1978 

National Cancer Institute 

CARCINOGENESIS 

Technical Report Series 

No. 21 

BIOASSAYS OF 

ALDRIN and DIELDRIN 

FOR POSSIBLE CARCINOGEN ICITY 

CAS No's. 309-00-2 and 60-57-1 

NCI-CG-TR-21 

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

Public Health Service 

National Institutes of Health 
BIOASSAYS OF
 

ALDRIN AND DIELDRIN
 

FOR POSSIBLE CARCINOGENICITY
 

Carcinogen Bioassay and Program Resources Branch
 

Carcinogenesis Program
 

Division of Cancer Cause and Prevention
 

National Cancer Institute
 

National Institutes of Health
 

Bethesda, Maryland 20014
 

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

Public Health Service
 

National Institutes of Health
 

DHEW Publication No. (NIH) 78-821
 

BIOASSAYS OF
 

ALDRIN AND DIELDRIN
 

FOR POSSIBLE CARCINOGENICITY
 

Carcinogenesis Program
 

Division of Cancer Cause and Prevention
 

National Cancer Institue
 

National Institutes of Health
 

CONTRIBUTORS; This report presents the results of the bioassays
 

of aldrin and dieldrin for possible carcinogenicity, conducted
 

for the Carcinogen Bioassay and Program Resources Branch,
 Carcinogenesis Program, Division of Cancer Cause and Prevention,
 National Cancer Institute (NCI), Bethesda, Maryland. This
 

bioassay was conducted by the Gulf South Research Institute, New
 

Iberia, Louisiana, initially under direct contract to NCI and
 

currently under a subcontract to Tracer Jitco, Inc., prime
 

contractor for the NCI Carcinogenesis bioassay program.
 

The experimental design was determined by Drs. J. H.
 Weisburger ' and R. R. Bates^'^. The doses were selected by
 

Drs. T. E. Shellenberger^'5, J. H. Weisburger, and R. R. Bates.
 Animal treatment and observation were supervised by Drs. T. E.
 Shellenberger and H. P. Burchfield , with the technical assis­ tance of Ms. D. H. Monceaux and Mr. D. Broussard .
 

Necropsies were performed under the supervision of Drs. E.
 Bernal and B. Buratto . The histopathology was performed by
 

Drs. R. A. Renne6'7 and J. F. Ferrell" at Experimental Pathology
 

Laboratories, Inc., and the diagnoses included in this report
 

represent the interpretation of these pathologists.
 

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

Mason Research Institute . The statistical analyses were
 

performed by Dr. J. R. Joiner , using methods selected for the
 

bioassay program by Dr. J. J. Gart . Chemicals used in these
 

bioassays were analyzed under the direction of Dr. H. P.
 Burchfield, and the analytical results were reviewed by Dr. S. S.
 Olin9

.
 

iii
 
This report was prepared at Tracer Jitco under the direction of
 

NCI. Those responsible for the report at Tracor Jitco were
 

Dr. Marshall Steinberg9, Director of the Bioassay Program; Drs.
 

J. F. Robens9 and 0. G. Fitzhugh9, toxicologists; Dr. R. L.
 

Schueler , pathologist; Mr. W. D. Reichardt9 and Ms. L. A.
 

Waitz9, bioscience writers; and Dr. E. W. Gunberg , technical
 

editor, assisted by Ms. Y. E. Presley9

.
 

The statistical analysis was reviewed by a member or members of
 

the Mathematical Statistics and Applied Mathematics Section of
 

NCI (Dr. John J. Gart, Mr. Jun-mo Nam, Dr. Hugh M. Pettigrew, and
 

Dr. Robert E. Tarone served as reviewers on an alternating
 

basis).
 

The following other scientists at the National Cancer Institute
 

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. Dawn G. Goodman
 

Dr. Richard A. Griesemer
 

Mr. Harry A. Milman
 

Dr. Thomas M. Orme
 

Dr. Robert A. Squire11
 

Dr. Jerrold M. Ward
 

^arcinogenesis Program, Division of Cancer Cause and Prevention,
 

National Cancer Institute, National Institutes of Health,
 

Bethesda, Maryland.
 

^Now with the Naylor Dana Institute for Disease Prevention,
 

American Health Foundation, Hammond House Road,
 

Valhalla, New York.
 

•^Now with the Office of the Commissioner, Food and Drug
 

Administration, Rockville, Maryland.
 

^Gulf South Research Institute, Atchafalaya Basin Laboratories,
 

P.O. Box 1177, New Iberia, Louisiana.
 

iv
 
%ow with the National Center for Toxicological Research,
 

Jefferson, Arkansas.
 

^Experimental Pathology Laboratories, 17 Pine Street,
 

Herndon, Virginia.
 

''NOW with Battelle Pacific Northwest Laboratories,
 

Battelle Boulevard, Richland, Washington.
 

8

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

Rockville, Maryland.
 

^Tracer Jitco, Inc., 1776 East Jefferson Street,
 

Rockville, Maryland.
 

^Mathematical Statistics and Applied Mathematics Section, Field
 

Studies and Statistics Branch, Division of Cancer Cause and
 

Prevention, National Cancer Institute, National Institutes of
 

Health, Bethesda, Maryland.
 

UNOW with the Division of Comparative Medicine, Johns Hopkins
 

University, School of Medicine, Traylor Building, Baltimore,
 

Maryland.
 

V 

SUMMARY
 

Bioassays of technical-grade aldrin and dieldrin for possible
 

carcinogenicity were conducted by administering the test
 

materials in feed to Osborne-Mendel rats and B6C3F1 mice.
 

Aldrin
 

Groups of 50 rats of each sex were administered aldrin at one of
 

two doses, either 30 or 60 ppm. Male rats were treated for 74
 

weeks, followed by 37-38 weeks of observation; female rats were
 

treated for 80 weeks, followed by 32-33 weeks of observation.
 Matched controls consisted of groups of 10 untreated rats of each
 

sex; pooled controls, used for statistical evaluation, consisted
 

of the matched-control groups combined with 58 untreated males
 

and 60 untreated females from similar bioassays of other
 

chemicals. All surviving rats were killed at 111-113 weeks.
 

Groups of 50 mice of each sex were administered aldrin at one of
 

two doses for 80 weeks, then observed for 10-13 weeks. Time-


weighted average doses were 4 or 8 ppm for males and 3 or 6 ppm
 

for females. Matched controls consisted of groups of 20
 

untreated male mice and 10 female mice; pooled controls, used for
 

statistical evaluation, consisted of the matched-control groups
 

combined with 92 untreated male and 79 untreated female mice from
 

similar bioassays of other chemicals. All surviving mice were
 

killed at 90-93 weeks.
 

Mean body weights attained by the rats and mice fed diets
 

containing aldrin were similar to those of the controls during
 

the first year of the study; however, mean body weights of the
 

treated rats were lower than those of the controls during the
 

second year of the study. Hyperexcitability was observed in all
 

treated groups with increasing frequency and severity during the
 

second year. Aldrin produced no significant effect on the
 

mortality of rats or of male mice, but there was a dose-related
 

trend in the mortality of female mice, primarily due to the early
 

deaths in the high-dose groups.
 

vii
 
There was an increased combined incidence of follicular-cell
 

adenoma and carcinoma of the thyroid both in male rats fed aldrin
 

(matched controls 3/7, pooled controls 4/48, low-dose 14/38,
 

high-dose 8/38) and female rats fed aldrin (matched controls 1/9,
 

pooled controls 3/52, low-dose 10/39, high-dose 7/46). These
 

incidences were significant in the low-dose but not in the
 

high-dose groups both of males (P = 0.001) and females (P =
 

0.009) when compared with the pooled controls. Comparisons with
 

matched controls, however, were not significant.
 

Cortical adenoma of the adrenal gland was also observed in
 

aldrin-treated rats in significant proportions (P = 0.001) in
 

low-dose (8/45) but not in high-dose (1/48) females when compared
 

with pooled controls (0/55). Because these increased incidences
 

were not consistently significant when compared with matched
 

rather than pooled control groups, it is questionable whether the
 

incidences of any of these adrenal tumors were associated with
 

treatment.
 

In male mice, there was a significant dose-related increase in
 

the incidence of hepatocellular carcinomas (matched controls
 

3/20, pooled controls 17/92, low-dose 16/49, high-dose 25/45)
 

when compared with either matched controls (P = 0.001), or pooled
 

controls (P < 0.001). The incidence in the high-dose group was
 

significant when compared with matched controls (P = 0.002) or
 

pooled controls (P < 0.001).
 

Dieldrin
 

Groups of 50 rats and 50 mice of each sex were administered
 

dieldrin at one of two doses. Low-dose rats and both low- and
 

high-dose mice were treated for 80 weeks, followed by observation
 

periods of 30-31 weeks for rats and 10-13 weeks for mice.
 

Treatment of high-dose rats was terminated after 59 weeks and
 

followed by 51-52 weeks of observation. Time-weighted average
 

doses for rats were 29 or 65 ppm; doses for mice were 2.5 or 5
 

ppm. Matched controls consisted of groups of 10 untreated rats
 

of each sex and 20 untreated male mice and 10 female mice; pooled
 

controls, used for statistical evaluation, consisted of the
 

matched-control groups combined with untreated animals from
 

similar bioassays of other chemicals (58 male and 60 female rats,
 

viii
 
92 male and 79 female mice). All surviving rats were killed at
 

110-111 weeks, and all surviving mice at 90-93 weeks.
 

Mean body weights attained by the rats and mice fed diets
 

containing dieldrin showed little or no differences compared with
 

those of the controls during the first year of the study;
 

however, mean body weights of the treated rats were lower than
 

those of the controls during the second year of the study.
 Hyperexcitability was observed in all treated groups with
 

increasing frequency during the second year, especially in
 

high-dose rats.
 

There was a marked increase in the mortality rate of rats during
 

the first 90 weeks of the study. However, because of the high
 

rates of mortality in the control groups during the remaining 20
 

weeks, survival could not be shown to be statistically dose
 

responsive.
 

In rats, there was a significant (P = 0.007) difference between
 

the combined incidence of adrenal cortical adenoma or carcinoma
 

in the low-dose females (6/45) and that in the pooled controls
 

(0/55). Although this tumor was also found in animals treated
 

with aldrin, it is not clearly associated with treatment, because
 

the incidence in the high-dose (2/40) was not significant, and
 

the incidences were not significant when matched, rather than
 

pooled, controls were used for comparison.
 

In male mice, there was a significant positive dose-related trend
 

(P = 0.020) in the incidence of hepatocellular carcinomas using
 

the pooled controls (pooled controls 17/92, low-dose 12/50,
 

high-dose 16/45). When high-dose males were compared with the
 

pooled controls, the results were also significant (P = 0.025).
 

It is concluded that under the conditions of these bioassays,
 

none of the tumors occurring in Osborne-Mendel rats treated with
 

aldrin or dieldrin could clearly be associated with treatment.
 

ix
 
Aldrin was carcinogenic for the liver of male B6C3F1 mice
 

producing hepatocellular carcinomas. With dieldrin, there was a
 

significant increase in the incidence of hepatocellular
 

carcinomas in the high-dose males which may be associated with
 

treatment.
 

X 
TABLE OF CONTENTS
 

I.	 Introduction . 1
 

II.	 Materials and Methods 3
 

A.	 Chemicals • 3
 

1.	 Aldrin 3
 

2.	 Dieldrin 3
 

B.	 Dietary Preparation * 4
 

C.	 Animals 6
 

D.	 Animal Maintenance 6
 

E.	 Subchronic Studies , 7
 

1.	 Aldrin 8
 

2.	 Dieldrin 9
 

F.	 Designs of Chronic Studies.... 10
 

G.	 Clinical and Pathologic Examinations 16
 

H.	 Data Recording and Statistical Analyses 17
 

III. Results - Aldrin	 23
 

A.	 Rats 23
 

1.	 Body Weights and Clinical Signs
 

(Rats) - Aldrin 23
 

2.	 Survival (Rats) - Aldrin 25
 

3.	 Pathology (Rats) -Aldrin 25
 

4.	 Statistical Analyses of Results
 

(Rats) - Aldrin 28
 

B.	 Mice 31
 

1.	 Body Weights and Clinical Signs
 

(Mice) - Aldrin 31
 

2.	 Survival (Mice) -Aldrin 31
 

3.	 Pathology (Mice) - Aldrin 35
 

4.	 Statistical Analyses of Results
 

(Mice) - Aldrin 37
 

IV.	 Results - Dieldrin 39
 

A.	 Rats 39
 

1.	 Body Weights and Clinical Signs
 

(Rats) - Dieldrin 39
 

2.	 Survival (Rats) -Dieldrin 41
 

3.	 Pathology (Rats) -Dieldrin 41
 

4.	 Statistical Analyses of Results
 

(Rats) - Dieldrin 44
 

xi
 
Page
 

B.	 Mice 46
 

1.	 Body Weights and Clinical Signs
 

(Mice) - Dieldrin 46
 

2.	 Survival (Mice) -Dieldrin 49
 

3.	 Pathology (Mice) - Dieldrin 49
 

4.	 Statistical Analyses of Results
 

(Mice) - Dieldrin 52
 

V.	 Discussion 55
 

VI.	 Bibliography 61
 

APPENDIXES
 

Appendix A Summary of the Incidence of Neoplasms in
 

Rats Fed Aldrin in the Diet 65
 

Table Al Summary of the Incidence of Neoplasms in
 

Male Rats Fed Aldrin in the Diet 67
 

Table A2 Summary of the Incidence of Neoplasms in
 

Female Rats Fed Aldrin in the Diet 71
 

Appendix B Summary of the Incidence of Neoplasms in
 

Mice Fed Aldrin in the Diet 75
 

Table Bl Summary of the Incidence of Neoplasms in
 

Male Mice Fed Aldrin in the Diet. 77
 

Table B2 Summary of the Incidence of Neoplasms in
 

Female Mice Fed Aldrin in the Diet 80
 

Appendix C Summary of the Incidence of Neoplasms in
 

Rats Fed Dieldrin in the Diet 83
 

Table Cl Summary of the Incidence of Neoplasms in
 

Male Rats Fed Dieldrin in the Diet 85
 

Table C2 Summary of the Incidence of Neoplasms in
 

Female Rats Fed Dieldrin in the Diet 89
 

xii
 
Page 

Appendix D Summary of the Incidence of Neoplasms in 

Mice Fed Dieldrin in the Diet 93 

Table Dl Summary of the Incidence of Neoplasms in 

Male Mice Fed Dieldrin in the Diet 95 

Table D2 Summary of the Incidence of Neoplasms in 

Female Mice Fed Dieldrin in the Diet 98 

Appendix E Summary of the Incidence of Nonneoplastic 

Lesions in Rats Fed Aldrin in the Diet 101 

Table El Summary of the Incidence of Nonneoplastic 

Lesions in Male Rats Fed Aldrin in 

the Diet 103 

Table E2 Summary of the Incidence of Nonneoplastic 

Lesions in Female Rats Fed Aldrin in 

the Diet 109 

Appendix F Summary of the Incidence of Nonneoplastic 

Lesions in Mice Fed Aldrin in the Diet 113 

Table Fl Summary of the Incidence of Nonneoplastic 

Lesions in Male Mice Fed Aldrin in 

the Diet 115 

Table F2 Summary of the Incidence of Nonneoplastic 

Lesions in Female Mice Fed Aldrin in 

the Diet 118 

Appendix G Summary of the Incidence of Nonneoplastic 

Lesions in Rats Fed Dieldrin in the Diet.... 123 

Table Gl Summary of the Incidence of Nonneoplastic 

Lesions in Male Rats Fed Dieldrin in 

the Diet 125 

Table G2 Summary of the Incidence of Nonneoplastic 

Lesions in Female Rats Fed Dieldrin in 

the Diet 130 

xiii
 
Page 

Appendix H Summary of the Incidence of Nonneoplastic 

Lesions In Mice Fed Dieldrin in the Diet.... 135 

Table Hi Summary of the Incidence of Nonneoplastic 

Lesions in Male Mice Fed Dieldrin in 

the Diet 137 

Table H2 Summary of the Incidence of Nonneoplastic 

Lesions in Female Mice Fed Dieldrin in 

the Diet 140 

Appendix I Analyses of the Incidence of Primary 

Tumors in Rats Fed Aldrin in the Diet 145 

Table II Analyses of the Incidence of Primary 

Tumors in Male Rats Fed Aldrin in the Diet.. 147 

Table 12 Analyses of the Incidence of Primary 

Tumors in Female Rats Fed Aldrin 

in the Diet 151 

Appendix J Analyses of the Incidence of Primary 

Tumors in Mice Fed Aldrin in the Diet 157 

Table Jl Analyses of the Incidence of Primary 

Tumors in Male Mice Fed Aldrin in the Diet.. 159 

Table J2 Analyses of the Incidence of Primary 

Tumors in Female Mice Fed Aldrin 

in the Diet 161 

Appendix K Analyses of the Incidence of Primary 

Tumors in Rats Fed Dieldrin in the Diet 163 

Table Kl Analyses of the Incidence of Primary 

Tumors in Male Rats Fed Dieldrin 

in the Diet 165 

Table K2 Analyses of the Incidence of Primary 

Tumors in Female Rats Fed Dieldrin 

in the Diet 169 

xiv
 
Appendix L


Table Ll


Table L2


Appendix M


Table 1


Table 2


Table 3


Table 4


Figure 1


Figure 2


Figure 3


Figure 4


Figure 5


Page 

 Analyses of the Incidence of Primary 

Tumors in Mice Fed Dieldrin in the Diet 175 

 Analyses of the Incidence of Primary 

Tumors in Male Mice Fed Dieldrin 

in the Diet

 Analyses of the Incidence of Primary 

Tumors in Female Mice Fed Dieldrin 

in the Diet

 177 

 179 

 Analyses of Formulated Diets for 

Concentrations of Aldrin or Dieldrin 181 

TABLES 

 Design of Aldrin Chronic Feeding Studies in 

Rats 11 

 Design of Aldrin Chronic Feeding Studies in 

Mice 12 

 Design of Dieldrin Chronic Feeding Studies in
 

Rats 14
 

 Design of Dieldrin Chronic Feeding Studies in
 

Mice 15
 

FIGURES
 

 Growth Curves for Rats Fed Aldrin in the
 

Diet 24
 

 Survival Curves for Rats Fed Aldrin in the
 

Diet 26
 

 Growth Curves for Male Mice Fed Aldrin in
 

the Diet 32
 

 Growth Curves for Female Mice Fed Aldrin in
 

the Diet 33
 

 Survival Curves for Mice Fed Aldrin in the
 

Diet 34
 

xv
 
Page
 

Figure 6 Growth Curves for Rats Fed Dieldrin in the 

Diet 40 

Figure 7 Survival Curves for Rats Fed Dieldrin in the 

Diet 42 

Figure 8 Growth Curves for Male Mice Fed Dieldrin in 

the Diet 47 

Figure 9 Growth Curves for Female Mice Fed Dieldrin 

in the Diet 48 

Figure 10 Survival Curves for Mice Fed Dieldrin in the 

Diet 50 

xvi
 
I. INTRODUCTION
 

Aldrin (CAS 309-00-2; NCI C00044) and dieldrin (CAS 60-57-1; NCI
 

C00124) are organochlorine insecticides of the cyclodiene group.
 

These chemicals are neurotoxins, and their predominant effect is
 

the stimulation of the nervous system. Both aldrin and dieldrin
 

are lipophilic and accumulate in mammalian tissues. Aldrin
 

undergoes metabolic conversion to the epoxide, dieldrin (Brooks,
 

1975), and because of this structural relationship, reports of
 

the bioassays of both chemicals have been combined in this single
 

report.
 

Two of the major uses of aldrin since its introduction in 1950
 

have been foliage application on cotton plants and soil application for corn fields. A small amount has also been used for
 

soil application for vegetables and root crops. These
 

applications have resulted in residues of the chemical in food
 

products.
 

Dieldrin was first introduced in the 1950's by cotton growers,
 

when the chemical was found to be more effective than aldrin.
 

Dieldrin has also been used as an insecticide on crops other than
 

cotton, for public health pest control, and for mothproofing
 

woolen goods (Federal Register, 1974).
 

Based partly on the evidence of the hepatocarcinogenicity of
 

1 
dieldrin in the mouse (Thorpe and Walker, 1973; Walker et al.,
 

1972), the registration of products containing aldrin and
 

dieldrin was canceled in 1974 (Federal Register, 1974).
 

Aldrin and dieldrin were selected for testing in 1969 because
 

data regarding their carcinogenicity were controversial and often
 

inadequate and because there was potential for long-term human
 

exposure to residues, especially in foods.
 

2 
II. MATERIALS AND METHODS
 

A. Chemicals
 

1. Aldrin
 

The material tested was technical-grade aldrin, obtained in one
 

batch from the Shell Chemical Company, San Ramon, California, for
 

use in the chronic study. According to the manufacturer's
 

specifications, the product was > 85% pure.
 

Gas chromatography using electron capture detection showed three
 

components, with the major component accounting for 95% of the
 

total peak area. Elemental analyses (C, H, Cl) were correct for
 

t

*ie
 ^12^8^6' molecular formula of aldrin. Infrared, nuclear
 

magnetic resonance, and mass spectra compared well with those of
 

the analytical-grade reference standard (Shell Chemical Co.). No
 

attempt was made to identify or quantitate impurities.
 

The chemical was stored in its original container at 4°C for the
 

duration of the study.
 

2. Dieldrin
 

The material tested was technical-grade dieldrin, obtained in one
 

batch from the Shell Chemical Company, San Ramon, California, for
 

3 
use in the chronic study. According to the manufacturer's
 

specifications, the product was > 85% pure.
 

Gas chromatography using electron capture detection showed two
 

components, with the major component accounting for > 96% of the
 

total peak area. Elemental analyses (C, H, Cl) were correct for
 

Ci2HgCl50, tne molecular formula of dieldrin. Infrared, nuclear
 

magnetic resonance, and mass spectra compared well with those of
 

the analytical-grade reference standard (Shell Chemical Co.). No
 

attempt was made to identify or quantitate impurities.
 

The chemical was stored in its original container at 4°C for the
 

duration of the study.
 

B. Dietary Preparation
 

®
 All diets were formulated using Wayne Lab Blox (Allied Mills,
 

Inc., Chicago, 111.) to which was added the required amount of
 

aldrin or dieldrin for each dietary concentration. The respective test chemical was first dissolved in a small amount of
 

acetone (Mallinckrodt, Inc., St. Louis, Mo.), which was then
 

®
 

added to the feed. Corn oil (Louana , Opelousas Refinery Co.,
 

Opelousas, La.) was also added to the feed, primarily as a dust
 

suppressant, and the diets were mixed mechanically to assure
 

homogeneity of the mixtures and evaporation of the acetone.
 

Final diets, including those for the control groups of animals,
 

4 
contained corn oil equal to 2% of the final weight of feed. The
 

diets were stored at approximately 17°C until used, but no longer
 

than 1 week.
 

The stability of the aldrin or dieldrin in feed was tested by
 

determining the concentrations of the chemical in formulated
 

diets at intervals over a 7-day period. Diets containing 4 or 30
 

ppm aldrin or 5 or 40 ppm dieldrin showed no change in
 

concentration on standing at ambient temperature for this period.
 

As a quality control test on the accuracy of the preparation of
 

the diets, the concentration of aldrin or dieldrin was determined
 

in different batches of formulated diets during the chronic
 

study. The results are summarized in Appendix M. At each
 

dietary concentration, the mean of the analytical concentrations
 

for the checked samples was within 3% of the theoretical
 

concentration, and the coefficient of variation was never more
 

than 5.4%. Thus, the evidence indicates that the formulated
 

diets were prepared accurately.
 

Three batches of the basal feed (Wayne- Lab Blox Meal) used
 

during this period were analyzed by Gulf South Research Institute
 

for pesticide residues. No aldrin was found at a 0.5 ppb limit
 

of detection; however, dieldrin was found in small amounts (2.5 ­

4.4 ppb) in three samples at a 1 ppb limit of detection.
 

5 
C. Animals
 

Rats and mice of both sexes, obtained through contracts of the
 

Division of Cancer Treatment, National Cancer Institute, were
 

used in these studies. The rats were of the Osborne-Mendel
 

strain obtained from Battelle Memorial Institute, Columbus, Ohio,
 

and the mice were B6C3F1 hybrids obtained from Charles River
 

Breeding Laboratories, Inc., Wilmington, Massachusetts. Upon
 

arrival at the laboratory, all animals were quarantined for an
 

acclimation period (rats 8-9 days, mice 14-15 days) and were then
 

assigned to control and test groups.
 

D. Animal Maintenance
 

All animals were housed in temperature- and humidity-controlled
 

rooms. The temperature range .was 22-24°C, and the relative
 

humidity was maintained at 40-70%. The air in each room was
 

changed 10-12 times per hour. Fluorescent lighting provided
 

illumination 10 hours per day. Food and water were supplied ad
 

libitum.
 

The rats were housed individually in hanging galvanized steel
 

mesh cages, and the mice were housed in plastic cages with filter
 

bonnets, five per cage for females, and two or three per cage for
 

males. Initially, rats were transferred weekly to clean cages;
 

later in the study, cages were changed every 2 weeks. Mice were
 

6 
transferred weekly to clean cages with filter bonnets; bedding
 

®


used for the mice was Absorb-Dri (Lab Products, Inc., Garfield,
 

N.J.). For rats, absorbent sheets under the cages were changed
 

three times per week. Feeder jars and water bottles were changed
 

and sterilized three times per week.
 

Cages for control and treated mice were placed on separate racks
 

in the same room. Animal racks for both species were rotated
 

laterally at weekly intervals; at the same time each cage was
 

changed to a different position in the row within the same
 

column. Rats receiving aldrin or dieldrin, along with their
 

respective matched controls, were housed in rooms by themselves.
 

Mice receiving aldrin were maintained in a room housing mice
 

administered captan (CAS 133-06-2) or photodieldrin (CAS
 

13366-73-9), together with their respective matched controls.
 

Mice receiving dieldrin were maintained in a room housing mice
 

administered malathion (CAS 121-75-5) or tetrachlorvinphos (CAS
 

961-11-5), together with their respective matched controls.
 

E. Subchronic Studies
 

Subchronic studies were conducted with rats and mice to estimate
 

maximum tolerated doses of aldrin or dieldrin, on the basis of
 

which low and high concentrations (hereinafter referred to as
 

"low doses" and "high doses") were determined for administration
 

7 
in the chronic studies. In these subchronic studies, aldrin or
 

dieldrin was added to the animal feed in the doses below for 6
 

weeks, followed by an observation period of 2 weeks.
 

Experimental and treatment groups each consisted of five male and
 

five female animals.
 

1. Aldrin
 

In these subchronic studies, aldrin was added to the animal feed
 

in twofold increasing concentrations ranging from 40 to 320 ppm
 

for rats. At concentrations of 40 or 80 ppm, there were no
 

adverse effects on mean body weights of either male or female
 

rats; however, at 160 ppm, mean body weights of both males and
 

females were depressed initially, and at 320 ppm, mean body
 

weights of males were lower than those of controls. One male and
 

one female fed 160 ppm died, and three males and five females fed
 

320 ppm died. On the basis of these results, the low and high
 

doses for rats were set at 60 and 120 ppm for the chronic
 

studies.
 

Aldrin was added to the animal feed in twofold increasing concentrations ranging from 2.5 to 80 ppm for mice. These doses had
 

no apparent effect on the mean body weights of surviving treated
 

animals. However, all males and females fed 40 or 80 ppm died,
 

8 
and one male and one female fed 20 ppm died. The low and high
 

doses for mice were set at 8 and 15 ppm for the chronic studies.
 

2. Dieldrin
 

Dieldrin was added to the animal feed in twofold increasing concentrations ranging from 40 to 320 ppm for rats. Mean body
 

weights of male rats receiving 80, 160, and 320 ppm were
 

initially depressed, and two male rats fed 320 ppm died. Mean
 

body weights of female rats at 40, 80, and 160 ppm were also
 

initially depressed; one female fed 160 ppm died, and all five
 

females fed 320 ppm died. Based on these results, the low and
 

high doses for rats were initially set at 80 and 160 ppm for
 

males and 40 and 80 ppm for females for the chronic studies.
 

