1977 

National Cancer Institute 

CARCINOGENESIS 

Technical Report Series 

No. 17 

BIOASSAY OF 

PHOTODIELDRIN 

FOR POSSIBLE CARCINOGENICITY 

CAS No. 13366-73-9 

NCI-CG-TR-17 

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

Public Health Service 

National Institutes of Health 

BIOASSAY OF
 

PHOTODIELDRIN
 

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
 

DHEW Publication No. (NIH) 77-817
 

BIOASSAY OF
 

PHOTODIELDRIN
 

FOR POSSIBLE CARCINOGENICITY
 

Carcinogenesis Program
 

Division of Cancer Cause and Prevention
 

National Cancer Institute
 

National Institutes of Health
 

CONTRIBUTORS; This report presents the results of the bioassay
 

of photodieldrin 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. The bioassay was conducted
 

by 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.
 

Weisburgerl>2 and R. R. Batesl»3; the doses were selected by
 

Drs. T. E. Shellenberger^'^, 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
 

assistance of Ms. D. H. Monceaux^ and Mr. D. Broussard^.
 

Histopathology was performed by Drs. E. Bernal^ and B. Buratto^
 

at Gulf South Research Institute, 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^. 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 under the direction of Dr. H. P. Burchfield, and the
 

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

This report was prepared at Tracer Jitco under the direction of
 

NCI. Those responsible for the report at Tracer Jitco were
 

Dr. Marshall Steinberg, Director of the Bioassay Program;
 

ill
 
Drs. J. F. Robens? and C. H. Williams?, toxicologists; Dr. R. L.
 

Schueler?, pathologist; Ms. Y. E. Presley?, technical writer; and
 

Dr. E. W. Gunberg?, technical editor, assisted by Ms. P. J.
 

Graboske?.
 

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
 

Dr. Thomas W. Orme
 

Mr. Harry A. Milman
 

Dr. Robert A. Squire9
 

Dr. Jerrold M. Ward
 

1-Carcinogenesis Program, Divison of Cancer Cause and Prevention,
 

National Cancer Institute, National Institutes of Health,
 

Bethesda, Maryland.
 

with the Naylor Dana Institute for Disease Prevention,
 

American Health Foundation, Hammond House Road, Valhalla,
 

New York.
 

%ow with the Office of the Commissioner, Food and Drug
 

Administration, Rockville, Maryland.
 

^Gulf South Research Institute, Atchafalaya Basin Laboratories,
 

P. 0. Box 1177, New Iberia, Louisiana.
 

^Now with the National Center for Toxicological Research,
 

Jefferson, Arkansas.
 

iv
 
6

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

Rockville, Maryland.
 

?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.
 

^Now with the Division of Comparative Medicine, Johns Hopkins
 

University, School of Medicine, Traylor Building, Baltimore,
 

Maryland.
 

V 

SUMMARY
 

A bioassay of dieldrin-free photodieldrin (synthesized by Gulf
 

South Research Institute) for possible carcinogenicity was conducted by administering the test material in feed to Osborne-


Mendel rats and B6C3F1 mice.
 

Groups of 50 rats of each sex were initially administered photo-


dieldrin at one of two doses, either 5 or 10 ppm. Because of
 

neurotoxic signs, doses in the females were reduced after 30
 

weeks. Total periods of treatment for low- and high-dose males
 

and low-dose females were 80 weeks, followed by periods of 31 or
 

32 weeks of additional observation; the total period of treatment
 

for the high-dose females was 59 weeks, followed by a period of
 

additional observation of 53 weeks. The' time-weighted average
 

doses for the females were 3.4 or 7.5 ppm. Matched controls
 

consisted of 10 untreated rats of each sex; pooled controls, used
 

for statistical evaluation, consisted of the matched controls
 

combined with 65 untreated male and 65 untreated female rats from
 

similarly performed bioassays of six other test chemicals. All
 

surviving rats were killed at 111-112 weeks.
 

Groups of 50 mice of each sex were administered photodieldrin at
 

one of two doses, either 0.32 or 0.64 ppm, for 80 weeks, then
 

observed for an additional 13 weeks. Matched controls consisted
 

of groups of 10 untreated mice of each sex at each dose; pooled
 

controls, used for statistical evaluation, consisted of the
 

matched controls combined with 60 untreated male and 60 untreated
 

female mice from similarly performed bioassays of six other test
 

chemicals. All surviving mice were killed at 93 weeks.
 

Mean body weights attained by low- and high-dose male and female
 

rats and mice were essentially unaffected by photodieldrin. Convulsions and hyperactivity were noted in treated male and female
 

rats and in male mice. Mortality rates of either sex or either
 

species were not affected by treatment.
 

vii
 
In rats, benign tumors (adenoma and fibroadenoma) of the mammary
 

gland in females showed a dose-related trend (P = 0.039) compared
 

with matched, but not pooled, controls (8/72 pooled controls, 0/9
 

matched controls, 5/50 low-dose, 10/49 high-dose). Adenocarcinoma of the mammary gland occurred in two additional low-dose
 

females. The incidences of these tumors in either of the treated
 

groups were not significantly higher than those in the control
 

groups using either matched or pooled controls. Three papillary
 

and follicular-cell adenomas and one papillary adenocarcinoma of
 

the thyroid occurred in the low-dose females, giving a statistically significant increase over the pooled controls (P =
 

0.022), but these thyroid tumors did not occur in the high-dose
 

animals. The dose-related trend was not statistically significant using either pooled or matched controls, and the incidence
 

in the low-dose group is not greater than that in the historical
 

controls. In male rats, the incidence of hemangiomas showed a
 

statistically significant dose-related trend (P = 0.021) using
 

pooled controls, but the direct comparison of the three
 

hemangiomas in the high-dose group with the pooled-control group
 

was not statistically significant. Furthermore, three
 

hemangiomas is a small number, and the tumors occurred in more
 

than one anatomic site (two in the spleen, one in subcutaneous
 

tissue). The occurrence of these tumors cannot clearly be
 

associated with treatment.
 

In mice, there were no tumors that were statistically significant
 

in treated groups of either sex.
 

It is concluded that under the conditions of this bioassay,
 

photodieldrin was not carcinogenic for Osborne-Mendel rats or
 

B6C3F1 mice.
 

viii
 
TABLE OF CONTENTS
 

Page
 

I. Introduction	 1
 

II. Materials and Methods	 3
 

A. Chemical	 3
 

B. Dietary Preparation	 4
 

C. Animals	 5
 

D. Animal Maintenance	 5
 

E. Subchronic Studies	 7
 

F. Designs of Chronic Studies	 8
 

G. Clinical and Pathologic Examinations	 11
 

H. Data Recording and Statistical Analyses	 12
 

III. Results - Rats	 19
 

A. Body Weights and Clinical Signs (Rats)	 19
 

B. Survival (Rats)	 19
 

C. Pathology (Rats)	 21
 

D. Statistical Analyses of Results (Rats)	 23
 

IV. Results - Mice	 27
 

A. Body Weights and Clinical Signs (Mice)	 27
 

B. Survival (Mice)	 27
 

C. Pathology (Mice)	 30
 

D. Statistical Analyses of Results (Mice)	 31
 

V. Discussion	 33
 

VI.	 Bibliography 37
 

APPENDIXES
 

Appendix A Summary of the Incidence of Neoplasms in
 

Table Al Summary of the Incidence of Neoplasms in
 

Rats Fed Photodieldrin in the Diet 39
 

Male Rats Fed Photodieldrin in the Diet 41
 

Table A2 Summary of the Incidence of Neoplasms in
 

Female Rats Fed Photodieldrin in the Diet 45
 

ix
 
Page 

Appendix B Summary of the Incidence of Neoplasms in 

Mice Fed Photodieldrin in the Diet 49 

Table Bl Summary of the Incidence of Neoplasms in 

Male Mice Fed Photodieldrin in the Diet 51 

Table B2 Summary of the Incidence of Neoplasms in 

Female Mice Fed Photodieldrin in the Diet 54 

Appendix C Summary of the Incidence of Nonneoplastic 

Lesions in Rats Fed Photodieldrin in the Diet 57 

Table Cl Summary of the Incidence of Nonneoplastic 

Lesions in Male Rats Fed Photodieldrin 

in the Diet 59 

Table C2 Summary of the Incidence of Nonneoplastic 

Lesions in Female Rats Fed Photodieldrin 

in the Diet 63 

Appendix D Summary of the Incidence of Nonneoplastic 

Lesions in the Mice Fed Photodieldrin 

in the Diet 67 

Table Dl Summary of the Incidence of Nonneoplastic 

Lesions in the Male Mice Fed Photodieldrin 

in the Diet 69 

Table D2 Summary of the Incidence of Nonneoplastic 

Lesions in Female Mice Fed Photodieldrin 

in the Diet 72 

Appendix E Analyses of the Incidence of Primary Tumors 

in Rats Fed Photodieldrin in the Diet 75 

Table El Analyses of the Incidence of Primary Tumors 

in Male Rats Fed Photodieldrin in the Diet 77 

Table E2 Analyses of the Incidence of Primary Tumors 

in Female Rats Fed Photodieldrin in the Diet 82 

X 
Page 

Appendix F Analyses of the Incidence of Primary Tumors 

in Mice Fed Photodieldrin in the Diet 87 

Table Fl Analyses of the Incidence of Primary Tumors 

in Male Mice Fed Photodieldrin in the Diet 89 

Table F2 Analyses of the Incidence of Primary Tumors 

in Female Mice Fed Photodieldrin in the Diet 92 

Appendix G Analysis of Formulated Diets for 

Concentrations of Photodieldrin 95 

TABLES 

Table 1 Design of Photodieldrin Chronic Feeding 

Studies in Rats 9 

Table 2 Design of Photodieldrin Chronic Feeding 

Studies in Mice 10 

FIGURES 

Figure 1 Growth Curves for Rats Fed Photodieldrin 

in the Diet 20 

Figure 2 Survival Curves for Rats Fed Photodieldrin 

in the Diet 22 

Figure 3 Growth Curves for Mice Fed Photodieldrin 

in the Diet 28 

Figure 4 Survival Curves for Mice Fed Photodieldrin 

in the Diet 29 

xi
 

I. INTRODUCTION
 

Photodieldrin (CAS 13366-73-9; NCI C00599) is a photochemical conversion product of dieldrin with the systematic name l,l,2,3,3a,
 

7a-hexachloro-exo-5,6-epoxydecahydro-2,4,7-metheno-IH-cyclopenta[a]
 

pentalene. It is a half-cage structure derived from the bridging
 

of C-12 to C-9 in dieldrin with transfer of a C-12 hydrogen to
 

C-10. Photoconversion is carried out in sunlight and by certain
 

microorganisms that have been isolated from soil, water, rat
 

intestine, and the rumen stomach contents of cows (Matsumura et
 

al., 1970). The photochemical rearrangement and oxidation of
 

aldrin and photoaldrin also will yield photodieldrin (Brooks,
 

1975). Under certain conditions, photodieldrin is persistent in
 

the environment as a terminal residue of dieldrin (Matsumura,
 

1973; Brooks, 1975). Photodieldrin is more toxic than dieldrin to
 

rats and mice but less toxic to dogs, chickens, and pheasants
 

(Brooks, 1975).
 

