE 1 (5X) 1 (2*)
 

"ALI3NAN"- LYMPHOMA, MIXED TYPE 2 (10X) 2 (U%) 1 (2%)
 

LYMPHOCYTIC LEUKEMIA 1 (2«)
 

tSPLEEN (19) («6) (46)
 

HEMANGIOSAFCOMA 1 (2*)
 

tLYMPH NODE (20) (<I6) (46)
 

SARCOMA, NOS, METASTATIC 1 (2«)
 

*ABDOMINAL LYMPH NODE (20) (46) (46)
 

FIBROSAPCOMA, METASTATIC 1 (2«)
 

*MESENTERY (20) («7) (49)
 

BAIISNAS! I.IMPHOM2t.-J5IXED_nPE 1_J2«L.__,
 

* NUHBER OF ANIMALS HITH TISSUE EXAMINED MICROSCOPICALLY
 * NUMBER OF ANIMALS NECROPSIED
 

61
 
TABLE B2. FEMALE MICE: NEOPLASMS (CONTINUED) 

MATCHED
 

CONTROL LOW DOSE
 

•CECUM	 (20) (UU)
 

MALIG. LYMPHOMA, HISTIOCYTIC TYPF
 

tTHYMUS (18) («1)


THYMOMA 1 (2%)
 

CIRCULATORY ^YS^EM
 

NONE
 

DIGESTIVE SYSTEM 

*LIVEP 

HEPATOCELLtTLAB ADENOMA 

HEPATOCEIIULAP CARCINOMA 

(19) 

1 (5%) 

(a?) 

1 (2%) 

2 (UK) 

OPINARY SYSTEM
 

HONE
 

ENDOCRINE SYSTEM
 

•PITUITARY	 (18) («2)
 

ADENOMA, NOS 1 (2X)
 

CHFOMOPHOEE ADENOMH 1 (6*) a (10%)
 

IADFENAL (20) (U6)
 

PHEOCHPOMOCYTOMA, MALIGNANT
 

tTHYROID (18) (41)
 

PAPILLARY ADENOMA
 

C-CELL ADENOM A
 

*PANCREATIC ISLETS (19) (1*5)
 

ISLET-CELL ADENOMA 1 (2%)
 

REPRODUCTIVE SYSTEM
 

*MAMBAPY GLAND (20) (HI)
 

.ADENOMA^ NOS
 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED HICPOSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

HIGH DOSE
 

(1»8)
 

1 (2«)
 

(UU)
 

(H7)
 

1 (2%)
 

10 (21%)
 

C*6)
 

5 (1U)
 

(« 5)
 

1 (2«)
 

(U6)
 

1 (2%)
 

1 (2*)
 

C»6)
 

(«9)
 

J_J2S1_
 

62
 
TABLE B2. FEMALE MICE: NEOPLASMS (CONTINUED) 

MATCHED
 

CONTROL LOW DOSE HIGH DOSE
 

FIBROSAFCCMA 1 (2%)
 

*UTERUS (19) (US) (12)
 

LEIOMYOMA 1 (2%)
 

LEIOMYOSARCOMA 1 (2*) 1 (2%)
 

tOVAEY/OVIDUCT (19) (45) (42)
 

PAPILLARY ADENOMA 1 (2*)
 

»O7ARY (19) (42) {««)
 

GRANOLOSS-CELL TOMOH 1 (2%)
 

NSP70US SYSTEM
 

NONE
 

SPECIAL SENS' ORGANS
 

*HARDERIAN GLAND (20) (47) (U9)
 

CYSTADENOMA, NOS 1 (2X)
 

MUSCULOSKELETAL SYSTEM
 

NONE
 

BODY CAVITIES
 

*MESENTERY (?0) («t 7) (U9)
 

HEMANGIOMA 1 (2%)
 

ALL OTHEP SYSTEMS
 

NONfi
 

t NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NITMBEP OF ANIMALS NECROPSIED
 

63 
TABLE B2. FEMALE MICE: NEOPLASMS (CONTINUED) 

ANIMAL DISPOSITION SUMMAPY
 

ANIMALS INITIALLY IN STUDY
 

NATURAL DEATHS
 

MORIBUND SACRIFICE
 

SCHEDULED SACRIFICE
 

ACCIDENTALLY KILLED
 

TERMINAL SACRIFICE
 

ANIMAL MISSING
 

9 INCLUDES AUTCLYZED ANIMALS
 

TUMO" SUMMAR Y
 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

20 50 50 

2 8 6 

2 

1 

17 39 41 

3 1 

TOTAL ANIMALS WITH PRIPAPY TUMORS* 

TDTAL PRIMARY TUMORS 

7 

7 

2U 

31 

26 

34 

TOTAL ANIMALS WITH BENIGN TUMOPS 

TDTAL BENIGN TUMORS 

1 

1 

12 

in 

10 

11 

TOTAL ANIMAL? WITH MALIGNANT TUMORS 

TOTAL MALIGNANT TUMORS 

6 

6 

15 

17 

21 

22 

TOTAL ANIMALS WITH SECONDAPY TUMOPS* 

TDTAL SECONDARY TU^RS 

1 

1 

3 

3 

TOTAL ANIMAL S WITH TUMORS UNCFPTAIN­ BENIGN OR KALIGNAN'" 

TO^AL UNCERTAIN TUMOPS 

1 

1 

TO^AL ANIMALS WITH TUMORS UNCEPTAIN­ PRIMARY OR METASTATIC 

TDTAL UNCERTAIN TUMORS
 

* PRIMARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 

# SECONDARY TUMORS: METASTATIC TU10PS OR TUMORS INVASIVE INTO AN ADJACENT OP5AN
 

64
 
APPENDIX C
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN
 

RATS ADMINISTERED p,p'-ETHYL-DDD IN THE DIET
 

65
 
66

 
TABLE C1.

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE RATS 

ADMINISTERED p, p'-ETHYL-DDD IN THE DIET 

t NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

67 
TABLE C1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED
 

CONTROL LOW DOSE HIGH DOSE
 

•SPLEEN	 (19) (50) (48)
 

HE10R"HAGE 1 (2%)
 

SCLFROSI? 1 (2*)
 

INFARCT, ACtJTE 1 (2*)
 

HYPEPPLASIA, LYMPHOID 1 (2*)
 

HEMATOPOIESI" 1 (S%) 1 (2%) 1 (2X)
 

tSPIENIC CAPSULE (19) (50) (48)
 

INFLAMMATION, CHRONIC FOCAL 1 (*%)
 

•SPLENIC FED PULP (19) (S

0) (48)
 

LEOKOCYTOSTS, NO" 1 (5%)
 

•SUBMANDIBULAR	 L.NODE (18) (SO) (48)
 

INFLAMMATION, ACUTF 1 (2%)
 

•MEDIASTINAL	 L.NODE (18) (50) (48)
 

INFLAMMATION, CHPONIC FOCAL 1 (2%)
 

•MESENTERIC L. NODE (18) (50) (48)
 

HISTIOCYTOSI3 1 (2%)
 

CIRCULATORY SYS^TM
 

#HEART (19) (»9) (49)
 

THROMBOSIS, NOS 1 (5*)
 

THROMBUS, MT JPAL 1 (2%)
 

ATROPHY, NOS 1 (2%)
 

*HE?RT/ATRI!?M (19) (49) (49)
 

THROMBOSIS, NOS 1 (2X)
 

•MYOCARDIUM	 (19) (U9) (49)
 

INFLAMMATION, INTERSTITIAL 1 (2%)
 

INFT AMNATION, CHRONIC 3 (16*)
 

INFL»MMA'"ION, CHRONIC FOCAL i* (a*) 8 (16%)
 

INFLAMMATION, CHRONIC DIFFUSE 1 (2*)
 

FIBROSIS 1 r%) 2 (4%) S (10%)
 

FIBROSIS, FOCAL 1 (5?) 2 («%) 5 (10%)
 

SCAP 1 (2%) 1 (2%)
 

FIBROSIS, POLTIFOCAL U (21*) 25 (51%) 15 (31%)
 

FIBROSIS, DIFFUSE 4 (21X)
 

DEGENEPATIONt NO" 6_i32%L___.
 