Before the chronic study was initiated, doses for males were
 

lowered to those of the females.
 

Dieldrin was added to the animal feed in twofold increasing concentrations ranging from 2.5 to 40 ppm for mice. The chemical
 

had no apparent adverse effect on mean body weights of male or
 

female mice at any of the dietary concentrations used in this
 

study. Three male and four female mice fed 20 ppm died, as did
 

all animals fed 40 ppm. The low and high doses for mice were set
 

at 5 and 10 ppm for the chronic studies.
 

9 
F. Designs of Chronic Studies
 

Designs of the chronic studies are shown in tables 1, 2, 3, and
 

4. Initially, higher doses of each test chemical than are shown
 

in the tables were fed to rats and mice. These initial doses
 

were found to be too toxic for the animals, and studies were
 

restarted as indicated in the footnotes of each respective table.
 

Since the numbers of animals in the matched-control groups were
 

small, pooled-control groups also were used for statistical
 

comparisons. Matched controls from the current studies on aldrin
 

and dieldrin were combined with matched controls from studies
 

performed on chlordane (CAS 57-74-9), heptachlor (CAS 76-44-8),
 

dichlorvos (CAS 62-73-7), and dimethoate (CAS 60-51-5). The
 

pooled controls for statistical tests using rats consisted of 58
 

males and 60 females; using mice, 92 males and 79 females. The
 

studies on chemicals other than aldrin and dieldrin were also
 

conducted at Gulf South Research Institute and overlapped the
 

aldrin and dieldrin studies by at least 1 year. The matched-


control groups for the different test chemicals were of the same
 

strain and from the same supplier, and they were examined by the
 

same pathologists. Because additional matched controls were
 

started simultaneously with restarted treatment groups for some
 

of these chemicals, the number of animals in the pooled-control
 

groups varied.
 

10
 
Table 1. Design of Aldrin Chronic Feeding Studies in Rats
 

Sex and 

Treatment 

Initial 

No. of 

Aldrin 

in Dietb 

Time 

Treated 

on Study 

Untreatedc 

Group Animalsa (ppm) (weeks) (weeks ) 

MALE 

Matched-Control 10 0 111 

Low-Dose 50 30 74 

0 37-38 

High-Dose 50 60 74 

0 37-38 

FEMALE
 

Matched-Control 10 0 111-112
 

Low-Dose 50 30 80
 

0 32
 

High-Dose 50 60 80
 

0 32-33
 

a

All animals were approximately 35 days of age when placed
 

on study.
 

^Initially, concentrations of 60 or 120 ppm aldrin were fed
 

to rats of each sex; these doses were too toxic and the
 

studies in rats were terminated and restarted as shown in
 

the table.
 

c

When diets containing aldrin were discontinued, all rats
 

were fed the control diet (2% corn oil added) for 30 or 36
 

weeks.
 

11
 
Table 2. Design of Aldrin Chronic Feeding Studies in Mice
 

Sex and

Treatment

Group

 Initial 

 No. of 

Animals3 

Aldrin 

in Dietb 

(ppm) 

Time on Study 

Treated Untreated0 

(weeks) (weeks) 

Time-Weighted 

Average Dose^ 

(ppm) 

MALE 

Matched-Control 20e 0 90-92 

Low-Dose 50 8 7 4 

4 73 

0 10 

High-Dose 50	 8 80 8
 

0 12-13
 

FEMALE
 

Matched-Control 10	 0 90
 

Low-Dose 50	 8 7
 

4 12 3
 

2 61
 

0 10
 

High-Dose 50 15 7
 

8 12 6
 

4 61
 

0	 10-11
 

a

All animals were approximately 35 days of age when placed on study.
 

^Initially, a concentration of 15 ppm aldrin was fed to the high-dose
 

group of male mice; this dose was too toxic and the group was
 

terminated and a new high-dose group started at 8 ppm. At this time,
 

the low-dose males were lowered from 8 to 4 ppm and the females from 8
 

or 15 ppm to 4 or 8 ppm, respectively.
 

c

When diets containing aldrin were discontinued, all mice were fed
 

the control diet (2% corn oil added) until termination of the study.
 

12
 
Table 2. Design of Aldrin Chronic Feeding Studies in Mice
 

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

I(no. of weeks receiving each dose)
 

e

lnitially, 10 animals of each sex were placed on study as matched
 

controls; however, when the study was restarted, 10 additional
 

male mice were placed on study as matched controls.
 

13
 
Table 3. Design of Dieldrin Chronic Feeding Studies in Rats
 

Sex and 

Treatment 

Initial 

No. of 

Dieldrin 

in Dietb 

Time 

Treated 

on Study 

Untreated0 

Time-Weighted 

Average Dose^ 

Group Animalsa (ppm) (weeks ) (weeks ) (ppm) 

MALE 

Matched-Control 10 0 110 

Low-Dose 50 40 37 29 

20 43 

0 30 

High-Dose 50 80 37 

40 22 65 

0 52 

FEMALE 

Matched-Control 10 0 110 

Low-Dose 50 40 37 

20 43 29 

0 30-31 

High-Dose 50 80 37 

40 22 65 

0 51-52 

a

All animals were approximately 35 days of age when placed on study.
 

^The initial doses of dieldrin were too toxic and the doses were lowered
 

at 37 weeks on study because of toxic signs.
 

c

When diets containing dieldrin were discontinued, all rats were fed
 

the control diet without corn oil for 8 weeks, then the control diet
 

(2% corn oil added) for an additional 27 weeks.
 

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

£(no. of weeks receiving each dose)
 

14
 
Table 4. Design of Dieldrin Chronic Feeding Studies in Mice
 

Sex and 

Treatment 

Initial 

No. of 

Dieldrin 

in Dietb 

Time on Study 

Treated Untreated0 

Group Animals3 (ppm) (weeks) (weeks ) 

MALE 

Matched-Control 20d 0 91-93 

Low-Dose 50 2.5 80 

0 11 

High-Dose 50 5 80 

0 13 

FEMALE 

Matched-Control 10 0 91-93 

Low-Dose 50 2.5 80 

0 10-11 

High-Dose 50 5 80 

0 13 

a

All animals were approximately 35 days of age when placed
 

on study.
 

^Initially, a concentration of 10 ppm dieldrin was fed to
 

high-dose mice of each sex; this dose was too toxic and the
 

groups were terminated at 10 weeks and a low-dose group of
 

10 males was started at 2.5 ppm. The original low-dose
 

groups then became the high-dose groups.
 

c

When diets containing dieldrin were discontinued, all mice
 

were fed the control diet (2% corn oil added) until termination of the study.
 

^Initially, 10 animals of each sex were placed on study as
 

matched controls; however, when the study was restarted, 10
 

additional male mice were placed on study as matched
 

controls.
 

15
 
G. Clinical and Pathologic Examinations
 

All animals were observed twice daily for signs of toxicity,
 

weighed at regular intervals, and palpated for masses at each
 

weighing. Those animals that were moribund at the time of
 

clinical examination were killed and necropsied.
 

The pathologic evaluation consisted of gross and microscopic
 

examination of major tissues, major organs, and all gross lesions
 

from killed animals and from animals found dead. The following
 

tissues were examined microscopically: skin, lungs and bronchi,
 

trachea, bone and bone marrow, spleen, lymph nodes, heart,
 

salivary gland, liver, gallbladder (mice), pancreas, stomach,
 

small intestine, large intestine, kidney, urinary bladder,
 

pituitary, adrenal, thyroid, parathyroid, mammary gland, prostate
 

or uterus, testis or ovary, and brain. Occasionally additional
 

tissues were also examined microscopically. The different
 

tissues were preserved in 10% buffered formalin, embedded in
 

paraffin, sectioned, and stained with hematoxylin and eosin.
 

Special staining techniques were utilized when indicated for more
 

definitive diagnosis.
 

A few tissues from some animals were not examined, particularly
 

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

16
 
autolysis as to preclude histopathologic evaluation. Thus, the
 

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

the number of animals that were placed on experiment in each
 

group.
 

H. Data Recording and Statistical Analyses
 

Pertinent data on this experiment have been recorded in an automatic data processing system, the Carcinogenesis Bioassay Data
 

System (Linhart et al., 1974). The data elements include descriptive information on the chemicals, animals, experimental design,
 

clinical observations, survival, body weight, and individual
 

pathologic results, as recommended by the International Union
 

Against Cancer (Berenblum, 1969). Data tables were generated for
 

verification of data transcription and for statistical review.
 

These data were analyzed using the statistical techniques
 

described in this section. Those analyses of the experimental
 

results that bear on the possibility of carcinogenicity are
 

discussed in the statistical narrative sections.
 

Probabilities of survival were estimated by the product-limit
 

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

report in the form of graphs. Animals were statistically
 

censored as of the time that they died of other than natural
 

17
 
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's methods for testing for a dose-related trend.
 

One-tailed P values have been reported for all tests except the
 

departure from linearity test, which is only reported when its
 

two-tailed P value is less than 0.05.
 

The incidence of neoplastic or nonneoplastic lesions has been
 

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

at a specific anatomic site (numerator) to the number of animals
 

in which that site 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
 

18
 
a control group with that of a group of treated animals at each
 

dose level. When results for a number of treated 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 Bonferroni inequality (Miller, 1966)1 requires that the
 

P value for any comparison be less than or equal to 0.05/k. In
 

cases where this correction was used, it is discussed in the
 

narrative section. It is not, however, presented in the tables,
 

where the Fisher exact P values are shown.
 

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

continuity correction (Armitage, 1971), 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
 

19
 
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
 

of tumors (Fisher exact tests, Cochran-Armitage tests, etc.) were
 

followed.
 

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

incidence of tumors. Curves of the proportions surviving without
 

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

The week during which animals died naturally or were sacrificed
 

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 < 0.05, two-tailed test)
 

were also noted.
 

The approximate 95 percent confidence interval for the relative
 

risk of each treated group compared to its control was calculated
 

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

relative risk is defined as pt/pc where pt is the true binomial
 

probability of the incidence of a specific type of tumor in a
 

20
 
treated group of animals and pc 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
 

a specific tumor in a treated 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 treated group than in the control.
 

The lower and upper limits of the confidence interval of the
 

relative risk have been included in the tables of statistical
 

analyses. The interpretation of the limits is that in
 

approximately 95% of a large number of identical experiments, the
 

true ratio of the risk in a treated group of animals to that in a
 

control group would be within the interval calculated from the
 

experiment. When the lower limit of the confidence interval is
 

greater than one, it can be inferred that a statistically
 

significant result (a P < 0.025 one-tailed test when the control
 

incidence is not zero, P < 0.050 when the control incidence is
 

zero) has occurred. When the lower limit is less than unity, but
 

the upper limit is greater than unity, the lower limit indicates
 

the absence of a significant result while the upper limit
 

indicates that there is a theoretical possibility of the
 

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

detected under the conditions of this test.
 

21
 

III. RESULTS - ALDRIN
 

A. Rats
 

1. Body Weights and Clinical Signs (Rats) - Aldrin
 

Beginning at about the second year of the study, the mean body
 

weights of the treated rats were consistently lower than those of
 

the matched controls (figure 1).
 

During the first 6 months of the study, the treated animals were
 

generally comparable to the controls in appearance and behavior,
 

with the exception of seven treated animals that developed
 

exophthalmus and corneal opacity, with occasional thickening of
 

the palpebral conjunctival membranes. This condition was
 

diagnosed as viral conjunctivitis by the pathologists at the
 

laboratory. During the second 6 months of the study, beginning
 

at week 32, convulsions were observed in several of the high-dose
 

female rats.
 

At week 52, most high-dose male rats appeared to be nervous and
 

excitable. Throughout the second year of the study, clinical
 

signs including pale mucous membranes, rough hair coats, loss of
 

weight, vaginal bleeding, hyperactivity, and convulsions were
 

apparent in all treated groups. Several animals showed evidence
 

23
 
Figure 1. Growth Curves for Rats Fed
 

Aldrin in the Diet
 

24 
of discolored (dark) urine. Surviving rats were generally in
 

poor physical condition at termination of the study.
 

2. Survival (Rats) - Aldrin
 

The male rats that received aldrin experienced a substantial
 

decrease in survival over the period from weeks 45-90 (figure 2);
 

however, the Tarone test result for life-table analyses over the
 

entire period of the study was not significant (P > 0.05)
 

indicating that the mortalities were not dose related. The
 

median time on study at death was 97 weeks in the high-dose group
 

and longer in the other male groups.
 

In female rats, there was no indication of a dose response, since
 

there were more early deaths in the low-dose group, in which 68%
 

of the rats lived to termination of the study, than in the high-


dose group, in which 82% of the rats lived to termination of the
 

study.
 

There were adequate numbers of both male and female treated rats
 

for meaningful statistical analyses of the incidence of tumors.
 

3. Pathology (Rats) - Aldrin
 

Histopathologic findings on neoplasms in rats are summarized in
 

Appendix A, tables Al and A2; findings on nonneoplastic lesions
 

are summarized in Appendix E, tables El and E2.
 

25
 
Figure 2. Survival Curves for Rats Fed
 

Aldrin in the Diet
 

26 
Numerous inflammatory, degenerative, and proliferative lesions
 

commonly seen in aged rats occurred with approximately equal
 

frequency in aldrin-treated and control animals. These included
 

biliary hyperplasia; chronic nephritis with scarring, tubular
 

dilatation and regeneration; C-cell hyperplasia of the thyroid;
 

and testicular atrophy.
 

Both follicular-cell and C-cell neoplastic lesions of the thyroid
 

were observed frequently, with no obvious difference in incidence
 

between treated and control rats. Pituitary adenomas occurred
 

frequently in all groups, and there was a low incidence of
 

neoplasms of the adrenal cortex and medulla, parathyroid, and
 

pancreatic islets.
 

A low incidence of hepatocellular carcinoma or neoplastic
 

nodules, classified according to Squire and Levitt (1975), was
 

observed in liver sections, with no apparent increased frequency
 

for treated groups over controls.
 

Renal neoplasms occurred infrequently in both treated and control
 

males. These renal lesions, classified as malignant mixed
 

tumors, contained neoplastic tissue components having the appearance of renal mesenchymal stroma, adipose tissue, and primitive
 

renal epithelium, in various proportions.
 

27
 
Primary vascular neoplasms occurred at several sites, including
 

the spleen, subcutis, lung, and uterine cervix.
 

Endometrial stromal polyps were the most frequently occurring
 

neoplasms of the reproductive tract. Numerous mammary fibroadenomas, some of which were multiple, were observed in both
 

treated and control females.
 

There were instances where neoplasms occurred only in treated
 

animals, or with increased frequency when compared with those in
 

control groups. In the judgment of the pathologist, however, the
 

nature, incidence, and severity of the lesions observed provided
 

no clear evidence of a carcinogenic effect of aldrin on rats.
 

4. Statistical Analyses of Results (Rats) - Aldrin
 

Tables 11 and 12 of Appendix I contain the statistical analyses
 

of the incidences of those specific primary tumors that were
 

observed in at least 5% of one or more treated groups of either
 

sex.
 

A significant positive linear trend (P = 0.002) in the incidence
 

of follicular-cell adenoma or follicular-cell carcinoma of the
 

thyroid was observed in the low-dose group of male rats when
 

compared with that in the pooled controls; however, the proportion in the matched-control group of 3/7 (43%) was so high that a
 

28
 
negative trend (P = 0.075) was found. A time adjustment,
 

eliminating all male rats dying before 1 year on study, resulted
 

in incidences of 14/36 (39%) in the low-dose group and 8/36 (22%)
 

in the high-dose group. There were no practical differences, however, between the statistical results of the tests made using the
 

adjusted incidences and the results of the tests made without the
 

adjustment. The occurrence of follicular-cell adenoma or
 

follicular-cell carcinoma of the thyroid was also significant
 

(P = 0.009) in low-dose female rats when compared with that in
 

the pooled controls, but not when compared with that in the
 

matched controls. Both male and female high-dose groups failed
 

to confirm the significance seen in the low-dose group, even when
 

survival was taken into account. The matched-control groups
 

indicated a possible spontaneous rate of tumors of 11% in females
 

and 43% in males, which is higher than that indicated by pooled
 

controls (6% females, 8% males).
 

Cortical adenoma of the adrenal gland was not observed in significant proportions in the treated male rats (matched controls 2/10,
 

low-dose 1/38, high-dose 2/43) but was observed in significant
 

proportions (P = 0.002) in the low-dose females (8/45) when
 

compared with those incidences in the pooled controls (0/55).
 

The high-dose group, although having better survival, had only
 

1/48 (2%) of such tumors. The test for dose-related positive
 

29
 
linear trend In females was not significant, but there was a
 

significant departure from linearity when either the pooled (P <
 

0.001) or matched (P - 0.010) controls were used. These
 

departures resulted from the high incidence in the low-dose
 

females compared with that in the high-dose group. The incidence
 

of adrenal cortical adenoma or carcinoma in control groups of
 

this strain of female rat so far reported in the laboratory is
 

3/240 (1.25%), which is somewhat, but not significantly, higher
 

than 0/55 (0.0%) found in the pooled-control group.
 

In male rats, although the Cochran-Armitage tests of the proportions of islet-cell adenoma or carcinoma of the pancreatic islets
 

are not significant, the Fisher exact tests show that the incidence in the low-dose group (5/37) is significantly higher than
 

that in the pooled controls (1/52). However, one would not
 

conclude that this incidence in the low-dose group is dose
 

associated, since the simultaneous comparison criteria required a
 

probability level of < 0.025 for significance. The incidence of
 

this tumor in females was not significant.
 

In summary, significant statistical results are obtained for the
 

combination of incidences of follicular-cell adenoma and
 

follicular-cell carcinoma of the thyroid in both male and female
 

rats and for cortical adenoma of the adrenal gland in female
 

30
 
rats, indicating a possible dose association of aldrin with these
 

tumors.
 

B. Mice
 

1. Body Weights and Clinical Signs (Mice) - Aldrin
 

The administration of aldrin in the diet did not affect the mean
 

body weights of mice (figures 3 and 4).
 

During the first 6 months of the study, the treated animals were
 

generally comparable to the controls in appearance and behavior.
 

During the second 6 months of the study, most of the treated
 

animals, with the exception of the low-dose males, appeared to be
 

hyperexcitable.
 

Clinical signs including rough hair coats, alopecia, and
 

abdominal distention (noted in all treated groups, but
 

predominantly in the high-dose males) appeared with increasing
 

frequency during the second year of the study. Many of the
 

treated males were observed fighting during the last half of the
 

study.
 

2. Survival (Mice) - Aldrin
 

There was no significant dose-related trend in the mortality of
 

the male mice (figure 5). In female mice, there was a
 

31
 
Figure 3. Growth Curves for Male Mice Fed
 

Aldrin in the Diet
 

32 
Figure 4. Growth Curves for Female Mice Fed
 

Aldrin in the Diet
 

33
 
Figure 5. Survival Curves for Mice Fed
 

Aldrin in the Diet
 

34 
significant (P - 0.037) dose-related trend in mortality
 

represented by the early deaths in the high-dose group shown in
 

figure 5. These early deaths were not associated with tumors,
 

since only 3/17 (18%) of the high-dose females that died before
 

termination of the study were found to have tumors.
 

3. Pathology (Mice) - Aldrin
 

Histopathologic findings on neoplasms in mice are summarized in
 

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

are summarized in Appendix F, tables Fl and F2.
 

Several nonneoplastic lesions were observed in both treated and
 

control mice. Peribronchial and/or perivascular lymphoid
 

hyperplasia, generally mild in degree, was noted in sections of
 

lung from many control and treated mice. Purulent oophoritis,
 

endometritis, and cystic endometrial hyperplasia occurred
 

frequently in both treated and control females. There was a low
 

incidence of other inflammatory, degenerative, and nonneoplastic
 

proliferative lesions in all groups.
 

Nodular proliferative lesions involving hepatocytes were classified as either hepatocellular carcinoma or nodular hyperplasia.
 

The morphology of those lesions classified as hepatocellular
 

carcinoma varied widely. Some were present as one or more small,
 

discrete nodules containing solid cords and nests of well-differ35
 
entiated but hyperbasophilic hepatocytes with an increased
 

nuclear : cytoplasmic ratio. These lesions appeared to have
 

grown by expansion, with distinct compression but with no obvious
 

invasion of adjacent normal hepatic parenchyma. Other hepatocellular carcinomas appeared as very large masses which had completely replaced one or more hepatic lobes, and which were composed of
 

large anaplastic hepatocytes forming confluent sheets, papillae,
 

and pseudoacini, with large foci of necrosis and complete loss of
 

normal lobular architecture. The morphological appearances of
 

the majority of hepatocellular carcinomas were somewhere between
 

these two extremes. Those lesions classified as hepatocytomegaly
 

were also considered to be proliferative in nature.
 

The data indicate an increased incidence of hepatocellular
 

carcinomas in both the low- and high-dose male mice. The
 

incidence of this neoplasm in treated females is much lower and
 

is probably not biologically significant. Lesions classified as
 

nodular hyperplasia were noted in a small number of treated
 

animals, both male and female, but not in controls. Alterations
 

classified as hepatocytomegaly were noted in several low- and
 

high-dose males. The numbers in tables Fl and F2 indicate the
 

incidence of hepatocytomegaly in animals which did not have
 

hepatocellular carcinoma or nodular hyperplasia, although
 

36
 
hepatocytomegaly may also have been present to some degree in the
 

animals with hyperplastic or neoplastic lesions in the liver.
 

There was a low incidence of other types of neoplasms involving
 

various organs and tissues, with no obvious difference in incidence between treated and control groups.
 

4. Statistical Analyses of Results (Mice) - Aldrin
 

Tables Jl and J2 of Appendix J contain the statistical analyses
 

of the incidences of those specific primary tumors that were
 

observed in at least 5% of one or more treated groups of either
 

sex.
 

There was a significant dose-related increase in hepatocellular
 

carcinoma in the male mice when the treated groups were compared
 

with the matched controls (P = 0.001) or with the pooled controls
 

(P < 0.001). The results of the statistical analyses of the
 

incidences of hepatocellular carcinoma in female mice were not
 

significant. The laboratory historical controls showed hepatocellular carcinoma in 44/285 (16.8%) male mice, and in 6/259
 

(2.3%) female mice. These proportions were comparable to the
 

observations in the matched controls of this experiment and to
 

the pooled controls used in the analyses. There were no other
 

tumors which appeared in statistically significant proportions
 

when compared with the matched or the pooled controls.
 

37
 

IV. RESULTS - DIELDRIN
 

A. Rats
 

1. Body Weights and Clinical Signs (Rats) - Dieldrin
 

The mean body weights of the treated rats were consistently
 

somewhat lower than those of the matched controls (figure 6).
 

During the first 6 months of the study, the treated animals were
 

generally comparable to the controls in appearance and behavior,
 

with the exception of the high-dose females. At week 8,
 

convulsions were observed in two high-dose females. At week 19,
 

five of the treated animals developed exophthalmus and corneal
 

opacity, with occasional thickening of the palpebral conjunctival
 

membranes. This condition was diagnosed as viral conjunctivitis
 

by the pathologists at the laboratory. At week 21, approximately
 

28% of the high-dose males and high-dose females had convulsions.
 

During the second 6 months of the study, clinical signs including
 

diarrhea, alopecia, epistaxis, hematuria, discolored hair coats,
 

tremors, and loss of weight were observed, predominantly in
 

high-dose females.
 

These same clinical signs were observed with increasing frequency
 

during the second year of study in both high- and low-dose
 

groups, together with clinical signs including pale mucous
 

39
 
Figure 6. Growth Curves for Rats Fed
 

Dieldrin in the Diet
 

40
 
membranes, vaginal bleeding, dermatitis, dyspnea, ataxia,
 

tachypnea, abdominal distention, rough hair coats, and discolored
 

(dark) urine. Surviving animals were generally in poor physical
 

condition at termination of the study.
 

2. Survival (Rats) - Dieldrin
 

The survival curves of male and female rats (figure 7) indicate
 

that the treated groups had higher mortality rates than the
 

control groups during the first 90 weeks, but after that time,
 

the increased number of deaths in the male and female matched
 

controls prevented the Tarone test result for positive
 

dose-related mortality from being significant over the study.
 

Since over half of the treated male and female rats lived beyond
 

100 weeks, sufficient animals were available for meaningful
 

statistical analyses of the incidences of late-developing tumors.
 

3. Pathology (Rats) - Dieldrin
 

Histopathologic findings on neoplasms in rats are summarized in
 

Appendix C, tables Cl and C2; findings on nonneoplastic lesions
 

are summarized in Appendix G, tables Gl and G2.
 

Numerous inflammatory, degenerative, and proliferative lesions
 

commonly seen in aged rats occurred with approximately equal
 

frequency in dieldrin-treated and control animals. These
 

41
 
Figure 7. Survival Curves for Rats Fed
 

Dieldrin in the Diet
 

42 
included biliary hyperplasia, chronic nephritis with scarring,
 

tubular dilatation and regeneration, C-cell hyperplasia of the
 

thyroid, and testicular atrophy.
 

In the thyroid gland, both follicular-cell and C-cell neoplastic
 

lesions were observed, with no obvious difference in incidence
 

between treated and control rats. Pituitary adenomas occurred
 

frequently in all groups, and there were infrequent incidences of
 

neoplasms of the adrenal cortex and medulla, parathyroid, and
 

pancreatic islets.
 

A low incidence of neoplastic nodules, classified according to
 

Squire and Levitt (1975), was observed in liver sections, with no
 

apparent increased frequency for treated groups over controls.
 

Three of the four hemangiosarcomas observed in treated animals
 

were in the spleen, as were two of the hemangiomas. All three
 

malignant lymphomas observed in treated rats involved multiple
 

hematopoietic organs and abdominal viscera.
 

Endometrial stromal polyps in the uterus were the most frequently
 

occurring neoplasms of the reproductive tract. Numerous mammary
 

f ibr oadenomas, some of which were multiple, were observed in both
 

treated and control females.
 

Renal neoplasms, classified as malignant mixed tumors, contained
 

43
 
neoplastic tissue components having the microscopic appearance of
 

renal mesenchymal stroma, adipose tissue, and primitive renal
 

epithelium, in various proportions.
 

There were instances where neoplasms occurred only in treated
 

animals, or with increased frequency when compared with those in
 

control groups. In the judgement of the pathologists, however,
 

the nature, incidence, and severity of the lesions observed
 

provide no clear evidence of a carcinogenic effect of dieldrin on
 

rats.
 

4. Statistical Analyses of Results (Rats) - Dieldrin
 

Tables Kl and K2 of Appendix K contain the statistical analyses
 

of the incidences of those specific primary tumors that were
 

observed in at least 5% of one or more treated groups of either
 

sex.
 

There was no statistically significant increase when the
 

incidence of any tumor in the male or female treated groups was
 

compared with that in the matched controls using the Fisher exact
 

test. When the treated groups were compared with the pooled-


control group, there was a significant (P = 0.007) difference
 

between the proportions of combined adrenal cortical adenomas and
 

carcinomas in the low-dose group of female rats and the pooled
 

controls. However, the results obtained with the high-dose group
 

44
 
did not confirm this finding. An adjustment eliminating all
 

animals that died in the first year on study did not change the
 

results reported for the unadjusted groups of animals.
 

The results of the laboratory controls indicate an incidence of
 

3/240 (1.3%) cortical tumors of the adrenal gland in female rats,
 

compared with 0/9 and 0/55 in the matched and pooled controls,
 

respectively, as reported in table K2.
 

In high-dose female rats the comparison of the incidence of the
 

combination of follicular-cell adenoma and carcinoma of the
 

thyroid between the high-dose group and the pooled controls
 

indicates P = 0.043 by the Fisher exact test, but this is above
 

the 0.025 level required by the multiple comparison criterion.
 