Although it has never been produced commercially, photodieldrin
 

was selected for testing in 1969 because it was a photochemical
 

conversion product of dieldrin. At that time dieldrin was used
 

extensively as a pesticide.
 

1 

II. MATERIALS AND METHODS
 

A. Chemical
 

Gulf South Research Institute synthesized two batches of photo-


dieldrin for use in the chronic study. The method, based on that
 

described by Chau et al. (1971) for the preparation of
 

photoheptachlor ketone, involved irradiating a solution of
 

dieldrin in acetone at 2537 A under nitrogen.
 

The first batch was synthesized from dieldrin obtained from Shell
 

Chemical Company, Modesto, California, which had been purified by
 

recrystallization. Photodieldrin was obtained in a 59% yield
 

after three recrystallizations of the irradiated product from
 

ethanol.
 

The second batch was prepared from technical-grade dieldrin,
 

giving photodieldrin in a 48% yield after seven recrystallizations.
 

All analytical tests performed showed that both batches were
 

identical to a reference sample of photodieldrin. Parameters
 

compared included melting point (191.5-193°C), ir spectrum,
 

thin-layer chromatograms, and gas-liquid chromatograms on two
 

dissimilar columns. Neither batch contained any detectable
 

residual dieldrin. The absence of dieldrin was also confirmed in
 

3 
analyses of these batches by Shell Development Company, Modesto,
 

California. No attempt was made to identify or quantitate
 

impurities.
 

The chemical was stored in amber glass containers at 0°C.
 

B. Dietary Preparation
 

All diets were formulated using Wayne

(R) Lab Blox (Allied Mills,
 

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

photodieldrin for each dietary concentration. The test chemical
 

was first dissolved in a small amount of acetone (Mallinckrodt
 

Inc., St. Louis, Mo.), which was then added to the feed. Corn
 

(R)
 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, 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 photodieldrin in feed was tested by determining
 

the concentration of the chemical in formulated diets at
 

intervals over a 7-day period. Diets containing 0.32, 0.64, 2.5,
 

5.0, or 10.0 ppm photodieldrin showed no change in concentration
 

on standing at ambient temperature for this period.
 

4 
As a quality control test on the accuracy of preparation of the
 

diets, the concentration of photodieldrin was determined in
 

different batches of formulated diets during the chronic study.
 

The results are summarized in Appendix G. At each dietary
 

concentration, the mean of the analytical concentrations for the
 

checked samples was within 1.6% of the theoretical concentration,
 

and the coefficient of variation was never more than 5.8%. Thus,
 

the evidence indicates that the formulated diets were prepared
 

accurately.
 

C. Animals
 

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

Division of Cancer Treatment, National Cancer Institute, were
 

used in these bioassays. 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. On
 

arrival at the laboratory, all animals were quarantined for an
 

acclimation period (rats for 9 days, mice for 14 days) and were
 

then assigned to control and treated groups.
 

D. Animal Maintenance
 

All animals were housed in temperature- and humidity-controlled
 

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

5 
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 once per week to clean
 

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

Mice were transferred once per week to clean cages covered 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 once per week; at the same time each cage was changed
 

to a different position in the row within the same column. Rats
 

receiving photodieldrin, along with their matched controls, were
 

housed in a room by themselves. Mice receiving photodieldrin
 

were maintained in a room housing mice administered aldrin (CAS
 

6 
309-00-2) or captan (CAS 133-06-2), together with their
 

respective matched controls.
 

E. Subchronic Studies
 

Subchronic feeding studies were conducted with rats and mice to
 

estimate the maximum tolerated doses of photodieldrin, on the
 

basis of which low and high concentrations (hereinafter referred
 

to as "low doses" and "high doses") were determined for administration in the chronic studies. In the subchronic studies, photo-


dieldrin was added to the animal feed in twofold increasing
 

concentrations, ranging from 2.5 to 80.0 ppm for rats and 0.01 to
 

0.32 ppm for mice. Control and treated groups each consisted of
 

five male and five female animals. The chemical was provided in
 

feed to treated groups for 6 weeks, followed by a 2-week period
 

of observation. Because there were no deaths in the mice, and
 

because the gains in body weights of the treated groups of mice
 

were similar to those of the control group during the entire
 

study, a second study was performed in mice, with doses ranging
 

from 0.04 to 2.56 ppm. In the second study, the chemical was
 

provided in feed to treated groups for 6 weeks, followed by a
 

3-week period of observation.
 

At 40 and 80 ppm, all rats died during week 2. In males receiving 20 ppm or less there was no evidence of significant
 

7 
behavioral changes or other clinical signs except heavy shedding
 

of hair. Throughout the 8-week study, all treated females lost
 

weight. At 20 ppm the females appeared hyperactive. During
 

week 6 tachypnea was noted in one female and hyperactivity in
 

another female receiving 10 ppm photodieldrin. The low and high
 

doses for rats were set at 5 and 10 ppm for the chronic studies.
 

There were no marked adverse effects in mice receiving 1.28 ppm.
 

At 2.56 ppm all mice died by week 6. The low and high doses for
 

mice were set at 0.32 and 0.64 ppm for the chronic studies.
 

F. Designs of Chronic Studies
 

The designs of the chronic studies are shown in tables 1 and 2.
 

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
 

photodieldrin were combined with matched controls from studies
 

performed on malathion (CAS 121-75-5), tetrachlorvinphos (CAS
 

961-11-5), toxaphene (CAS 8001-35-2), lindane (CAS 58-89-9),
 

endrin (CAS 72-20-8), and captan. The pooled controls for
 

statistical tests using rats consisted of 75 males and 75
 

females; using mice, 80 males and 80 females. The studies on
 

chemicals other than photodieldrin were also conducted at Gulf
 

South Research Institute and overlapped the photodieldrin study
 

8
 
Table 1. Design of Photodieldrin Chronic Feeding Studies in Rats
 

Photo-


Sex and

Treatment

Group

 Initial 

 No. of 

Animals3 

dieldrin 

in Diet 

I2ESI 

Time 

Treated 

(weeks) 

on Study 

Untreatedb 

(weeks) 

Time-Weighted 

Average Dosec 

(ppm) 

Male 

Matched-Control 10 0 111-112 

Low-Dose 50 5 

0 

80 

31-32 

5 

High-Dose 50 10 

0 

80 

32 

10 

Female 

Matched-Control 10 0 111 

Low-Dose 50 5 

2.5d 

0 

30 

50 

32 

3.4 

High-Dose 50 10 

5d 

0 

30 

29 

53 

7.5 

a

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

bwhen diets containing photodieldrin were discontinued, high-dose females
 

and their matched controls were fed control diets without corn oil
 

for 8.5 weeks, then control diets (2% corn oil added) for an
 

additional 44 weeks. All males, low-dose females, and their matched
 

controls were fed control diets until termination of the study.
 

G

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

£(no. of weeks receiving each dose)
 

Because of neurotoxic signs, doses in female rats were reduced
 

after 30 weeks.
 

9 
Table 2. Design of Photodieldrin Chronic Feeding Studies in Mice
 

Sex and 

Treatment : 

Initial 

No. of 

Photodieldrin 

in Diet 

Time on 

Treated 

Study 

Untreatedb 

Group Animals.3 (ppm) (weeks ) (weeks ) 

Male 

Low-Dose 

Matched-Control 10 0 93 

High -Dose 

Matched-Control c

 10 0 93 

Low-Dose 50 0.32 80 

0 13 

High-Dosec 50 

0.64 80 

0 13 

Female 

Low-Dose 

Matched-Control 10 0 93 

High-Dose 

Matched-Control c

 10 0 93 

Low-Dose 50 0.32 80 

0 13 

High-Dosec 50 0.64 80 13 

0 13 

a

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

"When diets containing photodieldrin were discontinued, mice received
 

control diets until termination of the study.,
 

c

Due to high mortality caused by an error in the preparation of the
 

feed mix, studies for high-dose male and high-dose female mice were
 

terminated; the studies were then restarted using 10 additional
 

matched-control mice.
 

10
 
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.
 

G. Clinical and Pathologic Examinations
 

All animals were observed twice daily for signs of toxlcity,
 

weighed at regular intervals, and palpated for masses at each
 

weighing. 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.
 

11
 
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 autolysis as to preclude histopathologic evaluation. 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 ;hat bear on the possibility of carcinogenicity are
 

discussed in the statistical narrative sections.
 

Probabilities of survival were estimated by the product-limit
 

12
 
1 

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

report in the form of graphs. Animals were statistically
 

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

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

causes were not statistically censored. Statistical analyses for
 

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

(1972) for testing two groups for equality and Tarone's (1975)
 

extensions of Cox'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
 

13
 
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
 

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
 

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
 

14
 
first tumor was observed were excluded by basing the statistical
 

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

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

such an early tumor was found, comparisons were based exclusively
 

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

the first tumor was found. Once this reduced set of data was
 

obtained, the standard procedures for analyses of the incidence
 

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
 

15
 
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
 

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
 

16
 
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.
 

17
 

III. RESULTS - RATS
 

A. Body Weights and Clinical Signs (Rats)
 

Mean body weights were generally comparable for treated and
 

control rats of both sexes throughout the study (figure 1).
 

During the first 16 weeks, the treated animals were generally
 

comparable to the controls in appearance and behavior, with the
 

exception of the high-dose females. Beginning in week 16,
 

convulsions were observed in three high-dose females, and by week
 

24 convulsions were observed in a few animals in the high-dose
 

male and low- and high-dose female groups. At week 28, all
 

high-dose females appeared to be hyperactive. Concentrations of
 

photodieldrin in feed were lowered for both high- and low-dose
 

females at week 30.
 