* NUMBEP OF ANIMALS KITH ""ISSUE EXAMINED MICROSCOPICALLY
 * NUM3FP OF ANIMALS NFCPOPSIED
 

68
 
TABLE C1.MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED)

 

MATCHED
 

CONTROL LOW DOSE
 

*POLHONARY ARTERY (19) (50)
 

MINERALIZATION 1 (5X) 6 (12*)
 

CALCIFICATION, FOCAL
 

tHEPATIC SINUSOID (19) (50)
 

LEOKOCYTOSIS, NDS 1 (2%)
 

DIGESTIVE SYSTEM
 

*TOOTH (19) (50)
 

DYSPLASIA, NOS
 

iSALIVAPY GLAND (18) (50)
 

INFLAMMATION, ACUTE DIFFUSE 1 (2%)
 

INFLAMMATION, ACUTE/CHRONIC 1 (6X) 6 (12X)
 

INFLAMMATION, CHRONIC FOCAL 1 (6X)
 

INFLAMMATION, CHRONIC DIFFUSE 2 (11X) 9 (18X)
 

fSALIVASY SEPCtIS GLAN (18) (50)
 

INFLAMMATION, ACUTE/CHRONIC 1 (2%)
 

INFLAMMATION, CHRONIC DIFFUSE 1 (6%) 1 (2%)
 

tLIVEP (19) (50)
 

THROMBOSIS, NOS 1 (2%)
 

CONGESTION, CHRONIC PASSIVE 1 (5*)
 

INFLAMMATION, ACUmF FOCAL 1 (5«)
 

INFIAMMATION, CHPONIC FOCAL U (21%) 2 (t*)
 

CHOIANGIOFIBROSIS 1 (5X) 2 («*)
 

CIRPHOSIS, NOS 1 (5X)
 

HEPATITIS, TOXIC 3 (16X) 1 (2X)
 

PELIOSIS HEPATIS 1 (5%) 2 (<»X)
 

METAMORPHOSIS FATTY 1 (2X)
 

BASOPHILIC CYTO CHANGE 1 (2%)
 

FOCAL CELLULAP CHANGE
 

CLEAR-CELL CHANGE
 

HEMATOPOIESIS 1 (5%)
 

tLIVER/CENTRHOBOLAR (19) (50)
 

METAMORPHOSIS FATTY 1 (5*)
 

*LIVER/PERIPORTAL (19) (50)
 

INFLAMMATION, CHRONIC FOCAL 3 (16X) 3 (6X)
 

t LIVER/HEPATOCYTES (19) (50)
 

SXT2P.LA.SHIC_V?CU2LIZA.TI2N__
 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

HIGH DOSE
 

(50)
 

2 C»X)
 

1 (2%)
 

(50)
 

(50)
 

1 (2X)
 

(48)
 

16	 (33X)
 

« (8X)
 

(18)
 

2 («*)
 

3 (6X)
 

(50)
 

1 (2%)
 

7 (1ttX)
 

6 (12X)
 

1 (2X)
 

1 (2X)
 

1 (2X)
 

(50)
 

(50)
 

1 (2X)
 

(50)
 

J.12S1­

69
 
TABLE C1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

IBILE DUCT
 

HYPERPLASIA, NOS
 

HYPERPLASIA, FOCAL
 

fPANCPEAS
 

INFLAMMATION, INTERSTITIAL
 

INFLAMMATION, CHRONIC FCCAL
 

tPANCREATIC ACINUS
 

FIBROSIS, FOCAL
 

ATROPHY, NOS
 

*STOMACH
 

ULCER, NO?
 

ULCER, CHRONIC
 

*GASTPIC SUBMUCOSA
 

GRANULOMA , FOREIGN BODY
 

tPEYEPS PATCH
 

HYPERPLASIA, LYMPHOID
 

URINARY SYSTEM
 

tKIDN^Y
 

INFLAMMATION, CHRONIC
 

NEPHROPATHY
 

*KIDNEY/TUBULE
 

NEPHROPATHY
 

tURINARY BLADDER
 

INFLAMMATION, NOS
 

ULCER, FOCAL
 

INFLAMMATION, ACU^E
 

ENDOCRINE SYSTEM
 

tpjruiTAPY
 

CYST, NOS
 

tADRENAL CORTEX
 

CONGESTION,, _NQS
 

MATCHED
 

CONTROL
 

(19)
 

1 (5«)
 

11 (^8X)
 

(16)
 

1 (6*)
 

(16)
 

1 (6%)
 

1 (6X)
 

(18)
 

(18)
 

1 (6*)
 

(19)
 

(19)
 

11 (585S)
 

(19)
 

(18)
 

(19)
 

(19)
 

LOW DOSE
 

(50)
 

3 (6%)
 

7 (1U«)
 

1*7)
 

1 (2%)
 

1 (2«)
 

(U7)
 

1 (2«)
 

(50)
 

1 (2%)
 

1 (2%)
 

(50)
 

(50)
 

1 (2%)
 

(50)
 

32	 (6U%)
 

2 (UX)
 

(50)
 

1 (2%)
 

(19)
 

(U7)
 

1 (2%)
 

(50)
 

1_J28L
 

HIGH DOSE
 

(50)
 

1 (2%)
 

9 (18%)
 

(47)
 

2 (US)
 

(47)
 

(49)
 

(49)
 

(49)
 

(49)
 

34 (69%)
 

(49)
 

(46)
 

1 (2«)
 

1 (2%)
 

1 (2%)
 

(48)
 

1 (2%)
 

(49)
 

# NUMBE" OF ANIMALS HITH ""ISSUE EXAMINED MICPOSCOPICILLY
 * NUMBFP OF ANIMALS NFCPOPSIFD
 

70
 
TABLE C1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED
 

CONTROL LOW DOSE HIGH DOSE
 

HEMORRHAGE 1 (2%)
 

ATROPHY, FCCAt 1 (5%)
 

HYPERPLASIA, NODULAR 1 («;%)
 

tTHYHOID (19) (SO) (50)
 

CYST, NOS 1 (2%)
 

COIIOID CYST 1 (2%)
 

REPRODUCTIVE SYSTEM
 

*NAM«APY GLAND (19) (50) (50)
 

HEMORPHAGE 1 (2%)
 

METAPLASIA, SQUAMOUS 1 (2%)
 

*PPEPUTIAL GLAND (19) (50) (50)
 

DILATATION, NO? 1 (2%)
 

CYST, NOS 1 (2%)
 

ABSCESS, NOS 1 (2v,)
 

fPP.OSTP.TE (1») (US) (43)
 

INFLAMMATION, SUPPUR»TIVE 1 (2%)
 

INFLAMMATION, ACOTE FOCAL 1 (2%) 1 (2«)
 

INFLAMMATION, ACUTE/CHEONIC 1 (7*) 3 (7*) 1 (2%)
 

INFLAMMATION, CHRONIC 1 (2%)
 

INFLAMMATION, CHPONIC FOCAL 1 (2%)
 

INFLAMMATION, CHRONIC DIFFUSE 3 (7S) 1 (2«)
 

HYPERPLASIA, NOS 1 (2%)
 

HYPERPLASIA, FOCAL 2 (1U») 2 (US) 1 (2%)
 

*TESTIS (19) (50) (a 9)
 

GRANULOMA, SPEPMATIC 1 (5%) 1 (2%)
 

ATROPHY, NOS 1 (2%)
 

*VAS DEFEREN? (19) (50) (50)
 

INFLAMMATION, CHRONIC 1 (5%)
 

NERVOUS SYSTEM
 

*CHOEOID PLEXUS (19) (50) (50)
 

INFLAMMATION, CHRONIC DIFFUSE 1 (2%)
 

SPECIAL SENSE ORGANS
 

*EYE (19) (50) (SO)
 

Cft.TA.BACT. 5_J2SS1__.,
 

« NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBED OF A»'IMALS NECROPSIED
 

71
 
TABLE C1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED
 

.CONTROL LOW DOSE HIGH DOSE
 

*EYE/CHOROID (19) (50) (50)
 

INFLAMMATION, CHRONIC DIFFUSE 1 (•?%)
 

*EYE/CILIARY BODY (19) (SO) (50)
 

INFLAMMATION, CHRONIC 1 (5%)
 