There were six adenomas and two carcinomas in the high-dose
 

group. The Cochran-Armitage test result for positive linear
 

trend is also significant (P •0.030). The Fisher exact test
 

result of the incidence of adenoma alone (pooled controls 2/52
 

[4%], high-dose 6/41 [15%]) was not significant at the 0.05
 

level, nor was the test of the incidence of carcinoma alone.
 

While a significant result is observed in fibroadenoma of the
 

mammary gland in female rats, the probability level of 0.041 in
 

the low-dose group is above the Bonferroni value of 0.025 neces45
 
sary for significance when the multiple comparison criterion is
 

applied to the incidence in the low-dose group.
 

There were no other tumors appearing in statistically significant
 

proportions. In each of the 95% confidence intervals shown in
 

the tables, except those for adrenal cortical tumors in the
 

low-dose females compared with the pooled-control group, the
 

value of one is included, indicating the negative aspects of the
 

results. It should also be noted that each of these intervals
 

has an upper limit greater than one, indicating the theoretical
 

possibility of the induction of tumors by dieldrin, which could
 

not be detected under the conditions of this test.
 

B. Mice
 

1. Body Weights and Clinical Signs (Mice) - Dieldrin
 

The administration of dieldrin produced essentially no effect on
 

the mean body weights of mice (figures 8 and 9).
 

During the first 6 months of the study, the treated animals were
 

generally comparable to the controls in appearance and behavior.
 

During the second 6 months, clinical signs including tremors,
 

abdominal distention, alopecia, tachypnea (noted predominantly in
 

the low-dose males), and hyperexcitability (especially among male
 

mice).
 

46
 
Figure 8. Growth Curves for Male Mice Fed
 

Dieldrin in the Diet
 

47
 
Figure 9. Growth Curves for Female Mice Fed
 

Dieldrin in the Diet
 

48
 
Beginning at week 54, rough hair coats were observed in all
 

treated male mice. At week 63, all of the low-dose females
 

appeared hyperactive. During the second half of the study, all
 

of the previously described clinical signs were noted, together
 

with pale mucous membranes, dyspnea, and loss of weight. A 

majority of both low­ and high-dose male mice were observed 

fighting. 

2. Survival (Mice) - Dieldrin
 

The statistical tests for dose-related trend in mortality were
 

not statistically significant for either sex (figure 10). In
 

male mice, there was a greater rate of mortality in the high-dose
 

group than in the low-dose group. Sufficient animals were
 

available for meaningful statistical analyses of the incidence of
 

tumors.
 

3. Pathology (Mice) - Dieldrin
 

Histopathologic findings on neoplasms in mice are summarized in
 

Appendix D, tables Dl and D2; findings on nonneoplastlc lesions
 

are summarized in Appendix H, tables Hi and H2.
 

Several nonneoplastic lesions occurred frequently in both treated
 

and control female mice. These included purulent oophoritis,
 

fendometritis, and cystic endometrial hyperplasia. There were
 

49
 
Figure 10. Survival Curves for Mice Fed
 

Dieldrin in the Diet
 

50 
infrequent incidences of other inflammatory, degenerative, and
 

nonneoplastic proliferative lesions in all groups.
 

The most frequently occurring neoplasms were hepatocellular
 

carcinomas. The morphology of these lesions varied widely. Some
 

were present as one or more small, discrete nodules containing
 

solid cords and nests of well-differentiated but hyperbasophilic
 

hepatocytes with an increased nuclear : cytoplasmic ratio. These
 

lesions appeared to have grown by expansion, with distinct
 

compression but with no obvious invasion of adjacent normal
 

hepatic parenchyma. Other hepatic neoplasms appeared as very
 

large masses which had completely replaced one or more hepatic
 

lobes, and which were composed of large anaplastic hepatocytes
 

forming confluent sheets, papillae, and pseudoacini, with large
 

foci of necrosis and complete loss of normal lobular
 

architecture. The morphological appearances of the majority of
 

hepatocellular carcinomas were between these two extremes.
 

Metastasis was observed in two cases: multiple pulmonary
 

metastases in a low-dose male; and metastases to heart, lung,
 

kidney, diaphragm, and pleura in a high-dose male.
 

The overall incidence of hepatocellular carcinoma in both treated
 

and control mice was much higher in males than in females. There
 

was a definite increase in the incidence in treated male mice
 

when compared with that in control males, and the amount of this
 

51
 
increase was greater in those males which received the higher
 

dose of the test chemical (pooled control 17/92 [18.5%], low-


dose 12/50 [24%], high-dose 16/45 [36%]). There was also a very
 

slight increase in the incidence of this neoplasm in treated
 

females (pooled controls 3/78 [3.8%], fow-dose 6/50 [12%],
 

high-dose 2/49 [4%]).
 

There was a low incidence of other types of neoplasms involving
 

various organs and tissues, with no obvious difference in incidence between treated and control groups.
 

4. Statistical Analyses of Results (Mice) - Dieldrin
 

Tables Ll and L2 of Appendix L contain the statistical analyses
 

of the incidences of those specific primary tumors that were
 

observed in at least 5% of one or more treated groups of either
 

sex.
 

With the exception of hepatocellular carcinoma, no tumors
 

appeared in statistically significant proportions in the treated
 

groups compared with those in either the matched or pooled
 

controls. Using the pooled controls, the Cochran-Armitage test
 

result for linear positive dose-related trend in the proportion
 

of this liver tumor in male mice is significant (P = 0.020), with
 

a statistically significant (P = 0.025) increase between the
 

proportions in the high-dose and pooled-control groups. The test
 

52
 
for linear trend in the incidence of hepatocellular carcinoma in
 

female mice indicated a significant departure from trend. This
 

departure was due to the increased proportion of such tumors in
 

the low-dose animals compared with that in either the control
 

group or in the high-dose group; however, the probability level
 

(P = 0.08) of the difference between the proportions observed in
 

the low-dose animals and pooled controls was greater than P a
 

0.05. It may be concluded from the statistical analyses that the
 

incidence of hepatocellular carcinoma in male mice increased as
 

doses of dieldrin increased. The laboratory historical controls
 

showed spontaneous incidences of hepatocellular carcinoma in
 

48/285 (16.8%) male mice and in 6/259 (2.3%) female mice.
 

There were no other tumors appearing in statistically significant
 

proportions in these mice. In each of the 95% confidence
 

intervals shown in the tables, with the exception of liver tumors
 

in male mice, the value of one is included, indicating the
 

negative aspects of the results. It should also be noted that
 

each of the intervals, except for liver tumors in male mice, has
 

an upper limit greater than one, indicating the theoretical
 

possibility of the induction of tumors by dieldrin, which could
 

not be detected under the conditions of this test.
 

53
 

V. DISCUSSION
 

Aldrin and dieldrin are organochlorine insecticides of the cyclodiene group whose predominant clinical signs of toxicity relate
 

to effects on the central nervous system. Hyperexcitability, a
 

manifestation of toxicity which is characteristic of these
 

chemicals, was observed in all treated groups of both rats and
 

mice, with increasing frequency and severity during the second
 

year of the bioassays. In both the aldrin- and dieldrin-treated
 

groups, convulsions occurred in the high-dose male and high-dose
 

female rats.
 

Various nonspecific clinical signs appeared with increasing frequency in the treated rats and mice during the second year of the
 

bioassays. These included alopecia, pale mucous membranes,
 

dyspnea, abdominal distention, rough hair coats, and vaginal
 

bleeding in rats, and alopecia, tachypnea, rough hair coats, and
 

abdominal distention in mice. Mean body weights of the rats fed
 

either aldrin or dieldrin were lower than those of the matched
 

controls, particularly during the second year of the studies.
 

Mean body weights of the mice fed either aldrin or dieldrin were
 

not appreciably different from those of the matched controls.
 

Prior to 90 weeks on study, survival decreased in male rats
 

treated with aldrin or dieldrin; however, deaths as calculated by
 

55
 
life-table analyses over the entire period of the study were not
 

dose related in either sex. Adequate numbers of rats treated
 

with either aldrin or dieldrin survived to provide meaningful
 

statistical analyses of the incidences of tumors. For mice,
 

survival was significantly affected only among high-dose females
 

fed aldrin.
 

In rats, follicular-cell adenoma and carcinoma of the thyroid,
 

taken together, occurred at significantly higher incidences in
 

treated groups than in pooled controls in tests performed on
 

low-dose males fed aldrin (controls 4/48, low-dose 14/38, P =
 

0.001) and in low-dose females fed aldrin (controls 3/52,
 

low-dose 10/39, P = 0.009). The incidences in the treated groups
 

were not significant, however, when matched controls were used
 

instead of pooled controls for the comparisons. In the high-


dose groups the incidences of these tumors, (males 8/38, females
 

7/46) were elevated but not statistically significant.
 

Also in rats, cortical adenoma of the adrenal occurred at a
 

significantly higher incidence in low-dose females fed aldrin
 

than in pooled controls (control 0/55, low dose 8/45, P = 0.001),
 

and cortical adenoma and carcinoma of the adrenal, taken
 

together, occurred at a significantly higher incidence in
 

low-dose females fed dieldrin than in pooled controls (controls
 

0/55, low-dose 6/45, P = 0.007). The incidences in the treated
 

56
 
groups were not significant, however, when matched controls were
 

used instead of pooled controls for the comparisons. In the
 

high-dose groups there was one animal with cortical adenoma in
 

the aldrin study and two animals with cortical adenoma in the
 

dieldrin study.
 

It is interesting to note that the incidences of follicular cell
 

tumors of the thyroid in both males and females in the aldrin
 

study and cortical adenomas of the adrenal in females in both the
 

aldrin and dieldrin studies were higher in the low dose than in
 

the high-dose groups.
 

In mice, hepatocellular carcinoma occurred at incidences that
 

were significantly dose related when pooled controls were used in
 

tests performed on males fed aldrin (controls 17/92, low-dose
 

16/49, high-dose 25/45, P < 0.001) or dieldrin (controls 17/92,
 

low-dose 12/50, high-dose 16/45, P = 0.020). Further, incidences
 

in the individual treated groups were significantly higher than
 

in the pooled controls in the tests performed on high-dose males
 

fed either aldrin (P < 0.001) or dieldrin (P = 0.025). When
 

matched controls were used for the comparisons, hepatocellular
 

carcinoma occurred at a significantly high rate only in tests of
 

dose-related trend performed on male mice fed aldrin (P = 0.001)
 

and in direct comparison of high-dose aldrin-fed males with the
 

matched controls (P = 0.002). However, as shown below, the
 

57
 
incidences of these tumors in male mice fed dieldrin and in
 

female mice fed either aldrin or dieldrin also were consistently
 

higher than those in the corresponding matched controls, even
 

though they were not all statistically significant.
 

Matched
 

Controls Low Dose High Dose
 

Males: Aldrin 3/20 (15.0%) 16/49 (32.7%) 25/45 (55.6%)
 

Dieldrin 3/18 (16.6%) 12/50 (24.0%) 16/45 (35.6%)
 

Females: Aldrin 0/10 (0%) 5/48 (10.4%) 2/43 (4.7%)
 

Dieldrin 0/20 (0%) 6/50 (12.0%) 2/49 (4.1%)
 

These data demonstrate, in addition, that aldrin and dieldrin,
 

which are structurally related compounds that are metabolized in
 

a similar manner, produce a similar lesion in the liver of mice.
 

Aldrin is known to be rapidly converted to the epoxide, dieldrin,
 

in vivo, and further metabolic degradation of both chemicals is
 

similar (IARC, 1974). Therefore, it is not unexpected that
 

similar tumors were encountered in these bioassays for both
 

aldrin and dieldrin. Chronic toxicity studies have been
 

conducted using Osborne-Mendel rats (Deichmann et al. , 1970;
 

Fitzhugh et al. , 1964), Carworth Farm "E" strain rats (Walker et
 

al. , 1969; Stevenson et al., 1976), rats of unindicated strain
 

(Cleveland, 1966), C3Heb/Fe/J mice (Davis and Fitzhugh, 1962), or
 

CFl mice (Walker et al., 1972; Thorpe et al. , 1973). In a review
 

of these studies (IARC, 1974), there was no convincing evidence
 

58
 
that either aldrin or dieldrin was carcinogenic. However,
 

several of the studies in mice showed an increase in liver
 

lesions, usually termed "hepatoma," in this species. Evaluation
 

was not always possible because detailed data were lacking.
 

The data for the rats in the present bioassays confirm previous
 

chronic toxicology studies, in that aldrin and dieldrin were not
 

shown to be carcinogenic for the livers of rats. In the present
 

bioassays for rats, there were questionable incidences of tumors
 

in the thyroid and adrenal glands. These organs have not
 

previously been cited as target organs for these chemicals.
 

It is concluded that under the conditions of these bioassays,
 

none of the tumors occurring in Osborne-Mendel rats treated with
 

aldrin or dieldrin could clearly be associated with treatment.
 

Aldrin was carcinogenic for the liver of male B6C3F1 mice
 

producing hepatocellular carcinomas. With dieldrin, there was a
 

significant increase in the incidence of hepatocellular
 

carcinomas in the high-dose males which may be associated with
 

treatment.
 

59
 

VI. BIBLIOGRAPHY
 

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

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

Berenblum, I., ed., Carcinogenicity Testing; A Report of the
 

Panel of Carcinogenicity of the Cancer Research Commission
 

of UICC, Vol. 2., International Union Against Cancer,
 

Geneva, 1969.
 

Brooks, G. T., Chlorinated Insecticides. Technology and
 

Application, Vol. II, Chemical Rubber Company, Cleveland,
 

Ohio, 1975.
 

Cleveland, F. P., A summary of work on aldrin and dieldrin
 

toxicity at the Kettering Laboratory. Arch. Environ. Health
 

H;195, 1966.
 

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

Soc. B. 34:187-220, 1972.
 

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

1970, pp. 48-52.
 

Davis, K. J. and Fitzhugh, 0. G. , Tumorigenic potential of aldrin
 

and dieldrin for mice. Toxicol. Appl. Pharmacol. 4^:187-189,
 

1962.
 

Deichmann, W. B., MacDonald, W. E. , Blum, E. , Bevilacqua, M.,
 

Radomski, J., Keplinger, M., and Balkus, M., Tumorigenicity
 

of aldrin, dieldrin and endrin in the albino rat. Indust.
 

Med. 39(10);426-434. 1970.
 

Federal Register, Fed. Reg. 37246 et seq. (Oct. 18, 1974) Shell
 

Chemical Co. et al. (EPA FIFRA Docket Nos. 145 etc.), U.S.
 

Government Printing Office, Washington, D.C.,
 

39(203):37246-37272.
 

Fitzhugh, 0. G. , Nelson, A. A., and Quaife, M. L. , Chronic oral
 

toxicity of aldrin and dieldrin in rats and dogs. Fd.
 

Cosmet. Toxicol. 2:551-562. 1964.
 

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

significance tests, confidence limits and adjustments for
 

stratification. Rev. Int. Stat. Inst. 39:148-169. 1971.
 

61
 
Hayes, W. J. , Jr., Toxicology of Pesticides. The Williams and
 

Wilkins Co., Baltimore, Maryland, 1975.
 

International Agency for Research on Cancer, IARC Monographs on
 

the evaluation of the carcinogenic risk of chemicals to man;
 

Some organochlorine pesticides, Vol. 5^, World Health
 

Organization, Geneva, 1974, pp. 25-38; 125-156.
 

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

incomplete observations. J. Amer. Statist. Assn. 53;
 

457-481, 1958.
 

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.
 

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

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

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

Kauffman, D. G. , Respiratory tract carcinogenesis in
 

hamsters induced by different numbers of administrations of
 

benzo (a) pyrene and ferric oxide. Cancer Res. 32;1073-1079,
 

1972.
 

Squire, R. A. and Levitt, M., Report of a workshop on
 

classification of specific heptocellular lesions in rats.
 

Cancer Res. 35;3314, 1975.
 

Stevenson, D. E. , Thorpe, E. , Hunt, P. F., and Walker, A. I. T.,
 

The toxic effects of dieldrin in rats: a reevaluation of
 

data obtained in a two-year feeding study. Toxicol. Appl.
 

Pharmacol. 38(2);247-254. 1976.
 

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

Biometrika 62;679-682. 1975.
 

Thorpe, E. and Walker, A. I. T., The toxicology of dieldrin
 

(HEOD), II. Comparative long-term oral toxicity studies in
 

mice with dieldrin, DDT, phenobarbitone, 3-BHC and Y-BHC.
 

Fd. Cosmet. Toxicol. _U:433-442, 1973.
 

Walker, A. I. T. , Thorpe, E., and Stevenson, D. E., The
 

toxicology of dieldrin (HEOD), I. Long-term oral toxicity
 

studies in mice. Fd. Cosmet. Toxicol. 11;415-432. 1972.
 

62
 
Walker, A. I. T., Stevenson, D. E. , Robinson, J. , Thorpe, E. and
 

Robert, M., The toxicology and pharmacodynamics of dieldrin
 

(HEOD): Two-year oral exposure of rats and dogs. Toxicol.
 Appl. Pharmacol. 15; 345-373, 1969.
 

63
 
APPENDIX A
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS
 

IN RATS FED ALDRIN IN THE DIET
 

65
 

TABLE A1

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE RAT; 

FED ALDRIN INTHE DIET 

-f, __ •»•._.__.._*»•___. „-. IT _L- II __ .1 __.« 1 —
 

MATCHED 

CONTROL LOW DOSE HIGH DOSE
 

HIIMAIS IKITULLY IN S1DDY 

JNIMALS NECROPSIID 

SNIHALS EXAMINED HISTOPATHOLOGICALLY 

10 

10 

10 

50 

48 

l»8 

50
 

50
 

U9
 

INTEGOMENTABY SYSTEM
 

*SKIH 

HEMAHGIOSARCOMA (10) («8)
 

1 (2%)
 

(50)
 

*SUBCOT TISSUE 

SQOAMOUS CEL1 CABCINOBA
 

SARCOMA, NOS 

HEHAHGIOSA8COHA
 

(10) 

1 (10«)
 

1*8)
 (50)
 

1 I2K)
 

2 (1%)
 

EESPIBATOBY SYSTIM
 

ITHACFEA 

SAPCCHA, MOS '.9) 

1 (11«)
 

138)
 :<»2)
 

ILONG 

ALVEOLAH/BEOHCHIOLAR ADEBOHA 

CORTICAL CABCIHOHA, HETASTATIC 

C-CEL1 CARCIHOHA, HETASTATIC 

MIXED 10HOR, METASTATIC HEBABGIO SARCOMA 

(10) («7)
 

1 (2X)
 1 ;2«)
 

1 (10*)
 

1 (2X)
 

1 t2«)
 

(l»7)
 

1 <2X)
 

HIMATOPOIETIC SYSTEM
 

ISPLEEN (10) tt5)
 

nEHANGIOSARCOHA
 

(»5)
 

1 (2«)
 

INARDIBOLAR L. RODE (9) (3«)
 

SQOAMOOS CELL CARCIBOMA, HETASTA
 

(»5)
 

1 (2X)
 

CIRCULATORY SYSTEM
 

fHEAPT (10) !«5)


SiRCCBA. MOS 1 it o?i 1 (2H1
 

t»5)
 

I NOHBEB OF AHIHALS WITH TISSDE IXAHIHBD P1ICROSCOPICXL1I 

* NORBEB OF AMIHALS BECBOFSIBD 

67 
TABLE A1 MALE RATS: NEOPLASMS (CONTINUED) 

MATCHED LOW DOSE 

CONTROL 

*AORTA (10) (»8) 

HEPATOCIILUIAS CARCIROHA, BETA ST 1 (2«) 

DIGESTITE STSTEH 

tSALIVABY GLAND (9) I36) 

SARCCHA, NOS 

ILIVER (10) (»7) 

HEPATOCEILOLAH CARCIROHA 1 (10X) 1 (2*) 

CORTICAL CARCIHOHA. HETASTATIC 1 :2«) 

*BILE DUCT (10) (U8) 

BILE DOCT ADENORA 

•ESOPHAGUS (9) (39) 

SARCOHA, NOS 1 (11*) 

iSTOHACH (9) (37) 

C-CELL CABCIMOHA, HETASTATIC 1 (11*) 

SABCOHA, SOS 1 (11*) 

OBINABY SI STEM 

tKIDNET 

TDBOLAB-CELL ADINOBA 

(10) 

1 (10*) 

t«6) 

RIXED TO HOB, HALIGRART 1 (2«) 

IHDOCBIRE STSTEH 

IPITDITABT (9) (37) 

CRBOHOPHOBE ADEROHA 3 (33*) 13 (35*) 

CHBOHOPR08E CARCIROHA 

IADRERA L (10) (38) 

CORTICAL ADBHORA 2 (20*) 

CORTICAL CABCIROHA 1 (3*) 

PREOCRBOHOCYTOHA 1 [3*) 

fTRTROIE (7) (38) 

FOLLICDLAB-CELL ADBRORA 3 0»3«) 10 (26*) 

POI,LICOtAB-CBLL CABCIIORA « mo 

I ROBBER OP JMIHALS *ITR TISSUE EZAHIIED HICROSCOPICAIII
 

* ROHBER 01 AKIHALS IECRCPSI1D
 

HIGH DOSE 

(50) 

;uo) 

1 (3*) 

(»7) 

1 (2*) 

(50) 

1 (2«) 

(«D 

(«D 

(«6) 

1 (2«) 

1 12*) 

t»0) 

11 (28X) 

2 (5«) 

(»3) 

2 (5*) 

(38) 

6 (16«) 

2 fSSI 

68
 
TABLE A1 MALE RATS: NEOPLASMS (CONTINUED)

 

MATCHED LOW DOSE 

CONTROL 

C-CII1 ADEVCHA 

C-CELL CABCHOHA 1

1

 I1»«) 

 (1»«) <» (11*1 

•PARATHYROID (7) (22) 

ADEKOHA , HOS 1 (1U«) 

IPANCP.EATIC ISLETS 

ISLK-CHLL ADESCHA 

ISLET-CELL CARCINOHA 

(9) (37) 

5 (1»«) 

REPRODOCTIVE STSTEH 

• HAHHAR Y GLAND ;10) ;i»8) 

FIBPCSARCOHA 1 (2«) 

•EPIDIDYHIS (10) ("»8) 

LIPOHA 1 (2*) 

KHSVOO S SYSTEM 

IBPMH !?) !"»0) 

SQOAHOOS CEII CARCISCMA, HETASTA 

HENIMGIOHA 1 [3X) 

SFECUL SEHSE OPGAHS 

NONE 

HOSCOIOSKUMAL SYSTEM 

*SKDLL (10) C»8) 

SQOAHOOS CEII CMtCIBOHl, METASTA 

•SKELETHL NOSCLE (10) («8) 

HEHANGIOS1PCOHA 

*NOSCLE OF READ (10) (»8) 

SQOAHOOS CEII CAP.CIROHA, HETASTA 

»HOSCLE OP HECIt (10) I»8) 

SARCORA. HOS 1 !1°.?1 

I HOHBER OP ANIMALS KITH TISSUE EXARIKED MICROSCOPICALLY
 

* NUMBER OP ANIHALS NECROPSI1D
 

HIGH DOSE 

2 <5«) 

1 I3«) 

(3«) 

1 (3«) 

(39) 

1 (3«) 

1 I3«) 

;50) 

(50) 

;u2) 

1 (2«) 

(50) 

1 [2«) 

(50) 

1 !2«) 

(50) 

1 I2«) 

(50) 

69
 
TABLE A1 MALE RATS: NEOPLASMS (CONTINUED) 

EODY CAVITIES
 

*PEEITOHEUM
 

MFSOTHELIOMA , NOS
 

ALL OTHER SYSTEMS
 

*MULTIPLE OEGANS
 

FIBHCOS HISTICCYTOMA, MALIGNANT
 

JNIMAI. DISPOSITION SUMMAR Y
 

ANIMAL S INITIALLY IN STUDY
 

NATORA I DEATHS
 

MOBIEUND SACRIFICE
 

SCHEtUIED SACRIFICE
 

ACCIDENTALLY KILLED
 

TERMINA L SACPIFTCF
 

ANIMA L MISSING
 

3 INCLUDES M1TOLYZED ANIMAL S
 

Tl'MOR SU«H»P?
 

