National Cancer Institute 

CARCINOGENESIS 

Technical Report Series 

No. 22 

1978 

BIOASSAY OF 

DIELDRIN 

FOR POSSIBLE CARCINOGENICITY 

CAS No. 60-57-1 

NCI-CG-TR-22 

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

Public Health Service 

National Institutes of Health 

BIOASSAY OF
 

DIELDRIN
 

FOR POSSIBLE CARCINOGENICITY
 

Carcinogenesis Testing Program
 

Division of Cancer Cause and Prevention
 

National Cancer Institute
 

National Institutes of Health
 

Bethesda, Maryland 20014
 

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

Public Health Service
 

National Institutes of Health
 

DHEW Publication No. (NIH) 78-822
 

BIOASSAY OF
 

DIELDRIN
 

FOR POSSIBLE CARCINOGENICITY -


Carcinogenesis Testing Program
 

Division of Cancer Cause and Prevention
 

National Cancer Institute
 

National Institutes of Health
 

CONTRIBUTORS; This report presents the results of the bioassay
 

of dieldrin for possible carcinogenicity, conducted for the
 

Carcinogenesis Testing Program, Division of Cancer Cause and
 

Prevention, National Cancer Institute (NCI), Bethesda, Maryland.
 

The bioassay was conducted by Stanford Research Institute, Menlo
 

Park, California, initially under direct contract to NCI and
 

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

contractor for the NCI carcinogenesis bioassay program.
 

The experimental design and doses were determined by Drs. R. R.
 

Bates1»2, D. C. L. Jones3, D. P. Sasmore3, G. W. Newell3, and R.
 

M. Elashoff^, and Mr. W. E. Davis3. The principal investigator
 

was Dr. D. C. L. Jones; the technical supervisor of animal
 

treatment, observation, and data handling was Mr. W. E. Davis;
 

necropsy and tissue fixation were supervised by Dr. D. P.
 

Sasmore.
 

Histopathologic examinations were performed by Dr. H. Elster ,
 

and the diagnoses included in this report represent his
 

interpretation. Neoplasms and compound-related hyperplastic
 

lesions were reviewed by Dr. W. M. Busey^, who also prepared the
 

interpretive pathology summary included in this report.
 

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 this
 

bioassay were analyzed at Stanford Research Institute and the
 

analytical results were reviewed by Dr. S. S. Olin^.
 

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

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

Marshall Steinberg**, Director of the Bioassay Program; Drs. J. F.
 

Robens8 and C. H. Williams8, toxicologists; Dr. R. L. Schueler8,
 

pathologist; Ms. L. A. Waitz8

 and Mr. W. D. Reichardt8,
 

bioscience writers; and Dr. E. W. Gunberg8

, technical editor,
 

assisted by Ms. Υ. Ε. Presley8

.
 

The statistical analysis was reviewed by members of the
 

Mathematical Statistics and Applied Mathematics Section of NCI9

:
 

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

Robert E. Tarone.
 

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 W. Orme
 

Dr. Robert A. Squire1 0
 

Dr. Jerrold M. Ward
 

•••Carcinogenesis Testing Program, Division of Cancer Cause and
 

Prevention, National Cancer Institute, National Institutes of
 

Health, Bethesda, Maryland.
 

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

Administration, Rockville, Maryland.
 

^Stanford Research Institute, Menlo Park, California.
 

^Department of Biomathematics, Center for the Health Sciences,
 

University of California, Los Angles, California.
 

iv
 
^Department of Pathology, David M. Brotman Memorial Hospital,
 

3828 Hughes Avenue, Culver City, California.
 

^Experimental Pathology Laboratories, Inc., P.O. Box 474,
 

Herndon, Virginia.
 

7

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

Rockville, Maryland.
 

8

Tracor Jitco, Inc., 1776 East Jefferson Street, Rockville,
 

Maryland.
 

^Mathematical Statistics and Applied Mathematics Section,
 

Biometry Branch, Field Studies and Statistics, Division of
 

Cancer Cause and Prevention, National Cancer Institute, National
 

Institutes of Health, Bethesda, Maryland.
 

w with the Division of Comparative Medicine, Johns Hopkins
 

University, School of Medicine, Traylor Building, Baltimore,
 

Maryland.
 

ν
 

SUMMARY
 

A bioassay of purified technical-grade dieldrin for possible
 

carcinogenicity was conducted by administering the test chemical
 

in feed to Fischer 344 rats.
 

Groups of 24 rats of each sex were administered dieldrin at one
 

of three doses, either 2, 10, or 50 ppm, for 104-105 weeks.
 

Matched controls consisted of groups of 24 untreated rats of each
 

sex. All surviving rats were killed at 104-105 weeks.
 

Body weights of the rats were essentially unaffected by the
 

treatment, but typical signs of organochlorine intoxication
 

including hyperexcitability, tremors, and coma were observed in
 

high-dose males beginning in week 76 and in high-dose females
 

beginning in week 80. Survival was not adversely affected, and
 

adequate numbers of rats were available for meaningful
 

statistical analyses of the incidences of tumors.
 

A variety of neoplasms occurred in control and treated rats;
 

however, the incidences were not related to treatment.
 

It is concluded that under the conditions of this bioassay,
 

dieldrin was not carcinogenic in Fischer 344 rats.
 

vii
 

TABLE OF CONTENTS
 

Page
 

I· Introduction 1
 

II. Materials and Methods 3
 

A. Chemical 3
 

· Dietary Preparation ······ 3
 

C. Animals 4
 

D. Animal Maintenance 5
 

E. Subchronic Studies 6
 

F. Design of Chronic Studies 7
 

G. Clinical and Pathologic Examinations 7
 

H· Data Recording and Statistical Analyses 9
 

III. Results - Rats 15
 

A· Body Weights and Clinical Signs 15
 

B. Survival 15
 

C. Pathology 18
 

D. Statistical Analyses of Results 19
 

IV. Discussion 21
 

V. Bibliography 23
 

APPENDIXES
 

Appendix A Summary of the Incidence of Neoplasms in
 

Rats Fed Dieldrin in the Diet 25
 

Table Al Summary of the Incidence of Neoplasms in
 

Male Rats Fed Dieldrin in the Diet 27
 

Table A2 Summary of the Incidence of Neoplasms in
 

Female Rats Fed Dieldrin in the Diet 30
 

Appendix Β Summary of the Incidence of Nonneoplastic
 

Lesions in Rats Fed Dieldrin in the Diet 35
 

Table Bl Summary of the Incidence of Nonneoplastic
 

Lesions in Male Rats Fed Dieldrin in the Diet 35
 

Table B2 Summary of the Incidence of Nonneoplastic
 

Lesions in Female Rats Fed Dieldrin in the Diet.... 39
 

ix
 
Page 

Appendix C Analyses of the Incidence of Primary Tumors 

in Rats Fed Dieldrin in the Diet 43 

Table CI Analyses of the Incidence of Primary Tumors 

in Male Rats Fed Dieldrin in the Diet 45 

Table C2 Analyses of the Incidence of Primary Tumors 

in Female Rats Fed Dieldrin in the Diet 47 

TABLES 

Table 1 Design of Dieldrin Chronic Feeding 

Studies in Rats 8 

FIGURES 

Figure 1

Figure 2

 Growth Curves for Rats Fed Dieldrin 

in the Diet

 Survival Curves for Rats Fed Dieldrin 

in the Diet

 16 

 17 

χ
 
I. INTRODUCTION
 

Dieldrin (CAS 60-57-1; NCI C00124) is a chlorinated cyclodiene
 

pesticide. It is also a metabolic conversion product of aldrin,
 

another pesticide, and can be expected to appear in the
 

environment following the use of either chemical· Dieldrin was
 

first introduced in the 1950's for use by cotton growers when the
 

chemical was found to be more effective than aldrin, and later,
 

was used as an insecticide for other crops, for public health
 

pest control, and for mothproofing woolen goods (Federal
 

Register, 1974).
 