*EYE/IRIS (19) (SO) (50)
 

INFLAMMATION, ACUTE DIFFUSE 1 (5%)
 

INFLAMMATION, ACUTE/CHRONIC 2 (11«)
 

INFLAMMATION, CHRONIC 1 (SX)
 

* EYE/PETI MR (19) (-50) (^0)
 

DEGENERATION, NOS 2 (11%)
 

A1POPHY, DIFFUSE 3 (16X)
 

MUSCULOSKELETAL SYSTEM
 

*FEMUP (19) (50) (50)
 

INFLAMMATION, NOS 1 (2X)
 

BODY CAVITIES
 

*ABDOMINAL CAVITY (19) (50) (50)
 

NECROSIS, FAT 2 (U%)
 

*PERITONEUM (19) (50) (50)
 

INFLAMMATION, ACUTE/CHRONIC 1 (2%)
 

*PLEOPA (19) (50) (50)
 

INFTAMMATION, NOS 1 (2%)
 

INFLAMMATION, CHRONIC FOCAL 1 (2%) 1 (2%)
 

*EPICARDIUM (19) (50) (50)
 

INFLAMMATION, CHRONIC FOCAL 1 (2%) 1 (2*)
 

*MESENTE?Y (19) (50) (50)
 

STEATITIS 1 (2%)
 

NECROSIS, FAT 1 (2%)
 

ALL OTHER SYSTEMS
 

NONE
 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 * NUMBFP OF ANIMALS NECROPSIED
 

72
 
TABLE C1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

SPECIAL lOFPHOLOGY SUMMAF Y 

f NOHBER OF ANIMAL S HITH TISSUE EXAMINE D MICPOSCOPIC ALL Y 

* NUMBE1? OF ANIMAL S NECPOPSIED 

ANIMA L MISSING/NO NECPOPSY 

A(JTO/NECPOPSY/HIS^n PSHF 

1 

1 

73 
TABLE C2.

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE RATS 

ADMINISTERED p, p'-ETHYL-DDD IN THE DIET 

ANIMALS INITIALLY IN STUDY
 

ANIMALS NECROPSIED
 

ANIMALS EXAMINFD HISTOPATHOLOGICALLY
 

INTEGUMENTARY SYSTEM
 

*SKIN
 

ABSCESS, NOS
 

RESPIRATORY SYSTEM
 

tTRACHEA
 

INFLAMMATION, ACUTE DIFFUSE
 

INFLAMMATION, ACUTE/CHRONIC
 

INFLAMMATION, CHRONIC FOCAL
 

ILUNG
 

INFLAMMATION, NOS
 

INFLAMMATION, INTERSTITIAL
 

PNEUMONIA, ASPIRATION
 

INFLAMMATION, ACUTE/CHRONIC
 

PNEUMONIA INTEPSTITIAI CHRONIC
 

INFLAMMATION, CKPONIC FOCAL
 

BRONCHOPNEUMONIA CHRONIC SOPPUPA
 

GRANULOMA, FOREIGN BODY
 

HISTIOCYTOSIS
 

*LUNG/ALVEOLI
 

HISTIOCYTOSIS
 

HEMATOPOIETIC SYSTEM
 

*BONE MARRO W
 

HYPERPLASIA, NOS
 

•SPLEEN
 

HEMOSIDEROSIS
 

MATCHED
 

CONTROL LOW DOSE
 

20 50
 

20 50
 

20 50
 

(20) (50)
 

(20)	 (50)
 

1 (2%)
 

1 (5%)
 

(20)	 (50)
 

1 (2*)
 

2 (4%)
 

1 (5%)
 

1 (2%)
 

1 (5%) 8 (16%)
 

2 (4%)
 

(20) (50)
 

(20)	 (50)
 

1 (2%)
 

(20)	 (48)
 

_1_(2%)
 

HIGH DOSE
 

50
 

50
 

50
 

(50)
 

1 (2%)
 

(49)
 

5 (10%)
 

1 (2%)
 

(50)
 

5 (10%)
 

5 (10%)
 

2 (4%)
 

1 (2%)
 

2 (4%)
 

2 (4%)
 

(50)
 

1 (2%)
 

(50)
 

(50)
 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICPOSCOPICAILY
 

* NUMBFR OF ANIMALS NECROPSIED
 

74
 
TABLE C2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE 

HEMATOPOIESIS 1 (5%) 2 (<*%) 

tKEDZASTIN? ! L.NO

INFLAMMATION ,

D E 

 CHPONIC DIFF U SE 

(20) (50) 

1 12%) 

tTHYMH S 

HEMORRHAG E 

ATROPHY , NOS 

(19) (<40 ) 

1 (3%) 

CIRCULATORY SYSTEM
 

tMYOCARDIUH (20) (50)
 

INFLAMMATION, CHRONIC FOCAL 4 (20%) 1 (2%)
 

FIBROSIS
 

FIBROSIS, FOCAL 1 (5%) 3 (6%)
 

FIBROSIS, MHLTIFOCAL 8 (U0%) 32 (64%)
 

FIBROSIS, DIFFUSE 1 (2%)
 

DEGSN3RATICN, NOS
 

*PULMONABY SR^ERY (20) (50)
 

MINERALIZATION 3 (15%) 1 (2%)
 

MEDIAL CALCIFICATION
 

DIGESTIVE SYSTEM
 

tSALIVARY GLAND (70) («9)
 

INFLAMMATION, NOS 1 (2%)
 

INFLAMMATION, ACUTE DIFFUSE 1 (5%) 2 («%)
 

INFLAMMATION, ACUTE/CHPONIC 5 (25%) 21 (U3%)
 

INFLAMMATION, CHRONIC 1 (2%)
 

INFLAMMATION, CHRONIC DIFFUSE U (8X)
 

ATROPHY, FOCAL 1 (2%)
 

#SALIVARY SEPCaS GLA N (20) (49)
 

INFLAMMATION, ACUTE/CHRONIC
 

INFLAMMATION, CHRONIC DIFFUSE 1 (2%)
 

tLIVEP (20) (49)
 

INFLAMMATION, NECROTIZING 1 (5%)
 

INFLAMMATION, ACUTE NECROTIZING 1 (5%)
 

INFLAMMATION, ACUTE/CHRONIC
 

INFLAMMATION, CHRONIC FOCAL 2 (4%)
 

____ INFLAMMATIONi_FOCAL_GgANULO«ATOU _____________________ !_
 

f NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

HIGH DOSE 

1 (2%) 

(49) 

(46) 

1 (2% ) 

1 (2%) 

C»9)
 

12 (24S)
 

5 (10%)
 

H (8%)
 

7 (U%)
 

3 (6%)
 

(50)
 

1 (2«)
 

1 (2%)
 

(49)
 

1 (2%)
 

17 (35%)
 

5 (10%)
 

(49)
 

7 (14%)
 

{50)
 

2 (4%)
 

3 (5%)
 

75
 
TABLE C2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE 

CHOHNGIOFIBROSIS 1 (S%) 1 (2%) 

HEPATITIS, T3XIC 1 (2%) 

NECROSIS^ F6CA1 1 (2%) 

METAMORPHOSIS FAT-Hf 2 (10X) 

BASOPHILIC CYTO CHANGE 1 (2%) 

HYPERPLASIA, FOCAL 1 (*,%) 

HEMAT3POIESIS 

KLlVER/PERIPOFTAL (20) (149) 

INFLAMMATION, MULTIFOCAL 1 (S%) 

INFLAMMATION, CHRONIC FOCAL 

• BILE DUCT (20) (49) 

HYPERPLASIA, NOS 1 (Sf) 1 (2%) 

HYPERPLASIA, FOCAt 3 (15*) 12 (24%) 

IPANCFEAS (19) (SO) 

INFLAMMATION, CHROMIC 

INFLAMMATION, CHRONIC FOCAL 1 (•>*) 

1 (2%) 

s (in«) 

F1BPOSIS 

FIBROSIS, FOCAL 1 (2%) 

#P?«CPEAT?IC ACINUS (19) (50) 

AT"OPHlf, NOS 

*?TOM?CH 

INFL?M1A^ICU, ACtJTE/CHHONIC 

(20) (SO) 

f5>?rRIC MUCOSA (20) (50) 