TOTAL ANIMAL S WITH PRIMAR Y TOMOES*
 

TOTRI EHIMAF Y TUMOFS
 

TO-^AL ANIMALS WITK BFNIGN TUMCES
 

TOTAL BENIGN TUMOBE
 

TOT51 ANIMALS KITH MALIGNAN T TDMOBS
 

TOTAL MSIIGNANT TOHOES
 

TO^AL ANIMALS WITH SECONDARY TUMORS*
 

TOTAL SECONDARY TUMCES
 

TOTAL ANIMAL S KITH TUMOES UNCEETATNBENTGN OB MALIGNANT
 TOTAI UNCERTAIN TIKCSS
 

TOTAL BNIMALS WITH TUMORS UNCEBTAINPRIMAEY OR METASTATIC
 

TOTAL UNCERTAIN TUMORS
 

MATCHED
 

CONTROL
 

(10)
 

;10)
 

10
 

u
 

1
 

5
 

9
 

19
 

7
 

11
 

3
 

8
 

1
 

2
 

LOW DOSE
 

(«8)
 

;<t8)
 

?o
 

12
 

12
 

26
 

30
 

«7
 

25
 

35
 

10
 

12
 

3
 

U
 

HIGH DOSE
 

(50)
 

1 (2X)
 

;50)
 

2 («*)
 

50
 

13
 

17
 

20
 

30
 

«3
 

20
 

26
 

13
 

16
 

1
 

U
 

1
 

1
 

* PRIMARY 1DBORS: All TUMOPS EXCEPT SECONDARY TUMORS
 

* SECONDARY TUMORS: N31ASTATIC TUMORS OR TUMORS INVASIVE INTO AN ADJACENT OFGAN
 

70
 
TABLE A2

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS 

FEDALDRININTHE DIET 

MATCHED LOW DOSE HIGH DOSE 

CONTROL 

JNIHALS IHITIAIIY IS STUDY 10 50 50 

JNIHALS RECSOPSIED 10 50 50 

ABIHALS EXAMINE D HISTOPATHOLOGICALLI 10 »9 50 

IHTIGOHEHIIIRI SYSTEH 

*SDBCDT TISSU1 (10) (50) (50) 

HEHARGIOSABCOHA 1 !2«) 

FispiHAioRY SISTER 

tTRACHEA (9) [«3) ;«6) 

C-CE1L CABCIROHA, BETASTATIC 1 (2*) 

*LDNG (9) («7) <«9) 

C-CCLL CABCIROHA, HITASTATIC 2 (M) 

REHATOPOIE1IC SYSTEM 

•H01TIPLE OHSARS HO) t50) [50) 

HAII6RAIIT 1THPROHA, ROS 1 (2U) 

tSPLEER (8) («7) (»8) 

HEHAR6IOHA 1 (2«) 

IHAROIBULA B L. RODI (9) (31) (l»2) 

C-CELL CABCIROH1, BITASMTIC 1 (2«) 

CIBCOLATORI SYSTEM 

RORE 

CIGISTIVI SYSTEM 

ILIfEB (10) (»8) <«9)

•EOP1|STIC RODD1E 1 jlpft

 3 IKO 

I lOMBEH OF ANIMALS 8ITH TISSOB EXABIIED MICROSCOPICALLY 

* IOHBEB OP ANIMALS RBCROPSIED 

71 
TABLE A2 FEMALE RATS: NEOPLASMS (CONTINUED)

 

HIGH DOSE
 

t«9)
 

;us)


11 (23*)
 

(B8)
 

1 (2«)
 

(«6)


3 (7*)
 » t«)
 8 (17*)
 

2 (»«)
 

(«0)


1 (3*)
 

(50)
 

7 (1»«)
 

(*8)


1 (2*)
 

9 (19*)
 

<«8)
 

(»6)
 

» |9«)
 

HEPATOCIU0LAR CARCINOMA
 

DBINARY SYS1BM
 

IKIDNEY
 HEMANGIOSABCOHA
 

INDOCPINE SYSTEM
 

•PITUITARY
 

CHROHOPHOBI ADENOMA
 

•ADRENAL
 CORTICAL ADENOMA
 

•THYROID
 

FOLLICULAB-CELL ADINOHA
 FOLLICOLAB-CELL CARCINOMA
 C-CELL ADENOMA
 

C-CEIL CARCINOMA
 

fPANCREATIC ISIETS
 

ISLET-CELL ADENOMA
 

REPRODUCTIVE SYSTEM
 

*HAHHARY GLAND
 

PAPILLARY ADENOCARCIICHA
 

FIBROMA
 FIBROSARCOMA
 PIBROADENOHA
 

•OTEROS
 

LEIOHYOSABCOHA
 ENDOMETRIAL STBOMAL POLYP
 

•CERTIX OTIFI
 

REMANGIOSARCOHA
 

(OTARY
 GRAIOLOSA-CELL TDMCR
 

1EBTOOS SYSTEM
 

HONE
 

MATCHED
 

CONTROL
 

;10)
 

(9)
 

4 (1UX)
 

(10)
 

(9)
 

1 (11*)
 

1 111*)
 

(9)
 

[10)
 

3 (30*)
 

(9)
 

(9)
 

(8)
 

LOW DOSE
 

1 (2*)
 

:«8)


1 (2*)
 

:«3)


15 (35*)
 

(»S)


8 (18X)
 

(39)
 

8 (21*)
 

2 (5*)
 

6 115*)
 

(»»)


1 (2«)
 

£50)
 

1 (2*)
 

1 (2*)
 

1 (2*)
 

7 [1»«)
 

(»5)
 

6 t13«)
 

(15)
 

1 (2*)
 

(»3)
 

1 (2«)
 

I NOMBER OF ANIMALS BITH TISSDE EXAMINED MICROSCOPICALLY
 * HOMBER OF AIIMALS NBCROPSilD
 

72 
TABLE A2 FEMALE RATS: NEOPLASMS (CONTINUED) 

SPECIAL SEISE ORGANS
 

NONE
 

HOSCOLOSKELETAL SYSTEM
 

NOME
 

EODY CAVITIES
 

•MESENTERY
 

LIPCHi
 

All OTHER SYSTEMS
 

NONE
 

ANIMAL DISECSITICN SUMMARY
 

ANIMALS imilALtY IN STUEY
 

NATDPAL DEATHS
 

MORIBUND SACBIFICE
 SCHFEOLJD SACRIFICE
 ACCIDENTALLY KILLED
 

TERMINAL SACRIFICE
 »NIMSL MISSING
 

2 ISC1DDES AOTOLIZED UNIHALS
 

MATCHED LOW DOSE HIGH DOSE CONTROL 

[10) ;5o> :so) 

1 (2%) 

10 50 50 

1 4 It 

12 6 

9 31 HO 

t NUMBER 01 ANIMALS ilTH TISSOE EXUHINED MICROSCOPICALLY
 

* NUMBEB OF ANIHAIS NECBOPSIID
 

73
 
TABLE A2 FEMALE RATS: NEOPLASMS (CONTINUED)

 

TONOR SOHBARY
 

TOTAL ANIMALS WITH PRIMARY TOMORS*
 

TOTAL PRIMARY TUMORS
 

TOTAL ANIMALS WITH BIHIGN TOHOFS
 

TOTAL EENIGN TOMORS
 

TOTAL ANIMALS WITH MALIGNANT TDBOSS
 

TOTAL BALIGNANT TUCCHS
 

TOTAL ANIMALS BITH SECCNDABY TOBOFSt
 

TOTAL SICONDART TOBORS
 

TOTAL ANIMALS WITH TOMORS UNCERTAINBENIGN OR (1ALIGNANT
 

TOTAL ONCEHTUN TOMORS
 

TOTAL ANIMALS WITH TOMORS UNCERTAINPRIHARY CR MfTASTATIC
 

TOTAL ONCEPTAIN TOMORS
 

MATCHED
 

CONTROL
 

5
 

10
 

5
 

9
 

1
 

1
 

LOW DOSE
 

35
 

62
 

33
 

53
 

6
 

8
 

1
 

1
 

HIGH DOSE
 

32
 

56
 

26
 

«1
 

7
 

8
 

2
 

a
 

7
 

7
 

* PFIHARY TUMORS: ML TDHOBS EXCEPT SECONDARY TUMORS
 

I SECONDASY TUMORS: MtfTASTATIC TOMOBS OR TOHORS INVASIVE INTO All ADJACENT ORGAN
 

74 
APPENDIX B
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS
 

IN MICE FED ALDRIN IN THE DIET
 

75
 

TABLE B1

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE MICE 

FEDALDRININTHEDIET 

HIGH DOSE LOW DOSE LOW DOSE HIGH DOSE 

CONTROL CONTROL 

Ill I HALS IRITIAILI III STUDY 10 10 SO 50

 

1 HI HALS lECEOPSIED 10 10 50 48

 

I»IR»IS EXAHIHED BISTO PATHOLOGIC ALLY 10 10 50 46

 

I«TIGOBE»TAHY SYSTEM 

• OWE 

RESPIRATORY SYSTEH 

ILOHG (10) 110) (»9) (45) 

REPATOCEILULAR CARCIIOHA, BETAST 1 (10«) 1 (2«) 1 (2«) 

ALYEOLAR/BROBCHIOLAR ADEIOHA 3 (6*) « (9») 

ALVEOLAR/BBOICHIOLAR CARCIBOHA 1 [2«) 

HEHATOPOIETIC SYSTEH 

•HOLTIPLE ORGABS [10) ;io> [50) t«8) 

HALIG.IYHPHOHA, LY8PHOCYTIC TYPE 1 (2*) 

HI1IG.LYBPHOBA, RTSTIOCYTIC TYPE 1 J10S) 

tSPLEER (9) (10) (19) (««) 

SAHCOHA, IOS 1 (2«) 

IIYBPR MODE (9) (9) (»3) (45) 

BALIG.IYHPHOHA, IYRPBOCYTIC TYPE 1 (2«) 

•TRYBUS (1) (5) (3) (3) 

SiKCOBA, IDS 1 (33«) 

CIICOLATOFY SISTER 

•OH 

DIOIS1ITI SYSTEH 

•LZfll (10) (10) (»9) (»«) •IVATOCILI.OL11 C1KCIIOH1 1 MOV 2 (20<! 16 I33tl if titfi 

« IOBBBB OF.1RIRALS WITH TISSUE EIARIIRD HICBOSCOPICALLY 

• IDBBII OF ARIHALS BBCIOffSIID 

77
 
TABLE B1 MALE MICE: NEOPLASMS (CONTINUED) 

HIGH DOSE LOW DOSE LOW DOSE 

CONTROL CONTROL 

SARCOHH, IOS 1 (2«) 

IPAHCREAS (9) (10) («9) 

SARCOHA, HOS 1 (2*) 

iSTOHAcn (10) (10) (»9)

 

PUPIILCH*, HOS 

tSHXLL IMTISTINE (10) (19)

 

ADEHOHA , HOS 

OBItURY SYE1EH 

•KIDNEY ;10) ;ioj !»9) 

SARCCIIA, NOS 

IHDOCPINE SYSTEM 

ITHIPOID !9) I8) :<»6)

FOltlCOUa-CELI, »DE»CK» 1 (13%) 1 (2«) 

BEPRODOCTIVE StSTBM 

ITBSTIS •10) I9) :z)

 IHTERSTITHl-CEIL -TOBCF 1 (10*)

 

DERVOnS STSTEN 

HOUE 

SPECIAL SIRSE 01GXNS 

•EYE/IACRIHIIL GIAN C (10) (10) (50)

 

CTSTADIVOHA, NOS 1 (10«)

 

BOSCOLOSKElITil SYSTEM 

MOXE 

BODY OVITIIS 

*MHSEHTI5J (10) (10) (50)

 

SARC01A. NOS 

t NOHBBR Of ANIMALS SITH TISSUE EXAMINED MICROSCOPICALLY
 

* ROMBER OF AHIHALS NICSOFSIIE
 

HIGH DOSE 

1 |2») 

(»5) 

(15) 

1 |2») 

(l»5) 

1 (2«) 

t»5) 

1 (2») 

(»D 

(<»5) 

(«8) 

(US) 

1 f2«> 

78 
TABLE B1 MALE MICE: NEOPLASMS (CONTINUED)

 

HIGH DOSE 

CONTROL LOW DOSE 

CONTROL 

LOW DOSE HIGH DOSE 

AIL OTHER SYSTEMS 

NONE 

ANIMA L DISPOSITION SUHCARY 

ANIMALS INITIALLY IN STDDY 

NATUPSL DEATHS MORIBUND SACRIFICE 

SCHEDULED SACRIFICE 

ACCIDENTALLY KILLED 

TERMINAL SACRIFICE 

ANIMAL HISSING 

10 

2 

2 

6 

10 

1 

9 

50 

1 

3 

H6 

50 

9 

4 

37 

8 INCLUDES AUTOLYZED ANIMALS 

TCNOR SUMMAR Y 

TOTAL ANIMALS WTTH PRIMARY TOMOPS* 

TOTAL PRIMARY TDSCPS 

3 

3 

It 

4 

18 

25 

28 

36 

TOTAL ANIMALS WITH BF.SIGN TUKCBS 

TOTAL BENIGN TOMORS 

2 

2 

1 

1 

U 

4 

5 

6 

TOTAL ANIMALS WITH MALIGNANT TOMOFS 

TOTAL MALIGNANT TUMCPS 

1 

1 

3 

3 

17 

21 

25 

30 

TOTAL ANIMALS WITH SECONDARY TOMOPSt 

TOTAL SECONDARY TUHCRS 

1 

1 

1 

1 

1 

1 

TOTAL ANIMALS WITH TUBCRS nNCEFTAINEENIGN OR MALIGNANT 

TOTAL UNCERTAIN THPCRS 

TOTAL ANIMALS WITH TOMCRS UNCERTAINPRIMARY OR METASTATIC 

TOTAL UNCERTAIN TUffCRS 

* PRIMARY TOMORS: All TDHCRS EXCEPT SECONDARY TUMORS 

I SECONDARY TUMORS: METASTATIC TUMORS OR TUMORS INVASIVE INTC AN ADJACENT OEGAN 

79
 
TABLE B2 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE MICE 

FEDALDRININTHEDIET 

1 MATCHED LOW DOSE 1 CONTROL HIGH DOSE
 

JNIHALS IHITIAIIT I» STODT 10 SO »NIHALS NECPOPSIED 10 us IHIHALS EXAHINED HISTOPATHOLOGICALLT 10 as 

50
 

it 6
 

US
 

IHTIGUHEimRT STSTEH
 

*SKI»	 (10) (48)
 

BASAL-CELL CARCINOHA	 1 [2*)
 

LEIOHTOSARCOHA	 1 [10*)
 

(«6)
 

FESPIPHTOBT StSTEH
 

•LONG	 no> :<»8)
 

XIVEOLXB/BFORCRIOLAB AEIKOHA 1 (2*)
 

LEIOHIOSARCOHA 1 [10*)
 

t»«)


1	 (2«)
 

HEHATOPOIE1IC STSTEH
 

*MDITIP1E OBGAHS 110) [»8)
 

NAIIG.ITRPHOHA, LIHPHOCTIIC TTPI 2 («*)
 

lULIG.LTHPHOMA, HISTIOCITIC TTPI 1 [2*)
 

GRAHOLOCI1IC LEOKEHIA 1 [10*)
 

:«6)
 

2 («*)
 

CIFCOLATOPI STSTEH
 

•HEART	 (10) (»8)
 

1EIORTCSABCOHA 1 (10*)
 

[39)
 

DIGESTIVI STSTEH
 

tSAITVIBT GLAHD (10) (1)
 

LEIOHTOSABC08A 1 (10*)
 

(38)
 

ILIYEH	 (10) (*8)


HBPATOCE1LOLAR CARCII01A	 5 MOO
 

(«3)
 2	 is«>
 

t ROHBER OF AIIHALS WITH TISSUE EXABIRED MICROSCOPICALLY * IOHBER OP AHIHALS IECROPSIED 

80 
TABLE B2 FEMALE MICE: NEOPLASMS (CONTINUED)

 

OHIHAHY SYSTEM
 

tKIDHEY
 LEIOHYOSABCOHA
 

1MDOCRIHE SYSTEH
 

tllTHITARY
 

CHROHOPHOBE ADENOHA
 

•ADRENAL
 

LEIOHYOSABCOHA
 

tTHYHOID
 

ADEROHA, DOS
 

BEPRODOCTIYE SYSTEH
 

"HJLMRARY GLAND
 

LEIOHYOSABCOHA
 

fOTlROS
 

EMDOH1TRIAL STROHM P01YB
 

tOVARY
 

1EIOHYOSA8COHA
 

1ERTOOS SYSTEH
 

HOHI
 

SPECIAL SEISE ORGANS
 

MORE
 

HUSCOLOSMIET1L SYSTEM
 

fOUt
 

BODY CATITIES
 

1011
 

MATCHED LOW DOSE HIGH DOSE CONTROL 

(10) 

1 (10U) 

(«8) (»3) 

f«5) !32) 

1 (2*) 

i|10) 

,1 (10*) 

(»7) (36) 

(10) (»6) 

1 (2*) 

(32) 

(10) 

1 (10*) 

(«8) t«6) 

(10) 0»7) 

1 (2*) 

(«3) 

(10) 

1 (10X) 

(»7) (39) 

I IORBBR Of I1IH1LS IITH TISSUE EX1HIIBO BICROSCOPIC1HT
 

* IDBBER OF kKIRlLS HBCBCPSI1D
 

81
 
TABLE B2 FEMALE MICE: NEOPLASMS (CONTINUED)

 

ILL OTHER SYSTEMS
 

HONE
 

AMIBAL DISJCSITICN SUMMARY
 

AMIHALS INITIALLY IN STUDY
 

NATUBAL DEATHS
 

MORIBUND SACBIPICE
 

SCHECUIID SAC5IFTCI
 

ACCIDENTALLY KILLED
 

TEBBINAL SACBIFICE
 

ANIMAL MISSING
 

a INCLUDES AOTOLYZED ANIMALS
 

TCBOB SUMMAR Y
 

TOTAL ANIMALS BITH PRIMARY TUMORS*
 

TOTAL PRIBAEY TDHOBS
 

TOTAL ANIMALS BITS BENIGN TDMCBS
 

TOTAL BENIGN TDMORS
 

TOTAL ANIMALS KITH MALIGNANT TDHOBS
 

TOTAL BA1IGBANT TDHORS
 

TOTAL ANIMALS BITH SECONDARY TDMORSI
 

TOTAL SECONDABY TDHOBS
 

TOTAL ANIMALS ilTB TOHOBS OSCERTAIBBENIGN OB MALIGNANT
 

TOTAL OSCEBTAIN TDMOBS
 

TOTAL ANIMALS BITH TUMORS ONCERTAINPRIMARY OB METASTATIC
 

TOTAL UNCERTAIN TDBOBS
 

MATCHED LOW DOSE HIGH DOSE 

CONTROL 

10 50 50 

It 12 

2 2 5 

8 44 33 

1 11 5 

9 13 5 

3 1 

a 1 

1 8 U 

9 9 M 

* PRIMARY TOBORS: AIL TOHORS EXCEPT SECONDARY TUMORS
 

I SECONDARY TUBOFS: METASTATIC TUHORS OR TUTORS INVASIVE INTO AH AEJACENT ORGAN
 

82
 
APPENDIX C
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS
 

IN RATS FED DIELDRIN IN THE DIET
 

83 

TABLE C1

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE RATS 

FED DIELDRIN INTHE DIET 

CONTROL LOW DOSE HIGH DOSE
 

ANIMALS INITIALLY IN STUDY 10 50 50
 ANIMALS HECROPSIED 10 i»6 50
 ANIMALS EXAMINED HIS10PATHO LOGICALLY 10 06 50
 

INTEGUMENTARY SYSTEM
 

*SKIN 110) (<»6)
 (50)
 

SQUAMOUS CELL CARCINOMA 1 <2X)
 

SARCOMA, NOS
 1 (2%)
 

NEURItEflOHA
 1 (2X)
 

RESPIRATORY SYSTEM
 

*LUNG (10) C«5)
 (46)
 

ALVEOLAR/BRONCHIOLAR ADENOMA 1 (2X)
 1 (2X)
 

HEMATOPOIET1C SYSTEM
 

*NULTIPLE ORGANS (10) (U6)
 (50)
 

MALIGNANT LYMPHOHA, NOS 2 (»%)
 1 (2S)
 

ISFLEEN (10) C«1)
 (i«3)
 

HENANGICMA 1 (2X)
 

HENANGIOSARCOMA 2 (5X)
 1 (2X)
 

« LYMPH NODE (10) (38)
 (3«)
 

SARCCMA, NOS 1 (10X)
 

HEMANGICHA 1 OX)
 

CIRCU1ATOBY SYSTEM
 

NCNE
 

DIGESTIVE SYSTEM
 

•SALIVABY GLAND (10) (i»1)
 (l»3)
 

HEM.ANGIQ6ARCOMA.
 J_J2J1_
 

t NUMBER OF ANIMALS KITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

85 
TABLE C1 MALE RATS: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE 

•LIVER (10) (i»«)

 

NEOPLASTIC NODULE 1 (10*)

 

SARCCHA , NOS 1 (10%)

 

IPANCREA S (10) («0)

 

SARCOMA, NOS 1 (10%)

 

ISTCMAC H (10) (12) 

SABCCHA, NOS 1 (10%)

 

LEICMYOSARCON A 

URINAR Y SYSTEM 

(KIDNE Y (10) («6)

 

TUBULAR-CEL L ADENOCARCINOH A 

SARCCMA , NOS 1 (10%)

 

ENDOCRIN E SYSTE M 

•PITUITARY (10) (35) 

CHRONOPHOE E ADENOM A 2 (20X) 11 (31%) 

CHROHOPIIOBE CARCINOM A 1 (10%) 

ACIDCPHIL ADENOM A 1 (3%) 

IADRENA L (10) (HI) 

CORTICAL ADENOM A 1 (2%) 

PHECCHRCHOCYTOMA 

SABCCMA, NCS 1 (10%) 

GANGLIONEUROH A 

ITHYEOID (10) («0) 

FOLLICULAR-CELL ACENOH A 3 (8%) 

FCLLICULAR-CELL CARCINOMA 

C-CELL ADENOM A 6 (15%) 

C-CELL CARCINOM A 1 (3%) 

tFARAIHYROI D (6) (32) 

ACENOMA . NOS 

IPANCHEATIC ISLETS (10) C»0) 

ISLET-CELL ADENOM A 1 (10%) 3 (8%)

 

REPRODUCTIVE SYSTEM 

*NAMNAR Y GLAN D (10) (t6) j

__ZI£i£!lA_- __ i_jia%.i _. J_J23L.._. 

I NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMEER OF ANIMALS NECROPSIED
 

HIGH DOSE 

(i»7) 

1 (2%) 

(39) 

(«3) 

1 (2%) 

(U5) 

1 (2%) 

(37) 

12 (32%) 

(«3) 

3 (7%) 

1 (2%) 

1 (2%) 

(36) 

5 <W) 

1 (3%) 

U (11%) 

(28) 

1 (<»«) 

(39) 

2 (5%) 

(50) 

86
 
TABLE C1 MALE RATS: NEOPLASMS (CONTINUED)

 

tTBSTIS 

INTERSTITIAL-CELL TORCH 

HESOTHELICNA. MOS 

NERVOU S SYSTEM 

NONE 

SPECIAL SENSE ORGANS 

NONE 

HUSCULOSKELETAL SYSTEM 

• SKE1ETAL MUSCLE 

NEU8ILEHOH A 

BODY CAVITIES 

NON E 

ALL CTHE f SYSTEMS 

*MULTim ORGANS 

PIBBOUS HISTIOCITOHA, MALIGNANT 

ANIMA L CISFOSITIOM SUMMAR Y 

ANIMALS INITIALLY IN STUDY 

NATURA L DEATHS 

MORIBUN D SACRIFICE 

SCHEDULE D SACRIFICE 

ACCIDENTALLY KILLED 

TERMINA L SACRIFICE 

ANIMA L HISSING 

4_lfi£Laff5_Ai!IfiiIJlC_iJitBAIi5 

CONTROL LOW DOSE HIGH DOSE 

(10) (»1) («6) 

1 (2») 

1 (2*) 

(10) (H6) (50) 

1 (2») 

(10) (»6) (50) » (9«) 

10 50 50 

11 9 

10 39 41 

* NUMBER OF ANIMAL S KITH TISSUE EXAMINE D MICROSCOPICALLY
 

* NUHEER OF ANIMALS NECROPSIED
 

87 
TABLE C1 MALE RATS: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE
 

TUMOR SUMMARY
 

TOTAL ANIMALS WITH PRIMARY TUMORS* 5 24
 TOTAL P.RIMARlt TUMORS 12 <n
 

TOTAL ANIMALS WITH BENIGN TUMORS 3 22
 TOTAL BENIGN TUMORS <t 30
 

TOTAL ANIMALS KITH MALIGNANT TUMORS 1 10
 TOTAL MALIGNANT TUMORS 7 10
 

TOTAL ANIMALS KITH SECONDARY TUMORSI
 

TOTAL SECONDARY TUMORS
 

TOTAL ANIMALS WITH TUMORS UNCERTAINBENIGN OR MALIGNANT 1 1
 

TOTAL UNCERTAIN TUMORS 1 1
 

TOTAL ANIMALS WITH TUMORS UNCEHTAINPHIHAFY OR METASTATIC
 

TOTAL UNCERTAIN TUMORS
 

* PHIHAR Y TUMORS: ALL TUHORS EXCEPT SECONDARY TOHORS 

t SECONDAR Y TUHORS: HITASTATIC TUHORS OR TUHORS INVASIV E INTO

HIGH DOSE
 

22
 

10
 

19
 

32
 

6
 

7
 

1
 

1
 

 AN ADJACENT ORGA N 

88
 
TABLE C2

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS 

FED DIELDRININTHEDIET 

CONTROL LOW DOSE HIGH DOSE 

ANIMAL S INITIALL Y IN STUDY 10 50 50 

ANIMAL S HECROPSIED 10 «9 »9 

ANIMAL S EXAMINE D HISIOPATHOLOGICALL1 10 «7 i»8 

INTEGUMENTAR Y SYSTEM 

*SKIN (10) («9) C»9) 

SQUAHOUS CELL CARCINOM A 1 (2X) 

RESPIRATOR Y SYSTEM 

ILUNG (9) <«5) C»6) 

FOLLICULAH-CELL CARCINOMA, METAS 1 (2*) 

CORTICAL CARCINOMA , HETASTATIC 1 (2X) 

HEMATOFOIETIC SYSTEM 

tSPLEEN (7) (US) C»0) 

HEMANGIOH A 1 <2X) 

• LYMP H NODE (10) ("»«) (38) 

CORTICAL CARCINOMA, METASTATIC 1 (2*) 

tMAHDIBULA R L. NODE (10) (««) (38) 

SQUAHOUS CELL CARCINOMA, METASTA 1 (10*) 

CIRCULATORY SYSTEM 

1 ENDOCARDIU M (8) (l»6) («0) 

SARCCMA , NOS 1 (13%) 

DIGESTIVE SYSTEM 

• SALIVAR Y GLAN D (9) (l»6) (HO) 

SQUAHOUS CELL CARCINOM A 1 (11*) 

ILIVEH (9) (U7) (H<\) 

NEOPIASTIC NODULE 1 (2*) 1 (2X) £OJIJ£Al-CJI£IJ!SJ!Ji_JllliSTJllI£__

 1-J2X1 

t NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

89 
TABLE C2 FEMALE RATS: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE 

*BILE DOCT (10) (i»9)

 

HAMAETOM A 

URINAR Y SYSTEM 

IKIDNE Y (9) («6) 

HIXIC TUMOR. MALIGNAN T 1 (11%)

 

ENDOCRIN E SYSTEM 

tPITUITABY (6) <U1 ) 

CHROMOPHOEE ADENOMA 3 (50%) 9 (22%) 

CHROMOPHOBE CARCINOMA 2 <5X) 

• ADRENA L (9) («5) 

CORTICAL ADENOM A 5 (11X) 

CORTICAL CARCINOM A 1 (2X) 

PHECCHROMOCYTOMA 

ITHYBOID («•) (<»5) 

FOL1ICULAR-CELL AEENOH A 3 (7*) 

FOLLICULAR-CELL CARCINOM A 2 (<•*) 

C-CELL ADENOM A 1 (25%) 10 (22X) 

C-CEIL CARCINOM A 2 (IX) 

• PARATHYROI D (7) (2«)

 

C-CELL CARCINOMA , INVASIV E 

IPANCREATIC ISLETS (9) (<*6) 

ISLET-CELL ADENOM A 1 (2X)

 

REPRODUCTIV E SYSTEM 

*MAHHAR I GLAN D (10) («9) 

ADENCHA , NOS 

ADENOCARCINOMA , NOS 1 <2X ) 

FIBROADENCH A 1 (10*) 13 (27X) 

* UTERU S (10) (M6 ) 

LEIOHYOSARCOM A 1 (2X) MB£BEI-BIAL._£l.£9JLiL._P.2L,iP_ . __j_jia5i__ a_j(3Sl_.. 

I NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

HIGH DOSE 

(l»9) 

1 (2X ) 

(»2) 

1 (2X) 

(33) 

9 (27X) 

(10) 

2 (5X) 

1 (3X) 

(HI ) 

6 (15X) 

2 (5X) 

5 (12X) 

1 (2X) 

(2«) 

1 0»X) 

(37) 

(i»9) 

2 («X) 

1 (2X) 

3 (6X) 

(UO) 

1_J11S1_. 