Based partly on the evidence of the hepatocarcinogenicity of
 

dieldrin in the mouse, the registration of all products
 

containing dieldrin was cancelled in 1974 (Federal Register,
 

1974).
 

Dieldrin and aldrin were selected for testing in both rats and
 

mice in the bioassay program in 1969, because data regarding
 

their carcinogenicity were controversial and often inadequate,
 

and because there was a potential for long-term human exposure to
 

residues, particularly in foods. A report on the bioassays of
 

both chemicals in both species has been published (National
 

Cancer Institute, 1977). A second abbreviated study of dieldrin
 

was conducted as a part of a larger study that was designed to
 
assess the combined effects of a group of known or suspected
 

carcinogens. Only the results of this second study pertinent to
 

dieldrin are reported herein.
 

2 
II . MATERIAL AND METHODS 

A. Chemicals
 

Technical-grade dieldrin was purchased from Shell Development Company, Modesto, California, in a single batch (Lot No. 8-JCD-32)*
 

The chemical was purified before analysis and use in the bioassay. Purification was by treatment of a hot hexane solution with
 

Norit and by filtration, recrystallization from hexane, and
 

finally, recrystallization from absolute methanol.
 

The identity and purity of this product were confirmed by
 

analyses at Stanford Research Institute. The melting point was
 

179-181°C (literature: 175-176°C), and the elemental analyses (C,
 

H, CI) were correct for C^He^lo^» the molecular formula of
 

dieldrin· The identity of the chemical was determined by nuclear
 

magnetic resonance and infrared spectra, which were in agreement
 

with the structure and matched the spectra given in the literature. No attempt was made to identify or quantitate impurities·
 

The chemical was stored at room temperature in capped plastic
 

bottles.
 

B. Dietary Preparation
 

/B)
 

All diets were formulated every 2 weeks using Low Fat Lab Chow·
 
(Ralston Purina Co., St. Louis, Mo.). A stock diet containing
 

250 ppm dieldrin was prepared by first grinding the dieldrin to a
 

fine powder and then mixing by hand a weighed amount with a small
 

amount of feed. Corn oil and more feed were then added to give a
 

final concentration of 250 ppm dieldrin and 3% corn oil, and
 

final mixing was accomplished with a Hobart blender. Each stock
 

diet was analyzed for content of dieldrin by a method involving
 

®
 extraction, Florisil chromatography, and quantitation by
 

gas-liquid chromatography. Concentrations of 250 ppm + 25 ppm
 

were considered acceptable for use in preparing test diets.
 

Dieldrin at 250 ppm in the stock diet was found to be stable when
 

held in rat feeders at room temperature for a 2-week period.
 

To obtain test diets having appropriate concentrations of
 

dieldrin, the stock diet was diluted, as required, with control
 

diet containing 3% corn oil and mixed in a Hobart blender. Stock
 

and test diets were stored at room temperature in covered plastic
 

containers.
 

C. Animals
 

Male and female Fischer 344 rats, obtained through contracts of
 

the Division of Cancer Treatment, National Cancer Institute, were
 

used in these bioassays. The rats were obtained from Simonsen
 

Laboratory, Gilroy, California. On arrival at the laboratory,
 

4 
all animals were quarantined for 2 weeks as an acclimation
 

period. Following this period, all males gaining less than 25
 

grams, all females gaining less than 15 grams, and all unhealthy
 

animals were culled. The remaining animals were assigned to
 

cages, one per cage, until each cage contained three animals.
 

Cages were then numbered and assigned to control and treated
 

groups using a computer-generated randomization table. Rats were
 

ear-clipped for individual identification.
 

D· Animal Maintenance
 

All animals were housed in temperature- and humidity-controlled
 

rooms. The temperature was maintained at 22°C with a range of
 

21-24°C, and the relative humidity was maintained at approximately 45%. The room air was changed 10 times per hour and was
 

maintained under positive pressure to the access halls.
 

Fluorescent lighting provided illumination 12 hours per day.
 

Food and water were available axi libitum. Drinking water was
 

softened, filtered, sterilized with ultraviolet light, and
 

supplied by means of an automatic watering system.
 

The rats were housed three per cage in polycarbonate cages
 

equipped with disposable polyester woven filter tops. Autoclaved
 

hardwood chips (Iso-Dri®, Becton, Dickinson, and Carworth,
 

Warrensburg, N. Y.) were used as bedding. The cages were
 

5
 
changed, washed, and provided with fresh bedding twice per week.
 

Filter tops were replaced once per month.
 

Rats fed dieldrin were housed in the same room as rats treated
 

with hexachlorophene (CAS 70-30-4), aflatoxin Bx (CAS 1162-65-8),
 

Aroclor® 1254 (CAS 27323-18-8), or lead (II) acetate (CAS
 

301-04-2).
 

E« Subchronic Studies
 

Subchronic feeding studies were conducted with male and female
 

Fischer 344 rats to estimate the maximum tolerated dose of
 

dieldrin, on the basis of which low, mid, and high concentrations
 

(hereinafter referred to as "low doses11, "mid doses", and "high
 

doses") were determined for administration in the chronic
 

studies. In the subchronic studies, dieldrin was added to feed
 

in concentrations of 25, 50, 100, 200, or 300 ppm. Treated and
 

control groups each consisted of 15 male and 15 female rats. The
 

chemical was provided in the feed to the treated groups for 8
 

weeks.
 

All rats fed at 200 or 300 ppm dieldrin died within 2 weeks. At
 

100 ppm, during the first week, body weights of females were less
 

than those of controls, while those of males appeared comparable
 

to those of controls. Neuronal necrosis of the brain was noted
 

on histologic examination of those animals receiving 100 ppm, but
 
not 50 ppm, dieldrin. The low, mid, and high doses for the
 

chronic studies were set at 2, 10, and 50 ppm.
 

F. Design of Chronic Studies
 

The design of the chronic studies is shown in table 1.
 

G· Clinical and Pathologic Examinations
 

All animals were observed twice daily for signs of toxicity and
 

palpated for masses at each weighing. Animals were weighed
 

individually every other week for 12 weeks, and every fourth week
 

for the remainder of the study. Animals that were moribund at
 

the time of clinical examination were killed and necropsied.
 

The pathologic evaluation consisted of gross examination of major
 

tissues, major organs, and all gross lesions from killed animals
 

and from animals found dead. The following tissues were
 

routinely examined microscopically from both control and treated
 

animals: brain, liver, kidney, lung, pituitary, spleen, and
 

testis. In addition, sections of stomach, thyroid, trachea,
 

urinary bladder, and uterus were examined from a majority of the
 

control animals; these tissues were examined from treated animals
 

only if a lesion was found at necropsy. Gross lesions from any
 

other tissues in all animals were also examined microscopically.
 