EOSINOPHILIC INFILTRATE 

HYPERPLASIA, PSF.ODOEPITHELIOM AT0 

aPINARY SYSTEM
 

•KIDNEY	 (20) (50)
 

CALCOLOS, NOS 1 (2«)
 

HULTILOCHLAR CYST
 

INFLAMMATION, DIFFUSE
 

INFLAMMATION, ACUTE DIFFUSE 1 (S%)
 

INFLAHMAf ION, CHRONIC 11 (*S%) 33 (66%)
 

INFLAMMATION, CHRONIC DIFFUSE
 

NEPHROPATHY
 

CALCINOSIS, NOS
 

•KIDNFY/CAPSULE (20) (50)
 

____Sg£NgLCHA. NOS _ J_i2SL
 

# NUMBER OF ANIMALS BITH TISSUE EXAMI^fED MICPOSCOPICAILY
 * NUMBER OF ANIMALS NECPOPSIED
 

HIGH DOSE
 

3


1


(50)
 

1


(50)
 

1


9


(U8)
 

1


1


(<48)
 

 (6%)
 

 (2%)
 

 (2%)
 

 (2%)
 

 (18%)
 

(2%)
 

 (2%)
 

1 (2%)
 

(U8)
 

1


(U8)
 

1


1


(1*9)
 

1


1


33


1


1


 (2%)
 

 (2X)
 

 (2%)
 

 (2%)
 

 (2%)
 

 (67%)
 

 (2%)
 

 (2%)
 

2 (UX)
 

(49)
 

76
 
TABLE C2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED
 

CONTROL LOW DOSE HIGH DOSE
 

f KIDNFY/MEDULLA (20) (50) (49)
 

MINERALIZATION 1 (255)
 

#KIDNEY/PELVIS (20) (50) (49)
 

CALCULUS, NOS 1 (2%)
 

MINERALIZATION 2 (H%)
 

CALCINOSIS, NOS 1 (2%)
 

iUPINARY BLADDEP (20) (50) (U3)
 

CALCULUS, NOS 1 (2t)
 

HYPERPLASIA, EPITHELIAL 2 (U«)
 

ENDOCRINE SYSTEM
 

•PITUITARY	 (20) (50) (49)
 

CYST, NOS 1 (2%) 1 (2%)
 

*AD5i.NAL (20) (50) («8)
 

DEGENERATION, CYSTIC 1 (2«)
 

CIDRSN^L CORTEX (20) (50) («8)
 

DEGENERATION, NOS 1 (•?«)
 

ATFOPHY, FOCAL 1 (5%)
 

HYPERPLASIA, NODULAR 1 (*S) 1 (2%) 1 (2%)
 

HYPERPLASIA, FOCAL 1 (5%)
 

#ADPENAL MEDULLA (20) (50) («8)
 

HYPERPLASIA, FOCAL 1 (5«)
 

#mHYEOID (19) (49) (U 9}
 

COLLOID CYST 1 (2*) 1 (2%)
 

HYPERPLASIA, C-CELL 2 (11%) 2 (US)
 

REPRODUCTIVE SYSTEM
 

*M?1MARY GL^ND (20) (50) (50)
 

INFI SMMATICN, ACU^E 1 (2*)
 

INFLAFMATICN, ACUTK FOCAL 1 (2%)
 

AdSCESS, NOS 1 (2%)
 

HYPERPLASIA, CYSTIC 1 (2%)
 

HYFFRPLASI?, STROMAL 2 (4*)
 

EPITHELJALIZATION 1 I5J1
 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 * NUMBEE OF ANI1ALS NECROPSIED
 

77
 
TABLE C2. FEMALE RATS: NONNEOPLASTIC LLSIONS (CONTINUED) 

*MAMMJ>°Y LOPUIE
 

HYPERPLASIA, NOS
 

*PREPCTIAL GLAND
 

HYPERPLASIA, DIFFUSE
 

*VAGINA
 

INFLAMMATION, ACUTE/CHRONIC
 

*UTERUS
 

DECIDUAL ALTERATION, NOS
 

*UTER US /ENDOMETRIUM
 

TY?T, NOS
 

HYPERPLASIA, STROMAL
 

*OVARY
 

CYSTIC FOLLICLES
 

FOLLICULAR CYST, NOS
 

CORPUS LflTFUP CYST
 

NEPVOUS SYSTFM
 

t EPA IN
 

INFLAMMATION, FnC?L
 

SPECTAT SENSE C5GANS
 

*FYE
 

CATARACT
 

*SYF/CHOROID
 

INFLAMMAmICN, CHRONIC
 

*EYE/IPIS
 

INFLAMMATION, ACDTS/CHPONIC
 

* EYE/PETI NA
 

DEGENERATION, NOS
 

MUSCULOSKELETAL SYSTEM
 

MATCHED
 

CONTROL
 

(20)
 

1 (5%)
 

(20)
 

(20)
 

(19)
 

1 (5%)
 

(19)
 

(20)
 

(20)
 

1 (5%)
 

(?0)
 

2 (10%)
 

(20)
 

1 (*X)
 

(20)
 

1 (SX)
 

(20)
 

3 (15%)
 

LOW DOSE
 

(50)
 

(50)
 

1 (2%)
 

(50)
 

(50)
 

1 (2%)
 

(50)
 

3 (6*)
 

(50)
 

(49)
 

(50)
 

(50)
 

(50)
 

(50)
 

HIGH DOSE
 

(50)
 

(50)
 

(50)
 

1 (2X)
 

(H9)
 

1 (2%)
 

(U9)
 

1 (2%)
 

1 (2%)
 

(i»7)
 

1 (2%)
 

5 (11%)
 

1 (225)
 

(50)
 

(50)
 

(50)
 

(50)
 

(50)
 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NU*BF" TF ANIMALS NECROPSIED
 

78
 
TABLE C2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED
 

CONTROL LOW DOSE HIGH DOSE
 

BODY CAVITIES
 

*HEPENTE9Y (20) (50) (50)
 

NECPOSIS, FAT 2 (US)
 

AIL OTHER SYSTEMS
 

NONE
 

SPECIAL MORPHOLOGY SUMMARY
 

NONE
 

t NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

79
 
80

 
APPENDIX D
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN
 

MICE ADMINISTERED p,p'-ETHYL-DDD IN THE DIET
 

81
 
82

 
TABLE 01. 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE MICE 

ADMINISTERED p, p'-ETHYL-DDD IN THE DIET 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

ANIMAL S INITIALLY IN STUDY 20 50 50 

ANIMAL S MISSIN G 1 

ANIMAL S NECROPSIE D 19 50 50 

ANIMAL S EXAMINE D HISTOPATHOLOGICALLY 19 50 50 

INTMEGUMFNTAFY SYSTEM
 

*SKIN (19) (50) (50) 

EPIDERMA L INCLUSION CYST 1 (2%) 

GRANULATION , TISSUE 1 (2%) 

*SUBCOT TISSUE (19) (50) (50) 

.ABSCESS, NOS 1 (5%) 

RESPIRATORY SYSTEM
 

#LUNG (19) (50) (U9)
 

HEMORRHAGE 1 (?%)
 

BRONCHOPNEUMONIA, FOCAL 1 (S«)
 

INFLAMMATION, INTERSTITIAL 1 (5«) 1 (2X)
 

PNEUMONIA, ASPIRATION 1 (2%)
 

HEMOSIDEROSIS 1 (2%)
 

HISTIOCYTCSIS 1 (2«)
 

HEMATOPOIETIC SYSTEM 

*BONE MP.RFOW 

HYPERPLASIA, HEHAT1POIETIC 

HYPE?PLA?IA, ET?YTHPOID 

(18) 

1

1

 (*%) 

 (6T) 

(50) (U9) 

tSPLEEN 

THROMBOSIS, NOS 

INFLAMMATION ACTIVE CHRONIC 

INFLAMMATION, ACUTE/CHRONIC 

FIBROSIS 

INFARCT, FOCAL 

HEMATOPOIESIS 

(19) 

1 (5%) 

(US) 

1

1 (2%) 

 (2%) 

(HI) 

1 

1 

1 

1 

1 

(2%) 

(2%) 

(2%) 