90
 
TABLE C2 FEMALE RATS: NEOPLASMS (CONTINUED)

 

IOVAEI 

GRANULOSA-CELL TUBOR 

NERVOUS SYSTE M 

• BRAIN 

SQUAHOOS CELL CARCINOMA, HETASTA 

SARCCNA, NOS 

SPECIAL SENSE ORGANS 

NCNE 

NUSCULOSKELETAL SYSTE M 

NONE 

BOD* CAVITIES 

NONE 

ALL OTHER SYSTEMS 

•MULTIPLE ORGANS 

FIBROUS HISTIOCYTOMA, MALIGNANT 

ANIMAL EXPOSITION SUMMAR Y 

ANIMALS INITIALLY IN STUDY 

NATURAL DEATHS 

MOBIEUND SACRIFICE 

SCHEEDLED SACRIFICE 

ACCIDENTALLY KILLED 

TERMINAL SACRIFICE 

ANIMAL HISSING 

*_JU!£iUj2fS_lUlfiiYZf£_JJ!j;flAIi5 

CONTROL LOW DOSE HIGH DOSE 

(10) WSJ («1) 

2 <««) t (2«) 

(8) (16) (»0) 

1 «M) 

1 O«) 

(10) («9) (»9)

 

2 («») 

10 SO SO

 

2 6 to

 

8 44 40 

B_ —— — ———— — 

, 

* NUMBER OF ANIMALS HITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

91
 
TABLE C2 FEMALE RATS: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE
 

TUMOR SUMMAR Y
 

TOTAL ANIMALS WITH PRIMARY TUMORS* 7 39
 TOTAL PRIMARY TUMORS 9 60
 

TOTAL ANIMALS WITH BENIGN TUMORS 4 34
 TOTAL BENIGN TUMORS 6 46
 

TOTAL ANIMALS WITH MALIGNANT TUMORS 3 10
 TOTAL MALIGNANT TUMORS 3 11
 

TOTAL ANIMALS HI Til SECONDARY TUMORS* 1 1
 TOTAL SECONDARY TUMORS 1 3
 

TOTAL ANIMALS WITH TUMORS UNCERTAINEENIGN OR MALIGNANT 3
 TOTAL UNCERTAIN TUMORS 3
 

TOTAL ANIMALS WITH TUMORS UNCERTAINPRIMARY OR METASTATIC
 

TOTAL UNCERTAIN TUMORS
 

* PRIMAR Y TUHORS: ALL TUMORS EXCEPT SECONDAR Y TUHORS 

I SECONDAR Y TUMORS: METASTATIC TUMORS OR TUMORS INVASIV E INTO

HIGH DOSE
 

27
 

39
 

22
 

30
 

7
 

7
 

3
 

3
 

2
 

2
 

 AH ADJACENT OPGAN 

92 
APPENDIX D
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS
 

IN MICE FED DIELDRIN IN THE DIET
 

93
 

TABLE D1 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE MICE 

FEDDIELDRININTHE DIET 

HIGH DOSE LOW DOSE 

CONTROL CONTROL LOW DOSE 

MURALS INITIALL Y IN STUD Y 10 10 50 

ANIMALS NECROPSIED 10 10 50 

ANIMAL S EXAMINE D HISTOPATHOLOGICALLY 8 10 50 

INTEGUMENTAS Y SYSTEM 

NON E 

RESPIRATOR Y SYSTEM 

ILUH G (8) (10) (50) 

HEPATOCELLULA F CARCINOMA , HETAST 1 (2X) 

ALVEOLAH/BRONCHIOLAB ADENOMA 1 (10X) 2 (««) 

ALVEOLAR/BRONCHIOLA E CARCINOM A 1 (2%) 

IIEHATOP01ETIC SYSTEM 

• MULTIPL E ORGANS (10) (10) (50) 

MALIG.LYMPHOHA , LYHPHOCYTIC TYP E 1 (10X) 

HALIG. LYMPHOMA, HISTIOCYTIC TYPE 

CIECULAtCRY SYSTEM 

•HEART (8) (10) (50) 

HEPATOCELLULA R CARCINOMA , METAST 

DIGESTIVE SYSTFH 

• LIVER (8) (10) (50) 

HEPATOCELLULA R CARCINOM A 3 (30%) 12 (2<t%) 

ALTECLAB-CELL ADENOMA 1 (2X) 

URINAR Y SYSTEM 

tKIDNE Y (8) (10) (50) 

JUEiXfi&UUlJUfi £M£JNSflAx JBEIiSI 

t NUMBER OP ANIMALS NITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBE R OF ANIMAL S NECROPSIED 

. HIGH DOSE 

5t) 

48 

145 

(«6) 

1 (2X) 

2 (»%) 

1 (2X) 

(»8) 

1 (2*) 

<"»5) 

1 (2*) 

(H5) 

16 (36X) 

(t5) 

_1_J1SI— 

Q5 
TABLE 01 MALE MICE: NEOPLASMS (CONTINUED)

 

_______«. _ 

HIGH DOSE 

CONTROL 

LOW DOSE 

CONTROL LOW DOSE HIGH DOSE 

ENDOCRIN E SYSTEM 

NCN E 

REPRODUCTIV E SYSTEM 

NOM E 

NERVOU S SYSTEM 

NON E 

SPECIAL SENSE ORGAN S 

NrN E 

MUSCULOSKELETA L SYSTE M 

NON E 

BODY CAVITIES 

*PLEUR A 

HEPATOCELLULA R CARCINOMA , METAST 

(10) (10) (50) («8) 

1 (2%) 

A LL OTHE R SYSTEMS 

DIAPHRAG M 

HEPATOCELLULA R CARCINOMA , METAST 1 

ANIMA L DISPOSITION SUKHAB Y 

ANIMAL S INITIALL Y IN STUDY 

NATURA L DEATHS 

MORIBUN D SACRIFICE 

SCHEDULE D SACRIFICE 

ACCIDENTALL Y KILLE D 

TERMINA L SACRIFICE 

ANIRA L MISSING 

10 

3 

7 

10 

10 

50 

50 

50 

8 

42 

3-INCLVDJ5 AUTOLYZE0 ANIflALS 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY * NUMBER OF ANIMALS NECHO.PSIED 

96
 
TABLE D1 MALE MICE: NEOPLASMS (CONTINUED) 

HIGH DOSE 

CONTROL 

LOW DOSE 

CONTROL LOW DOSE HIGH DOSE 

TOHOB SUMMAR Y 

TOTAL ANIMALS WITH PRIMARY TUMORS* TOTAL PRIMARY TUMORS 

1 

1 

3 

u 

1V 

16 

18 

20 

TOTAL ANIMALS WITH BENIGN TUMORS 

TOTAL BENIGN TUMORS 

1 1 

3 

3 

2 

2 

TOTAL ANIMALS WITH MALIGNANT TUMORS TOTAL MALIGNANT TUMORS 

1 

1 

3 

3 

12 

13 

17 

18 

TOTAL ANIMALS WITH SECONDARY TUHORSt 

TOTAL SECONDARY TUBORS 

1 

1 

1 

5 

TOTAL ANIMALS WITH TUMORS

BENIGN OR MALIGNANT 

TOTAL UNCERTAIN TUMORS 

 UNCERTAINTOTAL ANIMALS WITH TUMORS

PRIMAEY OB METASTATIC 

TOTAL UNCERTAIN TUMORS 

 UNCERTAIN­

* PRIMAR Y TUMORS: ALL TUMORS EXCEPT SECONDARY TUHORS 

* SECONEAR Y TUMORS: MITASTATIC TUMORS OH TUMORS INVASIV E INTO AN ADJACEN T ORGA N 

Q7 
TABLE 02

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE MICE 

FEDDIELDRININTHEDIET 

••— — ••——-••»"• TM«»TM—~~ 

HIGH DOSE 

CONTROL 

LOW DOSE 

CONTROL LOW DOSE HIGH DOSE 

ANIMALS INITIALLY IN STUDT 

ANIHALS BECBOPS1ED 

ANIMAL S EXAMINE D HISTOPATHO LOGICA LLY 

10 

10 

10 

10 

1.0 

10 

50 

50 

50 

50 

50 

50 

INTEGUMENTAR Y SYSTEM 

NON E 

RESPIEA10RY SYSTEM 

I LUNG 

ALVEOLAH/BRONCHIOLAR ADENOMA 

(10) (10) (50) 

2 (IX) 

(50) 

2 (U«) 

HEHATOfOIETIC SYSTEM 

•MULTIPLE ORGANS 

HALIG.LYHPHOHA, UNDIFRBH-TYPE 

NAUG. LYNPHOHA, LYHEHOCYIIC TYPE 

HALIG.LIHPHOHA. HISTIOCYTIC TYPE 

GRANULOCYTIC SARCCMA 

(10) 

1 (10*) 

(10) 

1 dOX) 

(50) 

2

1

 («*) 

 (2«) 

(50) 

1 (2*) 

1 (2*) 

3 (6X) 

CIRCDIAIORY SYSTEM 

MCN E 

DIGESTIVE SYSTEM 

tLIVER 

HEEA10CELLULAR

HENANGICHA 

tSTCMACH 

PAPILLOHA, NOS 

 CARCINOMA 

(10) 

(10) 

(10) 

(D 

1 (100*) 

(50) 

6 (12%) 

(»9) 

C*9) 

2

1

(50) 

 ("»«) 

 (2*) 

URINAR Y SYSTEM 

HOM! 

t NUMBE R OF ANIMAL S WITH TISSUE EXAMINE D MICROSCOPICALLY 

* NOHEER OF ANIMALS NECROPSIED 

98
 
TABLE 02 FEMALE MICE: NEOPLASMS (CONTINUED) 

~ ' " • "~~ ^ TM"J •"""-"""- •»——t-m 

HIGH DOSE LOW DOSE ! 

CONTROL CONTROL LOW DOSE HIGH DOSE 

ENDOCRIN E SYSTEM 

I PITUITARY (9) (9) (i»0) (36) 

CHROMOPHOEE ADENOM A 1 q*) 1 (3%) 

tTHYKOI D (10) (9) (50), 0»9)

 

FOL1ICULAR-CELL ADENOM A 1 (10X)

 

REPaOEUCTIV E SYSTEM 

IUTEHUS (10) (10) (l»8) (50)

 

ENDOHETRIA L STROHAL POLYP 1 (2«)

 

NERVOU S SYSTEM 

NOM E 

SPECIAL SENSE ORGAN S 

NONE 

MUSCDLOSKELETAL SYSTEM 

*SKULL (10) (10) (50) (50)

 

OSTEOHA 1 <2X)

 

BODY CAVITIES 

NON E 

ALL OTHIR SYSTEMS 

USflfi- _ 

t NUMBER OF ANIMALS KITH TISSUE EXAMINED MICROSCOPICALLY
 

* MUHEER OF ANIMALS NECROPSIED
 

99
 
TABLE 02 FEMALE MICE: NEOPLASMS (CONTINUED) 

1HIGH DOSE CONTROL LOW DOSE CONTROL LOW DOSE HIGH DOSE 

ANIMAL CISPCSITlUN SUBMARY 

ANIHALS INITIALLY IN STUDY 

NATURA L DEATHS 

HOBIBUND SACRIFICE 

SCHtCULED SACRIFICE 

ACCIDENTALLY KILLED 

TERMINAL SACRIFICE 

ANIMAL HISSING 

10 

10 

10 

10 

50 

50 

50 

1 

49 

3 INCLUDES AUTOLYZED ANIMALS 

TUHOR SUMMARY 

TOTAL ANIMALS WITH PRIMARY TUMORS* 

TOTAL PRIMARY TUMORS

2 

2 

1 

2 

13 

1i» 9 11 

TUMOR

 TUMOR

TOTAL ANIMALS WITH BENIGN TUHORS

TOTAL BENIGN TUHOR SS

1

1

1

1

1 a

5

3 

It 

TOTAL ANIMALS WITH MALIGNAN MALIGNANT TUMOR TS

TOTAI MALIGNAN MALIGNANT TUMOR TUMORSS

1

1

1

1

9

9

6 

7 

TOTAL ANIMALS WITH SECONDAB SECONDARY TUMOBSRt *

TOTAL SECONDAR SECONDARY TUMORS 

UNCERTAIN

 UNCERTAI TUMOR

TOTAL A N I M A LA N I M A LS WITH TUMORS UNCEBTAIN-­

EENIGN OR MALIGNAN MALIGNANT 

TOTAL UNCEBTAIN TUHOBS 

INIMAL TUMOR UNCERTAIN 

PRIMAR R METASTATI

 TUMOR 

TOTAL INIHALS WITH TUHORS UNCEBTAIN­-

PBIHAEY OB HETASTATIC

TOTAL UNCEBTAI UNCEBTAIN TUHOBS

* PBIHABY TUHORS: ALL TUHOHS EXCEPT SECONDABY TUMOBS 

t SECONEABY TUHOBS: HETASTATIC TUHOBS OB TUMORS INVASIVE INTO AN ADJACENT ORGAN 

100
 
APPENDIX E
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN RATS FED ALDRIN IN THE DIET
 

101
 

TABLE E1

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE RATS 

FED ALDRIN INTHEDIET 

MATCHED CONTROL 

INIMALS INITIALIY IS STUDY JNIMALS NECROPSIED JHIMALS EXAMINED HISTOPATHCLOGICALLY 10 

10 

10 

INTBGUHENTARY SYSTEM
 

*SK1N (10)
 

INFLAMMATION, SOPPCRATIVE
 

fISPIRAIORY SYSTEM
 

fTHACHEA I9>
 INFLAMMATION, SOS
 

ILQMG (10)
 

INFLAMMATION, INTERSTITIAL
 PNEUMONIA, ASPIRATION
 IHFLAHHATIOM, SOPPOBATIVE
 CALCIFICATION, NOS
 

ALVEOLAR. HACROPRAGIS
 

HYPERPLASIA, ALVEOLAR EPITBELIOR
 

HEHATOPOIE1IC SYSTEM
 

ISPLEEN [10)
 

THROHBCSIS, DOS
 

FIBROSIS
 

LYMPHOID DEPLETION
 HYPERPLASIA, RBTICOLUH CELL
 

tRANDIBOLAR L. NODE (9)
 

INFLAMMATION, SOPPORATIVF.
 PERIARTERITIS
 

BYPEBPLASIA, PLASMA CELL
 HYPERPLASIA, RETICQLDH CELL
 

tCEBVICIL LYHPH NODE (9)
 

HYP1HPIASIA. NOS
 

LOW DOSE
 

50
 

<»8
 

48
 

(18)
 

1 12*)
 

138)
 

2 (5%)
 

(»7)
 

2 ;t%)
 

1 t2«)
 

2 [«%)
 

!»5)
 

1 (2*)
 

1 (2«)
 

1 t2«)
 

(3»)
 

1 13*)
 

1 13*)
 

(3l»)
 

HIGH DOSE
 

50
 

50
 

49
 

(50)
 

C»2)
 

(<»7)
 

1 (2*)
 

2 [«*)
 

1 (2*)
 

2 («*)
 

t<»5)
 

1 (2«)
 

2 (»*)
 

5 t11«)
 

(«5)
 

1 (2*)
 

1 (2«)
 

1 I2«)
 

(«5)
 

1 (2(1
 

t NOHBER OF AMIMALS WITH TISSUE EXAMINED HICROSCOPICALLY
 * NOHBER OF AHIHALS NECROPSIED
 

103 
TABLE El MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

HIGH DOSE
 

(17)
 

« (2««)
 

,"»5)
 

2 (»*)
 

(«5)
 

« 19*)
 

3 !7«)
 

(50)
 

(50)
 

1 ;2t)
 

:to>
 

1 (3*)
 1 ;3X)
 1 ;3«)
 

(17)
 

1 ;2x>
 

1 ;2«)
 

1 (2«)
 

17 ;36t)
 

2 ;4X)
 

(«7)
 

tTHTBOS
 

CYST, MOS
 

CIRCULATORY SYSTEM
 

•HEART
 

THROMBUS, HURAI
 

•MYOCARDIUM
 

INFLAMMATION, NOS
 

FTBROSIS
 

DEGENERATION, NOS
 

CALCIFICATION, NOS
 

* AORTA
 ANEORYSM DISSECTING
 

INFLAMMATION, NOS
 

CALCIFICATION, NOS
 

*COPONARY ARTERY
 

CALCIFICATION, NOS
 

DIGESTIVE SYSTEM
 

ISALIVAPY GLAND
 

FIBROSIS, FOCAI
 

CALCIFICATION, NOS
 

ATPOFHY, FOCAL
 

HYPEPPLASIA, NOS
 

•LIVER
 

THROMEOSIS, NOS
 

INFLAMMATION, GRANOLCNATOUS
 GRANOLOHA, NOS
 

FIBPOSIS
 

PEHIARTERITIS
 

NECROSIS, FOCAL
 

METAMORPHOSIS PATTY
 

HEPATOCYTOMEGALY
 HYPERPLASIA, FOCAL
 

tLIVER/HEPATOCYTES
 

HYPEEPLJSIS. NOS
 

MATCHED
 

CONTROL
 

(6)
 

3 (50 *)
 

(10)
 

(10)
 

(10)
 

1 [10*)
 

(10)
 

I9)
 

(10)
 

I) (10*)
 

(10)
 

3 130 Tit
 

LOW DOSE
 

(27)
 

1 («)
 

;<»5)
 

(15)
 

1 (2%)
 3 ;7«)
 

2 ;«*)
 

(t8)


1 ;2%)
 

1 ;2%)
 

3 J6X)
 

(l»8)
 

1 ;2%)
 

;38)
 

1 I3«)
 

(U7)
 

2 <t%)
 

1 J2X)
 

2 ;ix)
 1 ;2%>
 

20 [»3«)
 

C»7)
 

I NUMBER OF ANIMALS WITH TISSUE EXABINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIID
 

104
 
TABLE E1 MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED)

 

HIGH DOSE
 

1 (2%)
 

(50)
 

3 I6%)
 

16 (32%)
 «U (88%)
 

1 12%)
 

(39)
 

1 (3%)
 

2 15%)
 

H (10«)
 3	 :s%)
 

3	 (8%)
 

(39)
 

(39)
 

1 (3%)
 

(«D
 

1 (2%)
 

1 t2%)
 

(«1)


2 (5%)
 

1 (2%)
 

<»1)


1 (2%)
 

(38)
 

2 (5%)
 

1 (3%)
 

(<»2)
 

1 (2%)
 

t"»6)
 

RTPIBPLASIA, FOCAL
 

•BILE DOCT
 DILA1ATIOH, HOS
 

IHFLAHHATIOH, HOS
 

FIBBOSIS
 

HYPEBPLASIA, HOS
 

HYPEBPLASIA, CYSTIC
 

IPAHCREAS
 

ECTOPIA
 THROMBOSIS, HOS
 

IIBHOSIS
 PERIABTEBITIS
 

ATBOPHT, HOS
 

tPAHCREATIC DOCT
 DILATATION, HOS
 

FIBBOSIS
 HYPERPLAEIA, HOS
 

*PAHCBEATIC ACIHOS
 

HYPERTROPHY, HOS
 

HTPEBPLASIA, HODOLAR
 

HYPEBPLASIA, ROS
 

fSTOHACH
 

OLCER, FOCAL
 

ABSCESS, HOS
 

CALCIFICATIOH, HOS
 

IGASTFIC HOCOSA
 1ROSIOH
 

CALCIFICATIOH, HOS
 

•GASTRIC SOEHOCOSA
 CALCIFICATIOH, HOS
 

•SHALL	 IHTESTIRE
 PERIART1RITIS
 

HTPEBPLASIA, EPITHELIAL
 

•LARGE IHTESTIHE
 PCBIIRTIRITIS
 

OBI HAFT SI SltS
 

•KIDIEY
 PIELCHIPHHITIS. HOS
 

MATCHED
 CONTROL
 

(10)
 

10 !100»)
 

10 [100H)
 

(9)
 

(9)
 

1 (11*)
 

(9)
 

(9)
 

(9)
 

(9)
 

(9)
 

(9)
 

(10)
 

LOW DOSE
 

(48)
 

5 POU)
 

1 C2%)
 H 18%)
 «2 ;88X)
 

(37)
 

"»	 ;n«)
 

5	 ;1»%)
 

(37)
 

2 (5«)
 

2 [5«)
 

2 [5%)
 

(37)
 

1 (3%)
 

1 [3%)
 

(37)
 

1 (3%)
 

(37)
 

(37)
 

(39)
 

3 (8%)
 

(38)
 

5 (13%)
 

(»6)


1 (2(1
 

* HOHBBB 01 AHIHALS IITH TISSUE EIAHIHED HICBOSCOPICAILT
 * HOHBBB OF AIIBAIS HECBOPSIED
 

105 
TABLE E1 MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED)

 

MATCHED LOW DOSE 

CONTROL 

nmnBiTioi, CRBOHIC 10 (100») «2 (91*) 

PERIIR1IRITIS 3 (7*) 

*KIDNBY/CORTBX (10) («6) 

CIST, SOS 1 (10U) 

tKIDNEY/PBLVIS 

INFL»I1HATION, SUPPUPATI?E 

HYPERPLASIA , EPITHELIAL 

(10) 

10 (100X) 

(«6) 

1 (2*) 

28 J61X) 

IDRINHR Y BLADDER (9) (40) 

CALCOLOS, NOS 1 (3*) 

HIPESPLAEIA, EPITHELIAL 3 [33X) 9 ;23X) 

•URETHR A (10) («8) 

HYPEBPLASIA , EPITHELIAL 1 !10«) 2 t«) 

ENDOCRINE SYSTEM 

IPITDITAPY ;?) I37) 

CYST, NOS 

• ADRENA L (10) (38) 

PIRIHRTERITI S 

CYTOHEGALY 

• ADRENA L CORTEX (10) (38) 

CYTOHEGAIY 5 (50*) 25 (66*) 

ATROPHY, FOCAL 

HYPE8PLAEIA, HOS 2 (20*) 

HYPEBPLASIA , FOCAL 3 ;8X) 

fTHYROID (7) (38) 

ULTIBOERANCHIA L CYST 2 (29 X) 3 <8X) 

GRANDLOHA, NOS 1 ;3«) 

ATROPHY, NOS 

HYPERPLASIA, C-CILL 6 (86X) 16 ;«2X) 

HYPEFPLASIA, FOILICDLAR-CELL 1 ;3X) 

fPARATHYROI D (7) (22) 

HYPIRPLASIA, NOS 5 (23*) 

*PAHCHEATIC IS1ETS (9) (37) 

HYPIRPIASIA, NOS 7 [19*1 

I NDHBEH OF ANIHALS WITH TISSUE EXAHINED MICROSCOPICALLY
 

* NUMBER OF ANIHALS NECROPSIED
 

HIGH DOSE 

«6 (100X) 

(»6) 

(«6) 

18 (39X) 

(38) 

1* [37X) 

(50) 

2 (KX) 

ttO) 

1 (3*) 

(«3) 

1 (2*) 

1 ;2*) 

(«3) 

28 (65*) 

1 (2*) 

2 ;5«) 

11 I26X) 

(38) 

2 ;s*) 

20 ;53«) 

2 15*) 

(31) 

7 (21*) 

(39) 

106
 
TABLE El MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

REPRODUCTIVE STSTRH
 

•HAHMABY GIAHD
 

GRAROLQHA. ROS
 

•PROSTATE
 

IRFLAHBAT10R, GRAHOICHA100S
 PERIARTEFITIS
 

HYPERPLAEIA, EPITHELIAL
 

tTESTIS
 

PFBIART1RITIS
 

ATROPHY, BOS
 

ASPERNATOSERESIS
 

•EPIDIDYHIS
 

IRFLAHHATIOR, GRARULCHATOOS
 

HYPERPLASIA, EPITHELIAL
 

DYSPLASIA, EPITHELIAL
 

RERVOOS SYSTEM
 

IBRAIR/HERIRGBS
 

IRFLAHRATIOR, NOS
 

FIBROSIS
 

CALCIIICmOH, HOS
 

IERATN
 

IRFLAHHATIOR, M05
 

SPECIAL SENSE ORGARS
 

*EYE
 

IRFLAHHATIOH, SOPPORATIVE
 

*IYE/CORNIA
 

OLCER, ROS
 

IRFLAHHATIOH, SOPPDRATIVE
 

•ITH/IRIS
 

INFLAHRA1IOR, SOPPORATIVE
 

»1YE/RETI«A
 DEGEVE8AHOR. ROS
 

MATCHED
 CONTROL
 

(10)
 

(9)
 

1 I11«)
 

(10)
 

6 (60%)
 

(10)
 

[9)
 

(9)
 

HO)
 

(10)
 

(10)
 

(10)
 

LOW DOSE
 

(»8)
 

1 (2*)
 

(«1)
 

1 (2*)
 

2 -5«)
 

<»2)
 

7 (17*)
 

30 ;71»)
 

1 12%)
 

(K8)
 

;uO)
 

1 (3*)
 

3 (8«)
 

1 C3«)
 

(«0)
 

:«B)
 

(U8)
 

(»8)
 

(l»8)
 

t NUMBER OF ANIMALS NITH TISSUE EXAMINED RICROSCOPICAILY
 * NUMBER OF ANIMALS NECRCPSIED
 

107
 

HIGH DOSE
 

(50)
 

(«0)
 

2 (5«)
 

1 13%)
 

(«3)
 

» (9«)
 35 ;ei«)
 

(50)
 

1 I2«)
 

2 :»«)
 2 :«*)
 

:<«2)
 

(»2)
 

1 (2*)
 

[50)
 

1 (2«)
 

(50)


1 t2H)
 

1 !2«)
 

(50)
 

1 (2%)
 

(50)
 

1 T?*>
 
TABLE E1 MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED LOW DOSE HIGH DOSE 

CONTROL 

H05CD10SKELET1L SYSTEM 

HOSE 

BODY CUVITIIS 

HOWE 

AIL OTHER STSTEHS 

BORE 

SPECIAL HOBPHOLOGY SOHHAR Y 

AOTO/HZCSOPSY/fllSTO PIS? 1 2 

»OTO/IHCROPSY/BO HISTO 1 

AOT01YSIS/HO HECBOPSY 2 

I HOHBEP 01 JMIHALS BTTH TISSUE EIABIHED HICEOSCOPICiIIT
 

* H0HBER OF ANIMALS HECROPSIED
 

108 
TABLE E2

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE RATS 

FED ALDRIN INTHEDIET 

MATCHED LOW DOSE HIGH DOSE 

CONTROL 

HUHUS IRITIUIT ID S10DI 10 50 50 

ARTHALS RECBOPSIED 10 50 50 

IRIBALS IXAHIMBD HISTOEATHOLOGICALLT 10 «9 50 

TRTIGOHERTABT STSTEH 

ROUE 

BESPIBATOBT SISTER 

tLORG (9) (l»7) (19) 

EHBOLISB, SOS 1 (2*) 

PHE0BORI1, ASPIBATIOR 2 [«) 

IHFIABHATIOH, GBAR01CHATODS 2 [«*) 

HEPATOCTTOHEGALT 1 t2«) 

M.TEOLH BACROPHAGES 1 (2*) 

HTPEBP1ASIA, ALTEOIAR EPITHELIOH <» (9*) 2 [«*) 

*LORG/tIVIOII (9) (»7) (»9) 

IRFL1HHATIOM, SDPPORATIV! 1 (2«) 

HEBATOPOIE1IC STSTEH 

tSPlEEH t8) {«7) («8) 

FIBBOSIS 1 (2«) 1 (2«) 

ATROPHT, IOS 1 [2%) 

LTHPHOID DBPLETIOR 1 (2») 

HTPEBPLASIA, BETICD10H CELL 2 t»«) 

IRARDIBOLAB L. RODE (9) (31) (»2) 

HTPEBPLASIA, PLASBA CELI 1 (11*) 1 (3%) 

HTPBBPLASIA, BBTICDLOB CELL 1 13*) 1 (2*) 

ITHTHOS (6) (33) (33) 

CTST, IOS 3 (50 «) 8 (2«) 9 (27*) 

CIBCOLATOBT SIStlH 

•1OBTA (10) (50) [50) CALCIFICATIOI. IOS 1 (2*1 

I ROHBIR Of AIIIALS 1ITH TISSUE El ARTRED BICBOSCOPICA1LT
 

* ROHBBB Of AIIHALS RKIOCSIBD
 

109 
TABLE E2 FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED LOW DOSE 

CONTROL 

DIGESTIVE SYSTEM 

ILIVEH ;10) [48) 

ECTOPIA . 1 (2*) 

INFLAMMATION, SUPPORATIVE ' 1 12*) 

HEPATOCYTOHEGALY 8 [SOU) 21 •«»%) 

HYPEHPLASIA, FOCAL 1 no*) 3 (6») 

ANGIECTASIS 1 [2*) 

HENATOPOIESIS 2 (»*) 

*BILI DDCT (10) (50) 

DILATATION, NOS 5 [10*) 

FIBROSIE 3 I30X) 12 [24*) 

HTPEFPLASIA. NOS 9 I90X) 46 [92*) 

IPANCHEA S (9) (44)

 

ATROPHY , FOCAL 

tSTOMACH (9) (42) 

ECTOPIA 

URINARY STSTEH 

IKIDNEY ;10) [48) 

PYELONEPHRITIS, NCS 1 (10*) 

INFLAMMATION, CHRONIC 8 (80%) 41 (85*) 

METAMORPHOSIS FATTY 

HYPBRPLAEIA , NOS 1 '.2*) 

tKIDNEY/PILVIS (10) (48) 

INFLAMMATION , NOS 1 (10*) 

HTPEBPLAEIA, EPITHELIAL 5 ISO*) 34 [71*) 

HORINAR Y EIADDER (9) («D 

HYPERPLASIA , EPITHILIAI 1 (11*) 1 (2X) 

ENDOCRINE SYSTEM 

IADRENAL CORTEX [10) [45) 

CYTOHEGALY 0 (40*) 21 (47*) 

ATROPHY, MOS 

HYPERPLASIA, NOS 1 HO*) 1 ;2«) 

HYPERPLASIA^ FOCAL I) 140 X) 6 113*1 

I NOHBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NOMBER OF ANIMALS NECROPSIED
 

HIGH DOSE 

;»9) 

35

2

1

(50) 

5

5

40

(«0) 

1

(46) 

1

(49) 

46

1

(49) 

21

(46) 

3

J48) 

19

1

2

9

 (71*) 

 [«*) 

 [2«) 

 [10«( 

 (10*) 

 (80*) 

 0*) 

 (2*) 

 (94*) 

 !2X) 