The different tissues were preserved in 10% buffered formalin,
 
Table 1. Design of Dieldrin Chronic Feeding Studies in Rats
 

Sex and Initial Dieldrin Time on Study
 

Treatment No. of in Dietb Treated Untreated
 

Group Animals^ (ppm) (weeks) (weeks)
 

Male
 

Matched-Control 24 0 105
 

Low-Dose 24 2 104
 

Mid-Dose 24 10 105
 

High-Dose 24 50 105
 

Female
 

Matched-Control 24 0 105
 

Low-Dose 24 2 104
 

Mid-Dose 24 10 105
 

High-Dose 24 50 105
 

aAll animals were 53+ 2 days of age when placed on study.
 

°A11 diets contained 3% corn oil.
 
embedded in paraffin, sectioned, and stained with hematoxylin and
 

eosin. Special staining techniques were utilized when indicated
 

for more definitive diagnosis·
 

A few of the tissues selected by design from some animals were
 

not examined, particularly from those animals that died early.
 

Also, one animal was missing· Thus, the number of animals from
 

which particular organs or tissues were examined microscopically
 

varies, and does not necessarily represent the number of animals
 

that were placed on study in each group.
 

H. Data Recording and Statistical Analyses
 

Pertinent data on this experiment have been recorded in an 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.
 

9 
Probabilities of survival were estimated by the product-limit
 

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

report in the form of graphs· Animals were statistically
 

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

causes or were found to be missing; animals dying from natural
 

causes were not statistically censored. Statistical analyses for
 

a possible dose-related effect on survival used the method of Cox
 

(1972) for testing two groups for equality and Tarone's (1973)
 

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

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

departure from linearity test, which is only reported when its
 

two-tailed Ρ 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
 

necropsied (denominator)·
 

The purpose of the statistical analyses of tumor incidence is to
 

determine whether animals receiving the test chemical developed a
 

significantly higher proportion of tumors than did the control
 

animals. As a part of these analyses, the one-tailed Fisher
 

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

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

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

10
 
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) requires that the
 

 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 Ρ values are shown.
 

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

continuity correction (Armitage, 1971), was also used. Under the
 

assumption of a linear trend, this test determines if the slope
 

of the dose-response curve is different from zero at the one-


tailed 0.05 level of significance. Unless otherwise noted, the
 

direction of the significant trend is a positive dose relationship. This method also provides a two-tailed test of departure
 

from linear trend.
 

A time-adjusted analysis was applied when numerous early deaths
 

resulted from causes that were not associated with the formation
 

of tumors. In this analysis, deaths that occurred before the
 

first tumor was observed were excluded by basing the statistical
 

tests on animals that survived at least 52 weeks, unless a tumor
 

was found at the anatomic site of interest before week 52. When
 

such an early tumor was found, comparisons were based exclusively
 

on animals that survived at least as long as the animal in which
 

11
 
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 an animal died naturally or was sacrificed
 

was entered as the time point of tumor observation. Cox's
 

methods of comparing these curves were used for two groups;
 

Tarone's extension to testing for linear trend was used for three
 

groups. The statistical tests for the incidence of tumors which
 

used life-table methods were one-tailed and, unless otherwise
 

noted, in the direction of a positive dose relationship.
 

Significant departures from linearity (P < 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
 

treated group of animals and pc is the true probability of the
 

spontaneous incidence of the same type of tumor in a control
 

12
 
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 (P < 0.025 one-tailed test when the control
 

incidence is not zero, Ρ < 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.
 

13
 

III. RESULTS
 

A. Body Weights and Clinical Signs
 

Mean body weights were essentially unaffected by the doses of
 

dieldrin used in this bioassay (figure 1). Fluctuations in the
 

growth curve may be due to mortality; as the size of the group
 

diminishes, the mean body weight may be subject to wide
 

variation. At week 40, an intercurrent infection caused respiratory problems and weight loss, but few animals died. No treatment for infection was given, and the animals recovered by the
 

next scheduled weighing period.
 

At week 76, clinical signs of central nervous system disorders
 

such as convulsions, muscle tremors, and nervous behavior were \/
 

first noted in high-dose males, and around week 80, these signs
 

were apparent in the high-dose females.
 

B. Survival
 

The Kaplan and Meier curves estimating the probabilities of
 

survival for male and female rats fed dieldrin at the doses of
 

this study, together with those of the controls, are shown in
 

figure 2.
 

In neither sex is the Tarone test result significant at the 0.05
 

level for positive dose-related trend in mortality over the
 

15
 
400 

350­

300 ­

2 

^ 250 

I 

CD 

in 

5 200 ­ >•

ο 

CO 150 ­

M 

100­

50 ­

MALE RATS 

D MATCHED CONTROL 

 LOW DOSE 

 MID DOSE 

 HIGH DOSE 

300 

10 20 30 40 50 60 70 

TIME ON STUDY (WEEKS) 

80 90 100 110 

—

250 ­

 200 ­ 0 

 Δ Δ Δ 0 

 Δ Δ Δ Δ 

150 ­

100 : ' 

50 ­

FEMALE RATS 

D MATCHED CONTROL 

 LOW DOSE 

 MID DOSE 

 HIGH DOSE 

30 60 

TIME ON STUDY (WEEKS) 

Figure 1. Growth Curves for Rats Fed Dieldrin in the Diet 

16
 
> 

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D 

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i 

CQ 

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0 80 

0 70 ­

0 60 ­

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MALE RATS
 

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 v 

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15 30 45 60 75 90 105 120 135 

TIME ON STUDY (WEEKS) 

Δ-: 

Δ-: 

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FEMALE RATS
 

D MATCHED CONTROL
 

 LOW DOSE
 

 MID DOSE
 

 HIGH DOSE
 

TIME ON STUDY (WEEKS) 

Figure 2. Survival Curves for Rats Fed Dieldrin in the Diet 

17
 
period. In male rats, 67% of the high-dose group, 75% of the
 

low- and mid-dose groups, and 92% of the matched-control group
 

lived to the end of the study. In females, 70% of the high-dose
 

group, 83% of the mid-dose group, and 88% of the low-dose and
 

matched-control groups survived to termination of the study.
 

Sufficient numbers of rats of both sexes were available for
 

meaningful statistical analyses of the incidences of late-


developing tumors.
 

C. Pathology
 

Histopathologic findings on neoplasms in rats are summarized in
 

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

are summarized in Appendix B, tables Bl and B2.
 

A variety of neoplasms were observed in both the control and
 

treated rats. The incidence of these neoplasms was comparable
 

among the control and treated animals. Interstitial-cell tumors
 

of the testes were the most frequently encountered neoplasms in
 

the control and treated males. The next most commonly seen
 

neoplasm was leukemia of either the lymphocytic or granulocytic
 

type, and it generally involved multiple organs. Here again, the
 

incidence of this neoplastic process was comparable among the
 

control and treated male rats.
 

The following neoplasms occurred randomly throughout the control
 

18
 
and treated male and female rats: pituitary adenomas, thyroid
 

adenomas, mammary gland adenomas and/or fibroadenomas, mesotheliomas involving the body cavities, and uterine endometrial
 

stromal polyps.
 