During the second year of the study, various clinical signs
 

including epistaxis, dermatitis, alopecia, rough hair coats, loss
 

of weight, pale mucous membranes, tachypnea, hematuria,
 

convulsions, hyperactivity, and abdominal distention were noted
 

with increasing frequency in the treated groups.
 

B. Survival (Rats)
 

The Kaplan and Meier curves estimating the probabilities of-


survival for male and female rats fed photodieldrin in the diet
 

19
 
Figure 1. Growth Curves for Rats Fed Photodieldrin in the Diet 

20 
at the doses of this experiment, together with those of the
 

controls, are shown in figure 2. The Tarone test results were
 

not significant in either sex at the 0.05 level for positive
 

dose-related trend in mortality over the period. In male rats,
 

46% of the high-dose group, 48% of the low-dose group, and 20% of
 

the matched controls lived to the end of the study. Survival was
 

longer in female rats than in the males. Sixty percent of the
 

high-dose females, 62% of the low-dose females, and 70% of the
 

matched controls lived to termination of the study. A sufficient
 

number of animals were available for meaningful statistical
 

analyses of the incidence of late-developing tumors.
 

C. Pathology (Rats)
 

Histopathologic findings on neoplasms in rats are summarized in
 

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

are summarized in Appendix C, tables Cl and C2.
 

Neoplastic, degenerative, inflammatory, and proliferative lesions
 

were encountered in both treated and control rats. The
 

nonneoplastic lesions occurred infrequently or approximately as
 

often among treated rats as among control rats.
 

Benign and malignant tumors of the pituitary gland occurred in
 

8/42 low-dose males and 7/46 high-dose males; benign tumors of
 

the pituitary appeared in 5/48 low-dose females and 8/39 high21
 
Figure 2. Survival Curves for Rats Fed Photodieldrin in the Diet 

22 
dose females. Benign and malignant tumors of the mammary gland
 

occurred in 7/50 low-dose females and 10/49 high-dose females.
 

These pituitary and mammary gland tumors were not found in rats
 

of the matched-control groups. The remaining neoplastic lesions
 

occurred with a random distribution and with a frequency in the
 

treated rats similar to that in the controls.
 

With the exception of the tumors of the pituitary and mammary
 

gland, the neoplastic lesions observed in rats occurred sporadically or with approximately equal frequency in treated animals
 

and in controls. However, spontaneous tumors of the pituitary
 

gland and mammary gland may occur at high incidences in the
 

female Osborne-Mendel rat. Therefore, in the judgment of the
 

pathologists, it is unlikely that photodieldrin was responsible
 

for the induction of these tumors.
 

D. Statistical Analyses of Results (Rats)
 

Tables El and E2 in Appendix E 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.
 

In female rats, when the incidences of papillary adenoma, papillary adenocarcinoma, and follicular-cell adenoma of the thyroid
 

are grouped, the Fisher exact test shows that the incidence of
 

23
 
these combined tumors in the low-dose group is significantly
 

higher than that in the pooled controls (P = 0.022). In male
 

rats, follicular-cell adenoma was observed in one low-dose and
 

one high-dose animal, and papillary adenocarcinoma was found in
 

one high-dose animal. Experimental results for the combined
 

group of papillary adenoma, papillary adenocarcinoma, and
 

follicular-cell adenoma compiled to date from historical-control
 

groups at this laboratory in the bioassay program indicate a
 

spontaneous rate of less than 2% in females and 5% in males.
 

These rates are not significantly different from those seen in
 

the treated groups of this bioassay.
 

The combined incidence of adenoma and fibroadenoma of the mammary
 

gland in female high-dose rats was double that in the low-dose
 

animals (low-dose 5/50, high-dose 10/49), and no incidence was
 

observed in the matched-control group; however, 8/72 (11%) were
 

observed in the pooled-control group. The Cochran-Armitage test
 

has a marginal significance using matched controls (P = 0.039),
 

but this positive finding is not confirmed by the Fisher exact
 

test results for either the low- or high-dose group or by the
 

tests made using the pooled controls. The historical controls
 

have an incidence of 42/235 (18%). Thus, the incidence in the
 

matched-control group is lower than expected, and statistical
 

significance may have occurred because of this low incidence
 

24
 
rather than the effect of the chemical. In male rats, no
 

fibroadenoma or adenoma was observed. It is questionable whether
 

tumors in the mammary glands of rats are associated with
 

treatment.
 

Three hemangiomas were observed in the male high-dose group. The
 

Cochran-Armitage test has a probability level of 0.021 when the
 

pooled-control group is used, but this positive result is not
 

supported by the Fisher exact test results, which show that the
 

incidence in the high-dose group is not significant. When the
 

Cochran-Armitage test result is based on the incidence in only
 

one group, and this incidence has minimal significance, the trend
 

analysis result is questionable. Two of the hemangiomas were
 

observed in the spleen and one in subcutaneous tissue.
 

Historical controls indicate a 0/240 incidence in male rats of
 

this strain. There were no hemangiomas in the female rats.
 

Time-adjusted analyses, based on animals that lived beyond 52
 

weeks, performed on the incidence of chromophobe adenoma of the
 

pituitary in male rats were not significant. When tumors are
 

grouped for statistical analysis, as in adenoma and fibroadenoma
 

of the mammary gland in female rats, the incidences of the
 

individual components are not included in tables El and E2;
 

however, a list of the incidences of each type of tumor is
 

provided in Appendix A, tables Al and A2.
 

25
 

IV. RESULTS - MICE
 

A. Body Weights and Clinical Signs (Mice)
 

Mean body weights were comparable for treated and control groups
 

of both male and female mice throughout the study (figure 3).
 

During the first year of the study, the treated animals were
 

generally comparable to the controls in appearance and behavior.
 

During this period, some loss of weight and a few cases of
 

alopecia were noted. During the second year of the study, other
 

clinical signs including discolored hair coats, alopecia, and
 

abdominal distention were observed with an increasing frequency
 

in treated groups. Hyperexcitability was noted in most of the
 

treated males from weeks 65 and 66 to the end of the study.
 

B. Survival (Mice)
 

The Kaplan and Meier curves estimating the probabilities of
 

survival for male and female mice fed photodieldrin in the diet
 

at the doses of this experiment, together with those of the
 

controls, are shown in figure 4. The separate control groups for
 

the high-dose group and the low-dose group for each sex are
 

combined and designated matched controls for survival analyses.
 

In male mice, the Tarone test result for positive dose-related
 

trend in mortality over the period is not significant. Ninety
 

percent of the matched controls, 90% of the high-dose group, and
 

27
 
Figure 3. Growth Curves for Mice Fed Photodieldrin in the Diet 

28 
Figure 4. Survival Curves for Mice Fed Photodieldrin in the Diet 

?Q 
78% of the low-dose group lived to the end of the study. In
 

females, the Tarone test has a probability level of 0.039, and
 

over 80% of all the animals survived to termination of the study.
 

A sufficient number of animals of both sexes were available for
 

meaningful statistical analyses of the incidences of late-


developing tumors.
 

C. Pathology (Mice)
 

Histopathologic findings on neoplasms in mice are summarized in
 

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

are summarized in Appendix D, tables Dl and D2.
 

A variety of neoplasms occurred both in the control and treated
 

groups. These neoplasms occurred with approximately equal
 

frequency in treated and control mice or appeared in
 

insignificant numbers. These lesions, however, are not uncommon
 

in this strain of mouse independent of any treatment.
 

In addition to the neoplastic lesions, a number of degenerative,
 

proliferative, and inflammatory changes were encountered also in
 

animals of the treated and control groups. These nonneoplastic
 

lesions are commonly seen in aged B6C3F1 mice.
 

In the judgment of the pathologists, there was no definitive
 

evidence of the carcinogenicity of photodieldrin in mice.
 

30
 
D. Statistical Analyses of Results (Mice)
 

Tables Fl and F2 in Appendix F 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.
 

In neither sex does the incidence of any specific tumor show a
 

statistically significant result. When the liver tumors in male
 

mice are grouped for analysis (as in neoplastic nodules and
 

hepatocellular carcinoma) the results are not significant. The
 

incidence of neoplastic nodules, alone, is not included in table
 

Fl, since neither the low-dose nor the high-dose group has an
 

incidence greater than 5%. A list of the incidences of each type
 

of tumor is provided in Appendix B, tables Bl and B2.
 

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

in the tables, the value of one is included; this indicates the
 

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

each of the intervals has an upper limit greater than one,
 

indicating the theoretical possibility of the induction of tumors
 

by this chemical, which could not be detected under the
 

conditions of this test.
 

31
 

V. DISCUSSION
 

In this bioassay of photodieldrin, mean body weights were generally comparable for treated and control rats of both sexes and
 

also for treated and control mice of both sexes. However,
 

hyperexcitability and convulsions were observed in treated male
 

and female rats and in male mice. This mode of toxicity, i.e.,
 

stimulation of the central and peripheral nervous system, is
 

similar to that of the parent chemical, dieldrin, and other
 

related organochlorine pesticides (Brooks, 1975). Although less
 

than 50% of the treated male rats lived until termination of the
 

study, survival among controls was also poor; mortality rates in
 

either sex of either species were not affected by treatment.
 

In rats, benign tumors (adenoma and fibroadenoma) of the mammary
 

gland in females showed a dose-related trend (P = 0.039) compared
 

with matched controls, but not with pooled controls (pooled
 

controls 8/72, matched controls 0/9, low-dose 5/50, high-dose
 

10/49). In addition, two other low-dose females had adenocarcinomas of the mammary gland. The incidences of these tumors in
 

either of the treated groups were not significantly higher than
 

those in the control groups using either matched or pooled
 

controls, and thus, their occurrence cannot clearly be associated
 

with treatment.
 

33
 
Three papillary and follicular-cell adenomas and one papillary
 

adenocarcinoma of the thyroid occurred in the low-dose females,
 

giving a statistically significant increase over the pooled
 

controls (P = 0.022), but these thyroid tumors did not occur in
 

the high-dose animals. The dose-related trend was not statistically significant using either pooled or matched controls, and
 

the incidence in the low-dose group is not greater than that in
 

the historical controls. Thus, these lesions are not considered
 

to be related to treatment.
 