(2*) 

(2*) 

ATROPHY, #SPLENIC FOLLICLE NOS_ S (19) (U8) («7) 

1.J2S1
 

I NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

83
 
TABLE D1. MALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED
 

CONTROL LOW DOSE
 

SMESENTERIC L. NODE (18) (05)
 

CYST, NOS 1 (2%)
 

HEMORRHAGE
 

INFLAMMATION, NOS
 

INFLAMMATION, GRANULOMA TOOS
 

HI?TIOCYTOSIS
 

HYPERPLASIA, LYMPHOID
 

HEMATOPOIESIS 1 (6%) 1 (2«)
 

CIRCULATORY SYSTEM
 

*HEART/ATRIUM (19) (47)
 

THROMBUS, MU^AL 1 (2^)
 

#MYOCARDIUM (19) (47)
 

INFLAMMATION, CHPONIC 1 (2«)
 

INFLAMMATION, CHPONIC FOCAL 1 (2%)
 

SCAP 1 (2%)
 

DEGENERATION, NOS
 

SCARDIAC VALVE (19) (07)
 

INFLAMMATION, FOCAL 1 (2%)
 

*AOPIA (19) (50)
 

INFLAMMATION, FOCAL 1 (2%)
 

INFLAMMATION, ACUTS/CHEONIC
 

*HEPATIC VEIN (19) (50)
 

TriPOMBOSIS, NOS
 

DIGESTIVE SYSTEM 

tLIVEP (19) (49) 

THROMBOSIS, NOS 1 (2%) 

INFLAMMATION, MDLTIFOCAL 

INFLAMMATION, ACUTE FOCAL 1 (5%) 

PELIOSIS HEPATIS 1 (5*) 1 (2%) 

NECROSIS, NOS 1 (2%) 

NECROSIS, COAGULATIVE 

CLEAR-CELL CHANGF 

HYPERPLASIA, NODOLAR 1 (2%) 

HYPEPPLJ.SI,JA_NOS l.lStl 2_Jfill. 

# NDMBEP OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 * NUMBER OF ANIMALS NECROPSIED
 

HIGH DOSE
 

(07)
 

1 (2%)
 

1 (2«)
 

1 (2%)
 

1 (2%)
 

1 (?.%)
 

3 (6%)
 

r-oj
 

(50)
 

1 (2%)
 

(50)
 

(50)
 

1 (2*)
 

(50)
 

1 (2*)
 

(^0)
 

1 (2X)
 

2 (OS)
 

1 (2%)
 

2 (0%)
 

2.1^1.
 

84
 
TABLE D1. MALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

HYPERPLASIA, FOCAL
 

HYPERPLASIA, DIFFUSE
 

HEMATOPOIESIS
 

,-*HEPATIC CAPSULE
 

INFLAMMATION, CHRONIC FOCAL
 

tPANCPEAS
 

INFLAMMATION, CHRONIC FOCAL
 

tSTOMJCH
 

A3SCESS, NOS
 

ACANTHOSIS
 

fPEYERS PATCH
 

HYPERPLASIA, NO?
 

URINABY SYSTEM
 

*KIDNEY
 

INFLAMMATION, INTERSTITIAL
 

GLOMERULONEPHRITIS, CHRONIC
 

NEPHROSIS, NOS
 

GLOMERULOSCLEROSIS, NOS
 

*KIDNEY/TDBULE
 

DEGENERATION, NOS
 

ENDOCRINE SYSTEM
 

tTHYECID
 

THYP3GLOSSAL DTJCT CYST
 

OLTIBOBRANCHIAL CYST
 

REPRODUCTIVE SYSTEM
 

*PRT;POTIAL GLAND
 

DILATJiTION/DOCTS
 

INFLAMMATION, ACWTE
 

*PROSTATE
 

— MEl5.S3SJ.ICSx IfiTSPSTITIAl
 

MATCHED
 

CONTROL
 

1 (5%)
 

(19)
 

(17)
 

(19)
 

1 (5%)
 

(18)
 

1 (6%)
 

(19)
 

2 (11%)
 

(19)
 

(18)
 

(19)
 

(16)
 

LOW DOSE
 

1 (2%)
 

1 (2*)
 

1 (2*)
 

(U9)
 

(t6)
 

1 (2«)
 

(«9)
 

(43)
 

(1*9)
 

1 (2X)
 

1 (2%)
 

(49)
 

(«7)
 

1 (2«)
 

(50)
 

(43)
 

HIGH DOSE
 

(50)
 

1 (2%)
 

(48)
 

(49)
 

1 (2%)
 

(49)
 

(50)
 

3 (6%)
 

1 (2«)
 

1 (2%)
 

(50)
 

1 (2%)
 

(50)
 

1 (2%)
 

(50)
 

1 (2X)
 

1 (2X)
 

(39)
 

.— —J-J3S1.
 

t NUMBER OF ANIMALS WITH TISSOE EXAMINED MICROSCOPICALLY
 * NUMBER OF ANIMALS NECROPSIED
 

85
 
TABLE D1. MALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED
 . CONTROL LOW DOSE HIGH DOSE
 

*SE«INAL VESICLE (19) (50) (50)
 

INFLAMMATION ACTIVE CHRONIC 1 (2%)
 

*EPIDIDYMTS (19) (50) (50)
 

ABSCESS, CHRONIC 1 C^*)
 

NEPVOUS SYSTEM
 

tCESEBELLUM (18) (U8) (47)
 

HtMOPRHAGE 1 (2%)
 

•MEDULLA	 OBLONGATA (18) (U8) (47)
 

HEMORRHAGE 1 (2*)
 

SPECIAL SENSE ORGANS
 

*HARDEPIAN GLAND (19) (50) (50)
 

CYST, tJOS 1 (2X)
 

MUSCULOSKELETAL SYSTEM
 

NOME
 

BODY CAVITIES
 

*ABDO«INAL CAVITY (19) (50) (50)
 

NECROSIS, FAT 1 (5«)
 

*PLEUPA (19) (50) (50)
 

INFLAMMATION, CHPONIC FOCAL 1 (2*)
 

*MESENTKRY	 (19) (50) (50)
 

STEATITIS 1 (2%)
 

NECROSIS, FAT 1 (2%)
 

ALL OTHEP SYSTEMS
 

OHENTUM
 

STEATITIS J
 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 * NtJMBEP OF ANIMALS
 

86 
TABLE 01. MALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

SPECIAL MORPHOLOGY SUMMARY 

NO LESION REPOFTED 1

ANIMAL HISSING/NO NECPOPSY 1 

t NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY * NUMBER OF ANIMALS NECROPSIED 

U 7 

87
 
TABLE D2.

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE MICE 

ADMINISTERED p, p'-ETHYL-DDD IN THE DIET 

MATCHED
 

CONTROL LOW DOSE HIGH DOSE
 

ANIMAL? INITIALLY IN STUDY 20 50 5C
 

ANIMALS MISSING 3 1
 

ANIMALS NECROPSIED 20 HI 49
 

ANIMALS EXAMINED HISTOPATHOLOGIC ALLY 20 47 48
 

INTEGUMENTARY SYSTEM
 

NONE
 

PESPIR«TORY SYSTEM
 

*LUNG (18) (47) (1*7)
 

INFLAMMATION, INTERSTITIAL 2 (11%) 1 (2«) 1 (2%)
 

PNEUMONIA INTERSTITIAL CHRONIC 1 (6%) 1 (2%)
 

HISTIOCY^CSIS 1 (2%)
 

HYPERPLASIA, LYMPHOID 1 (2%)
 

HEMATOPOIETIC SYSTEM
 

*BLOOD (70) (47) (49)
 

LYMPHOPENIA 1 (2%)
 

tBONS MARROW (20) (45) (47)
 

HYPERPLASIA, NOS 1 (2%)
 

• SPLEEN (19) (U6) (46)
 

TriPOMBOSIS, NOS 1 (2%)
 

SCLEROSIS 1 (2%)
 

NECPOSIS, FAT 1 (2«)
 

HYPERPLASIA, LYMPHOID 1 (5%)
 

HSHATOPOIESIS 1 (2%)
 

^MESENTERIC L. NODB (20) (46) (46)
 