The results of the histopathologic examination indicate that the
 

administration of dieldrin at the three doses used in this study
 

did not have a carcinogenic effect in the Fischer 344 rat. With
 

the exception of interstitial-cell tumors of the testes, a
 

relatively low incidence of neoplasia was seen in both the
 

control and treated animals. A variety of incidental neoplastic
 

processes were seen in both the control and treated rats at an
 

incidence that would be expected in this strain of rat.
 

D« Statistical Analyses of Results
 

Tables CI and C2 in Appendix C 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. Due to the nature of the pathology protocol, the number of
 

animals necropsied was used as the denominator.
 

In male rats, none of the incidences of tumors at any specific
 

site are statistically significant. In female rats, although the
 

Cochran-Armitage test result for positive dose-related trend in
 

the proportions of endometrial stromal sarcoma of the uterus is
 

19
 
significant (P = 0.039), this positive finding cannot be established by the Fisher exact test. Since the Cochran-Armitage test
 

is made to detect a linear trend, and in this instance only one
 

incidence (high-dose 2/23 [9%]) is not zero, it is questionable
 

whether a dose-associated trend has been found. When the
 

incidences of stromal polyp and stromal sarcoma are combined, the
 

results indicate a significant difference in the negative
 

direction, due to the large incidence (13/24 [54%]) in the
 

control group. The combined incidence of these two tumors in the
 

four control groups available from this laboratory is 22/95
 

(23%), of which 13 diagnoses are from this study. There is no
 

other specific incidence of tumors in female rats that is
 

statistically significant. Significant results in the negative
 

direction are also observed in the incidence of interstial-cell
 

tumor of the testis and the incidence of endometrial stromal
 

polyp of the uterus.
 

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

in the tables, the value of one is included. This indicates the
 

absence of positive significant results. It should also be noted
 

that some of the intervals have 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.
 

20
 
IV. DISCUSSION
 

In this bioassay, dieldrin did not adversely affect the body
 

weights of the treated rats, but typical signs of systemic
 

organochlorine intoxication were observed at the high dose from
 

approximately week 76 in males and week 80 in females. Survival
 

was not adversely affected, and adequate numbers of rats were
 

available for meaningful statistical analyses of the incidences
 

 tumors.
 

A variety of neoplasms were found in both control and treated
 

rats, none of which could be attributed to dieldrin. In this
 

study, the predominant tumors were interstitial-cell tumors of
 

the testes, which occurred in almost all the males in the control
 

and treated groups, and granulocytic leukemia, which occurred at
 

a low incidence in the control and treated groups of both sexes.
 

Females in each of the control and treated groups also developed
 

endometrial stromal polyps. Statistically, the incidences of
 

these tumors were not significant, and the tumors were considered
 

to be of spontaneous origin.
 

In another bioassay of dieldrin (National Cancer Institute,
 

1977), conducted with Osborne-Mendel rats and using time-weighted
 

average doses of 29 and 59 ppm, the predominant tumors occurred
 

in the pituitary and thyroid glands, but vere not clearly related
 

21
 
to the administration of dieldrin· These tumors were not seen in
 

the Fischer 344 rats in the present study, using a high dose of
 

50 ppm. However, the thyroids of the Fischer 344 rats treated
 

with dieldrin were not routinely examined microscopically.
 

This bioassay is in agreement with previously published studies
 

by Fitzhugh et al. (1964) and by Deichmann et al. (1970) using
 

Osborne-Mendel rats, and by Walker et al. (1969) using Carworth
 

ffEfl
 Farm strain rats, in which there were no significant
 

increases in tumors among treated rats.
 

It is concluded that under the conditions of this bioassay,
 

dieldrin was not carcinogenic in Fischer 344 rats.
 

22
 
V. 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 jof the
 

Panel of Carcinogenicity of the Cancer Research Commission
 

of UICC, Vol. j£, International Union Against Cancer, Geneva,
 

1969.
 

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

Soc. B34(2):187-220, 1972.
 

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

1970, pp. 48-52.
 

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

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

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

Medicine 19(10):37-45, 1970.
 

Federal Register, Shell Chemical Co. et al. Consolidated
 

Aldrin/Dieldrin Hearing. 3£(203):37246-37272, 1974.
 

Fitzhugh, 0. G. , Nelson, Α. Α., 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. Statist. Inst. 3^:148-169, 1971.
 

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

incomplete observations. JN. Amer. Statist. Assoc.
 

53:457-481, 1958.
 

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

Peters, J. Α., Carcinogenesis bioassay data system. Comp.
 

and Biomed. Res. Tj 230-248, 1974.
 

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

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

National Cancer Institute, Bioassays of aldrin and dieldrin for
 

possible carcinogenicity. Technical Report Series No. 21
 

(DHEW Pub. No. 77-821), 1977.
 

23
 
Saffiotti, U., Montesano, R., Sellakumar, A. R., Cefis, F., and
 

Kaufman, D. G., Respiratory tract carcinogenesis in hamsters
 

induced by different numbers of administrations of
 

benzo(a)pyrene and ferric oxide. Cancer Res. 32; 1073-1081.,
 

1972.
 

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

62(3);679-682, 1975.
 

Walker, A. 1. T. , Stevenson, D. E., Robinson, J., Thorpe, E., and
 

Roberts, M., The toxicology and pharmacodynamics of dieldrin
 

(HEOD): two-year oral exposures of rats and dogs. Toxicol.
 

Appl. Pharmacol. 15;345-373, 1969.
 

24
 
APPENDIX A
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS
 

IN RATS FED DIELDRIN IN THE DIET
 

25
 

TABLE ΑΙ.
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE RATS
 

FEDDIELDRININTHEDIET
 

CONTROL DOSE LOW DOSE MEDIUM DOSE HIGH DOSE
 

MIMALS INITIALLY IN STDDT 24 24 24 24
 ANIMALS NECROPSIED 24 24 24 24
 AMII1ALS IXAHIMID HISTOPATHOLOGICALLY 24 24 24 24
 

INTIEGUHENTARY SYSTEM 

(24) (24) (24) 

ANGICSARCOHA 1 (4%) 

OSTEOSARCOHA 1 (4%) 

•SUBCOT TISSUE	 (24)
 

ESPIRATORY SYSTEM
 

*1UVG (24) (24) (23) (22) 

CARCINOHA, NOS , HBTASTATIC 1 (5%) 

OSTEOSARCOHA. METASTATIC 1 (4%) 

HEMATOPOIETIC SYSTEM
 

•HU1TIEIE ORGANS	 (24) (24) (24) (24)
 

LYMPHOCYTIC LEUKEMIA 1 (4%)
 

GRANULOCYTIC LEUKEMIA 1 (4%) 5 (21%) 5 (21%) 5 (21%)
 

CIRCU1ATCRI SYSTEH
 

NONE
 

DIGESTIVE STSTEH
 

NC Ν f
 

URIMARY STSTEH
 

•KIDNEY/CORTEX	 (24) (24) (23) (23) 

CARCINCHA.NOS 1 (4%i 

* NUMBER OP ANIMALS KITH TISSUE EXAMINED MICROSCOPICALLY 

• NUHBER OF ANIHALS NECROPSIED 

27
 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED)

 

CONTROL DOSE LOW DOSE MEDIUM DOSE HIGH DOSE 

iOBINABY BLADDER 

PAPIILOHA, NOS 

(15) 