The incidence of hemangiomas in male rats showed a statistically
 

significant dose-related trend (P = 0.021) using pooled controls,
 

but the direct comparison of the three hemangiomas in the high-


dose group with the pooled-control group was not statistically
 

significant. In addition, three hemangiomas is a low number, and
 

the tumors occurred in more than one anatomic site (two in the
 

spleen, one in subcutaneous tissue). Thus, the hemangiomas in
 

male rats are not considered to be related to treatment of the
 

animals with photodieldrin.
 

In mice, there were no tumors that were statistically significant
 

in treated groups of either sex.
 

In another bioassay, dieldrin was fed to mice at 2.5 and 5 ppm
 

(NCI, 1977). In that study, hepatocellular carcinomas were
 

34 
associated with treatment with dieldrin in male mice. The doses
 

of dieldrin (2.5 and 5 ppm) were 7.8 times greater than the doses
 

of photodieldrin, (0.32 and 0.64 ppm) used in the present study,
 

which were not found to be associated with tumors of the liver in
 

mice.
 

It is concluded that under the conditions of this bioassay, photo-


dieldrin was not carcinogenic for Osborne-Mendel rats or B6C3F1
 

mice.
 

35
 

VI. BIBLIOGRAPHY
 

Armitage, P. , Statistical Methods in Medical Research, J. 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, Vol. _2. CRC Press,
 

Inc., Cleveland, Ohio, 1975, pp. 68-100 and 119-139.
 

Chau, A. S. Y. , Rosen, J. D. , and Cochrane, W. P. , Synthesis of
 

known and suspected environmental products of heptachlor and
 

chlordane. Bull. Environ. Contain.' Toxicol. j> (3): 225-230,
 

1971.
 

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

Soc. B34:187-220. 1972.
 

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

London, 1970, pp. 48-52.
 

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.
 

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

incomplete observations. J. Amer. Statist. Assoc.
 

j>3:457-481, 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.
 

Matsumura, F., Degradation of pesticide residues in the
 

environment. In: Environmental Pollution by Pesticides,
 

Edwards, C. A., ed., Plenum, New York, 1973, pp. 494-512.
 

Matsumura, F., Patil, K. C., and Boush, G. M. , Formation of
 

"Photodieldrin" by microorganisms. Science 170:1206-1207,
 

1970.
 

37
 
Miller, R. G. , Jr. , Simultaneous Statistical Inference, McGraw-


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

NCI, Bioassays of aldrin and dieldrin for possible
 

carcinogenicity, Technical Report No. 21, DREW Publication
 

77-821.
 

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 62:679-682, 1975.
 

38
 
APPENDIX A
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

RATS FED PHOTODIELDRIN IN THE DIET
 

39
 

TABLE A1. 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE 

RATS FED PHOTODIELDRIN IN THE DIET 

CONTROL LOW DOSE 

BNTMSI S INTTIAII Y I N STUD Y m 50 

• NTMAL S NECSOPSIE D 10 H9 

A!!:»I.MS EXAMINE D FISTOPATHOLOGICAIL Y U8 1 n 

INTEGUMENTAR Y SYSTE M 

*S'!BC!J- 1ISSUF (10 ) C»B) 

SA3COMA , SOS 1 (2%)

 

HEHSNGTOH A 

"FSPIFHT09 Y SYSTE M 

ll'JNG (10) (t8) 

C-CEII CARCINOMA , HFTAS m ATI C 1 (2% )

 M TYP D Tijnop f H5TAST.HTTC 1 (2*)

 

HEUATOPOIETT C SYSTE M 

• MOITTPL E 053SHS (10) (18)

 

nAlTG.LYMPHOMA , L Y "1PHOCYTIC TYPE 1 (2*)

 

IYWPHOCYTI C IEUKEM T A 1 (2% )

 

4SPIEE N (UB ) ( 9 ) 

"IBOOSARCOM A 1 (2% ) 

^EMANGIOM A 

ANIIOSl i 1 (11% )

 

C^PCU I ATO C Y SYSTE M 

SCN' 

rjTfjp^TTyi r cySTE l 

*I IV7? (1^ ) (U7 )

 

NEOPHSTT C MODUL E 

*PS"CEEA 5 (10) (12) 

SAPCOMAj, NOSX METHSTATC —

't N'lMEEP OE ANIMAL S WTTH TISSUE EXAMINED MICPOSCOPIC ALL Y
 

* NOBBE* 0' ANIMAL S N'ECPOPSIKD
 

41 

HIGH DOSE 

50 

C0 

49 

(5P) 

1 (2%) 

1 (2*) 

(1(9) 

(50) 

(17) 

2 (1%) 

(19) 

1 (2% ) 

(15) 

 __1_12«1_. 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

'IRINAP Y SYSTE M 

» K T DN;: Y (10 ) (U6 ) (19) 

"IXF D TUKOE , NALITNAN T 2 («*) 

t HAJ1APTQ1 A 1 (11%) 

ENDOCFIN E SYSTE M 

• PITUITAR Y (5) (12) (16) 

CARCINOMA , >IOS 2 (5%) 1 (2*) 

ADENOCAPCINONA , NO S 1 (2*) 

CH90NOPHOB E ADEN0.1" 6 (IK* ) 5 (11%) 

SAPC01" , NO S 1 (2% ) 

*AD?FN5T . (8) (12) (19) 

COB7ICAI CA"CINC1 A 1 (2*) 

PHSOCHPONOCYTOM A 1 (2*) 

tTHYR'lI D (9) (39) (12) 

PAPILLAR Y P.DENOCAOCINOB A 1 (2*) 

TOIITCUIA8-CELI ADEMON A 1 (3*). 1 (2*) 

C-CELL ADSNOfl A 3 (8*) 1 (2*) 

C-CELL CARCINOM A 1 (3*) 

• PANCREATI C ISLETS (10) (12) (15) 

ISI,?T-Cnt. ADENC1A 1 t11«) 

"EPHODUCTIV E SYSTE M 

*(1A1fAR Y GLRNT 1 

PAPILLAR Y ADENOCA

FTBR01A 

RCTNOM A 

(10) (IB) 

1 (2*) 

(50) 

1 (2*) 

•TESTIS 

INTER.STITIAL-CTIL TOMC R 

(10) 

1 (10*) 

(16) 

1 (2*) 

(19) 

NERVOU S SYSTE M 

NON E 

SPECIA L SENS E OSGAN S 

NON F 

t NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* N'JHBER OF ANIMALS NECBOESIED
 

f This is considered to be a benign form of the malignant mixed tumor of
 

the kidney and consists of lipocytes, tubular structures, and fibroblasts
 

in varying proportions.
 

A2
 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

CONTROL
 

«USCUT OSKELETAL SYSTT1
 

*^KEI'"T

'Al "U5CIF dr)
 

SA?C01A, NOS
 

BODY CAVTTT'S
 

NONF
 

SIL OTHFR SY?:F.HS
 

*1'' IT I PIE OP'.;'. NS (10)
 

FTBPOUS HISTII1CY7QKA, "If.ITGNANT
 

IFTOMYOSAHCOM".
 

*NIMJT DISFOSITTQN S'T>1«I»RY
 

ANIMAL S TNIIIAILY IN STUPY
 

N A T npA l D2ATHS
 

«Ot?TB'JND SACPIFTC'1;
 

SCHSD'IIEP SAC5IFTC"
 

ACCTD^NTAILY K*IT"D
 

TFFMIVAI SACEIFICE
 

SNI1A!. 1TSSIN6
 

9 TNCIODES AUIOIYZED ANIMT.IS
 

* NU1BF P OF AKT P1!1LS WTT " TISS'JF

* NUMBE " O f ANI1AL S NFC^OPSTE C 

10
 

2
 

f,
 

2
 

 EXAMINE D MICSOSCOPICMI Y 

43
 

LOW DOSE
 

("8)
 

1 (2%}
 

(«9)
 

1 (2%)
 

1 (2\)
 

50
 

1?
 

13
 

?U
 

HIGH DOSE
 

(50)
 

(SO)
 

50
 

11
 

16
 

23
 
TABLE At. MALE RATS: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

TU1C R St'llAF Y 

TOVAT . ANIHAL S WIT H "pr^gy Tnqc^S * t| 20 1 5

 

"CT'AL PPIMAP Y "IMORS u 25 18

 

TOTA L AKTMAL S WIT H BFNIG N T"NOR S n 11 10

 

TO^H L E"NIG N T'JMO"? n 13 10

 

T OTA I IN T MPL S WIT H 1 A IIGMf t S ? TUMOR S 11 7

 

TO"-?.! MALIGNAN T ^'IIOES 12

 7

 

TCTA L ANTM'i, S WIT H SECONDRB Y T'JMOFS * 2 1

 

TCi^AI SECONnAP Y T'linRS 2 1 

TOT» T AN T «AL S H T T H TUMOP S '! Nr^RT1TN ­

BENIG N 0 " MALIGNAN T 1

 

T O m SI UNC3PTAI N THfOR S 1

 

TCTA L P.NT1AL S WIT H TtlMOP S UNCfRTATN ­

rH^MA' Y O P METAS T ATI C

 

Trn-AL MNCEPTAI N TUKC5 S 

* PKTPH.P Y TUHOFS : AL T TUMOP S 5XCEP T SECONDAP Y TUMOR S 

* SFCO'IMR Y TUTORS : METASTftTI C TU«OF S O P TUMOR S INVASIV E INTO A N ADJACEN T ORGA N 

44
 
TABLEA2.

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE

 

RATS FED PHOTODIELDRIN IN THE DIET 

fSIIISLS INITIALL Y I N STTDY 

INITIAL S NECEOPSIE D 

ANIMAI S EXAMINE D H I STOPATHOLOGIC ALL Y 

INTEGUMENTAR Y SYSTE M 

NON F 

FESPIEATCF Y SYSTE M 

NCN E 

MFMA^OPCIETT C SYSTEM 

*MUITIPL E ORGAN S 

KALIG.IYMPHOMA , IY«PHOCYTI C TYPE 

CT'COIATOB Y SYSTE M 

*""APT/V3NTPICIl: ''IBSCM A 

DIGESTIV E SYSTE M 

*LIVr? 