 [43*) 

 (7*) 

 (40*) 

 (2*) 

 (4*) 

 119*1 

110
 
TABLE E2 FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED)

 

MATCHED LOW DOSE 

CONTROL 

•THIBOID (9) (39) 

HYTEBPLASIA, C-CELI 6 (67*) 23 (59X) 

HTPBBPLASIA, FOILICOLAB-CBLL 1 (3%) 

•PARATHYROID (7) (22) 

HYPBBPIASIA, NOS 3 («3«) 1 <5«) 

•PANCBEATIC ISLETS (9) (»») HTPERPIASIA, HOS "» <9«) 

PEPRODOCTIVE SYSTEM 

•OTRRUS/ENDOHETBIOH (?) t«5) 

INFLAMMATION, SOPPOBATIVI 1 (2«) 

HYPBBPLAEIA, NOS 

HYPEBPLAEIA, CTSTTC » !9%) METAPLASIA, SQOAHOOS 3 a*) 

DTSPLASIA, NOS 1 £2%) 

•OVARY (8) 0»3) 

FOLLICOLAB CIST, NOS 1 (13«) 1 (2*) 

HYPERPLA3IA, GRANOLOSA-CELL 1 E13U) 2 [5*) 

»EB»OOS SYSTEM 

•BRAIN/HENINGES £9) («l») 

FIBBCSIS 1 (11*)

 

•BRAIN (9) (««) 

ECTOPIA 

SPECIAL SENSE ORGANS 

NONE 

HOSCULOSKIIETAL SYSTEM 

NONE 

EODY CAVITIIS 

*PLEURA (10) (50) 

INFLAMMATION. CHRONIC 1 f2*> 

I HDBBER OF AHIRALS WITH TISSUE EXARIRED MICROSCOPICALLY
 * BOBBER OF AMIRALS HECBOPSIKE
 

HIGH DOSE 

(»6) 

26 (57») 

2 :»*) 

(28) 

2 (7») 

(10) 

I«8) 

3 (6%) 

» !8«) 

(»6) 

1 (2») 

3 [7«) 

(37) 

(37) 

1 (3%) 

(50) 

111
 
TABLE E2 FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED)

 

MATCHED LOW DOSE HIGH DOSE 

CONTROL 

GBANDLATIOH, TISSOI 1 (2«) 

*IL OTHIB SYSTEHS 

NONE 

SPECIAL MORPHOLOGY SOHtlART 

AUTO/NECBOPST/HISTO PE8F 1 1 

iOTO/HECBOPSI/NO HISTO 1 

* NOHBEB OF ASIB1LS illH TISSOI IXAHINID HICBOSCOPICALLT
 

* NOHESR OF ANIMALS NECBOPSIED
 

112
 
APPENDIX F
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN MICE FED ALDRIN IN THE DIET
 

113
 

TABLE F1

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE MICE 

FEDALDRIN INTHE DIET 

HIGH DOSE LOW DOSE 

CONTROL CONTROL 

llil BUS IlITIillT ID STDDT 10 10 

INIBALS MBCPOPSIED 10 10 » III HALS EXAHIHE D HISTOFATHOLOGICALLT 10 10 

INTIGOBENTABY SYSTBB 

»SKIN (10) (10) 

GBANOLATION , TISSUE 

RESPIBATOBY SYSTIB 

ILOHG/BBONCHOS [10) HO 

HYPEBPLASIA , LYHPHCTE 5 (50») 7 (70%) 

ILUN G (10) (10) 

INPLABBATION, INTERSTITIAL 

HTPEBP1ASIA, EPITHELIAL 1 ;io«) 

HTPEBPLASIA, ALVEOLAR EPITHELIUM 1 [10%) 

HIPERPHSIA, LTHPHOID 3 (30*) 

HEBATOPOIE1IC SISTEB 

ISPLEBN t9) [10) 

HEBATOECIESIS 

ILYMPH NODE (9) (9) 

HYPEBPLJISIA, LYBPHOIE 

CIBCOLA10RY SYSTEB 

tHEABT :ioj (10) 

PERIABTEBITIS 

IHEART/fEHTRICLE (10) (10) 

THROBEOSIS, NOS 1 (10X) 

• CORONAR Y ARTERY (10) (10) 

IRPLABHATION. NOS 1 MOXt 

I NOBBER OP ANIBALS WITH TISSOE EXABINED BICROSCOPICAIIY
 

* HDBBER Ot AHIBA1S HECRCFSIED
 

LOW DOSE HIGH DOSE 

50 50 

50 48 

50 46

 

(50) (48) 

1 !2X) 

;i»9> (45) 

20 (M1« ) 21 («7«) 

(1(9) (45) 

2 (4% ) 

:«9) (44) 

2 (5X) 

(43) (»5) 

1 (2») 

(49) t»3) 

1 (2K) 

(49) (43) 

(50) (48) 

115 
TABLE F1 MALE MICE: NONNEOPLASTIC LESIONS (CONTINUED)

 

DIGESTIVE SISTER
 

•LIVES
 

IHFLAHRATIOR, ROS
 

INFLARHATIOR. CHRORIC
 

NECROSIS, ROS
 

REPATOCTTOHBGALY
 

HYPEDPLASIA, RODOLAR
 

*BILE DUCT
 

IRFLAHHATIOR, ROS
 

»PA»CREAS
 

PERHRTEHITIS
 

ATROPHY. NOS
 

tPARCREITIC ACIROS
 

ATPOPHI, HOS
 

ILARGI TRTESTIRE
 

REBATODIASIS
 

ORIRABI STSTEH
 

IKIDRET
 

IRFLAHHATIOH, IRTIRSTITIAL
 INFLAMMATION, CHRONIC
 

PERIAHTBRITIS
 

ABTICID, ROS
 

*KIDREI/TOBDLE
 

CYTOPLASHIC VACOOLIZATIOR
 

tUBIRARY BLADDER
 IRFLAHHATIOR, ACOTI/CHRORIC
 

IHFLAHNATIOH, CRRORIC
 

PERIARTERITIS
 

HTPERPIASIA, EPITHELIAL
 

RETAELASIA, SQOARODS
 

IRDOCRINE SISTER
 

tADREHAL CORTEX
 CYTOBEGAIK
 

HIGH DOSE
 

CONTROL
 

(10)
 

1 (10«)
 

(10)
 

1 HO*)
 

(9)
 

1 (11«)
 

(9)
 

1 (11*)
 

(10)
 

MO)
 

8 (80*)
 

(10)
 

(10)
 

(9)
 

LOW DOSE
 

CONTROL
 

t10)
 

1 (10*)
 

(10)


1 ;io«)
 

(10)
 

1 :iox>
 

(10)
 

(9)
 

;10)


6 (60*)
 

4 («0<)
 

1 (10*)
 

(10)
 

(10)


1 (10X)
 

1 (10*)
 

1 (10*)
 

(10)
 

LOW DOSE
 

(»9)
 

1 12*)
 

1 (2X)
 5 no*)
 

3 (6*)
 

(50)
 

1 (2«)
 

(»9)
 

(«9)
 

2 (»*)
 

(«8)
 

:«9)
 

36 (73*)
 

(«9)
 

1 (2X)
 

(«9)
 

1 12*)
 

1 ;2«)
 

;i»7)


1 I2O
 

HIGH DOSE
 

(»6)
 

3 (7»)
 

1 (2X)
 

12 (26X)
 

6 (13X)
 

(»8)
 

(«5)
 

(«5)
 

3 (7X)
 

(«5)
 

1 (2»)
 

(«5)
 

27 (€OX)
 

1 (?*)
 

(»5)
 

1 |2«)
 

(tt«)
 

1 12*)
 

(«2)
 

* ROHBER OF ANIMALS RITR TISSOE EXAHIRED HICROSCOPICAILY
 * RUBBER OF AHIHAIS HECRCPSIED
 

116
 
TABLE F1 MALE MICE: NONNEOPLASTIC LESIONS (CONTINUED)

 

HIGH DOSE
 

35 (83*)
 

t»5)
 

(»5)
 

1 (2*)
 

1 (2*)
 

1 !2«)
 

2
 

2
 

HYPEBPIASIA, DOS
 

BEPSODOCTIT1 SISTER
 

IPBOSTRTE
 

INPLABRAtlOH. CHBORIC
 

*TESTIS
 

GBAHOLOHA, SPERMATIC
 

PBBIAB1EBITIS
 

ATROPHY, ROS
 

1ZB?OOS SYSTBH
 

RODE
 

SPECIAL SERSE OBGAIS
 

ROME
 

ROSCOLOSKEIETAL STSTEH
 

RORI
 

BODY CATITIBS
 

WORE
 

ALL OTHEH ST STEMS
 

MORE
 

SPECIAL HOIPBOL06T SDHRABT
 

10 LESIOR BBFOBTBD
 

AOTO/I1C10PST/BISTO PBRP
 

AOTO/RBCBOPST/110 RISTO
 

AOTOLISIS/RO BBCBOPST
 

• ITJRBBI Of IIIII1S »ITB TISSOI BIIBXBBO

* IDRBBI OP milLS BBCBOPSIBO 

HIGH DOSE LOW DOSE LOW DOSE
 

CONTROL CONTROL
 

8 (89V) 9 (90X) 41 (87%)
 

PO) tioj 12)
 

1 (10*)
 

(10) (9) (2)


1 |50«)
 

1 (50*)
 

1
 

1 1
 

 BIC10SCOPIC1L1T 

117 
TABLE F2

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE MICE 

FEDALDRIN INTHE DIET 

»NINALS IHITIAIII IS STODY
 

INIBALS NECBOPSIED
 

INIMALS EXAMINED HI STOPATHCLOGICALLY
 

INTIGOMEHTABY SYSTEM
 

HONE
 

RESPIBATOBY SYSTEM
 

ILONG/BBOSCHUS
 

HYPEHPLASIA, LYBPHOID
 

HEBATOPOIBSIS
 

HUNG
 

INFLAMMATION, INTEBSTITIAL
 

INFLAMMATION, GR ANOICMATOOS
 

HYPEBPLASIA, LYBPHOID
 

HEHATOPOIETIC SYSTEB
 

iBONE HABBON
 

HYPEBPLASIA, HEBATOPOIITIC
 

tSPLEBN
 

INFLABHATION, GRAMDICHATOOS
 

HYPEBPLASIA, LYHPHOID
 

HEBATOPOIBSIS
 

tLYBPH MODE
 

HYPEBPIASIA, PLASMA CELI
 

RYPEBPIASIA, BETICOLDH CELL
 

BYPEBPLASIA, LYHPHOID
 

tTHYHOS
 

HYPEBPLASIA, LYHPROID
 

CIHCOLATOBY SYSTEM
 

•HEABT
 FI1I11TIIITIS
 

MATCHED
 

CONTROL
 

10
 

10
 

10
 

(10)
 

4 (10K)
 

(10)
 

2 [20«)
 

<8)
 

(10)
 

1 HOX)
 

(10)
 

1 (10*)
 

(3)
 

110)
 

LOW DOSE
 

50
 

U8
 

U8
 

(«8)
 

21 (SOX)
 

(»8)
 

2 (»X)
 

1 I2«)
 

ID
 

1 (1001)
 

(»8)
 

3 t6«)
 

1 [2»)
 

(«7)
 

1 (2«)
 

(5)
 

(«8)
 

HIGH DOSE
 

50
 

«6
 

«5
 

(»«)
 

2« (551)
 

1 (2*)
 

(««)
 

t«)


4 (100»
 

(«2)
 

1 (2«)
 

3 t7«)
 

(36)
 

1 O»)
 

1 t3«)
 

(13)
 

1 <8«)
 

J39)
 

1 f3lt
 

» IOBBIR 01 MIHALS IITH TISSUE BXARIMED MICROSCOPICALLY 

* RIIBBBR OF AMIRA1S IBCBOPSIID 

118 
TABLE F2 FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED)

 

MATCHED LOW DOSE
 

CONTROL
 

DIGESTIVE SISTEH
 

ISALIVARY GLAND 110) !D
 HYPEBPIASIA, INTPACDCTAL 1 (100S)
 

ILIVIR (10) <«8)
 

CTST, HOS 1 (2*)
 

INFLAMMATION, NOS 2[20%)
 

INFLAMMATION, ACUTE
 

INFLAMMATION, ACUTE/CHRONIC 1 !2«)
 

INFLAMMATION, CHRONIC 11 [23*)
 

INFLA1MATION, GRANULCMATOOS
 

HEPATOCYTOHEGALY 1 !2«)
 

HYPERPLASIA, HODOLAR 2 («*)
 

METAPLASIA, OSSEOUS
 

•BILH DUCT (10) (U8)
 

INFLAMMATION, NOS 3 (30*)
 

INFLAMMATION, CHRONIC 7 !15*)
 

tPANCREAS (10) (l»8)
 

INFLAMMATION, INTERSTITIAL
 INFLAMMATION, ACUTE 1 [2X)
 

INFLAMMATION, CHRONIC 2 [It*)
 

INFLAMMATION, GRANULCMATOUS 1 [2*)
 PERIARTEBITIS
 

tPANCRBATIC ACINUS (10) (»8)
 

ATROPHY, NOS 2 («*)
 

ILARGE INTESTINE m («1)


NEMATOEIASIS 1 (2*)
 

UBINARY SYSTEM
 

tKIDNEY MO), ;l(8)
 

INFLAMMATION, INTERSTITIAL 5 (50*) 24 (SOX)
 

INFLAMMATION, CHRONIC 1 12*)
 

AMYLOIDOSIS 1 ;2»)
 

HYPERPLASIA, LYMPHOID 1 (10*)
 

«aPINARl EDDDER (10) (»D
 INFLAMMATION. GRANULCHATOUS 1 f2«)
 

I NDNBER OF ANIMALS HTTH TISSUE EXAMINED HICROSCOPICALLY
 

* NOSBER OF ANIHA1S HICHOPSIED
 

HfGH DOSE
 

(38)
 

(«3)
 

1 !2«)
 

2 [5*)
 

1 (2*)
 » (9*)
 

1 (2*)
 

3 !7«)
 

1 [2*)
 

(«6)
 

1 [2*1
 

it (9«)
 

(13)
 

1 (2*)
 

3 (7*)
 

1 !2«)
 

(»3)
 

(37)
 

!»3)
 

28 (65*)
 

(19)
 

119 
TABLE F2 FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED)

 

HIGH DOSE
 

(32)
 

(36)
 

(36)
 

1 (3*)
 

3I» [9I»X)
 

(32)
 

2 (6X)
 

1 !3«)
 

;»3)
 

C>3)
 

1 <2X)
 

5 112*1
 

28 [65*)
 

(39)
 

3 (8*)
 

11 [10*)
 

8 !21«)
 

(«6)
 

SHDOCTINE SYSTEM
 

IPITOITABY
 

HYPEBP1ASIA, CHHOMCPHOBE-CELI
 

IADBENAI
 INFLAMMATION, ACOTE
 

IADBENAL COBTEX
 CYTOMEGALY
 HYPEBPLASIA, NOS
 

ITHYBOIE
 

HYPEBPLASIA, NOS
 

HYPEBPLASIA, F01ITCDLAE-CE11
 

FEPBODOCTIVE SYSTEM
 

*OTE*DS
 

INFLAMMATION, ACUTB
 

fOTEBUS/ENDOSETBIUH
 

IKFLJMMATIOH, SOPPOPATIVE
 

INFLAMMATION, ACOT1
 

HYPEBPtASIA, CYSTIC
 

tOVARY
 

FOLLICDLAB CYST, !»OS
 

IKFLAMMATIOH, SOPPDBATIVE
 

IKFLAMBATION, ACOTE
 

INFLAMMATION, CHBONIC
 

tilBVODS SYSTEM
 

NONE
 

SPECIAL SENSE OBGANS
 

NONE
 

BUSCOLOSKEIETAL SYSTEM
 

*BONE
 

FIBBODS DYSPIASIA
 

MATCHED
 

CONTROL
 

(10)
 

1 (10*)
 

(10)
 

10 ;ioo«)
 

(10)
 

;io)
 

(10)
 

1 (10*)
 

8 ;80«)
 

(10)


3 (30U)
 

1 HO*)
 

(10)
 

2 (20*1
 

LOW DOSE
 

(»5)
 

2 {«*)
 

(»7)
 

(»7)
 

16 [98%)
 

C«6)
 

;it7)
 

1 (2X)
 

Cf)
 

9 ;19«)
 

31 172*)
 

(<»7)
 

10 (21X)
 

3 [6X)
 

7 ;15«)
 

1 !2X)
 

W8)
 

§ f13X)
 

t NOHBER OP ANIMALS WITH TISSUE EXAMINED MICBOSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

120
 
TABLE F2 FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED LOW DOSE
 CONTROL
 

EODY CAVITIES
 

*PERITOHBOM (10) (48)
 

IHFLAHHATIOH, ACUTE « (8%)
 

INFLAHHATION, CHPOHIC 1 (2«)
 

»HESENTEPY (10) («8)
 

INFLAHBATION, GKAHOlCHlTODb
 

HECBOSIS, FAT
 

AH OTHEH STSTEHS
 

ADIPOSE 1ISSOE
 IMFlABdATION, BOS
 

SPECIAL HORPBOLOGY SOHHARY
 

NO LBSICR REFORTID
 AUIO/NICROPSY/HO HISTO
 

AOT01YSIS/MO HECROPSY 2
 

I NUMBER OF XRIHK1S SITH TISSOB EIARIHED HICPOSCOPICHLLY
 * IOMBBR OF ANIMILS HBCBOPSIED
 

HIGH DOSE
 

(«6)
 

l«6)
 

1 (2*)
 

1 !2U)
 

1
 

5
 

1
 

4
 

121 

APPENDIX G
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN RATS FED DIELDRIN IN THE DIET
 

123
 

TABLEG1

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE RATS 

FED DIELDRIN INTHE DIET 

CONTROL LOW DOSE
 

ANIMA1S INITIALLY IN STUD! 10 50
 ANIMALS NECBOPSIBD 10 U6
 ANIMALS EXAMINED HISTOPATHOLOGICALLY 10 46
 

INTEGUMENTARY SYSTEM
 

*SKIN (10) C*6)
 

INFLAMMATION, GRANULCHATOUS 1 dOX) 1 (2X)
 

PERIARTERITIS 2 (<»X)
 

RESPIRATORY SYSTEM
 

tTRACHEA (10) (35)
 

INFLAMMATION, SUPPUBATIVE 1 <3X)
 

INFLAMMATION, CHRONIC 1 (3X)
 

ILUNG/EEONCHIOLE (10) C»5)
 

METAPLASIA, SQUAMOUS 1 (10X)
 

tLUNG (10) C»5)
 

INFLAMMATION, INTERSTITIAL 2 («X)
 

PNEUMONIA, ASPIRATION
 

PEHIAHTEHITIS 1 <2X)
 

CHOLESTEROL DEPOSIT 2 («X)
 

ALVEOLAR MACROPHAGES 2 (20X) 15 (33X)
 

HYPEDPLASIA, ALVEOLAE EPITHELIUM 1 (2X)
 

HYPEEPLASIA, LYHPHOID 8 (SOX) 1 (2X)
 

ILUNG/A1VEOLI (10) C»5)
 

INFLAMMATION, SUPPUBATIVE 1 (10X) 2 («X)
 

HEMATOE01ETIC SYSTEM
 

tSPLEEN (10) <41)
 

HEMORRHAGE 1 (2X)
 

FIBROSIS, FOCAL 1 (2X)
 

HEHOSIDEHOSIS 5 (12X)
 

HYPEBPLASIA, RETICULUN CELL 1 (10X)
 

_B£MMPJ(31£5I5_ 5_J12S1__
 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

HIGH DOSE
 

50
 

50
 

50
 

(50)
 

(37)
 

2 (5X)
 

(l»6)
 

(<«6)
 

1 (2X)
 

15 (33X)
 

1 (2X)
 

(i»6)
 

a (9X)
 

(t3)
 

1 (2X)
 

6 (14X)
 

1 (2X)
 

3_17J1
 

125
 
TABLE G1 MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED)

 

CONTROL LOW DOSE
 

ILYHPH MODE 

HEMORRHAGE 

(10) (38) 

1 (3%) 

INFLAMMATION, SUPEUBATI?B 

NECROSIS, FOCAL 1 O%) 

HYPEiPLASIA, PLASH* CELL HYPEBPLASIA, BETICULUH CELL 1 (10%) 

HYPEBPLASIA, LYNPHOID 1 (10%) 3 (8%) 

ITHYMUS 

CYST, MOS 

(6) (27) 

6 (22%) 

CIRCULATORY SYSTER
 

•HEART	 (10) («3)
 

FIBROSIS 1 (10*)
 

IHYOCABDIOH (10) («3)
 

INFLAHHATION, MOS 1 (10%)
 

FIBBCSIS e (sox) 23 (53%)
 

CALCIFICATION, NOS 1 (2%)
 

*AOBTA (10) (l»6)
 

CALCIFICATION, MOS 1 (2%)
 

•COROMAFY	 ABTERY (10) (l»6)
 

CALCIFICATION, NOS 1 (2%)
 

DIGESTIVE SYSTEM
 

ILIVER (10) (<•«>
 IMFL1HHATION, SUPPURATIVE 1 (10%)
 

GRAMULOHA, NOS 1 (10%)
 

NECROSIS, FOCAL
 

HEPAIOCY10HEGALY 6 (60%) 17 (39%)
 

HYPERPLASIA, FOCAL 1 (10%)
 

HEHATOPOIESIS
 

*BILE DUCT (10) (<46)
 

INFLAMMATION, NOS 6 (60%)
 

FIBBOSIS 2 (20%) 7 (15%)
 

HYPEBPLASIA, NOS 9 (90%) 3<t (7UX)
 

tPANCBEAS (10) («0)
 

INFLAMMATION, MOS 1 (10%)
 

INFLAMMATION, SUPPUBATIVE 2 (5%)
 

FIBBOSIS 2 (20%)
 

£££i4£XJE£ULS	 5_J12S1_.
 

* NUMBER OF ANIMALS HUH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

HIGH DOSE
 

(3«)
 

1 O%)
 

2 (6%)
 

1 (3%)
 

(23)
 

3 (13%)
 

(U5)
 

(l»5)
 

23 (51%)
 

(50)
 

2 <<•%)
 

(50)
 

1 (2%)
 

(17)
 

1 (2%)
 

20 (13%)
 

1 (2%)
 

(50)
 

3 (6%)
 

25	 (SOX)
 

(39)
 

1 (3%)
 

1 (3%)
 

S-J12SL-.
 

126 
TABLE G1 MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED)

 

CONTROL LOW DOSE
 

*PANCBEATIC ACINUS (10) (HO)
 

ATROPHY, NOS 6 (15X)
 

•STOMACH	 (10) («2)
 

ULCER, FOCAL
 

INFLAMMATION, CHBONIC FOCAL 1 (2X)
 

PEHIARTEHITIS 1 (2X)
 

HYPEBKERATOSIS 1 (2X)
 

tGASTHIC MUCOSA (10) C»2)
 

CALCIFICATION, NOS 2 <5X)
 

tSMALL INTESTINE (10) (10)
 

PERIARTERITIS 2 (5X)
 

ILARGE INTESTINE (10) (i»1)
 

EEEMA, NOS 1 (2X)
 PERIARTERITIS 1 (2X)
 

URINARY SYSTEM
 

tKIDNEY (10) («6)
 

INFLAMMATION, NOS 3 (30X)
 

INFLAMMATION, CHRONIC 6 (60%) i»5 (98X)
 

PEHIARTERITIS 1 (2X)
 

tKIDNEY/EELVIS (10) («6)
 

INFLAMMATION, SUPPUHATIVE * (9X)
 

HYPERPLASIA, EPITHELIAL 6 (60X) 10 (22X)
 

tURINAR Y BLADDER (10) (36)
 

INFLAMMATION, NOS
 

HYPEHPLASIA, EPITHELIAL 1 (10X) 10 (28*)
 

ENDOCRINE SYSTEM 

tPITUITARY 

CYST, NOS 

HYPEHPLASIA, CHROMO PHOBE-CELL 

(10) 

1 (10X) 

(35) 

6

«

 (17JS) 

 (11X) 

(ADRENAL 

PERIABTERITIS 

CYTCMEGALY _....__ . 

(10) («1) 

1 (2*) 

I NUMBEB OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

HIGH DOSE
 

(39)
 

C«3)
 

2 (5X)
 

C*3)
 

2 (5%)
 

(39)
 

1 (3X)
 

(38)
 

1 (3X)
 

(«5)
 

i»3 (96)S)
 

1 (2X)
 

(«5)
 

3 (7X)
 

18 (aOX)
 

(39)
 

7 (18X)
 

18 (M6%)
 

(37)
 

2 (5%)
 

<«3)
 

1 J2S1_
 

1 77
 
TABLE G1 MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED)

 

IADRENA I CORTE X 

CYTOHEGAL Y 

HYPERPLASIA , NODULA R 

HYPERPLASIA , NOS 

HYPERPLASIA , FOCAL 

ANGIECTASIS 

ITHYROID 

ULTIMOBRANCHIA L CYST 

CYTCMEGAL Y 

HYPEBPLASIA , C-CELL 

HYPEBPLASIA, FOLLICULAR-CELL 

f PARATHYROI D 

HYPERPLASIA , NOS 

(PANCREATI C ISLETS 

HYPIRPLASIA , NOS 

REPRODUCTIV E SYSTEM 

•PROSTATE 

INFLAMMATION, SUPPURATIVE 

PERIAHTER1TIS 

HYPERPLASIA , NOS 

METAPLASIA , SQUAHOUS 

ITESTIS 

PERIARTERITIS 

ATROPHY , NOS 

NERVOU S SYSTE M 

IBRAIM/BENINGES 

INFLAMMATION , NOS 

INFLAMMATION , FOCAL 

FIBRCSIS, FOCAL 

IDBAI N 

HEMORRHAG E 

INFLAMMATION , FOCAL 

NECROSIS, FOCAL 

AHfiliEIASiS. 

CONTROL LOW DOSE HIGH DOSE 

(10) 0»D (i»3) 

8 (SOX) 17 cm> 19 (UU% )

 

1 (10%) 

1 (10X) 

2 (20%) 6 (15%) 6 (1i»%)

 

1 (10%) 

(10) («0) (36) 

2 (5%) 

1 (3%) 

7 (70S) 23 (58X) 25 (69%) 

3 (8%) 

(6) (32) (28) 

5 (16%) 5 (18%) 

(10) («0) (39) 

2 (20X) 3 (8%) 7 (18%) 

(10) C»3) (»0) 

2 (20X) 18 (42%) 20 (50%) 

2 (5%) 

1 (3%) 

1 (10X) 1 (2%) 15 (38%) 

(10) (U1 ) (»6) 

1 (10X) U (10%) 3 (7%) 

6 (60X) 36 (88%) 32 (70%) 

(10) («3) (»6) 

1 (2%) 

1 (2%) 1 (2%) 

1 (2%) 

(10) («3) (»6) 

1 (10X) 

1 (10X) 

*	 NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

*	 NUMBER OF ANIMALS NECROPSIED
 

128
 

1 (2%) 

i_J2Sl__. 