1 (7%) 

(1) (1) 

ENDOCRINE SYSTEM 

•PITUITARY 

ADENOMA, NOS 

#THYBOIC 

SHALI-CELL CARCINOMA 

ADENOMA, NOS 

«PANCREATIC ISLETS 

ISLIT-CELL CARCINOMA 

(24) 

(15) 

1

(12) 

 (7%) 

(24) 

3 (13%) 

(6) 

1 (17%) 

(24) 

1 (4%) 

(23) 

1 (4X) 

(1) 

1 (10C 

(1) 

REPRODUCTIVE SYSTEM 

•TESTIS

INTERSTITIAL-CELL TOHOR

 (24)

 24 (100%)

 (24)

 23 (96%)

 (24)

 24 (100%)

 (24) 

 20 (83%) 

NERVOUS SYSTEM 

NONE 

SPECIAL SENSE ORGANS 

NCNE 

MUSCULOSKELETAL SYSTEM 

NONE 

BODY CAVITIES 

•TUNICA VAGINALIS

MESOTHELIOMA, NOS

 (24) (24) (24)

 1 (4%) 

 (24) 

ALL OTHEB SYSTEMS 

•MULTIF1E ORGANS

MESOTHELIOMA. MALIGNANT

 (24) (24) (24) y

 JLJUU 

 (24) 

# NUMEEF OP ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

• NUMBER CFV

 ANIMALS NECROPSIED 

28
 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

CONTROL DOSE LOW DOSE MEDIUM DOSE HIGH DOSE
 

ANIMAL DISPOSITION SUMMARY
 

ANIMALS INITIALLY IN STUDY 24 24 24 24
 

NATURAL DEATHS 2 1 6
 

MCRIEUND SACRIFICE 2 4 5 2
 

SCHIEULEC SACRIFICE
 

ACCIDENTALLY KILLED
 

TERMINAL SACRIFICE 22 18 18 16
 

ANIPAL MISSING
 

§ INCLUDES AUTOLYZED ANIMALS
 

TUPCR SUFPARY
 

TOTAL ANIMALS WITH PRIMARY TUPORS* 24 23 24 23
 

TOTAI PRIMARY TUMORS 29 32 32 29
 

TOTAL ANIMALS WITH BENIGN TUMCRS 24 23 24 20
 

TCTAL BENIGN TUMORS 26 26 25 21
 

TOTAL ANIMALS WITH MALIGNANT TUMORS 3 6 6 8
 

TOTAL MALIGNANT TUMORS 3 6 6 8
 

TOTAL ANIMALS WITH SECONDARY TUMORS· 1 1
 

TOTAL SECONDARY TUMORS 1 1
 

TOTAL ANIMALS WITH TUMORS UNCERTAINBENIGN OR MALIGNANT 1
 

TOTAL UNCERTAIN TUMORS 1
 

TOTAL ANIMALS WITH TUMORS UNCIRTAINPR:EMABY OR METASTATIC
 

TOTAL UNCERTAIN TUMORS
 

• PB1CMARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 

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

29 
TABLE A2.

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS 

FEDDIELDRININTHED1ET 

CONTROL DOSE LOW DOSE 

ANIMALS INITIALLY IN STUDY 

ANIMALS MISSING ANIMALS NECROPSIED ANIMALS EXAMINED HISTOPATHOLOGICALLY 

24 

24 

24 

24 

24 

24 

INTEGUMENTARY SYSTEM
 

*SKTN (24) (24)
 

SQUAMOUS CELL CARCINOMA
 

•SUBCUT TISSUE	 (24) (24)
 

SQUAMOUS CELL CARCINOMA 1 (4%)
 

PESPIRATCRY SYSTEM
 

#LUNG (23) (24)
 

ALVECLAR/BFONCHIOLAR ADENOMA 1 (4%)
 

HEMATOECIETIC SYSTEM
 

•HULTIFLE ORGANS	 (24) (24)
 

MALIG.LYMPHOMA, LYMPHOCYTIC TYPE 1 (4%)x
 

GRANULOCYTIC LEUKEMIA 1 <4X) 3 (13%)
 

#LIVEP (24) (24)
 

GRANULOCYTIC LEUKEMIA
 

CIRCULATORY SYSTEM
 

NONE
 

DIGESTIVE SYSTEM
 

NCNi
 

URINARY SYSTEH
 

•GENITOURINARY TRACT	 (24) (24)
 

PAEILLCUA. NOS
 

« NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 • NUMBER OF ANIMALS NECROPSIED
 

MEDIUM DOSE
 

24
 

24
 

24
 

(24)
 

1 (4«)
 

(24)
 

(24)
 

(24)
 

5 (21%)
 

(24)
 

(24)
 

HIGH DOSE
 

24
 

1
 

23
 

23
 

(23)
 

(23)
 

1 (4%)
 

(23)
 

(23)
 

4 (17%)
 

(23)
 

1 (4%)
 

(23)
 

30
 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED)

 

CONTROL DOSE LOW DOSE
 

«URINARY BLADDER (14)
 

TRAHSITIONAL-CELL CARCINOMA 1 (7%)
 

ENDOCRINI SYSTEM
 

«PITUITARY (2U) (23)
 

ACINCHA, NCS 2 (8X) 7 (30%)
 

REPRODUCTIVE SYSTEM
 

•MAMMARY	 GLANE (24) (24)
 

ADENCHA, NCS 2 (8%)
 

ADENOCARCINOMA, NOS 1 (4%)
 

CYSTADENOHA, NOS 1 (4%)
 

PIEROMA 1 (4%)
 

PIEHCADENOMA 2 (8%)
 

•UTERUS	 (22) (10)
 

ADENOCARCINOMA, NOS
 

LEICPYOMA 1 (10%)
 

ENDOMETRIAL STROMAL POLYP 13 (59%) l (70%)
 

ENDOMETRIAL STROMAL SARCOMA
 

NERVOUS SYSTEM
 

«ERAIN (24) (24)
 

HEMAHGIOSABCOMA
 

OLIGODENDPCGLICMA 1 (4%)
 

MENINGIOMA
 

SPECIAL SENSE OPGANS
 

NONE
 

MUSCULCSKELETAL SYSTEM
 

BODY CAVITIiS
 

« NUMEER OP ANIMALS HITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBIR OF ANIMALS NECPOPSIED
 

MEDIUM DOSE
 

(24)
 

4 (17%)
 

(24)
 

1 (4%)
 

(8)
 

1 (13%)
 

4 (50%)
 

(23)
 

1 (4%)
 

1 (4%)
 

HIGH DOSE
 

(23)
 

2 (9%)
 

(23)
 

2 (9%)
 

(13)
 

4 (31%)
 

2 (15%)
 

(23)
 

31
 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED)
 