HEPATOCEILULA B CAPCINCP1 A 

*STOWAC B 

LEIOPIYC1 A 

rjpT N , t Y SYSTE M 

*K"DN"!Y 

- _ Ci£CIBO'«AJ.N05 

CONTROL 

10 

Q 

q 

< q ) 

(9) 

1 (11ii) 

( 9 ) 

( 9 ) 

( Q ) 

LOW DOSE 

^0 

so 

SO 

(50) 

(49) 

(U9 ) 

1 (2% ) 

C*6) 

1 (2% ) 

(15) 

HIGH DOSE 

50 

UQ 

US 

(19) 

1 (2% ) 

(K7 ) 

(«*) 

(U6 ) 

(US ) 

1 (2*1 

* Kn«B" B Of 8NIMM. S WIT H TTSSU E EXA.HIN5 D HTCROSCOPT C MLY 

* NUMB" P O F "NIPISL S NECBOPSIE C 

45 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED) 

CONTROL
 

INDflCEISE SYSI17"
 

IPITDT^S:'Y («)
 ADENCMS , NOS
 

CF30MQPHCE" ADENOM A
 

»ADKFNA L m
 COMICAL ADENOM A
 

«THYFOIt (9)
 PAPIILAPY ADENOM A
 

PAPTLIABY ADFNOCARCINOMA
 

"OLLIC'JUR-CEIl ADENOM A
 

C-CELL ADENOMA
 

C-CE1L CA8CTNO»!A
 

IPANCPSATIC ISI'TS
 

ISLET-CEIL ADENCM A
 

fi'PHODOCTTV*; SYSTEM
 

*MHHMAE Y GLAND
 

ADENCMS , NOS
 

ACENOCAECINOHA, NOS
 

FT BEOMA
 

FIBEOABFNOMA
 

tUTEPUS
 ENDOBETEIAL STPCMAL


NERVOUS SYSTEM
 

NONE
 

SPECIAL SENSE ORGANS
 

NCNE
 

("JSCUIOSKEIETAI SYSTEM
 

NONE
 

BCDY CAVITIES
 

NCNE
 

(9)
 

(9)
 

(6)
 PCLYP 1 (1TX)
 

LOW DOSE
 

(49)
 

1 (2*)
 

14 (8*)
 

(18)
 

1 <2X)
 

(«3)
 

2 (5*)
 

1 (2«)
 

1 (2*)
 

2 (5*)
 

(«?)
 

(50)
 

2 (KX)
 

5 (10*)
 

(12)
 

5 (12%)
 

HIGH DOSE
 

(39)
 

8 (21X)
 

(13)
 

(39)
 

1 <3X)
 

1 (3X)
 

(12)
 

2 (5X)
 

(19)
 

1 (2*)
 

1 <2X)
 

9 (18*)
 

(37)
 

6 (16*)
 

I N'TME'R 0? ANIMAL S WITH TISSDE EXAMINED MICROSCOPICALLY
 

* NUMBEP OF ANIHALS NECFOFSIED
 

46 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

Ml. OTHH 3 SYST5« S 

NOK ? 

ANICA L CISFCSITIC N SH»II<AP Y 

ANIMAL S INTTIATL Y I N STUD Y 1" 5? 50

 

NATURA L DEATH S J 8

i 

MCPIB'JN D aACPI'IC* 16 12 

SCHEDULE D SACRT*IC F 

ACCID^N^ALI Y K T LL? D 

"? D !1IMAL SACEIFIC F 7 31 31 

^NIMS L MISSIN G 

1 tNCIUDE S A'lTOIYZE E ANIB>I 3 

TOKC P SI]f»f c Y 

TOTAT AN T 1»L S WTT H PFTNAP Y T'ISC"S* 2 2" 26 

TOTA 1 F5IKAE Y TU>!QFS 2 26 31 

2 

TOTA I E'NIG N TDMOP S 2 22 28 

TOTA L AKIMAL S WI^ H BENIG N T'JMCF S 18 2« 

TCTA L ANIMAL S WIT H MALIGNUN T TUMOR S U 3

 

T^rA I "AIIGNSN T T'lrOP S a 3 

TOTA: ANIMAL S WIT H S?CONDS?, Y T'J«OPS» T1TAI S^CONDAP Y T'!f"ORS

 

TOTA L ANIMAL S WIT H T n MCS S UKCEFTAIN ­

BENIG N O F MAIIGNAN T 

TCTA L 'JNCEPTAI N T'TMOP S 

TOTA L ANIflAL S WI^ H Tt'MCS S tlKC'FTAIN ­

PF'BAF Y 0 " MHTAST» T - : C 

TOTA L UNCERTAI N T"10RS

 

* PPItUFY 7"WOES: MI TUMORS 7XCEPT SECONDARY TU10"S 

» SECONDAR Y TUHOPS : METSSTdT' C T'JMOP S O R TMHORS INVAS T V E INTO A N «.DJACENT ORGA N 

47 

APPENDIX B
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

MICE FED PHOTODIELDRIN IN THE DIET
 

49
 

TABLE B1.

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE 

MICE FED PHOTODIELDRIN IN THE DIET

 

LOW DOSE HIGH DOSE LOW DOSE HIGH DOSE 

CONTROL CONTROL 

• SIMM S INITIALL Y I K STUD Y 10 10 •=0 50 

• HI MAT S NECFOPSTE D 10 1? if » 9 

JNTMM 5 EXAMINE D HIS^OFATHOLOGICAILY 8 10 n7 U9 

INTEG"M T 'NTA5 Y SYSTEM 

NOU E 

SESPIFATCF Y SYSTE M 

ItUN C (in j (10) («7) (U9 ) 

AIVECLAP/ERONCHIOLf P ADENCB A 1 (2%) 1 («*) 

Hl'HATOPOI5'I' rC SYSTE M 

*10I"^PLE ORGAN S (10) (10) (l»7) (19)

 

( If LIG.1YMPHOMA , HISTIOCYTIC TYPE 1 (2*)

 

CTRCHIST05 Y SYSTE M 

NON" 

IIGESTIV E SYSIE1 

C1IVE5 (10) (9) («7) (if) 

NFOPLASTI C NODDL " 1 (2% ) HEPATOCE1LUIA B C»SCTNO!1A 3 (30%) 10 (21X) 9 (19X) HEMANGTOH A 1 (2X) 

URINAR Y SYSTE M 

NCN E 

INCOCRI1 E SYSTE M 

NON E 

I NOMBS P 0 ? ANIMAL S WI1 H TISSU E EXAMINE D MICROSCOPICALL Y 

* N'JMB^ E O F ANIMAL S NECFOPSIE D 

51
 
TABLE B1. MALE MICE: NEOPLASMS (CONTINUED) 

REPEODUCTIV E SYSTE M 

«TESTT S 

HEMANGTOM A 

N'EVOt.'S SYSTE M 

HON E 

SFECIf L 5ENS E ORGAN S 

*E1E/HC"IMAL GLAN D 

PRP'ILAP. Y CYSTADENCM& , VO S 

PUSCUIOSKE1HTA 1 SYST51 

NON E 

E^H Y CAVITIE S 

NON E 

S I L CTHT F SYSTEM S 

NON E 

ANtM U DTSFOSITTO N ?'!1M«H Y 

T ANIMAL S INITIALL Y N STUD Y 

N»TUBA I CEP.TH 4 

10RIEUN E SACBIEICT, 

SCHEE'JIH D SACPIFIC" 

>.CCT DENTA1.I Y K T L!E D T E D MINA I SACFIFIC E 

ANI1H. HISSIN G 

a iNcjj'DES 5'JTOi.j[ZEC \JilDiis 

» NUMBE R O F ANIMAL S W T T H TI=SI'E

* NtlKP" B n» ANIMAL S !J"CPOPSI I E 

LOW DOSE HIGH DOSE

 

CONTROL CONTROL

 

( 9 ) (10) 

(1") (10) 

1" 1* 

2 

6 10 

 "XAMINE D MICPOSCOPIC AL L Y 

LOW DOSE 

(1*6) 

1 (2*) 

(»7) 

5") 

6 

5 

39 

HIGH DOSE 

(U7 ) 

(«9) 

1 (2% ) 

50 

1 

t| 

U 5 

52 
TABLE B1. MALE MICE: NEOPLASMS (CONTINUED) 

LOW DOSE 

CONTROL 

HIGH DOSE 

CONTROL 

LOW DOSE HIGH DOSE 

TIIKC P StlKMAP Y 

TO^A L ANIMAL S WIT H PRIMAR Y

TOTAL PRIMAR Y 7D"!OKS 

 10MCPS* 3 

3 

1 U 

11 

13 

15 

TOTA L AMMAL S WIT H 3FNI5N

TOTA L BENIG N TUMOR S 

 TUMOR S 3 

3 

5 

•5 

TOTftl ANIMAL S WITH MAIT5NAN T TUMORS 

TP^Al MAIIGNAN T T"MOFS 

3 

3 

11 

11 

9 

9 

IOTA' ANIMAL S WIT H SFCONDAP Y TUMOFS * 

TOTAL SFCONDAR Y T'JMOSS 

TOTAL ANIMAL S WITH TUMOP S nNCFPTMN -

BFNIG N O R MALIGNAN T 

TOT'L fJNCSPTAI N T'JMOPS 

1 

1 

TCTAL ANIMAL S KITH T'!M09S IJSCEBTAINPBTMAR Y 0 " M^TASTATIC 

TOTAL (1NC2P.TAIN TUMOR S 

* PRmRY TiJNOPS: All TUMORS EXCEPT SECONDARY TUMORS 

» SECONDARY TJMOFS: METASTATIC TUMORS OR TUMORS INVASIVE INTO AN ADJACENT OPGAN 

53
 
TABLE B2. 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE 

MICE FED PHOTODIELDRIN IN THE DIET

 

LOW DOSE HIGH DOSE LOW DOSE CONTROL CONTROL 

ANTMAt S IHITIAILY IN STOCY 10 10 50 

SNIBH.S NEC50PSIE D 10 10 U9 

JNIfUL S EXAMINE D H T STOPATHOLOGICA!L Y 10 10 U9 

INTHGUMEtiTAE Y SYSTE M 

•SUBCtJT TISSU E (10) (10) (1(9) 

HEMANGIOM A 1 <2X ) 

PESPTKHTOP Y SYSTEM 

1IDN G (10) d") («8) AIVECLAP/BBONCHIOLA S ADENCM f 1 (10*) 