INFLAMMATION, NOS 1 (2%)
 

INFLAMMATION, CHFONIC FOCAL 1 (5%)
 

CIPCULATORY SYSTEM
 

NONE
 

# NUMBEP OF »NI1ALS WITH TISSUE EXAMINED MICROSCOPICALLY
 * NUMBS" OF ANIMALS NECROPSIED
 

88
 
TABLE 02. FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

DIGESTIVE SYSTEM
 

•SALIVARY GLAND
 

INFLAMMATION, CHRONIC FOCAI
 

fLIVEP
 

INFLAMMATION, ACUTE FOCAL
 

INFLAMMATION, ACUTE NECROTIZING
 

INFLAMMATION, ACUTE/CHRONIC
 

INFLAMMATION, CHRONIC NFCPQTIZIN
 

INFLAMMATION, FOCAL GRANOLOMATCU
 

PEIIOSIS HEPATIS
 

NECROSIS, FOCAL
 

NECROSIS, COAGULATIVE
 

METAMORPHOSIS FATTY
 

BASOPHILIC CYTO CHANGE
 

HYPERPLASIA, NOS
 

tPANCPEAS
 

CYSTIC DUCTS
 

HEMORRHAGE
 

INFLAMMATION ACTIVE CHPONIC
 

INFLAMMATION, ACUTE/CHRONIC
 

NECROSIS, FAT
 

AIFOPHY, NOS
 

tILEUM
 

ULCEP, FOCAL
 

*COLON
 

INFLAMMATION, FOCAL
 

ABSCESS, NOS
 

URINARY SYSTEM
 

#KIDN'EY
 

CYST, NOS
 

INFLAMMATION, INTERSTITIAL
 

INFLAMMATION, CHRONIC FOCAL
 

INFLAMMATION, FOCAL GRANULOMATOU
 

____ SIPHROSISi_NQS
 

MATCHED
 

CONTROL
 

(18)
 

1 (6%)
 

(19)
 

1
 

(19)
 

1 (5%)
 

1 ('=•%}
 

(17)
 

(20)
 

(20)
 

(20)
 

2 (10X)
 

LOW DOSE HIGH DOSE
 

(43) (46)
 

(47)	 (47)
 

1 (2«)
 

1 (2%)
 

1 (2%)
 

1 (2%)
 

2 (4%)
 

1 (2%)
 

1 (2%)
 

1	 (2%)
 

1	 (2%) 1 (2%)
 

1 (2*) 2	 (4%)
 

(45)	 (46)
 

1 (2%)
 

1 (2%)
 

1 (2%)
 

2
 

1	 (2%)
 

(42)	 (44)
 

1 (2%)
 

(44)	 (48)
 

1 (2%)
 

(47)	 (49)
 

1 (2%)
 

(47)	 (47)
 

1 (2%)
 

1 (2«)
 

1 (2%)
 

#	 NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

*	 NUMBER OF ANIMALS NECROPSIED
 

89
 
TABLE 02. FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED
 

CONTROL LOW DOSE HIGH DOSE
 

GLOMERTJLOSCIEBOSIS, NOS	 1 (2%)
 

tKIDNFY/TUBt'LE (20) (47) (47)
 

DEGENERATION, NOS 1 (2%)
 

tUEINAPY BLADDER (18) (42) (45)
 

INFI AMMATTON, PYOGEANULOMATOHS 1 (2%)
 

ENDOCRINE SYSTEM
 

•THYKOID	 (18) (41) (46)
 

THYPDGLOSSAL DUCT CYST 1 (2%)
 

ULTIMOBRANCHIAL CYST 1 (*%)
 

REPRODUCTIVE SYSTEM
 

*MAMMARY GLAND (20) (47) (49)
 

«BSCE^S, NOS 1 (2%)
 

tUTEEUS (19) (1*5) (42)
 

HYPERPLASIA, ADENOMATOUS 1 (2%)
 

*TJTERUS/ENDOMETFIUM (19) (45) (42)
 

CYST, NOS 14 (31%) 13 (31*)
 

tnTERUS/MYOMETRITTM (19) (45) (42)
 

INFLAMMATION, CHRONIC l*OCAL 1 (2*)
 

NERVOUS SYSTEM
 

tnPAIN/IENINGES (18) (44) (48)
 

INFLAMMATION, NOS 2 (5%)
 

INFLAMMATION, FOCAL 1 (2%)
 

INFLAMMATION, "OLTIFOCAL 1 (2%)
 

PERIVASCULITIS 3 (7%)
 

*CHOEOID PLEXUS (20) (47) (49)
 

INFLAMMATION, FOCAL 1 (2%)
 

INFLAMMATION, M'TLTIFOCAL 1 (2%)
 

INFLAMMATION, CHRONIC FOCAL 1 (2%)
 

tBPAIN	 (18) (44) (48)
 

f NUMJF.R 3" ANIMALS WITH TISSUE EXAMINED MICPOSCOPI"A LLY
 * NUMBF" I? ANIMALS NECROPSIED
 

90
 
TABLE 02. FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED
 

CONTROL LOW DOSE HIGH DOSE
 

SPECIAL SENSE ORGANS
 

*BYE/LACRIMAL GLAND	 (20) (47) (49)
 •CYST, NO? 1 (2%)
 

INFLAMMATION, FOCAL 1 (2%)
 

•HARDERIAN	 GLAND (20) (<»7) (49)
 

DILATATION, NO0: 1 (2X)
 

MUSCULOSKELETAL SYSTEM
 

NONE
 

BODY CAVITIES
 

*MFDIASIINUM (20) (HI) (49)
 

PSRIVASCOLITIS 1 (2X)
 

*AEDOMINAL CAVITY (20) (<*7) (49)
 

CYST, NOS 1 (2%)
 

NECPOSIS, FAT 1 (5X) 1 (2%)
 

*PELVIS (20) (47) (49)
 

N2CPOSIS, FAT 1 (2%)
 

*PLEURA (20) (47) (49)
 

INFLAMMATION, CHRONIC 1 (2%)
 

INFLAMMATION, CHRONIC FOCAL 1 (5%)
 

•MESENTERY	 (20) (47) (49)
 

INFLAMMATION, PYOGRANtJlOMfiTOUS 1 (2«)
 

ALL OTHER SYSTFMS
 

•MULTIPLE ORGANS (20) (47) (49)
 

HEMATOPOIESIS 1 (5X) 1 (2)5)
 

SPECIAL HORPHOLOGY SUMMAR Y
 

NO_LESICN_R3POPTED	 6 4 2_
 

* NUHBEP OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 * NUMBER OF ANIMALS NECROPSIED
 

91
 
TABLE D2. FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

ANIMA L MISSING/NO NECROPSY

AUTO/NECROPSY/HISTO PERF

AUTO/NECROPSY/NO HISTO

 3 1 

1 

1 

# NUMBE R

* NUMBER

 OF

 OF

 ANIMAL S

 ANIMALS

 WITH TISSUE

 NECROPSIED 

 EXAMINE D MICROSCOPICALLY 

92 
APPENDIX E
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS IN
 

RATS ADMINISTERED p,p'-ETHYL-DDD IN THE DIET
 

93
 
94

 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats 

Administered p,p'-Ethyl-DDD in the Diet (a) 

Topography: Morphology

Matched 

 Control 

Low 

Dose 

High 

Dose 

Integumentary System: 

Squamous-cell Carcinoma of 

the Skin (b) 0/19 (0) 1/50 (2) 3/50 (6) 

P Values (c,d) N.S. N.S. N.S. 

Relative Risk (f) 

Lower Limit 

Upper Limit 

Infinite 

0.021 

Infinite 

Infinite 

0.238 

Infinite 

Weeks to First Observed Tumor — 87 87 

Ol 

Hematopoietic System: 

Neoplasm, NOS (b) 4/19 (21) 11/50 (22) 10/50 (20) 

P Values (c,d) N.S. N.S. N.S. 

Relative Risk (f) 

Lower Limit 

Upper Limit 

1.045 

0.367 

4.095 

0.950 

0.324 

3.782 

Weeks to First Observed Tumor 91 79 84 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats
 

Administered p,p'-Ethyl-DDD in the Diet (a)
 

(continued)
 

Matched Low
 

Topography: Morphology Control Dose
 

Pituitary: Adenoma, NOS (b) 0/19 (0) 1/47 (2)
 

P Values (c,d) N.S. N.S.
 