CONTROL DOSE LOW DOSE MEDIUM DOSE HIGH DOSE 

ALL CTHEF SYSTEMS 

NCNF 

ANIPAL USECSITION SDMHABY 

ANIMALS INITIALLY IN STUDY 

NATUFAL DEATHS 

«CRIEOND SACRIFICE 

SCHfEULED SACRIFICE 

ACCIDENTALLY KILLED 

TERMINAL SACRIFICE 

AKIPAL HISSING 

24 

1 

2 

21 

24 

3 

21 

2U 

3 

1 

20 

24 

7 

16 

1 

 INCLUDES AUTOLYZED ANIMALS 

TUPCR SUPPAFY 

TOTAL ANIMALS WITH PRIMARY TUBORS* 

TOTAL PRIMARY TUHOPS 

17 

23 

17 

23 

16 

19 

14 

16 

TOTAL iNIMALS WITH BENIGN TUHCRS 

TCTAI BENIGN TUMORS 

14 

19 

13 

18 

9 

9 

8 

8 

TOTAL ANIMALS WITH MALIGNANT 1UMORS 

TOTAL MALIGNANT TUMCRS 

4 

α 5 

5 

9 

10 

1 

8 

TOTAL ANIMALS WITH SECONDARY TUMORS· TCTAL SECONDARY TUHCRS 

TOTAL ANIMALS WITH TUPCFS UNCERTAINBENIGN OR MALIGNANT 

TOTAL UNCERTAIN TUMORS 

TCTAL ANIMALS WITH TUMORS

PRIMARY OR METASTATIC 

TOTAL UNCERTAIN TUHOPS 

UNCERTAIN­

* PRIMARY TUHCES: ALL TUMORS EXCEPT SECONDARY TUHORS 

# SECCNCARY TUMORS: METASTATIC 1OHORS OR TUMORS INVASIVE INTO AN ADJACENT CRGAN 

32
 
APPENDIX B
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS
 

IN RATS FED DIELDRIN IN THE DIET
 

33
 

TABLE B1.
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE RATS
 

FEDDIELDRININTHEDIET
 

CONTROL DOSE LOW DOSE MEDIUM DOSE HIGH DOSE 

ANIMALS INITIALLY IN STOEY 24 24 24 24 

ANIMALS; BECROPSIED 24 24 24 24 

ANIMALii EXAMINED HISTOP1THOLOGICALLY 2 4 24 24 24 

INTEGUMENTARY SYSTEM 

• SKIN	 (24) (24) (24) (24)
 

CYST, NOS 1 (4%)
 

*SUBCuT TISSUE (2U) (24) (24) (24) 

EPIDERMAL INCLUSION CYST 1 (4%) 

RESPIR/lTCRY SYSTEM 

•TRACHEA	 (15)
 

INFLAMMATION, NOS 2 (13%)
 

INFLAMMATION, ACDTE 1 (7%)
 

ILUNG/EiONCHUS (24) (24) (23) (22) 

BRONCHIECTASIS 1 (<•*) 1 (4%) 2 (9%) 

INFLAMMATION, NOS 1 (4%) 1 (4%) 

#LUNG (24) (24) (23) (2 1) 

ATELECTASIS 5 (21%) 1 (4%) 2 (9%) 

CONGESTION, NOS 14 (58%) 16 (67%) 11 (48%) 8 (36%) 

HEMORRHAGE 1 (4%) 

INFLAMMATION, NOS 1 (4%) 

INFLAMMATION, FOCAL 1 (4%) 

ABiiCESS, NOS 2 (8%) 2 (8%) 2 (9%) 2 (9%) 

HEMATOPOIETIC SYSTEM 

• SPLEI'N	 (23) (24) (2ϋ) ( 2 3) 

CONGESTION, NOS 1 (4%) 

Pli'PCCALCIFIC NODULE 1 (<•%) 

INFARCT, NOS 1 (4%) 

«LYMPH NCCE (6) (3) (3) 

LYf|PHANGIECTASIS I (100% ) 

# NUMEER OP ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBliR OF ANIMALS NECROPSIED 

35
 
TABLE B1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL DOSE LOW DOSE MEDIUM DOSE HIGH DOSE 

CONGESTION, NOS 

INFLAMMATION, GRANULOMATOUS 

REACTION, FOREIGN BODY 

HISTIOCYTOSIS 1 (17%) 2 (33%) 

1

1

 (33%) 

 (33%) 

•RENAL LYMPH NODE 

LYMPHANGIECTASIS (6) 

1 (17%) 

(3) (3) 

CIRCUIATCRY SYSTEM 

•HEART 

HEMORRHAGE 

INFLAMMATION, NOS 

(1) 

1 (100%) 

1 (100%) 

• HEABlT/ATRIUM 

DEGENERATION, NOS (1) 1 (100%) 

DIGESTIVE SYSTEM 

•LIVER 

CONGESTION, NOS 

SCAR 

HYPERPLASIA, NODULAR 

ANGIECTASIS . 

(24) 12 

1 

2 

(50%) 

(4%) 

(8%) 

(23) 

6 (26%) 

(23) 

3 (13%) 

1 (4%) 

(23) 

8 

4 

1 

(35%) 

(17%) 

(<»%) 

• LIVI.R/CENTRILOBULAR 

CONGESTION, NOS 

(24) (23) (23) (23) 

1 

•STOMACH 

DIVERTICULUM 

EPIDERMAL INCLUSION

CONGESTION, NOS 

DIVERTICULITIS 

 CYST 

(23) 

1

1

1

 (<»%) 

 (4%) 

 (4%) 

(4) 

1 (2 5%) 

(3) 

•CECOM 

CONGESTION, NOS 

NECRCSIS, NOS 

HYPERPLASIA, LYMPHOID 

(3) (1) 

1 

1 

(100%) 

(100%) 

(2) 

1 (50%) 

• ANUS 

DIVERTICULUM 

(24) (24) (24) (24) 

1 (<•%) 

1 (4%) 

• NUMEER OF ANIMALS WITH TISSUE EXAMINED

• NUMBER OF ANIMALS NECROPSIED 

 MICROSCOPICALLY 

36
 
TABLE B1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED)

 

CONTROL DOSE LOW DOSE
 

URIM^BY SYSTEM 

•KIDNEY (24) (24) CALCOLUS, NOS 1 (<*%) 

HYDRONEPHROSIS 1 (4%) 

CYST, NOS 

PYELONEPHRITIS, NOS 1 (4%) 

PYELONEPHRITIS, FOCAL
 

•URINARY BLADDER	 (15) (1) CONGESTION, NOS 1 (100%) 

INFLAMMATION, ACOTE 

ENDOCRINE SYSTEM
 

•PITUITARY	 (24) (24)
 

CONGESTION, NOS 1 (<*%)
 

•ADRENAL
 

CONGESTION, NOS
 

•TBiROIE	 (15)
 

CNFLAHMATION, NOS 1 (7%)
 

'SODUIE 1 (7%)
 

REPRODUCTIVE SYSTEM
 

•SEMINAL VESICLE	 (24) (24) 

DILATATION, NOS 2 (8%) 

HYPERPLASIA, FOCAL 

•TESTIS	 (24) (24) 

ATROFHY, NCS 1 (4%) 

NERVOUS SYSTEM
 

•ERAIN	 (24) (23) 

CONGESTION, NOS 1 (4%) 

HEMORRHAGE 1 (4%) 

CALCIFICATION, FOCAL 1 (4%) 

SPECIAL SENSE ORGANS
 

•	 NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* «UI1BER OF ANIMALS NBCROPSIEC
 

MEDIUM DOSE HIGH DOSE 

(23) (23)
 

2 (9%)
 

1 (U%) 2 (9%)
 

1 (<*%)
 

(1)
 