HE^ATOPOIETTC SYSTEM 

*NOITIPl! ORGAN S d") (10) (U9 ) MAIISNA1 I 1YMPH01A , DO S 1 (10*) WM. T G.!YMPHOMA , IYMPHOCY1I C TYP F 1 (10%) 1 (2*) MALIG.IYBPFOPH , HTSTIOCYTTC TYPE 

CIRCUIRTCS Y SYSTE M 

NON E 

DIG"STT V P SYSTE M 

«I

 TVF"

 I") ( 1n

> (13) HFPATCCFIL"!. A F CAPCINCM * 

U R T N!iP Y SYSTE M 

MC-N r 

ENDOCET"! 1' SYSTE M 

HIGH DOSE 

50 

149 

1*9 

(l»9) 

(118) 

2 («* ) 

(U9 ) 

1 (2« ) 

3 (6» ) 

(U 7) 

1 (2X ) 

54
 
TABLE B2. FEMALE MICE: NEOPLASMS (CONTINUED) 

LOW DOSE HIGH DOSE
 

CONTROL CONTROL
 

SfPSCDUCTIVE SYSTEM
 

• MAMMAR Y	 GIAND (I'M (11)
 

H&1APTCMA
 

*OVAPY	 (9) (8)
 CYSTADENOMA, NCS
 

NERVOUS SYSTEM
 

NO*!*
 

SFECTAL SENSE ORGANS
 

NCNE
 

PTJSCrjlOSKELETAI SYSlr1
 

NONE
 

BCDY CAVITIES
 

NONE
 

All CTH'B SYSTEMS
 

NONE
 

ANIHAI DISECSITICN SOMMAEY
 

ANIMALS 'INITIAIIY TN STUDY 1« 10
 

NATUBM DEATHS
 

MORIBHND SACRIFICE
 

SCHEDOIFE SACBIFICF
 

ACCTDENTALIY KIII?r
 

TERBTNAI SACPIFIC?. 10 10
 ANIMAL MISSING
 

3 INCLUDES AOTO^yZED ANIMAJ,?
 ^
 

t NUMBEF OF ANIdAIS KITH TISSDE EXAMINED «TCPOSCOPICAILY
 

* NOMBFP CB ANIMALS NECFOPSIfE
 

LOW DOSE
 

(19)
 

1 (2*)
 

(15)
 

50
 

3
 

1
 

16
 

HIGH DOSE
 

(1°)
 

(16)
 

1 (21)
 

50
 

3
 

5
 

U2
 

55
 
TABLE B2. FEMALE MICE: NEOPLASMS (CONTINUED) 

LOW DOSE HIGH DOSE LOW DOSE HIGH DOSE 

CONTROL CONTROL 

TOfC F SUMMAF Y 

TCTA L ANTfBL S WIT H PFTM'R Y

•"OTAL PPIHA8 Y T010P? 

 10MCSS* 1 

1 

2 

2 

3 

3 

I) 

n 

TOTA L ANIXAL S WIT H BFNIG N

TOTA L E'MG N TOHOS S 

 TDKCP S 1 

1 

2 

2 

3 

3 

TOT» I BNIMAL S WIT H MAIIGN4N T

TOTM M1IIGNAN T TUMOR S 

 T'JKOP S 2 

2 

1 

1 

5 

5 

TCTA I ANIHAL S WIT H SICCNDA-i Y

TO'-AL SECONDAR Y T'lHCP S 

 TO»ni=S * 

TOTA L ANIMAL ? WIT H Tt'HOa S

BENIG N C " MALIGNAN T 

TOTA L UNCHP"»I N THflOE S 

 nNCEET.>IM ­

T C T A L ANIHAL S WIT H TUMOR S

FFI1AP Y c ° .lE-'ASTATIC 

TOTA L UNCSPTAI N TUPICP ? 

 UKCERTAIN ­

* PKT1AP Y I'JMOES : Al l TUMOR S IXCJP? SECONDAR Y TU!10KS 

t S^CONDAS Y TUMORS : (1 ST'.STAT 1C T'JBOFS 0? TtlMOBS INVASIV E INTO AN ADJACEN T OBGA N 

56 
APPENDIX C
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS
 

IN RATS FED PHOTODIELDRIN IN THE DIET
 

57
 

TABLE C1.

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN 

MALE RATS FED PHOTODIELDRIN IN THE DIET 

CONTROL LOW DOSE HIGH DOSE
 

c
 JNIMAL S INITIALLY IS STUDY 10 ^n n
 ANtMST S N3CEOPSTED 10 K8 50
 

ANIHALS EXAMINED HI STOPS THOLOGICALLY 10 «8 U9
 

INTHGHHFNTAPY SYSTEM
 

*SKIN (10) (IS) (50)
 

HTC'R, N05 1 (2*)
 INFLAMMATION, FOCAT GP ANULOH ATOU 1 (2*)
 

PESPTPATOP.Y SYSTEM
 

• KING	 (10) («9) <t9)
 ^MPHYSEMA, NOS 2 (UX)
 

ATELECTASIS 1 (2X)
 PNEUMONTA, CHRONIC MDRIN5 1 (2%)
 

*LUNG/ALVEOLI (10) (»8) (<»9)
 EMPHYSEMA, NOS 3 (6«) 1 (2*)
 

HFMATOPOT'DTIC SYSTEM
 

•SPLEEN	 (9) (i»8) (47)
 

CONGESTION, NOS 1 (2%)
 HEHOEBHAGE 1 <2X>
 

INFLAMMATION, CHRONIC FOCAL 1 (2«)
 FIBROSIS, FOCAL 1 (2*)
 HEBOSIDEROSIS 1 (2*)
 

CIPCDLATORY SYSTEM
 

*HEART (10) (»•>) (48)
 

DEGENERATION PARENCHY MATOOS 1 (2X)
 DEGENERATION, HYDROPIC 1 <2X)
 

*HEAHT/ATRIOM '(10) (47) (48)
 

THHOMBO^J;?, 595 , __ _ _ , .1_ 12%±
 

* NDHBER OF ANIMALS BITH TISSOF, EXAMINED HICPOSCOPICALLY
 

* HOHBER OP ANIMALS NECROPSIBD
 

59
 
TABLE C1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

HIGH DOSE
 

(US)
 

(50)
 

1 (2*)
 

1 (2*)
 

1 (2*)
 

1 (?*)
 

(«")


2 («*)
 

9 (18*)
 

5 (10*)
 

(50)
 

(U5)
 

1 (2%)
 

(K6)
 

(K6)
 

1 (2%)
 

1 (2*)
 

(U9)
 

6 (12%)
 

13 (27%)
 

1 (2%)
 

(19)
 

1 (2%)
 

(U5)
 

-


HENDOCJFDTHM
 

FIB"OSIS, "OCAI
 

*A1FTA
 

T»PO(180SIS, NOS
 

SCIS POSTS
 MEDT AL CALCIFICATION
 CJICIFICATTON, NO'S
 

CTGESTTVF SYSTEM
 

»LTVEP
 

DEGENERATION PAPENCHYMATOUS
 

METAMORPHOSIS "ATTY
 CYTOIOGTC DEGENERATION
 

AKGT JCTASIS
 

*EiL" one?
 HYPFRPI ASIA, HOS
 

#P>SNCD F AS
 PERIARTEP.ITIS
 

NECROSIS, EAT
 

tSTOMACH
 DIC?B, NOS
 

CALCIFICATION, DYSTHOPHIC
 

*GAST3IC M'JCOSA
 EROSION
 NFCBOSIS, FOCM
 

OEINAFY SYSTEM
 

tKIDNEY
 FYDPONEPHROSIS
 

GLOME3UIONEPHRITIS, NOS
 

INFLAMMATION, CHRONIC
 

INFIA1BATION, CHRONIC DIFFOSI i
 

IKIDNEY/PELVIS
 

INF1AMBATION, NOS
 

*tIPINASY BLADDER
 INFLAMMATION. ACUTE N£CJOTIZ] :NG
 

CONTROL
 

(10)
 

d")
 

(1")
 

1 (10«)
 

1 (10%)
 

1 (1"%)
 

(10)
 

(10)
 

(10)
 

3 (30*)
 

(10)
 

(1")
 

3 (30*)
 

2 (20*)
 

(10)
 

(10)
 

LOW DOSE
 

CO
 

1 (2*)
 

(«°)
 

CO
 

3 (6%)
 

5 (11%)
 1

 (2*)
 

3 (6*)
 

(U8)
 

1 (2%)
 

(«2)
 

1 (2*)
 

(U5)
 

1 (2%)
 

(U5)
 

C«6)
 

1 (2%)
 

1 (9%)
 

15 (33%)
 

(16)
 

(«3)
 

1 (2%)
 

t NTJMEE F OF ANIMAL S WIT H TISSUE EXAMINE D MICROSCOPICALLY 

* NOMBE S OF ANIMAL S NECROPSIE D 

60 
TABLE C1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE • HIGH DOSE 

HYP*SFIA?H , EPITHEII M 1 (2») 

ENDOCP.TN E SYSTE M 

*PIT"!T A9Y 

CYST , NOS 

I"!"TT!P!Z CYST S 

CONGESTION , HO S 

HYPFHPIAEIA , NO S 

UYPESPLASIA , CHROIOPHOEE-CET L 

ANGT C CTASI S 

(5) 

1 (705S) 

(42) 

1 (2% ) 

1 (2% ) 

1 (2% ) 

3 (7%) 

(46) 

1

1

1

 (2% ) 

 (?% ) 

 (?<) 

tADPT»!».I 

NFC D nSIS , H"MOPPH»f,I C 

ANGTFC7ASI S 

( S) {»?) 