— -__ — — -——»—— 
TABLE G1 MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

SPECIAL SENSE ORGANS 

NCNE 

HUSCULOSKELETAL SYSTEM 

NONE 

BODY CAVITIES 

NONE 

ALL OTHEB SYSTEMS 

NONE 

SPECIAL eORPHOLOGY SUHNARY 

AOTO/NECBOESY PERF/IIISTO PEHF 

AUTOLYSIS/NO NECROPSY PERFORBED U 

1 

129
 
TABLE G2

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE RATS 

FED DIELDRIN INTHE DIET 

CONTROL LOW DOSE 

ANIMAL S INITIALL Y I N STUDY 10 50 

ANIMAL S NECBOPSIED 10 «9 

ANIMAL S EXAMINE D HISTOPATHOLOGICA LLY 10 «7 

INTEGUMENTAF Y SYSTEM 

*SKI N (10) (U9)

 

INFLAMMATION , GB ANULCNATOU S 

HESPIBATOB Y SYSTEM 

ILUN G (9) («5) 

INFLAMMATION , INTEBSTITIAL 1 111*) 

PNEUMONIA , ASPIRATIO N 

ABSCESS, NOS 

CHOLESTERO L DEPOSIT 1 <2X ) 

ALVECLA R BACBOPHAGE S 1 <11*> 16 (36X) 

ILUNG/ALVEOL I (9) (l»5)

 

INFLAMMATION , SUPPUHATIV E 3 (7X)

 

HEHATOCOIETIC SYSTEM 

ISPLEE N (7) («5)

 

HEMOSIDEROSIS 2 («X) 

HEMATOPOIESIS 3 <7X)

 

ITHYMU S (7) (3D

CYST, NOS "• (57%) 8 (26X) 

CIRCU1ATOB Y SYSTEM 

tMYOCABDIU N (8) (U6 ) 

F,.IBBOSIS 3 (38X) 18 (39%) 

DIGESTIV E SYSTE M 

(SALIVAB Y GLAN D (9) <t6 ) 

JNFlJflMMJON^ FO£,Bi _ J_J2ii... 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

HIGH DOSE 

50 

i»9 

1)8 

(19) 

2 («%) 

(U6 ) 

2 (1*) 

7 (15*) 

1 (2X) 

11 (2««) 

(«6) 

1 (2X ) 

<ao ) 

1 (3X) 

10 (25X) 

(32 ) 

9 (28%) 

(i»C) 

la (35*) 

(tO ) 

_J_J3*1 . 

130 
TABLE G2 FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED)

 

CONTROL LOW DOSE HIGH DOSE 

ILIVE R (9) (47) (1«) 

ECTOPIA 1 <2X) 

GRANULOHA , NOS 1 (2») 

FIBRCSIS, FOCAL 1 (2%) 

NECROSIS, FOCAL 

HEPATCCYTCMEGAL Y 1 (11%) 

<»

9

 (9X) 

 (19X) 

1

2

 (2%) 

 (5%) 

ANGIECTASI S 3 (6X) 2 (5%) 

HEMATOPOIESIS 1 (2X) 2 (5%) 

*BIL£ DUC1 

FIBBCSIS 

(10) 

1 (10%) 

(«9) 

i» (8X) 

(«9) 

« (8%) 

HYPEBPLASIA , NOS 7 (70%) 38 (78%) 22 C»5%) 

IPANCHEA S 

FIBROSIS 

(9) («6) 

7 (15%) 

(37) 

1 (3%) 

PERIARTERIII S 1 (2%) 1 (3%) 

IPANCREATI C

ATROPHY ,

 ACINU S 

 NOS 

(9) 

1 (11%) 

("»6) 

7 (15%) 

(37) 

8 (22%) 

ISTCMAC H 

ULCER , FOCAL 

(10) 

1 (10%) 

(«7) 

1 (2%) 

C»0) 

1 (3%) 

URINAR Y SYSTEH 

•KIDNE Y 

INFLAMMATION , CHRONIC 

(9) 

6 (61%) 

(i»6) 

39 (85%) 

(42 ) 

3U (81%) 

HYEERPLASIA , EPITHELIAL 1 (2%) 

*KIDNEY/fELVI S 

INFLAMMATION , SUPPUHATIV E 

(9) 

1 (11*) 

C»6) (i»2) 

HYPERPLASIA , EPITHELIAL 5 (56%) 9 (20%) 12 (29%) 

tURINAR Y BLADDER 

INFLAMMATION , NOS 

HYPERPLASIA , EPITHELIA L 

(9) 

1

1

 (11X) 

 (11%) 

(«3) 

1

7

 (2%) 

 (16%) 

(36) 

U (11%) 

ENDOCRIN E SYSTE M 

#PITUITAR Y 

CYST, NOS 

CYTCHEGAL Y 

(6) ( « D 

u (10%) (33) 

14

1

 (12%) 

 (3%) 

IADRENA L CORTE X 

CYTCBEGAL Y 

flIlEJPLASIAA_FOC,SL 

(9) 

u (a 14%) 

JLJim

(l>5) 

1U (31%) 

 J_J2*L

(<40 ) 

21 (53%) 

 e_i?o*L_. 

* NUMBE E OF ANIMAL S WIT H TISSUE EXAMINE D MICROSCOPICALLY 

* NUMEE R OF ANIMAL S NECEOPSIE D 

131
 
TABLE G2 FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

ITHYBOIC CO (45) <U1 ) 

ULTIMOBBANCHIA L CIST 2 («X) 3 (7X) 

CYSTIC FOLLICLES 1 (25*) 

ATHOEHY , HOS 1 (2*) 

HYPEBPLASIA, C-CELL t (100X) 32 (71*) 31 (76*) 

HYPEBPLASIA , FOLLICUL AB-CELL 1 (25%) <» (9*) 6 (15X) 

• PARATHYROI D (7) (2H) (2<t)

 

HYPERPLASIA, NOS 1 ("»*)

 

REPRODUCTIV E SYSTEH 

*VAGIN A (10) («9) («9)

 

HYPEEPLASIA , PSEUDOEPITHELIOH AIO 1 (2X)

 

*UTERU£/ENDOBETHIOH (10) ("46) (to> 

INFLAMMATION , SUPPUBATIV E 1 (10*) 2 («X) 1 (3X) 

HYPEBPLASIA , CYSTIC 1 (10X) 3 (7*) 

tOVABY (10) («5) (l»1)

 

FOLLICULAR CYST, BOS 3 (7*) 

HYPEBPLASIA , GEA N ULOSA-CELL 1 (2X)

 

NERVOU S SYSTEH 

tBBAIN/HENINGE S (8) (i»6) (HO) 

FIBROSIS, FOCAL 2 (25*) 1 (2X) 3 (6%) 

IBRAI N (8) («6) c»o)

MINERALIZATIO N 1 (3*) 

ATRCEHY, NOS 1 (3*) 

SPECIAL SENSE OBGANS 

NON E 

MUSCULOSKHLETA L SYSTEM 

•SKELETAL MUSCLE (10) («9) (»9)

 

INFIAHHAIJPN, SUPEUBAIIVE 1 110SI

 

I NUMBE R OF ANIMAL S HIT H TISSUE EXAMINE D MICROSCOPICALLY 

* MUHEE R OF ANIMALS NECROPSIED 

132
 
TABLE G2 FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED)

 

CONTROL LOW DOSE HIGH DOSE 

BODY CAVITIES 

•PERITONEUM 

INFLAMMATION, GBANULOHATO US 

(10) 

1 (10X) 

C»9) (U9) 

1 (2%) 

ALL OTHIB SYSTEMS 

NCNE 

SPECIAL BORPHOLOGY SOHMARY 

AUTO/NECHOPSY PEBF/HISTO PEHF 

ADTOLISIS/NECHOPSY PEBF/NO HISTO 

AUTOIYSIS/NO NECBOPSY PEBFOBMED 

1 

2 

1 

2 

1 

1 

133 

APPENDIX H
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN MICE FED DIELDRIN IN THE DIET
 

135
 

TABLE HI

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE MICE 

FEDDIELDRIN INTHE DIET 

HIGH DOSE LOW OOSE 

CONTROL CONTROL 

ANIHA1S mTIAlLI IN STUDY 10 10 

ANIMALS NECROPSIED 10 10 

ANIMALS EXAMINE D HISTOPATHOLOGICALLY 8 10 

INTEGUMENTAR Y SYSTEM 

*SKIN (10) (10) 

INFL1HHATION , FOCAL 

RESPIRA1CRY SYSTEM 

((LUNG/BRONCHIOLE (8) (10) 

HKPERPLASIA , EPITHELIAL 

ILUN G (8) (10) 

HEMORRHAG E 1 (13X) 

ALVECLAR MACROPHAGES 

HYPERPLASIA . ALVEOLA R EPITHELIUM 

HEHATOPOIETIC SYSTEM 

(CERVICAL LYMPH NODE (7) (10) 

HYPERPLASIA , LYflPHOID 

tTHACHEA L LYMP H NODE (7) (10) 

HYPERPLASIA, LYMPHOID 

CIRCULATORY SYSTEM 

• MYOCARDIU M (8) (10) 

FIBROSIS 

DIGESTIVE SYSTEM 

•LIVER (8) (10) 

INFLAMMATION. FOCAL 

« NUHBEB OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* MONGER OF ANIMALS MECROPSIED
 

LOW OOSE 

50 

50 

50 

(50) 

1 (2X) 

(50) 

(50) 

(«9) 

(H9) 

(50) 

1 <2X) 

(50) 

J_J2S1 

HIGH DOSE 

50 

U8 

«6 

(U8) 

(l»6) 

1 (2*) 

(<»6) 

1 (2«) 

1 (2X) 

(36) 

1 OX) 

(36) 

1 (3X) 

(l»5) 

("5) 

137 
TABLE H1 MALE MICE: NONNEOPLASTIC LESIONS (CONTINUED)

 

HIGH DOSE LOW DOSE 

CONTROL CONTROL 

LIVE R CCNT. 

NECBCSIS. FOCAL 1 (13*) 1 (10%) 

METAMORPHOSIS FATTY 

CYTCELASMIC V ACUOLIZATIOM 

HEPATOCYTCHEGALY 

HYPEBPLASIA , HODULAB 

HYPEBPLASIA. DIFFUSE 

ILIVEB/CAUDATE LOBE (8) (10) 

TOHSIOH 

*BILE EUCT (10) (10)

 

INFLAMMATION , FOCAL 

INFLAMMATION , SUPEUBATIV E 

HYPEFPLASIA, FOCAL 

tPAMCBEAS (7) (10) 

INFLAMMATION , GBANULOHATOUS 1 (UX)

 

ILABG E INTESTIN E (3) (8)

 

INFLAMMATION , FOCAL GRANULONATO U 

NEHATODIASIS 

URINAR Y SYSTEM 

*KIDME Y (8) (10)

 

MULTIPL E CYSTS 1 (13X)

 

PERIABTERITIS 

IKIDNEY/COBTEX (8) (10) 

REGENERATION , NOS 

(KIDNEY/TUBUL E (8) (10)

 

CALCIFICATION, FOCAL 1 (13X)

 

REGENERATION, NOS 

tUHINAB Y BLADOEB (7) (10)

 

HYPEBPLASIA , EPITHELIAL 

EMDCCBIN E SYSTEM 

• THYROI D (8) (9)

 

HYPEBPLASIA, FOLLICULAB-CELL 

I PARATHYROI D (6) (9)

 

tiYPiBPUei^ NOS 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* SUMBEB OF ANIMALS NECROESIED
 

LOW DOSE 

2 («») 

1 (2%) 

1 (2X) 

2 («*> 

(50) 

1 (2%) 

(50) 

1 (2X) 

1 (2X) 

1 (2X) 

(50) 

(19) 

1 (5X) 

(50) 

1 (2X) 

(50) 

1 <2X) 

(50) 

1 (2%) 

(49) 

1 (2X) 

C»2) 

3 (7*) 

(19) 

HIGH DOSE 

2 (t«) 

2 (tX) 

1 (2X) 

C»5) 

(18) 

(145) 

(28) 

1 («X) 

1 («X) 

(45) 

(l»5) 

C*5) 

(36) 

(38) 

(27) 

1_J2*L_. 

13R
 
TABLE HI MALE MICE: NONNEOPLASTIC LESIONS (CONTINUED)

 

REPRODUCTIVE SYSTEM 

(PROSTATE 

HYPERPLASIA, EPITHELIAL 

NERVOUS SYSTEM 

• BRAI N 

INFLAMMATION, FOCAL 

SPECIAL SENSE ORGANS 

NONE 

HUSCULOSKILETAL SYSTEM 

NONE 

BODY CAVITIES 

NON E 

ALL OTHER SYSTEMS 

NCNE 

SPECIAL FORPHOIOGY SUMMAR Y 

NO LESION REPORTED 

AUTOLYSIS/NECROPSY PERF/NO IIISTO 

AUTOIYSIS/NO NECROPSY PERFORMED 

HIGH DOSE 

CONTROL 

(7) 

(7) 

5 

2 

LOW DOSE LOW DOSE HIGH DOSE CONTROL 

(10) («9) («5) 

1 (2*) 

(10) (50) («5)

 

1 <2») 

6 26 23 

2 

2 

139 
TABLE H2

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE MICE 

FED DIELDRININTHEDIET 

HIGH DOSE 

CONTROL 

LOW DOSE 

CONTROL LOW DOSE 

ANIMAL S 1KITIALLY IN STUDY 10 10 50 

ANIMAL S NECROPSIED 10 10 50 

ANIMALS EXAMINE D HISTOPA1HOLOGICALLY 10 10 50 

INTEGUMENTARY SYSTEM 

NON E 

RESPIRATOR Y SYSTEM 

HUNG (10) (10) (50) 

ALVEOLA R MACHOPHAGE S 

HYEEEPLASIA, ALVEOLAR EPITHELIUM 1 <2X) 

HENATOPOIETIC SYSTEM 

IBONE MARBO H 

FIBROSIS 

(SPLEE N (10) (10) (18) 

INFLAMMATION, FOCAL GRANULCBATOU 1 (10X) 

HYPEBPLASIA , LYNPIiOID 

HEHATOPOIESIS 1 00%) 5 (10X) 

« LYMP H NODE (10) (3) («9) 

INFLAMMATION , SUPPURATIV E 

ANGIECTASIS 

HYPEFPLASIA , LYMPHOID 

tMESENIERIC L. NODE (10) <3) («9) 

INFLAMMATION , ACUTE 1 (2X) 

INFLAMMATION , GRA N ULOMATO US 

CIRCULATOR Y SYSTEM 

hCKE 

I NUMEER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

HIGH DOSE 

50 

50 

50 

(50) 

1 (2X) 

(50) 

2 («*) 

l» (8X) 

(50) 

1 (2%) 

1 <2X) 

2 (IX) 

(50) 

1 (2X) 

140 
TABLE H2 FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

HIGH DOSE LOW DOSE 

CONTROL CONTROL 

(10) (10) 

1 dOX) 

(10) (10) 

(10) (10) 

(10) (10) 

(10) (10) 

(10) 

1 (10X) 

(10) 

(10) (10) 

(10) (10) 

1 (10X) 2 (20X) 

DIGESTIVi SYSTEM
 

niVEH
 

INFLAMMATION, SUPPUBATIVE
 

NECBCSIS, FOCAL
 

HEPA10CYTOMEGALY
 

HYPEEPLASIA, NODULAB
 

HYPEEPLASIA, RETICULUM CELL
 

HEMATOPOIESIS
 

tLIVEH/CENTRILOBULAR
 

NECRCSIS, NOS
 

BETAMOBPHOSIS FATTY
 

*GALLBLADDEB
 

HYPEBPLASIA, EPITHELIAL
 

*BILE CUCT
 

INFLAMMATICN, NOS
 

tPANCREAS
 

INFLAMMATION, NOS
 

INFLAMMATION, FOCAL
 

INFLAMMATION, SUPEUBATIVE
 

INFLAMHATION, GRANULOMATOUS
 

FIBRCSIS
 

NECRCSIS, FAT
 

METAMORPHOSIS FATTY
 

*PANCRE*TIC DUCT
 

DILATATION, NOS
 

CYST, NOS
 

FIEBCSIS
 

tPANCBEATIC ACINUS
 

ATROPHY, NOS
 

URINAR Y SYSTEM
 

tKIDNEY
 

INFLAMMATION, SUPPUHATIVE
 

INFLAMMATION, CHRONIC
 

PERIVASCULAR CUFFING
 

NECRCSIS, FAT
 

LOW DOSE
 

(50)
 

1 (2X)
 

1 (2X)
 

1 <2X)
 

1 (2X)
 

(50)
 

1 (2X)
 

1 (2X)
 

(50)
 

T <2X)
 

(50)
 

(50)
 

2 (t%)
 

1 <2X)
 

1 <2X)
 

1 (2%)
 

1 (2X)
 

(50)
 

1 (2X)
 

1 (2X)
 

2 (tX)
 

(5C)
 

5 (10X)
 

(50)
 

1 (2%)
 

1 (2X)
 

t NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBE R OF ANIMALS NECROPSIED
 

HIGH DOSE
 

(49)
 

1 (2X)
 

2 («X)
 

1 (2X)
 

(09)
 

(50)
 

(50)
 

1 (2X)
 

(50)
 

1 (2X)
 

1 (2X)
 

1 (2X)
 

(50)
 

(50)
 

(l»9)
 

1 (2%)
 

3 <6X)
 

1 (2X)
 

141
 
TABLE H2 FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED)

 

IKIDNEi/COETEX
 

LYHPHOCYTIC INFLAM INFILTRATE
 

tKIDNEY/TUBULE
 

REGENERATION, NOS
 

ENDOCRINE SYSTEM
 

t ADRENAL CORTEX
 

HYPEBPLASIA, FOCAL
 

ITHYEOID
 

CYSTIC FOLLICLES
 

BEPBOEUCTIVE SYSTEM
 

1 UTERUS/ EN DONETRION
 

INFLAMMATION, NOS
 

INFLAMMATION, SUPPORATIVE
 

HYPERPLASIA, CYSTIC
 

ICVAHY/CVIDUCT
 

INFLIHHATION, SUPPURATIVE
 

tOVARY
 

CYST, NOS
 

INFLAMMATION. SUPPORATITE
 

IOVAHY/BETE OVAHII
 

HYPIRPLASIA. EPITHELIAL
 

NERVOUS SYSTEM
 

IBRAIN/MENINGES
 

INFLAMMATION, FOCAL
 

tCEREBELLUH
 

ATROPHY, NOS
 

SPECIAL SENSE CRGANS
 

BC.JU_ __
 

HIGH DOSE
 

CONTROL
 

(10)
 

(10)
 

(10)
 

(10)
 

(10)
 

2 (20%)
 

7 (70%)
 

(10)
 

(10)
 

2 (20%)
 

(10)
 

(10)
 

(10)
 

LOW DOSE
 

CONTROL
 

(10)
 

(10)
 

(10)
 

(9)
 

(10)
 

1 (10%)
 

1 (10%)
 

(10)
 

(10)
 

3 (30%)
 

(10)
 

(10)
 

(10)
 

LOW DOSE
 

(50)
 

(50)
 

C»9)
 

1 (2%)
 

(50)
 

2 («%)
 

(48)
 

« (8%)
 

16 (33%)
 

(«8)
 

(50)
 

M (8%)
 

10 (20%)
 

(50)
 

1 (2%)
 

(50)
 

(50)
 

1 (2%)
 

HIGH DOSE
 

("49)
 

1 (2%)
 

(t9)
 

2 («%)
 

(l»8)
 

("9)
 

2 («%)
 

(50) 

1

10

 (2%) 

 (20%) 

16 (32%) 

(50) 

2 («%)
 

(50)
 

1 (2%)
 

23 (46%)
 

(50)
 

(50)
 

1 (2%)
 

(50)
 

I NUMBER OF ANIMALS RITH TISSUE EXAMINED MICROSCOPICALLY
 * NUMBER OF ANIMALS NECROPSIED
 

142
 
TABLE H2 FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED)

 

HUSCUIOSKELETAL SISTER 

DC HE 

BOCY CAVITIES 

*PERITC«EUM 

INFLAMMATION , DOS 

INFLAMMATION , SUPEUHATIV E 

• PLEUR A 

INFLAMMATION . FOCAL 

ALL OTHEB SISTERS 

•MULTIPLE OBGANS 

HIPESPLASIA. LIHPHOID 

AOIEOSE TISSUE 

INFLAMMATION, SUPPUBATIVE 

SPECIAL B08PHOLOGI SUMMAE I 

HO LESION BE PORTED 

HIGH DOSE LOW DOSE

 

CONTROL CONTROL

 

(10) (10) 

(10) (10) 

(10) (10) 

2 2 

LOW DOSE 

(50) 

2 («*) 

1 (2%) 

(50) 

1 <2X) 

(50) 

1 

13 

HIGH DOSE 

(50) 

1 (2*) 

(50) 

(50) 

1 (2X) 

11 

143 

APPENDIX I
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS
 

IN RATS FED ALDRIN IN THE DIET
 

145
 

Table 11. Analyses of the Incidence of Primary Tumors in Male Rats
 

Fed Aldrin in the Diet3
 

Topography: Morphology 

Matched 

Control 

Pooled 

Control 

Low 

Dose 

High 

Dose 

All Sites: Hemangiosarcoma'3 0/10 (0.00) 4/58 (0.07) 1/47 (0.02) 3/49 (0.06) 

P Values0 » d N.S. N.S. N.S. N.S. 

Relative Risk (Matched Control)f 

Lower Limit 

Upper Limit 

Infinite 

0.012 

Infinite 

Infinite 

0.137 

Infinite 

Relative Risk (Pooled Control)f 

Lower Limit 

Upper Limit 

0.617 

0.079 

2.971 

0.888 

0.161 

4.985 

Weeks to First Observed Tumor Ill 

__ 

48 51 

Thyroid: Follicular-cell 

Adenoma or Carcinoma 3/7 (0.43) 4/48 (0.08) 14/38 (0.37) 8/38 (0.21) 

P Values0 » d P = 0.075(N) P = 0.069 P = 0.002** N.S. 

Departure from Linear Trend6 P = 0.006 

Relative Risk (Matched Control)f 

Lower Limit 

Upper Limit 

0.860 

0.381 

3.959 

0.491 

0.189 

2.470 

Relative Risk (Pooled Control)f 

Lower Limit 

Upper Limit 

4.421 

1.532 

16.808 

2.526 

0.734 

10.634 

Weeks to First Observed Tumor 111 

__ 

83 88 
Table II. Analyses of the Incidence of Primary Tumors in Male Rats
 

Fed Aldrin in the Diet3
 

(continued) 

Matched Pooled Low 

Topography: Morphology Control Control Dose 

Thyroid: C-cell Adenoma or 

Carcinoma'5 2/7 (0.29) 4/48 (0.08) 4/38 (0.11) 

P Values0 » d N.S. N.S. N.S. 

Relative Risk (Matched Control )f 0.368 

Lower Limit 0.077 

Upper Limit 3.716 

Relative Risk (Pooled Control)f 1.263 

Lower Limit 0.250 

Upper Limit 6.295 

Weeks to First Observed Tumor 104 111 — 

Pancreatic Islet: Islet-cell 

Adenoma or Carcinoma** 0/9 (0.00) 1/52 (0.02) 5/37 (0.14) 

P Values0 » d N.S. N.S. P = 0.043** 

Relative Risk (Matched Control)^ Infinite
 

Lower Limit 0.349
 

Upper Limit Infinite
 

Relative Risk (Pooled Control)f 7.027
 

Lower Limit 0.831
 

Upper Limit 327.268
 

Weeks to First Observed Tumor 66
 —
 —
 

High
 

Dose
 

3/38 (0.08)
 

N.S.
 

0.276
 

0.045
 

3.036
 

0.947
 

0.145
 

5.219
 

94
 

2/39 (0.05)
 

N.S.
 

Infinite
 

0.076
 

Infinite
 

2.667
 

0.143
 

151.423
 

95
 
(continued)
 

Topography: Morphology
 

Pituitary: Chromophobe
 

Adenoma or Carcinoma**
 

P Values0 »d
 

Relative Risk (Matched Control)^
 

Lower Limit
 

Upper Limit
 

Relative Risk (Pooled Control)*
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Adrenal: Cortical Adenoma
 

or Carcinoma"
 

P Values0 »d
 

Departure from Linear Trend6
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

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

Fed Aldrin in the Dieta
 

Matched Pooled
 

Control Control
 

3/9 (0.33) 15/49 (0.31)
 

N.S. N.S.
 

104
 —
 

2/10 (0.20) 3/55 (0.05)
 

N.S N.S.
 

P = 0.074
 

95
 —
 

Low
 

Dose
 

13/37 (0.35)
 

N.S.
 

1.054
 

0.411
 

4.972
 

1.148
 

0.574
 

2.232
 

92
 

1/38 (0.03)
 

P - 0.045*(N)
 

0.132
 

0.003
 

2.358
 

0.482
 

0.009
 

5.734
 

66
 

High
 

Dose
 

13/40 (0.33)
 

N.S.
 

0.975
 

0.378
 

4.660
 

1.062
 

0.528
 

2.086
 

64
 

2/43 (0.05)
 

N.S.
 

0.233
 

0.020
 

2.974
 

0.853
 

0.074
 

7.092
 

49
 
Table II. Analyses of the Incidence of Primary Tumors in Male Rats
 

Fed Aldrin in the Diet3
 

(continued)
 

a

Treated groups received doses of 30 or 60 ppm.
 

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

c

Beneath the incidence of tumors in a control group is the probability level for the Cochran-


Armitage test when P < 0.10; otherwise, not significant (N.S.) is indicated. Beneath the incidence of tumors in a treated group is the probability level for the Fisher exact test for the
 

comparison of that treated group with the matched-control group (*) or with the pooled-control
 

group (**) when P < 0.05 for either control group; otherwise, not significant (N.S.) is
 

indicated.
 

"A negative trend (N) indicates a lower incidence in a treated group than in a control group.
 

e

The probability level for departure from linear trend is given when P < 0.05 for any comparison.
 

•'The 95% confidence interval of the relative risk between each treated group and the specified
 

control group.
 
__ __ 

__ 

__ 

Table 12. Analyses of the Incidence of Primary Tumors in Female Rats
 

Fed Aldrin in the Diet3
 

Matched Pooled Low 

Topography: Morphology Control Control Dose 

All Sites: Hemangiosarcoma 

or Hemangioma" 0/10 (0.00) 0/60 (0.00) 3/49 (0.06) 

P Values0»d N.S. N.S. N.S. 

Departure from Linear Trend6 P = 0.010
 

Relative Risk (Matched Control)* Infinite
 

Lower Limit 0.136
 

Upper Limit Infinite
 

Relative Risk (Pooled Control)* Infinite
 

Lower Limit 0.733
 

Upper Limit Infinite
 

Weeks to First Observed Tumor 79
 

Liver: Neoplastic Nodules
 

or Hepatocellular Carcinoma 1/10 (0.10) 5/59 (0.08) 1/48 (0.02)
 

P Values0 »d N.S. N.S. N.S.
 

Relative Risk (Matched Control)f 0.208
 

Lower Limit 0.006
 

Upper Limit 16.007
 

Relative Risk (Pooled Control)* 0.246
 

Lower Limit 0.011
 

Upper Limit 2.063
 

Weeks to First Observed Tumor Ill 112
 —
 

High
 

Dose
 

0/49 (0.00)
 

N.S.
 

—
 

—
 

—
 

—
 

—
 

3/49 (0.06)
 

N.S.
 

0.612
 

0.062
 

31.446
 

0.722
 

0.117
 

3.510
 

112
 
__ 

__ 

(continued)
 

Topography: Morphology
 

Thyroid: Follicular-cell
 

Adenoma or Carcinoma
 

P Values0 »d
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumors
 

Thyroid: C-cell Adenoma or
 

Carcinoma
 

P Values0 »d
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Table 12. Analyses of the Incidence of Primary Tumors in Female Rats
 

Fed Aldrln in the Diet3
 

Matched Pooled
 

Control Control
 

1/9 (0.11) 3/52 (0.06)
 

N.S. N.S.
 

Ill
 

1/9 (0.11) 12/52 (0.23)
 

N.S. N.S.
 

Ill
 

Low
 

Dose
 

10/39 (0.20)
 

P = 0.009**
 

2.308
 

0.423
 

96.910
 

4.444
 

1.239
 

23.437
 

105
 

6/39 (0.15)
 

N.S.
 

1.385
 

0.205
 

62.466
 

0.667
 

0.235
 

1.737
 

64
 

High
 

Dose
 

7/46 (0.15)
 

N.S.
 

1.370
 

0.215
 

59.577
 

2.638
 

0.653
 

14.924
 

112
 

10/46 (0.22)
 

N.S.
 