1 (100%)
 

(2U) (23)
 

1 (<*%)
 

(1)
 

1 (100%)
 

(1)
 

(24) (24) 

1 (4%) 

(24) (24) 

1 (4%) 

(24) (24)
 

1 (<•*) 

37
 
TABLE B1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL DOSE LOW DOSE MEDIUM DOSE HIGH DOSE 

MUSCULOSKELETAL

NONE 

 SYSTEM 

BODY CAVITIES 

•INGUINAL REGION 

NECROSIS, FAT (24)

2 (8%) 

(24)

1 (4%) 

(24)

8 (33%) 

(24)

3 (13%) 

ALL OTREB SYSTEMS 

NONE 

SPECIAL POHFHOLOGY SUMMARY 

NCNE 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED

* NUMBER OF ANIMALS NECBOPSIEE 

 BICFOSCOPICALLY 

38
 
TABLE B2.
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE RATS
 

FEDDIELDRININTHEDIET 

CONTROL DOSE LOW DOSE
 

ANIHALS INITIALLY IN STUDY 24 24
 

ANIMALS HISSING
 

ANIMALS NECBOPSIED 24 24
 

ANIHALS EXAMINED HISTOPATHOLOGICALL Υ 24 24
 

INTEGUMEKTABY SYSTEM
 

•SKIN	 (24) (24)
 

EPICEBMAL INCLUSION CYST
 

•SOBCUT TISSUE	 (24) (24)
 

HEMOBBHAGE
 

ABSCESS, NOS
 

RESPIBATOBY SYSTEM
 

#TBACHEA (21)
 

INFLAMMATION, ACUTE 1 (5X)
 

#LUNG/EFCNCHUS (23) (24)
 

INFLAMMATION, NOS 1 (4X) 2 (8X)
 

«LUNG	 (23) (24)
 

ATELECTASIS 1 (4X) 1 (4X)
 

CONGESTION, NOS 10 (43X) 11 (46X)
 

EDEMA, NOS
 

PETECHIA
 

INFLAMMATION, FOCAL 1 (4X)
 

INFLAMMATION, INTEBSTITIAL 1 (4X)
 

AESCESS, NOS 2 (9X)
 

ADHESION, NOS
 

HEMATOPOIETIC SYSTEM
 

«SPLfEN (23) (22)
 

CONGESTION, NOS
 

REACTION, FOBEIGN BODY 1 (4X)
 

* NUHEEB OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECBOPSIED
 

MEDIUM DOSE
 

24
 

24
 

24
 

(24)
 

(24)
 

1 (4X)
 

(24)
 

1 (4X)
 

(24)
 

4 (17X)
 

14 (58X)
 

1 (4X)
 

1 <»X)
 

(24)
 

HIGH DOSE
 

24
 

1
 

23
 

23
 

(23)
 

(23)
 

(23)
 

(23)
 

3 (13X)
 

6 (26%;
 1 (4%)
 

1 (4%)
 

(22)
 

1 (5%)
 

2 (9X)
 

39
 
TABLE B2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED)
 

MEDIUM DOSE HIGH DOSE 

(2)	 (2)
 

1 (50%)
 

(24)	 (23)
 1 (*»%) 3 (13%)
 2 (8%)
 2 (9%) 

(4%) 

(Ό ( 6) 

1 (17%)
 

1 (2*5*)
 

1 (251)
 

(1)
 

1 (100%)
 

(24) (23)
 

(24) (23) 

2 (8%) 6 (26%) 

CONTROL DOSE 

HEMATOPOIESIS
 

#LYMPH NODE (3)
 

LYMPHANGIECTASIS
 

CIRCULATORY SYSTEM
 

NONE
 

DIGESTIVI SYSTEM
 

#LIVER (24)
 

CCNGiSTION, NOS 3 (13%)
 INFLAMMATION, GRANULOMATOUS
 

REACTION, FOREIGN


NECROSIS, FOCAL
 

NECROSIS, ISCHEMIC
 

iSTCMACH
 

DIVfFTICULUM
 

CONGESTION, NOS
 

INFLAMMATION, NOS
 

#CUOD1NUM
 

COMGISTICN, NOS
 

INFLAMMATION, NOS
 

URINARY SYSTEM
 

#KIDNEY
 

CALCINOSIS, NOS
 

#UBINAFY BLADDER
 

CALCULUS, NOS
 

ENDCCBINi SYSTEM
 

iFITUITARY
 

CYST, NOS
 

CONGESTION, NOS
 

HEMORRHAGE
 

 BODY	 2 (8%) 

1 (4%) 

(24) 

(3)
 

1 (33%)
 

(22)
 

)
 

1 (7%)
 

(24) 

4 (17%) 

LOW DOSE 

1 (5%)
 

(1)
 

(24) 

2 (8%) 

1 (4%) 

(24)
 

1 (4%)
 

(23)

1 (4%) 

2 (9%) 

- 2­(9%) 

# NUMEER OF ANIMALS iITH TISSUE EXAMINED MICROSCOPICALLY
 

*	 NUMBER OF ANIMALS NECROPSIED
 

40
 
TABLE B2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL DOSE LOW DOSE MEDIUM DOSE HIGH DOSE 

«ADBBKAI (2) (1) 

CONGESTION, NOS 1 (100%) 

REPRODUCTIVE SYSTEH
 

*HAMIiAFY GLANE (24) (24) (24) (23) 

HYPERPLASIA, NOS 1 (<•%) HYPERPLASIA, CYSTIC 1 (4%) 

•VAGINA	 (24) (24) (24) (23)
 

NECROSIS, FAT 1 (4%)

 

• UTF.RUS	 (22) (10) (8) (13) 

HYEBCMETRA 2 (9%) 3 (30%) 1 (13%) 1 (8%) 

CONGESTION, NOS 1 (8%) 

PYOMETRA 5 (23%) 4 4 (31%) 

ABSCESS, NOS 1 (5%) 2 (20%)	 1 (8%) 

#UTERUS/ENECMFTRIUM (22) (8) (13) 

INFLAMMATION, NOS (10) 1 (8%) 

INFLAMMATION, FOCAL 1 (5%) 

HYPEFPLASIA, NOS 1 (13%) 1 (8%) 

HYPERPLASIA, CYSTIC 2 (9*) 

#CVARY (21) (3) (1) CYST, NOS 1 (5%) 1 (33%) 1 (100%) 

ABSCESS, NOS 1 (5%) 3 (100%) 

CORPUS LUTEUM 1 (33%) 

NERVOUS SYSTEM
 

#BRAIN/PENINGES (24) (24) (23) (23)

 

INFLAMMATION, NOS 1 <<•%)

 

#BRAIN (24) (24) (23) (23)

 

CONGESTION, NCS 1 (4%)

 

SPECIAL SENSE ORGANS
 

NONF
 

MUSCULOSKELETAL SYSTEM
 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* »UHI?EF 0 * ANIMALS NECBOPSIEE 

41
 
TABLE B2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED)
 

CONTROL DOSE LOW DOSE MEDIUM DOSE HIGH DOSE 

BODY CAVITIES 

•INGUINAL BEGICN 

NECROSIS, FAT 

•PLSOΕA 

INFLAMMATION, DOS 

(24) 

1 (4X) 

(24) 

(24) 

1 (4%) 

(24) 

(24) 

1 (4*) 

(24) 

1 (4%) 

(23) 

(23) 

ALL OTHER SYSTEMS 

NONE 

SPECIAL HOBfHOLOGY SUMMARY 

NO LESION FEFORTED 

AN!PAL MISSING/NO NECROPSY 

# KUMBER OF ANIMALS HU H TISSUE EXAMINED

• KUMBF.R OF ANIMALS NECROPSIED 

 MICROSCOPICALLY 

42
 
APPENDIX C
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS
 

IN RATS FED DIELDRIN IN THE DIET
 

43
 

Table CI. Analyses of the Incidence of Primary Tumors in Male Rats Fed Dieldrin in the Dieta
 

Topography: Morphology 

Matched 

Control 

Hematopoietic System: Leukemia^ 2/24 (8) 

 Values0 > d N.S. 