1 (2% ) 

(49 ) 

1 (2% ) 

*AD9ENA L CCPTE X 

CYST, NOS 

NFTAfiOBPHOS T S *STTY 

RYP'KPIASH , DTFF'Js*r 

( B ) («') 

1 (2%) 1

 (2% ) 

(49 ) 

1 (2% ) 

*THY"OID 

FOLLIC'IIA H CYST , NO S 

HYPFHPLASIA , FO I ItcU L »K- C^IL 

(9) 

1 (11% ) 

(39) 

5 (11% ) 

(42) 

2 (5%) 

2 (5% ) 

(tPAPfTHY^OT D 

HYPER D IASIA , NO S 

(*) 

1 (17%) 

(15) (2M 

REPRODUCTIV E SYSTE M 

«^A«!MA" Y GTAN D 

NFCPOSIS , 'HI 

(10) (i»8) 

1 (2% ) 

(50) 

•HUPIMAR Y lOBUL F 

PYPEEP I ASIA , NO S 

(10) (US ) (50) 

1 (2%) 

tPEOST AT3 

IN'LAIH'TION , NCS 

TSFIMHATION , FOPPURATTV E T«IF! *PII«ATION , fC'JT" 

TM^ I A1BATION , AC'!TE SUPPCRATIV 5 

HYPEHFIAEIf , NO S 

(10) 

1 (1->%) 

1 pet) 

1 (ii%) 

(t n)

1 (3X) 

(46 ) 

1 (2%) 

1 (2%) 

•SEMINA L VFSICL F 

DFG£N?H AT;ON^_C YSIJC_^ (10) 

_„ («9)

1-12ZL 

(<;<•) 

« NUK8EP

* N'JHBTP

 0* PNTMAL S WITH TISSUE EXAMINED HICPOSCOPICAITY 

 OF SNIBALS NFCEOPSIIC 

61 
TABLE C1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE
 

•TESTIS	 (1")
 (i»6) (49)
 ATROPHY, NOS 3 (30*) a (20%) 12 (2«%)
 VPOFHY, FOCAL (2%)
 1


FYPESPLASIA, INTERSTITIAL CEtl	 1 (2%)
 

NEHVnns SYST'rt
 

1CNF
 

SPECIAL SENSE OPGAN S
 

NCNE
 

llt'SCUIOSK'iIFTAL SYSTE1
 

NCN?
 

ECDY CAVTTTIS
 

•MESFNTTp.y	 (1") (18) (50)
 

THOOM3CSIS, NOS 1 (10%)
 

PEPIAHTEBITIS 1 (10%) 3 (6%)
 

All OTHEB SYSTEMS
 

NCNE
 

SPECIAL P10BFHOLOQY SUMMAR Y
 

NO IESTON P'POETED 1 8 e


Al'TO/NECPOPSY/NC HISTO 1
 

AUTOLYSTS/NO NECROPSY 2
 

« NUPIBF R 0 ' ANIMAI S WIT H TISSUE EXAMINE D MICROSCOPICALL Y 

* NOBB^ F OF ANIMAL S NECPOPSI1?D 

62
 
TABLE C2.

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN 

FEMALE RATS FED PHOTODIELDRIN IN THE DIET 

«NI!<»L S INITIALL Y I N ST'JDY 

PNTMAI S NECSOPSJE D 

ANIPIAL S 'XSMINF D HI STOPATHOLOGIC AI LY 

INTEGTJMENTAP Y SYSTE M 

NON F 

FESPIPATCK Y SYSTE M 

*L'JNG/BRONCHIOL E 

HYPERPIASIA , LYP D HCI D

 

*L'JNG 

CONGESTION , NCS

 

HF*OEEHAG E 

INFLAMMATION , "OC1I 

ttONG/ALTEOL I 

EMPHYSEMA , NO S 

HEMATOPO'^rT C SYSTEM 

*SPLEFN 

CONGESTION, NOS 

HYPOPLASTA , IYMPHOT D 

CIRCOLATO1!? SYSTEM 

NON E 

DIGESTIV E SYSTE M 

ILIVEE 

HEHOHHHAG E 

LJIPfiOCUlIC JM?JLT?^1E 

CONTROL LOW DOSE 

10 50 Q 50

 

9 50

 

(?) (50) 

1 (2%) 

(9) (50) 

2 (<t%) 

(9) (50) 

1 (2%) 

(?) C*9) 

1 (2*) 

1 (2X) 

(9) (19) 

1 (2X) 

f NOMBEE OF ANIMALS WITH TISSUE EXAMINED MICROSCOPIC ALLY
 

* NUMBEH OF ANIMALS NECEOPSISC
 

63
 

HIGH DOSE 

?0 

l»9 

lt8 

(117) 

(<f) 

2 (M% ) 

1 (2X) 

(147) 

1 (2*) 

(t6) 

(16) 

1 (2X1 
TABLE C2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

DFGFNHFATIO N PA BENCHYP ! ATO OS 

NECFOSIS , NOS 

NECROSIS , FOCAL 

MFTAHOBPHOST S ? BTTY 

ANTTECTASI S 

• ilFPA^T C CAPS"LF 

HFHOPSH5G E 

#LIVFR/C1 : N m FII.OBUlA' 1

 

MET»MC9PHOSI S "ATTY 

*P>IL E tlHCT 

HYPi'BPIASIA . , NOS 

»P»NC9"A S 

METABCBPHOSI S FATT Y 

»r,AST?IC HUGO S A. 

NEC°CSIS, FOCAL 

«GASTPI C F nHD" S 

AEPAEE C WCUN D 

'JPTNtP Y SYP'^ M 

• KTDf'^ Y 

CYST , NC S 

GI OMEpniON I'PHRTT:iS , NOS 

~N° ! ANIMATION , NO S 

TM?IAMM»TION , FOCM 

TKF I A?t.1ftTION , CBPOM7 C 

TN'IAMHATION , CHRONI C FOCA I 

«KIDM"Y/CCFT' X 

It'T T ILOC"L?. P CYS T

 

SKIDN'JY/PrlVI S 

HYPF^PIASIA , EPITHELIA L 

?ND?C=TN I SYSTE M 

• P^TUTTA^ Y 

CCN^ESTION , NO S 

» NTJ1BE P I F AN T H»I. S KIT H TISSU E

* 'JM1BFP OF ANIIf.L S N"CROPSIEC 

2 (US') 

1

1

 (ini 

 <mi 

1

3

2

 (2U) 

 (6S) 

 (l»%) . 

( ? ) (»°) 

C?) (U9 ) 

( Q ) (50) 

2 («*) 

( «) I«0) 

1 (2X) 

O) (1*6) 

1

 (2%) 

( a) C*6) 

( ? ) (49) 

1 (2%) 

1 (2*) 

1 (2X ) 

1 (mi 

(9) («9) 

1 (2% ) 

( Q ) («9) 

1 (2%) 

(8) (H8 ) 

2 J2531 

 EXAMINE D MICROSCOPICALL Y 

S (17*) 

(U6 ) 

1 (2*) 

(»6) 

1 (2X ) 

(t9) 

(U2 ) 

(1*6) 

(U6 ) 

1 (2X ) 

(it? ) 

1 (2*) 

it (?X) 

(US ) 

(1*8) 

(39) 

1 (3J!) 

64 
TABLE C2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

HIGH DOSE
 

2 (c?)
 

1 (3%)
 

3 (8*)
 

(13)
 

2 (5«)
 

1 (2%)
 

1 (2*)
 

1 (2%)
 

1 (9%)
 

(13)
 

1 (2*)
 

1 (2%)
 

(39)
 

(12)
 

(19)
 

(37)
 

HEMCFFHBG::
 DEGENERATION, CYSTTC
 »NTT ECTASIS
 

*AD?FNAI
 CYST, NOS
 

HE10BRHAGE
 DEGENERATION, NOS
 

DEGENERATION, CYSTTC
 

NEC"OSTS, ^OCAt
 

NFCEO5TS, "EHOPBHAGTC
 

1ETAMOFFHOSIS F».TTY
 

•NRTECTASIS
 

*»DPFN» L CCPTFX
 DEGENERATION, NOS
 

NECROSIS, NOS
 NECROSIS, ''OCAL
 METAHOEPHOSIS FA^TY
 

ANGIECTASIS
 

ITHYROTD
 HYn"BPIASIA, C-CFL1
 

'PANCREATIC ISIETS
 

HYPEtiptASIA, NOS
 

RFPBODOCTIVE SYSTEM
 

• MAMMAR Y IOBU1E
 HYPF.EPIAEIA, NOS
 

*nT5ROS
 

HETAPtASIA, SQriAMOUS
 

NHPVOUS SYSTFB
 

NONE
 

SPECIAL SENSE ORGANS
 

NCNE
 

HUSCniOSKElETAL SYSTEM
 

NONE
 

CONTROL
 

2 (25%)
 

1 (11%) ,
 

("?)
 

(9)
 

1 (11%)
 

(?)
 

(9)
 

1 (11*)
 

(9)
 

(6)
 

LOW DOSE
 

2 (til)
 

5 (10%)
 

(«8)
 

1 (2«)
 

2 (it*)
 

1 (2%)
 

1 (2*)
 

1 (2*)
 

2 (U*)
 

C»8)
 

1 (2*)
 

2 («*)
 

(13)
 

1 (2*)
 

(U9)
 

(50)
 

1 (2X)
 

(t2)
 

1 (2*)
 

I NUMBER OP ANIMALS WITH TISSDE EXAMINED MICROSCOPICAILY
 

* NOHBEP OF ANIMALS N1CRCPSIED
 

65
 
TABLE C2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

8CD Y CAVITIE S 

NCN E 

A I L OTHF B SYSTHtt S 

NOHi F 

SPECIA L HOFF.HOLOG HOFF.HOLOGYY S'JMBAR S'JMBAR Y 

N O IESIOIONN EFFOBTE EFFOBTEDD 3 12 1133 

HUTC/NEC C O P S Y / NO P S Y / N O HIST HISTQQ 1 1

AUTOLYSTS/NO NECROPS NECROPS Y 1 1 1

» NIJMB5? P 0 ^ ANIMM S WIT H TISSUF FX!IM T O E D MICROSCOPICAIL Y 

« M'lMPE P O F ANI1AL S NECBOPSIE D 

66 
APPENDIX D
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS
 

IN MICE FED PHOTODIELDRIN IN THE DIET
 

67
 

JNIMAL S INITIAII Y I K STnCY 

fN^MAI S N^CPOPSIE D 

SNIBAL S EXAMINE D H I STOPATHQLOGICAL L Y 

I!H5GOMENT!>' > Y SYSTE M 

NON E 

F'SPIFSTOF Y SYSTE M 

• I TIN G 

FEMOUFPAG E 

INFLAMMATION , FOCAL 

HYPEBPLASIA , AIVEOLA R EPITHELIU M 

HFIATOPOI^TT C STSTE H 

*LY«P H NODE 

INFLAMMATION , NO S

 

#HESENTERI C L. NODE 

TNFLABHATION , NO S

 