Relative Risk (f) Infinite
 

Lower Limit 0.022
 

Upper Limit Infinite
 

Weeks to First Observed Tumor — 105
 

\o
 Pituitary: Chromophobe
 

Adenoma (b) 3/19 (16) 7/47 (15)
 

P Values (c,d) N.S. N.S.
 

Relative Risk (f) 0.943
 

Lower Limit 0.250
 

Upper Limit 5.246
 

Weeks to First Observed Tumor 105 105
 

High
 

Dose
 

3/48 (6)
 

N.S.
 

Infinite
 

0.248
 

Infinite
 

105
 

2/48 (4)
 

N.S.
 

0.264
 

0.024
 

2.160
 

105
 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats
 

Administered p,p'-Ethyl-DDD in the Diet (a)
 

(continued)
 

Matched Low
 

Topography: Morphology Control Dose
 

Pituitary: Chromophobe
 

Adenoma or Adenoma, NOS (b) 3/19 (16) 8/47 (17)
 

P Values (c,d) N.S. N.S.
 

Relative Risk (f) 1.078
 

Lower Limit 0.301
 

Upper Limit 5.847
 

Weeks to First Observed Tumor 105 105
 

v£>
 

Adrenal: Pheochromocytoma (b) 2/19 (11) 5/50 (10)
 

P Values (c,d) N.S. N.S.
 

Relative Risk (f) 0.950
 

Lower Limit 0.176
 

Upper Limit 9.498
 

Weeks to First Observed Tumor 105 105
 

High
 

Dose
 

5/48 (10)
 

N.S.
 

0.660
 

0.147
 

3.959
 

100
 

3/49 (6)
 

N.S.
 

0.582
 

0.074
 

6.640
 

105
 
(continued) 

Topography:

Table El.

 Morphology 

 Analyses of the Incidence of Primary Tumors in Male Rats 

Administered p,p"-Ethyl-ODD in the Diet (a) 

Matched Low 

Control Dose 

High 

Dose 

Thyroid: C-cell Adenoma (b) 2/19 (11) 7/50 (14) 6/50 (12) 

P Values (c,d) N.S. N.S. N.S. 

Relative Risk (f) 

Lower Limit 

Upper Limit 

1.330 

0.289 

12.469 

1.140 

0.232 

10.985 

Weeks to First Observed Tumor 105 105 105 

VO 

00 Testis: Interstitial-cell 

Tumor (b) 17/19 (89) 35/50 (70) 35/49 (71) 

P Values (c,d) N.S. N.S. N.S. 

Relative Risk (f) 

Lower Limit 

Upper Limit 

0.782 

0.675 

1.097 

0.789 

0.688 

1.115 

Weeks to First Observed Tumor 74 87 100 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats
 

Administered p,p'-Ethyl-DDD in the Diet (a)
 

(continued)
 

(a) Dosed groups received 3,500 or 7,000 ppm.
 

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

(c) Beneath the incidence of tumors in the control group is the probability level for the Cochran-


Armitage test when P is less than 0.05; otherwise, not significant (N.S.) is indicated. Beneath
 

the incidence of tumors in a dosed group is the probability level for the Fisher exact test for
 

the comparison of that dosed group with the matched-control group when P is less than 0.05;
 

otherwise, not significant (N.S.) is indicated.
 

(d) A negative trend (N) indicates a lower incidence in a dosed group than in the control group.
 

(e) The probability level for departure from linear trend is given when P is less than 0.05 for any
 

vo comparison.
 

(f) The 95% confidence interval of the relative risk between each dosed group and the control group.
 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Administered p,p'-Ethyl-DDD in the Diet (a)
 

Matched Low High
 

Topography: Morphology Control Dose Dose
 

Integumentary System:
 

Squamous-cell Carcinoma of
 

the Skin (b) 2/20 (10) 0/50 (0) 0/50 (0)
 

P Values (c,d) P = 0.024 (N) N.S. N.S.
 

Departure from Linear Trend (e) P = 0.042
 

Relative Risk ( f) 0.000 0.000
 

Lower Risk 0.000 0.000
 

Upper Limit 1.345 1.345
 

o
 

o Weeks to First Observed Tumor 100
 —
 

Hematopoietic System:
 

Neoplasm, NOS (b) 3/20 (15) 8/50 (16) 6/50 (12)
 

P Values (c,d) N.S. N.S. N.S.
 

Relative Risk (f) 1.067 0.800
 

Lower Limit 0.295 0.195
 

Upper Limit 5.813 4.615
 

Weeks to First Observed Tumor 105 93 70 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Administered p,p'-Ethyl-DDD in the Diet (a)
 

(continued)
 

Topography : Morphology
 

Pituitary: Chromophobe
 

Adenoma or Adenoma, NOS (b)
 

P Values (c,d)
 

Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Adrenal: Cortical
 

Adenoma (b)
 

P Values (c,d)
 

Departure from Linear Trend (e)
 

Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched


Control


5/20 (25)


N.S.


92


3/20 (15)


P = 0.005 (N)


P = 0.014
 

92
 

 Low
 

 Dose
 

 13/50 (26)
 

 N.S.
 

1.040
 

0.416
 

3.341
 

 105
 

 0/50 (0)
 

P = 0.021 (N)
 

0.000
 

0.000
 

0.659
 

High
 

Dose
 

6/49 (12)
 

N.S.
 

0.490
 

0.146
 

1.842
 

105
 

0/48 (6)
 

P = 0.023 (N)
 

0.000
 

0.000
 

0.686
 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Administered p,p'-Ethyl-DDD in the Diet (a)
 

(continued)
 

Topography: Morphology


Thyroid: C-cell Adenoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


Uterus: Endometrial Stromal
 

Polyp (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched Low High 

 Control Dose Dose 

 2/19 (11) 4/49 (8) 4/49 (8) 

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

0.776 0.776 

0.125 0.125 

8.165 8.165 

 105 105 105 

 0/19 (0) 5/50 (10) 3/49 (6) 

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

Infinite Infinite 

0.501 0.243 

Infinite Infinite 

105 105 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Administered p,p'-Ethyl-DDD in the Diet (a)
 

(continued)
 

(a) Dosed groups received 3,500 or 7,000 ppm.
 

(b) Number of tumor-bearing animaIs/number of animals examined at site (percent).
 

(c) Beneath the incidence of tumors in the control group is the probability level for the Cochran-


Armitage test when P is less than 0.05; otherwise, not significant (N.S.) is indicated. Beneath
 

the incidence of tumors in a dosed group is the probability level for the Fisher exact test for
 

the comparison of that dosed group with the matched-control group when P is less than 0.05;
 

otherwise, not significant (N.S.) is indicated.
 

(d) A negative trend (N) indicates a lower incidence in a dosed group than in the control group.
 

(e) The probability level for departure from linear trend is given when P is less than 0.05 for any
 

comparison.
 

£ (f) The 95% confidence interval of the relative risk between each dosed group and the control group.
 CO
 
104

 
APPENDIX F
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS IN
 

MICE ADMINISTERED p,p'-ETHYL-DDD IN THE DIET
 

105
 
106

 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice
 

Administered p,p'-Ethyl-DDD in the Diet (a)
 

Topography: Morphology

Matched 

 Control 

Low 

Dose 

High 

Dose 

Lung: Alveolar/Bronchiolar 

Adenoma (b) 0/19 (0) 4/50 (8) 9/49 (18) 

P Values (c,d) P = 0.017 N.S. P = 0.042 

Relative Risk (f) 

Lower Limit 

Upper Limit 

Infinite 

0.368 

Infinite 

Infinite 

1.066 

Infinite 

Weeks to First Observed Tumor — 100 105 

Lung: Alveolar/Bronchiolar
 

Carcinoma (b) 4/19 (21) 1/50 (2) 3/49 (6)
 

P Values (c,d) N.S. P = 0.018 (N) N.S.
 