1.957
 

0.343
 

82.313
 

0.942
 

0.408
 

2.134
 

106
 
__ 

Table 12. Analyses of the Incidence of Primary Tumors in Female Rats
 

Fed Aldrin in the Diet3
 

(continued)
 

High
 

Dose
 

11/48 (0.23)
 

P = 0.014**(N)
 

0.516
 

0.227
 

1.905
 

0.498
 

0.252
 

0.393
 

112
 

1/48 (0.02)
 

N.S.
 

Infinite
 

0.012
 

Infinite
 

Infinite
 

0.061
 

Infinite
 

112
 —
 

Topography: Morphology
 

Pituitary: Chromophobe
 

Adenoma or Carcinoma
 

P Values0 »d
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Adrenal: Cortical Adenoma*3
 

P Valuesc»d
 

Departure from Linear Trend6
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Pooled Control)*
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched
 

Control
 

4/9 (0.44)
 

P = 0.049(N)
 

111
 

0/10 (0.00)
 

N.S.
 

P - 0.010
 

—
 

Pooled
 

Control
 

23/50 (0.46)
 

P = O.Oll(N)
 

0/55 (0.00)
 

N.S.
 

P < 0.001
 

Low
 

Dose
 

15/43 (0.35)
 

N.S.
 

0.785
 

0.371
 

2.732
 

0.758
 

0.428
 

1.308
 

91
 

8/45 (0.18)
 

P = 0.002**
 

Infinite
 

0.567
 

Infinite
 

Infinite
 

2.787
 

Infinite
 

112
 
__ 

Table 12. Analyses of the Incidence of Primary Tumors in Female Rats
 

Fed Aldrin in the Diet8
 

(continued) 

Topography: Morphology 

Matched 

Control 

Pooled 

Control 

Low 

Dose 

Pancreatic Islet: Islet-cell 

Adenoma or Carcinoma'' 0/9 (0.00) 1/58 (0.02) 1/43 (0.02) 

P Values0 » d N.S. N.S. N.S. 

Relative Risk (Matched Control)f 

Lower Limit 

Upper Limit 

Infinite 

0.012 

Infinite 

Relative Risk (Pooled Control )f 

Lower Limit 

Upper Limit 

1.349 

0.018 

102.887 

Weeks to First Observed Tumor .._ 

__ 

112 

Mammary Gland: Fibroma,
 Fibrosarcoma or Fibroadenoma 3/10 (0.30) 7/60 (0.12) 9/49 (0.18)
 

d
 P Values0

 » N.S. N.S. N.S.
 

Relative Risk (Matched Control)f 0.612
 

Lower Limit 0.203
 

Upper Limit 3.150
 

Relative Risk (Pooled Control)^ 1.574
 

Lower Limit 0.572
 

Upper Limit 4.600
 

Weeks to First Observed Tumor Ill 62
 

High
 

Dose
 

1/40 (0.03)
 

N.S.
 

Infinite
 

0.013
 

Infinite
 

1.450
 

0.019
 

111.302
 

112
 

7/49 (0.14)
 

N.S.
 

0.476
 

0.143
 

2.568
 

1.225
 

0.406
 

3.800
 

107
 
Table 12. Analyses of the Incidence of Primary Tumors in Female Rats
 

Fed Aldrin in the Dieta
 

(continued)
 

Topography: Morphology
 

Uterus: Endometrial Stromal
 

Polypb
 

P Values0 »d
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Ovary: Granules a-cell Tumor*5
 

P Values0 »d
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched Pooled Low High 

Control Control Dose Dose 

0/9 (0.00) 6/56 (0.11) 6/45 (0.13) 9/48 (0.19) 

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

Infinite Infinite 

0.363 0.559 

Infinite Infinite 

1.244 1.750 

0.356 0.609 

4.328 5.274 __ 

_. 86 101 

0/8 (0.00) 1/57 (0.02) 1/43 (0.02) 4/46 (0.09) 

N.S. P = 0.071 N.S. N.S. 

Infinite Infinite 

0.011 0.186 

Infinite Infinite 

1.326 4.957 

0.017 0.544 

102.886 235.794 

107 107 — — 
Table 12. Analyses of the Incidence of Primary Tumors in Female Rats
 

Fed Aldrin in the Diet3
 

(continued)
 

a

Treated groups received doses of 30 or 60 ppm.
 

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

c

Beneath the incidence of tumors in a control group is the probability level for the Cochran-


Armitage test when P < 0.10; otherwise, not significant (N.S.) is indicated. Beneath the incidence of tumors in a treated group is the probability level for the Fisher exact test for the
 

comparison of that treated group with the matched-control group (*) or with the pooled-control
 

group (**) when P < 0.05 for either control group; otherwise, not significant (N.S.) is
 

indicated.
 

**A negative trend (N) indicates a lower incidence in a treated group than in a control group.
 

e

The probability level for departure from linear trend is given when P < 0.05 for any comparison.
 

*The 95% confidence interval of the relative risk between each treated group and the specified
 

control group.
 
APPENDIX J
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS
 

IN MICE FED ALDRIN IN THE DIET
 

157
 

__ 

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

Fed Aldrin in the Diet3
 

Matched Pooled Low
 

Topography: Morphology Control Control Dose
 

Liver: Hepatocellular
 

Carcinoma"3 3/20 (0.15) 17/92 (0.18) 16/49 (0.33)
 

P Valuesc»d P = 0.001 P < 0.001 P = 0.048**
 

Relative Risk (Matched Control)* 2.177
 

Lower Limit 0.731
 

Upper Limit 10.720
 

Relative Risk (Pooled Control)f 1.767
 

Lower Limit 0.913
 

Upper Limit 3.339
 

Weeks to First Observed Tumor 90 90
 

/
 

Lung: Alveolar /Bronchiolar
 

Adenoma or Carcinoma13 0/20 (0.00) 7/91 (0.08) 3/49 (0.06)
 

P Values0 »d P = 0.083 N.S. N.S.
 

Relative Risk (Matched Control)f Infinite
 

Lower Limit 0.255
 

Upper Limit Infinite
 

Relative Risk (Pooled Control)* 0.796
 

Lower Limit 0.137
 

Upper Limit 3.293
 

Weeks to First Observed Tumor 90
 —
 —
 

High
 

Dose
 

25/45 (0.56)
 

P = 0.002*
 

P < 0.001**
 

3.704
 

1.348
 

17.056
 

3.007
 

1.757
 

5.057
 

75
 

5/45 (0.11)
 

N.S.
 

Infinite
 

0.584
 

Infinite
 

1.444
 

0.379
 

4.947
 

96
 
Table Jl. Analyses of the Incidence of Primary Tumors in Male Mice
 

Fed Aldrin in the Diet3
 

(continued)
 

a

Treated groups received time-weighted average doses of 4 or 8 ppm.
 

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

G

Beneath the incidence of tumors in a control group is the probability level for the Cochran-


Armitage test when P < 0.10; otherwise, not significant (N.S.) is indicated. Beneath the
 

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

test for the comparison of that treated group with the matched-control group (*) or with
 

the pooled-control group (**) when P < 0.05 for either control group; otherwise, not
 

significant (N.S.) is indicated.
 

^A negative trend (N) indicates a lower incidence in a treated group than in a control group.
 

e

The probability level for departure from linear trend is given when P < 0.05 for any comparison.
 

*The 95% confidence interval of the relative risk between each treated group and the
 

specified control group.
 
__ __ 

Table J2. Analyses of the Incidence of Primary Tumors in Female Mice
 

Fed Aldrin in the Diet3
 

Matched Pooled Low 

Topography: Morphology Control Control Dose 

Liver: Hepatocellular 

Carcinoma 0/10 (0.00) 3/78 (0.04) 5/48 (0.10) 

P Valuesc»d N.S. N.S. N.S. 

Relative Risk (Matched Control)* Infinite
 

Lower Limit 0.293
 

Upper Limit Infinite
 

Relative Risk (Pooled Control)f 2.708
 

Lower Limit 0.551
 

Upper Limit 16.694
 

Weeks to First Observed Tumor 87
 

Hematopoietic System:
 

Lymphoma or Leukemia 1/10 (0.10) 8/79 (0.10) 3/48 (0.06)
 

P Values0»d N.S. N.S. N.S.
 

Relative Risk (Matched Control)f 0.625
 

Lower Limit 0.063
 

Upper Limit 31.921
 

Relative Risk (Pooled Control)f 0.617
 

Lower Limit 0.109
 

Upper Limit 2.417
 

Weeks to First Observed Tumor 84 75
 —
 

High
 

Dose
 

2/43 (0.05)
 

N.S.
 

Infinite
 

0.076
 

Infinite
 

1.209
 

0.103
 

10.078
 

92
 

2/46 (0.04)
 

N.S.
 

0.435
 

0.027
 

24.942
 

0.429
 

0.046
 

2.028
 

92
 
Table J2. Analyses of the Incidence of Primary Tumors in Female Mice
 

Fed Aldrin in the Dieta
 

(continued)
 

a

Treated groups received time-weighted average doses of 3 or 6 ppm.
 

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

°Beneath the incidence of tumors in a control group is the probability level for the Cochran-


Armitage test when P < 0.10; otherwise, not significant (N.S.) is indicated. Beneath the
 

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

for the comparison of that treated group with the matched-control group (*) or with the
 

pooled-control group (**) when P < 0.05 for either control group; otherwise, not significant
 

(N.S.) is indicated.
 

"A negative trend (N) indicates a lower incidence in a treated group than in a control group.
 

e

The probability level for departure from linear trend is given when P < 0.05 for any comparison.
 
APPENDIX K
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS
 

IN RATS FED DIELDRIN IN THE DIET
 

163
 

__ 

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

Fed Dieldrin in the Diet3
 

Matched
 

Topography: Morphology Control
 

Multiple Sites: Malignant Lymphj oma
 

or Histiocytoma 0/10 (0.00)
 

P Values0 »d N.S.
 

Departure from Linear Trend6 P = 0.033
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Pooled Control)^
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

All Sites: Hemangioma
 

or Hemangiosarcoma 0/10 (0.00)
 

P Values0>d N.S.
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 —
 

Pooled Low 

Control Dose 

3/58 (0.05) 6/46 (0.13) 

N.S. N.S. 

P = 0.029 

Infinite 

0.388 

Infinite 

2.522 

0.571 

14.779 __ 

101 

4/58 (0.07) 4/46 (0.09) 

N.S. N.S. 

Infinite 

0.225 

Infinite 

1.261 

0.247 

6.397 

94 — 

High
 

Dose
 

1/50 (0.02)
 

N.S.
 

Infinite
 

0.012
 

Infinite
 

0.387
 

0.008
 

4.628
 

98
 

2/50 (0.04)
 

N.S.
 

Infinite
 

0.065
 

Infinite
 

0.580
 

0.054
 

3.856
 

17
 
__ 

__ 

__ 

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

Fed Dieldrin in the Dieta
 

(continued) 

Matched Pooled Low 

Topography : Morphology Control Control Dose 

Pituitary: Chromophobe 

Adenoma or Carcinoma 3/10 (0.30) 15/48 (0.31) 11/35 (0.31) 

P Values0 » d N.S. N.S. N.S. 

Relative Risk (Matched Control)f 1.048
 

Lower Limit 0.377
 

Upper Limit 5.108
 

Relative Risk (Pooled Control )f 1.006
 

Lower Limit 0.475
 

Upper Limit 2.025
 

Weeks to First Observed Tumor 110 97
 

Adrenal: Cortical Adenoma'3 0/10 (0.00) 3/55 (0.05) 1/41 (0.02)
 

P Values0 »d N.S. N.S. N.S.
 

Relative Risk (Matched Control)f Infinite
 

Lower Limit 0.014
 

Upper Limit Infinite
 

Relative Risk (Pooled Control)f 0.447
 

Lower Limit 0.009
 

Upper Limit 5.309
 

Weeks to First Observed Tumor 105
 

High
 

Dose
 

12/37 (0.32)
 

N.S.
 

1.081
 

0.398
 

5.226
 

1.038
 

0.505
 

2.057
 

95
 

3/43 (0.07)
 

N.S.
 

Infinite
 

0.156
 

Infinite
 

1.279
 

0.179
 

9.065
 

104
 
Table Kl. Analyses of the Incidence of Primary Tumors in Male Rats
 

Fed Dieldrin in the Diet3
 

(continued)
 

Topography: Morphology 

Matched 

Control 

Pooled 

Control 

Low 

Dose 

High 

Dose 

Thyroid: Follicular-cell 

Adenoma or Carcinoma 0/10 (0.00) 4/51 (0.08) 3/40 (0.08) 6/36 (0.17) 

P Values0 » d P = 0.072 N.S. N.S. N.S. 

Relative Risk (Matched Control)* 

Lower Limit 

Upper Limit 

Infinite 

0.167 

Infinite 

Infinite 

0.497 

Infinite 

Relative Risk (Pooled Control)* 

Lower Limit 

Upper Limit 

0.956 

0.147 

5.315 

2.125 

0.542 

9.486 

Weeks to First Observed Tumor 

__ __ 

110 73 

Thyroid: C-cell Adenoma 

or Carcinoma 0/10 (0.00) 4/48 (0.08) 7/40 (0.18) 4/36 (0.11) 

P Values0 » d N.S. N.S. N.S. N.S. 

Relative Risk (Matched Control)* 

Lower Limit 

Upper Limit 

Infinite 

0.543 

Infinite 

Infinite 

0.287 

Infinite 

Relative Risk (Pooled Control)* 

Lower Limit 

Upper Limit 

2.100 

0.577 

9.102 

1.333 

0.264 

6.654 

Weeks to First Observed Tumor — — 103 78 
Table Kl. Analyses of the Incidence of Primary Tumors in Male Rats
 

Fed Dieldrin in the Dieta
 

(continued)
 

Matched Pooled Low High
 

Topography: Morphology Control Control Dose Dose
 

Pancreatic Islet: Adenoma'5 1/10 (0.10) 1/52 (0.02) 3/40 (0.08) 2/39 (0.05)
 

P Values0»d N.S. N.S. N.S. N.S.
 

Relative Risk (Matched Control)f 0.750 0.513
 

Lower Limit 0.076 0.038
 

Upper Limit 37.743 29.181
 

Relative Risk (Pooled Control)f 3.900 2.667
 

Lower Limit 0.327 0.144
 

Upper Limit 199.508 151.423
 

Weeks to First Observed Tumor 101 109 99
 —
 a

Treated groups received time-weighted average doses of 29 or 59 ppm.
 

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

c

Beneath the incidence of tumors in a control group is the probability level for the Cochran-


Armitage test when P < 0.10; otherwise, not significant (N.S.) is indicated. Beneath the
 

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

for the comparison of that treated group with the matched-control group (*) or with the
 

pooled-control group (**) when P < 0.05 for either control group; otherwise, not significant
 

(N.S.) is indicated.
 

"A negative trend (N) indicates a lower incidence in a treated group than in a control group.
 

e

The probability level for departure from linear trend is given when P < 0.05 for any comparison.
 

^The 95% confidence interval of the relative risk between each treated group and the
 

specific control group.
 
__ 

Table K2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Fed Dieldrin in the Dieta
 

Matched Pooled Low High
 

Topography: Morphology Control Control Dose Dose
 

Multiple Sites: Histiocytomab 0/10 (0.00) 2/60 (0.03) 2/49 (0.04) 0/49 (0.00)
 

P Values0 »d N.S. N.S. N.S. N.S.
 

_w
 

Relative Risk (Matched Control)f Infinite
 

Lower Limit 0.067
 

Upper Limit Infinite
 —


—
 

Relative Risk (Pooled Control)f 1.225 0.000
 

Lower Limit 0.092 0.000
 

Upper Limit 16.251 4.138
 

w_ __
 

Weeks to First Observed Tumor 79
 

Pituitary: Chromophobe Adenoma
 

or Carcinoma 3/6 (0.50) 23/50 (0.46) 11/41 (0.27) 9/33 (0.27)
 

P Values0 »d N.S. P = 0.038(N) N.S. N.S.
 

Relative Risk (Matched Control)f 0.537 0.546
 

Lower Limit 0.249 0.246
 

Upper Limit 2.511 2.601
 

Relative Risk (Pooled Control)f 0.583 0.593
 

Lower Limit 0.297 0.278
 

Upper Limit 1.085 1.139
 

Weeks to First Observed Tumor 110 76 111
 —
 
__ 

Table K2. Analyses of the Incidence of Primary Tumors in Female Rats 

Fed Dieldrin in the Diet3

 

(continued) 

Topography: Morphology
 

Adrenal: Cortical
 

Adenoma or Carcinoma
 

P Values0 »d
 

Departure from Linear Trend »e
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Thyroid: Follicular-cell
 

Adenoma
 

P Value0 »d
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Pooled Control)^
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched
 

Control
 

0/9 (0.00)
 

N.S.
 

0/4 (0.00)
 

N.S.
 

Pooled
 

Control
 

0/55 (0.00)
 

N.S.
 

P = 0.010
 

«...
 

2/52 (0.04)
 

N.S.
 

Low
 

Dose
 

6/45 (0.13)
 

P = 0.007**
 

Infinite
 

0.363
 

Infinite
 

Infinite
 

1.953
 

Infinite
 

109
 

3/45 (0.07)
 

N.S.
 

Infinite
 

0.073
 

Infinite
 

1.733
 

0.207
 

19.814
 

76
 

High
 

Dose
 

2/40 (0.05)
 

N.S.
 

Infinite
 

0.075
 

Infinite
 

Infinite
 

0.406
 

Infinite
 

111
 

6/41 (0.15)
 

N.S.
 

Infinite
 

0.215
 

Infinite
 

3.805
 

0.720
 

37.113
 

82
 —
 —
 
Table K2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Fed Dieldrin in the Dieta
 

(continued)
 

Topography: Morphology
 

Thyroid: Follicular-cell
 

Carcinoma'5
 

P Valuesc»d
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Thyroid: Follicular-cell
 

Adenoma or Carcinoma
 

P Values0>d
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched Pooled Low High 

Control Control Dose Dose 

0/4 (0.00) 1/52 (0.02) 2/45 (0.04) 2/41 (0.05) 

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

Infinite Infinite 

0.036 0.039 

Infinite Infinite 

2.311 2.537 

0.125 0.135 

131.973 146.183 __ __ 

100 111 

0/4 (0.00) 3/52 (0.06) 5/45 (0.11) 8/41 (0.20) 

N.S. P = 0.030 N.S. P = 0.043* 

Infinite Infinite 

0.154 0.307 

Infinite Infinite 

1.926 3.382 

0.397 0.876 

11.760 18.726 

76 82 — — 
__ 

Table K2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Fed Dieldrin in the Diet3
 

(continued) 

Topography: Morphology 

Matched 

Control 

Pooled 

Control 

Low 

Dose 

Thyroid:

or Carcino

 C-cell Adenoma 

ma" 1/4 (0.25) 12/52 (0.23) 12/45 (0.27) 

P Values0»d N.S. N.S. N.S. 

Relative Risk (Matched Control)f 1.067
 

Lower Limit 0.286
 

Upper Limit 44.456
 

Relative Risk (Pooled Control)* 1.156
 

Lower Limit 0.528
 

Upper Limit 2.514
 

Weeks to First Observed Tumor 110 100
 —~
 

Mammary Gland: Fibroadenoma'3 1/10 (0.10) 7/60 (0.12) 13/49 (0.27)
 

P Values0»d P = 0.069(N) N.S. P = 0.041**
 

Departure from Linear Trende P = 0.024 P = 0.004
 

Relative Risk (Matched Control)* 2.653
 

Lower Limit 0.502
 

Upper Limit 108.727
 

Relative Risk (Pooled Control)* 2.274
 

Lower Limit 0.919
 

Upper Limit 6.186
 

Weeks to First Observed Tumor 96 99
 

High
 

Dose
 

6/41 (0.15)
 

N.S.
 

0.585
 

0.128
 

26.318
 

0.634
 

0.213
 

1.657
 

69
 

3/49 (0.06)
 

N.S.
 

0.612
 

0.059
 

15.192
 

0.525
 

0.092
 

2.159
 

69
 
Table K2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Fed Dieldrin in the Diet3
 

(continued)
 

Matched Pooled Low High
 

Topography: Morphology Control Control Dose Dose
 

Uterus: Endrometrial
 

Stromal Polypb 1/10 (0.10) 6/56 (0.11) 4/46 (0.09) 1/40 (0.03)
 

P Values0 »d N.S. N.S. N.S. N.S.
 

Relative Risk (Matched Control)f 0.870 0.250
 

Lower Limit 0.104 0.004
 

Upper Limit 42.586 19.137
 

Relative Risk (Pooled Control)* 0.812 0.233
 

Lower Limit 0.178 0.005
 

Upper Limit 3.201 1.811
 

Weeks to First Observed Tumor 110 79 111
 —
 a

Treated groups received time-weighted average doses of 29 or 59 ppm.
 

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

c

Beneath the incidence of tumors in a control group is the probability level for the Cochran-


Armitage test when P < 0.10; otherwise, not significant (N.S.) is indicated. Beneath the
 

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

the comparison of that treated group with the matched-control group (*) or with the pooled-


control group (**) when P < 0.05 for either control group; otherwise, not significant
 

(N.S.) is indicated.
 

^A negative trend (N) indicates a lower incidence in a treated group than in a control group.
 

e

The probability level for departure from linear trend is given when P < 0.05 for any comparison.
 

APPENDIX L
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS
 

IN MICE FED DIELDRIN IN THE DIET
 

175
 

__ 

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

Fed Dieldrin in the Diet3
 

Matched Pooled Low
 

Topography: Morphology Control Control Dose
 

Liver: Hepatocellular
 

Carcinoma 3/18 (0.16) 17/92 (0.18) 12/50 (0.24)
 

P Values0 »d P = 0.065 P = 0.020 N.S.


Relative Risk (Matched Control)f 1.440
 

Lower Limit 0.449
 

Upper Limit 7.350
 

Relative Risk (Pooled Control)f 1.299
 

Lower Limit 0.622
 

Upper Limit 2.627
 

Weeks to First Observed Tumor 91 91
 

Lung: Alveolar /Bronchiolar
 

Adenoma or Carcinoma 1/18 (0.06) 7/91 (0.08) 3/50 (0.06)
 

P Values0 »d N.S. N.S. N.S.
 

Relative Risk (Matched Control)f 1.080
 

Lower Limit 0.096
 

Upper Limit 55.520
 

Relative Risk (Pooled Control)f 0.780
 

Lower Limit 0.135
 

Upper Limit 3.193
 

Weeks to First Observed Tumor 91 91
 —
 

High
 

Dose
 

16/45 (0.36)
 

P = 0.025**
 

2.133
 

0.714
 

10.449
 

1.924
 

1.000
 

3.602
 

88
 

3/46 (0.07)
 

N.S.
 

1.174
 

0.104
 

60.443
 

0.848
 

0.146
 

3.461
 

93
 
Table LI. Analyses of the Incidence of Primary Tumors in Male Mice
 

Fed Dieldrin in the Dieta
 

(continued)
 

a

Treated groups received doses of 2.5 or 5 ppm.
 

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

c

Beneath the incidence of tumors in a control group is the probability level for the Cochran-


Armitage test when P < 0.10; otherwise, not significant (N.S.) is indicated.
 

Beneath the incidence of tumors in a treated group is the probability level for the Fisher
 

exact test for the comparison of that treated group with the matched-control group (*) or
 

with the pooled-control group (**) when P < 0.05 for either control group; otherwise, not
 

significant (N.S.) is indicated.
 

^A negative trend (N) indicates a lower incidence in a treated group than in a control group.
 

e

The probability level for departure from linear trend is given when P < 0.05 for any comparison.
 

^The 95% confidence interval of the relative risk between each treated group and the
 

specified control group.
 
__ __ 

__ 

Table L2. Analyses of the Incidence of Primary Tumors In Female Mice
 

Fed Dieldrin in the Diet3
 

Topography: Morphology
 

Liver: Hepatocellular
 

Carcinoma
 

P Values0 »d
 

Departure from Linear Trend6
 

Relative Risk (Matched Control)*
 

Lower Limit
 

Upper Limit
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Multiple Sites: Lymphoma
 

P Values0 »d
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Pooled Control )f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched
 

Control
 

0/20 (0.00)
 

N.S.
 

P = 0.040
 

2/20 (0.10)
 

N.S.
 

91
 

Pooled
 

Control
 

3/78 (0.04)
 

N.S.
 

P = 0.047
 

8/79 (0.10)
 

N.S.
 

Low
 

Dose
 

6/50 (0.12)
 

N.S.
 

Infinite
 

0.667
 

Infinite
 

3.120
 

0.698
 

18.531
 

89
 

2/50 (0.04)
 

N.S.
 

0.400
 

0.032
 

5.282
 

0.395
 

0.042
 

1.899
 

91
 

High
 

Dose
 

2/49 (0.04)
 

N.S.
 

Infinite
 

0.125
 

Infinite
 

1.061
 

0.091
 

8.870
 

93
 

5/50 (0.10)
 

N.S.
 

1.000
 

0.187
 

10.036
 

0.988
 

0.267
 

3.205
 

80
 
Table L2. Analyses of the Incidence of Primary Tumors in Female Mice
 

Fed Dieldrin in the Dieta
 

(continued)
 

a

Treated groups received doses of 2.5 or 5 ppm.
 

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

c

Beneath the incidence of tumors in a control group is the probability level for the Cochran-


Armitage test when P < 0.10; otherwise, not significant (N.S.) is indicated. Beneath the
 

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

the comparison of that treated group with the matched-control group (*) or with the pooled-control
 

group (**) when P < 0.05 for either control group; otherwise, not significant (N.S.) is indicated.
 

"A negative trend (N) indicates a lower incidence in a treated group than in a control group.
 

e

The probability level for departure from linear trend is given when P < 0.05 for any comparison.
 

*The 95% confidence interval of the relative risk between each treated group and the
 

specified control group.
 
APPENDIX M
 

ANALYSES OF FORMULATED DIETS FOR
 

CONCENTRATIONS OF ALDRIN OR DIELDRIN
 

181
 

APPENDIX M
 

Analyses of Formulated Diets for
 

Concentrations of Aldrin or Dieldrin
 

A 10-g sample of the diet mixture containing aldrin or dieldrin
 

was shaken with 125 ml hexane at room temperature for 16 hours,
 

then filtered through Celite with hexane washes, and reduced to
 

10 ml in volume. After appropriate dilutions, the solution was
 

quantitatively analyzed for aldrin or dieldrin by gas-liquid
 

chromatography (electron capture detector; 10% QF-1 on Chromosorb
 

W column for aldrin, 10% DC-100 on Gas-Chrom Q column for
 

dieldrin). Recoveries were checked with spiked samples, and
 

external standards were used for calibration.
 

ALDRIN
 

Theoretical No. of Sample Coefficient of Range (ppm) 

Dietary Level Samples Analytical Variation (%) 

(ppm) Mean (ppm) 

2.0 13 1.9(9) 3.0 1.9-2.1 

4.0 18 3.9(3) 5.4 3.5-4.3 

7.5 2 7.3(5) 2.9 7.2,7.5 

8.0 17 7.9(4) 3.7 7.4-8.3 

15.0 2 14.8 1.0 14.7,14.9 

30.0 15 29.9 2.9 28.0-31.3 

60.0 16 59.3 3.8 54.5-63.5 

120.0 2 119.1 0.4 118.7,119.4 

183
 
Theoretical
 

Dietary Level
 

(ppm)
 

2.5
 

5.0
 

10.0
 

20.0
 

40.0
 

80.0
 

No. of
 

Samples
 

21
 

27
 

2
 

12
 

21
 

12
 

DIELDRIN
 

Sample
 

Analytical
 

Mean (ppm)
 

2.5(1)
 

5.0(3)
 

10.1
 

20.6
 

40.5
 

81.1
 

Coefficient of
 

Variation (%)
 

5.0
 

4.8
 

5.0
 

4.0
 

4.3
 

5.3
 

Range (ppm)
 

2.2(8)-2.7(4)
 

4.3(2)-5.5(8)
 

9. 7(9), 10. 5
 

19.2-21.3
 

36.1-43.7
 

72.7-91.0
 

4 U. S. GOVERNMENT PRINTING OFFICE : 1977 260-899/3164 

184 
DHEW Publication No. (NIH) 78-821