Relative Risk (Matched Control)f 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 83 

Pituitary: Adenoma, NOSb 0/24 (0) 

 Values0 > d N.S. 

Relative Risk (Matched Control)f 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 

Low
 

Dose
 

5/24 (21)
 

N.S.
 

2.500
 

0.459
 

24.045
 

74
 

3/24 (13)
 

N.S.
 

Infinite
 

0.622
 

Infinite
 

85
 

Mid
 

Dose
 

5/24 (21)
 

N.S.
 

2.500
 

0.459
 

24.045
 

86
 

1/24 (4)
 

N.S.
 

Infinite
 

0.055
 

Infinite
 

97
 

High
 

Dose
 

5/24 (21)
 

N.S.
 

2.500
 

0.459
 

24.045
 

80
 

1/24 (4)
 

N.S.
 

Infinite
 

0.055
 

Infinite
 

100
 
__ 

Table Cl. Analyses of the Incidence of Primary Tumors in Male Rats Fed Dieldrin in the Dieta
 

(continued) 

Matched Low Mid High 

Topography: Morphology Control Dose Dose Dose 

Testis: Interstitial-cell
 

Tumorb 24/24 (100) 23/24 (96) 24/24 (100) 20/24 (83)
 

 Values0>d = 0.009 (Ν) N.S. N.S. N.S.
 

Relative Risk (Matched Control)f 0.958 0.833
 

Lower Limit 0.000 — 0.000
 

Upper Limit 1.043 — 1.200
 

Weeks to First Observed Tumor 83 74 86 62
 

a

Treated groups received doses of 2, 10, or 50 ppm in feed.
 

^Number of tumor-bearing animals/number of animals necropsied (percent).
 

c

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


Armitage test when Ρ < 0.05; 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 when Ρ < 0.05 for the
 

control group; otherwise, not significant (N.S.) is indicated.
 

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

e

T he probability level for departure from linear trend is given when Ρ < 0.05 for any comparison.
 

95% confidence interval of the relative risk between each treated group and the matched-


control group.
 
Table C2. Analyses of the Incidence of Primary Tumors in Female Rats Fed Dieldrin in the Dieta
 

Topography: Morphology
 

Hematopoietic System: Leukemia*3
 

 Valuesc>d
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Pituitary: Adenoma, NOSb
 

 Valuesc>d
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched
 

Control
 

1/24 (4)
 

N.S.
 

79
 

2/24 (8)
 

N.S.
 

101
 

Low
 

Dose
 

3/24 (13)
 

N.S.
 

3.000
 

0.265
 

150.246
 

94
 

7/24 (29)
 

N.S.
 

3.500
 

0.759
 

31.328
 

84
 

Mid
 

Dose
 

5/24 (21)
 

N.S.
 

5.000
 

0.622
 

224.379
 

70
 

4/24 (17)
 

N.S.
 

2.000
 

0.321
 

20.335
 

98
 

High
 

Dose
 

5/23 (22)
 

N.S.
 

5.217
 

0.652
 

233.437
 

82
 

2/23 (9)
 

N.S.
 

1.043
 

0.081
 

13.306
 

105
 
00 

Table C2. Analyses of the Incidence of Primary Tumors in Female Rats Fed Dieldrin in the Dieta
 

(continued)
 

Topography: Morphology
 

Uterus: Endometrial
 

Stromal Polypb 

 Valuesc>d 

Departure from Linear Trende 

Relative Risk (Matched Control)f 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor
 

Uterus: Endometrial
 

Stromal Sarcoma
 

 Valuesc>d 

Relative Risk (Matched Control)^
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched Low Mid High 

Control Dose Dose Dose 

13/24 (54) 7/24 (29) 4/24 (17) 4/23 (18) 

 = 0.047 (Ν) N.S. = 0.007 (Ν) Ρ = 0.009 (Ν) 

 = 0.031 

0.538 0.308 0.321 

0.231 0.089 0.094 

1.179 0.828 0.862 

96 104 105 105 

0/24 (0) 0/24 (0) 0/24 (0) 2/23 (9) 

 = 0.039 N.S. N.S. N.S. 

Infinite 

0.318 

Infinite 

104 
Table C2. Analyses of the Incidence of Primary Tumors in Female Rats Fed Dieldrin in the Diet a 

(continued) 

Topography: Morphology 

Matched 

Control 

Low 

Dose 

Mid 

Dose 

High 

Dose 

Uterus: Endometrial Stromal 

Polyp or Sarcoma 13/24 (54) 7/24 (29) 4/24 (17) 6/23 (26) 

 Values0 > d N.S. N.S. = 0.007 (Ν) = 0.048 (Ν 

Departure from Linear Trende = 0.026 

Relative Risk (Matched Control)f 

Lower Limit 

Upper Limit 

0.539 

0.231 

1.179 

0.308 

0.089 

0.828 

0.482 

0.190 

1.106 

Weeks to First Observed Tumor 96 104 105 104 

Mammary Gland: Adenoma, NOSb 0/24 (0) 2/24 (8) 0/24 (0) 0/23 (0) 

 Valuesc > d N.S. N.S. N.S. N.S. 

Relative Risk (Matched Control)f 

Lower Limit 

Upper Limit 

Infinite 

0.305 

Infinite 

__ 

— 

— 

— 

— 

Weeks to First Observed Tumor — 104 — — 
* U. S. GOVERNMENT PRINTING OFFICE : 1977 260-899/3165 

Table C2. Analyses of the Incidence of Primary Tumors in Female Rats Fed Dieldrin in the Dieta
 

(continued)
 

Matched Low Mid High
 

Topography: Morphology Control Dose Dose Dose
 

Mammary Gland: Fibroadenoma^ 2/24 (8) 0/24 (0) 0/24 (0) 2/23 (9)
 

 Valuesc>d N.S. N.S. N.S. N.S.
 

Relative Risk (Matched Control)f 0.000 0.000 1.043
 

Lower Limit 0.000 0.000 0.081
 

Upper Limit 3.283 3.283 13.306
 

Weeks to First Observed Tumor 105 81
 

Ui
 

Ο a

Treated groups received doses of 2, 10, or 50 ppm in feed.
 

^Number of tumor-bearing animals/number of animals necropsied (percent).
 

c

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


Armitage test when Ρ < 0.05; 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 when Ρ < 0.05 for the control
 

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

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

e

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

95% confidence interval of the relative risk between each treated group and the matched-


control group.
 

DHEW Publication No. (NIH) 78-822