Departure from Linear Trend (e) P = 0.018
 

Relative Risk ( f) 0.095 0.291
 

Lower Limit 0.002 0.048
 

Upper Limit 0.895 1.587
 

Weeks to First Observed Tumor 105 103 105
 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice
 

Administered p,p'-Ethyl-DDD in the Diet (a)
 

(continued)
 

Topography: Morphology


Lung: Alveolar/Bronchiolar
 

Carcinoma or Adenoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


Hematopoietic System:
 

o Lymphoma (b)
 00
 

P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched
 

 Control
 

 4/19 (21)
 

 N.S.
 

 98
 

 2/19 (11)
 

 N.S.
 

98
 

Low
 

Dose
 

5/50 (10)
 

N.S.
 

0.475
 

0.118
 

2.201
 

66
 

9/50 (18)
 

N.S.
 

1.710
 

0.407
 

15.426
 

66
 

Ul>;!n
 

DC S5
 

12/49 (24)
 

N.S.
 

1.163
 

0.419
 

4.490
 

104
 

2/50 (4)
 

N.S.
 

0.380
 

0.030
 

5.009
 

104
 
(continued) 

Topography:

Table Fl.

 Morphology

 Analyses of the Incidence of Primary Tumors in Male Mice 

Administered p,p'-Ethyl-DDD in the Diet (a) 

Matched 

 Control 

Low 

Dose 

High 

Dose 

Liver: Hepatocellular Carcinoma (b) 7/19 (37) 19/49 (39) 20/50 (40) 

P Values (c,d) N.S. N.S. N.S. 

Relative Risk ( f) 

Lower Limit 

Upper Limit 

1.052 

0.530 

2.547 

1.086 

0.552 

2.611 

Weeks to First Observed Tumor 94 76 28 

o 

VD 

Liver: Hepatocellular Carcinoma, 

Adenoma, or Neoplastic 

Nodule (b) 8/19 (42) 27/49 (55) 25/50 (50) 

P Values (c,d) N.S. N.S. N.S. 

Relative Risk (f) 

Lower Limit 

Upper Limit 

1.309 

0.740 

2.765 

1.188 

0.662 

2.553 

Weeks to First Observed Tumor 94 76 28 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice
 

Administered p.p'-Ethyl-DDD in the Diet (a)
 

( continued)
 

(a) Dosed groups received 2,500 or 5,000 ppm.
 

(b) Number of tumor-bearing animaIs/number of animals examined at site (percent).
 

(c) Beneath the incidence of tumors in the control group is the probability le^el for the Cochran-


Armitage test when P is less than 0.05; otherwise, not significant (N.S.) is indicated. Beneath
 

the incidence of tumors in a dosed group is the probability level for the Fisher exact test for
 

the comparison of that dosed group with the matched-control group when P is less than 0.05;
 

otherwise, not significant (N.S.) is indicated.
 

(d) A negative trend (N) indicates a lower incidence in a dosed group than in the control group.
 

(e) The probability level for departure from linear trend is given when P is less than 0.05 for any
 

H1 comparison.
 

O
 

(f) The 95% confidence interval of the relative risk between each dosed group and the control group.
 
Table F2. Analyses of the Incidence of Primary Tumors in Female Mice
 

Administered p,p'-Ethyl-DDD in the Diet (a)
 

Topography: Morphology


Lung: Alveo lar/Bronchio lar
 

Carcinoma or Adenoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


Hematopoietic System: Malignant
 

Lymphoma or Lymphocytic
 

Leukemia (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched
 

 Control
 

 0/18(0)
 

 N.S.
 

—
 

 4/20 (20)
 

 N.S.
 

80
 

Low
 

Dose
 

3/47 (6)
 

N.S.
 

Infinite
 

0.241
 

Infinite
 

105
 

9/47 (19)
 

N.S.
 

0.957
 

0.313
 

3.880
 

86
 

High
 

Dose
 

1/47 (2)
 

N.S.
 

Infinite
 

0.021
 

Infinite
 

6/49 (12)
 

N.S.
 

0.612
 

0.168
 

2.710
 

101
 

105 
Table F2. Analyses of the Incidence of Primary Tumors in Female Mice
 

Administered p,p'-Ethyl-ODD in the Diet (a)
 

(continued)
 

Topography ; Morphology


Liver: Hepatocellular Carcinoma (b)


P Values (c,d)


Relative Risk ( f )
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


Liver: Hepatocellular
 

Carcinoma or Adenoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched
 

 Control
 

 1/19 (5)
 

P = 0.013
 

 105
 

 1/19(5)
 

P = 0.011
 

105
 

Low High 

Dose Dose 

2/47 (4) 10/47 (21) 

N.S. N.S. 

0.809 4.043 

0.046 0.653 

46.702 170.880 

105 105 

3/47 (6) 11/47 (23) 

N.S. N.S. 

1.213 4.447 

0.107 0.735 

62.303 186.311 

105 105 
Table F2. Analyses of the Incidence of Primary Tumors in Female Mice
 

Administered p,p'-Ethyl-DDD in the Diet (a)
 

(continued)
 

Topography: Morphology


Pituitary: Chromophobe
 

Adenoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


All Sites: Hemangioma or
 

Hemangiosarcoma (b)


P Values (c,d)


Departure from Linear Trend (e)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched
 

 Control
 

 1/18 (6)
 

 N S.
 

 105
 

 0/20 (0)
 

 N.S.
 

P = 0.044
 

Low	 High
 

Dose	 Dose
 

4/42 (10) 5/46 (11)
 

N.S.	 N.S.
 

1.714	 1.957
 

0.190	 0.246
 

82.316	 90.394
 

105 105
 

3/47 (6) 0/49 (0)
 

N.S.
 —
 

Infinite
 —
 0.266
 —
 Infinite
 —
 

95
 
Table F2. Analysis of the Incidence of Primary Tumors in Female Mice 

Administered p,p!-Ethyl-DDD in the Diet (a) 

(continued) 

(a) Dosed groups received time-weighted average doses of 2,828 or 6,200 ppm. 

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

(c) Beneath the incidence of tumors in the control group is the probability level for the CochranArmitage test when P is less than 0.05; otherwise, not significant (N.S.) is indicated. Beneath 

the incidence of tumors in a dosed group is the probability level for the Fisher exact test 

for the comparison of that dosed group with the matched-control group when P is less than 0.05; 

otherwise, not significant (N.S.) is indicated. 

(d) A negative trend (N) indicates a lower incidence in a dosed group than in the control group. 

(e) The probability level for departure from linear trend is given when P is less than 0.05 for any 

comparison. 

( f) The 95% confidence interval of the relative risk between each dosed group and the control group. 
Review of the Bioassay of P,P'-Ethyl DDD* for Carcinogenicity
 

by the Data Evaluation/Risk Assessment Subgroup
 

of the Clearinghouse on Environmental Carcinogens
 

October 25, 1978
 

The Clearinghouse on Environmental Carcinogens was established in
 

May, 1976, in compliance with DHEW 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, and State health officials.
 

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 responsibility of providing a
 

peer review of reports prepared on NCI-sponsored bioassays of chemicals
 

studied for carcinogenicity. It is in this context that the below
 

critique is given on the bioassay of p,p'-Ethyl DDD for carcinogenicity.
 

The reviewer for the report on the bioassay of p,p'-Ethyl DDD agreed
 

with the conclusion in the report that the compound was not carcinogenic
 

in either sex of treated rats or male mice. The increased incidence of
 

liver neoplasms in treated female mice suggested a possible carcinogenic
 

effect in this sex and strain. After briefly describing the experimental
 

design, the reviewer said that there were no unusual highlights or other
 

significant effects upon which to comment. There was no objection to a
 

recommendation that the report on the bioassay of p,p'-Ethyl DDD be
 

accepted as written.
 

Clearinghouse Members present:
 

Arnold L. Brown (Chairman), University of Wisconsin Medical School
 

Joseph Highland, Environmental Defense Fund
 

William Lijinsky, Frederick Cancer Research Center
 

Henry Pitot, University of Wisconsin Medical Center
 

Verne A. Ray, Pfizer Medical Research Laboratory
 

Kenneth Wilcox, Michigan State Health Department
 

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.
 

115
 

•ftU.S. GOVERNMEN T PRINTIN G OFFICE : 1978-281-217/3304
 


DHEW Publication No. (NIH) 79-1712