*SrjBSCAPULR R LYMP H N O 

INFAPCT , NO S 

tTHYMU S 

HYPEPPLASIB , LYBPHOI D 

CIPCOIATOH Y SYSTE M 

NON E 

EIGESTIV J SYSTE M 

*LIVEE 

JN'iSCJj, N0.5 

t NUMBER OF ANIMALS WITH TISSUE EXAMINED HICBOSCOPICALLY
 

* NUMBER 0? ANIMALS NECFOPSIED
 

TABLE D1. 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS 

IN MALE MICE FED PHOTODIELDRIN IN THE DIET 

•""""—-"••-"—"^-"••""•••"'•'—~—TMTMTMTM •"""•••• -»•"-• "-••••"TM 

LOW DOSE HIGH DOSE 

CONTROL CONTROL 

10 10

 

1 0 11

 

8 10

 

(10) (10) 

1 (10*) 

1 (11%) 

(9) (9) 

(8) (9) 

(8) (9) 

(D 

1 (100%) 

(10) (9) 

LOW DOSE 

"0 

1? 

in 

(17) 

1 (2% ) 

(12) 

(12) 

(t2) 

(d 7) 

HIGH DOSE 

50 

U9 

19 

(It 9) 

(Ktt) 

1 (2«) 

(UK ) 

1 (2») 

(i»U) 

1 (2% ) 

(«7) 

2 JAJl. 

69 
TABLE D1. MALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

HYPEBFLASU , NCWIP P 

LOW DOSE 

CONTROL 

HIGH DOSE 

CONTROL 

3 (33X ) 

LOW DOSE HIGH DOSE 

3 (61) 

URINAR Y

NCN F 

 SYSTF.1 

ENCCCPTN *

NCN ? 

SYSTrn 

SfPOT'ICTIVE

HCN F 

 SYSTEM 

**EVC'JS SYSTE M 

f EPAT N 

COPPO"A AMYLACFf t (?) 

1 (11*) 

(10) 

1 (10X) 

C»5) (U9 ) 

3 (6*) 

SPECTft L

NOH E 

 SENS E OPGRN S 

nUSCIlOSKSlFTM

NON ^ 

 SYSTFM 

EODK CAVITIE S 

HONE 

All OTHO

NONE 

 SYSTEBS 

SPECIAL MOEFHOIOGY SUHMAR Y 

NO JESION P.EFOETED 

I HUHBEB OF AHIHiLS HITH TISSOE EXAMINED

* NOMEER OF ANIMALS NECEOPSIED 

« ... . .6

 HICBOSCOPICALLY 

. 32 30 

70
 
TABLE D1. MALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

LOW DOSE HIGH DOSE LOW DOSE HIGH DOSE 

CONTROL CONTROL 

M'TC/NBCPCPSY/NC HISTC 

MJTOIYSTS/NO NECROPS Y 

2 

3 1 

O F ANIMAL S WIT H TISS'TE EXUMIN^ D MICPOSCCPICALI Y 

0 ­ 1NI1ALS N'CPOPSIE C 

71 
TABLE 02.

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS 

IN FEMALE MICE FED PHOTODIELDRIN IN THE DIET 

LOW DOSE HIGH DOSE LOW DOSE 

CONTROL CONTROL 

1NIWAL S INITIALL Y I N STUD Y 10 10 ;o 

.((THAIS NFCBOFSIE D 10 10 uq 

ASIKAI S FXAMIHF D HISTOFATHOLOGTCALL Y 10 T) ng 

TN'HGUMF.NTAR Y SYSTE H 

NON E 

5FSPIRATCR Y SYSTE M 

*LUNG/BRONCHIOI E (10) (10) C*s> 

HYP"3PIASIA , LYHPHCT D 

tltlNG (10) (10) (««) 

PME'JBONIA , ASPIEATTC N 

HEMATOPOTKTT C SYSTE M 

•SPLFFN (11) (11) (i»8) 

HYPTFP1ASIA , IYHPHOI D 1 (10t) 2 («*) 

CTRCM ! ^TOP Y SYSTF H 

#"!YOCARDTU K (10) (10) (»8) C IB5CSIS , FOCAI 

ETT-ESTTV E SYSTE M 

JT_T V F O ( 9 ) (10) (13) 

C^GFNiEATIO N P ARFNCH Y HAT O US 

METS1CFEHOSI S FATT Y 1 (2%) 

HY"F5FIAEIA , NOCUIAP . 1 (in*) 3 ( 7X) 

HYPEFP1ASIA , DT FFOS F 1 (11%) 2 (511) 

HYPFHPLASIA , lYflPHOT D 1 (2%) 

NODI'LA P FEG?N3 E ATIO N 1 (2*) 

»P«NCRFA S (1C ) (10) («7 ) 

ATROPHY , NOS ^ _. . __!_.! ?«],.__. 

t HUMEF. F 0 " ANIMA1 S WIT H TISSUE EXAMINE D MIC FOSCOPIC ALL Y 

* NIIMBE " 0 T S.NIHAL.S NECFOPSIE D 

HIGH DOSE 

50 

i»9 

to 

(US )

1 (2m 

(18) 

1 (2!!) 

(U8 ) 

3 <6» ) 

(«8) 

1 (2K ) 

(U7 ) 

3 (6» ) 

1 (2H ) 

1 (2») 

1 <2« ) 

C»6) 

,,_ _, 

72 
TABLE D2. FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

__ LU TT m .._...._.-___„____«_ ____«.____ "•-!--"— '———'• 

UPINAP Y SYSTE M 

• KIDNE Y 

INFLAMMATION , INTERSTITIA L 

KKIDNEY/CCPTE X HYPEFPIASIA , LYMPHCI D 

• USINAH Y BLADDE R 

HYPEBPIASIA , LYPPHHI D 

ENDOCSTN E SYST' M 

NCN F 

BFPPOD'JCTIV F SYSTE M 

»UTE n iJS/5NCr«FTEID H 

TN?1A1H«TIOV , SDPPUPATIV E 

DEC-ENFPSTIO N , CYST TC 

HYPFBEIBEIA , CYSTI C 

UnvAPY/OVIDUCT 

INFLSB^ATION , NC S 

JOV'.^Y 

rnii icniss CYS^ , >jcs "OIYCYSTT C OVAP Y 

HFXCF^HAR E 

TN?T. 9 M RATION , NCS 

T»'?T MMSTIO N , S'JPP'JP»TT7 E T SFL SMNHTION , ACUT F 

INT A119TION , »C'JT E S UPP CS A^IV! 

ABSCISS, NOS 

INF1 AVIATIO N 9C07F >N D CKBCNI C 

KEEVO'" S SYSTE M 

*E3» T N 

CCFFCP A A,1YIAC^ A 

= C E C T A I SENS E OFGAN E 

NCN F 

-'flEEP OF SNI1SLS WITH TISSUE EXAMINE D MIC POSCOPIC AIL Y
 

JT.^BYP 0<: JNIHALS NECFCFSI^D
 

LOW DOSE HIGH DOSE 

CONTROL CONTROL 

dn) (11) 

1 (10% ) 

(10) (10) 

C7) (11) 

dr) (9) 

2 (2"%) 2 (22X ) 

(10) 0) 

(9) (3) 

1 (11%) 

U (50% ) 

1 (11% ) 

1 (1U) 

(10 ) (1") 

LOW DOSE 

(US) 

(«8) 

(11) 

(US ) 

•• (16% ) 

(«5) 

1 (2% ) 

(145) 

8 (19% ) 

1 (2% ) 

1 (°K ) 

1 (2%) 

(»7) 

HIGH DOSE 

(18) 

(«9 ) 

1 (2*) 

(«2 ) 

1 (2») 

(U3 ) 

1 (2X ) 

3 {""») 

6 (1t% ) 

(03) 

(U6 ) 

1 (2* ) 

1 (2*) 

1 (2K ) 

2 («% ) 

(i»9) 

1 (2*) 

73
 
TABLE D2. FEMALE MICE: NQNNEOPLASTIC LESIONS (CONTINUED) 

LOW DOSE 

CONTROL 

HIGH DOSE 

CONTROL 

LOW DOSE HIGH DOSE 

WISC'JLOSKEIETAL SYSTEM 

NONE 

ECDY C4VITI5S 

*PIFTTONEAI CAVITY 

INFLAMMATION, CHRONIC 

(10) (10) (l>9) (U9) 

1 (2*) 

All CTHEE SYETHNS 

NON" 

SPECIAL finBPHOLOGY SUMMARY 

NO LESION RFEO?1ED 

AOTOLYSIS/NO NECROPSY 

t NUMEEK OF ANIMAL S KITH TISSUE EXAMINED

* SOMBER OF ANIMALS NECRCESI^D 

u 

 MICROSCOPICALLY 

1 23 

1 

21 

1 

74
 
APPENDIX E
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS
 

IN RATS FED PHOTODIELDRIN IN THE DIET
 

75
 

Table El. Analyses of the Incidence of Primary

Fed Photodieldrin in the Diet3 

Pooled Matched
 

Topography: Morphology Control Control
 

Pituitary: Carcinoma, NOSb 1/62 (2) 0/5 (0)
 

P Valuesc»d N.S. N.S.
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 —_
 

—
 

Pituitary: Carcinoma, NOS or
 

Adenocarcinoma, NOSb 1/62 (2) 0/5 (0)
 

P Values0 >d N.S. N.S.
 

Relative Risk (Pooled Control)^
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 —
 —
 

 Tumors in Male Rats 

Low
 

Dose
 

2/42 (5)
 

N.S.
 

2.952
 

0.158
 

169.961
 

Infinite
 

0.045
 

Infinite
 

93
 

2/42 (5)
 

N.S.
 

2.952
 

0.158
 

169.961
 

Infinite
 

0.045
 

Infinite
 

93
 

High
 

Dose
 

1/46 (2)
 

N.S.
 

1.348
 

0.017
 

103.525
 

Infinite
 

0.010
 

Infinite
 

106
 

2/46 (4)
 

N.S.
 

2.696
 

0.144
 

155.545
 

Infinite
 

0.041
 

Infinite
 

85
 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats
 

Fed Photodieldrin in the Diet3
 

(continued)
 

Topography: Morphology
 

Pituitary: Chromophobe
 

Adenoma"
 

P Valuesc»d
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)^
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Thyroid: C-cell Adenoma'3
 

P Values0 >d
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Pooled
 

Control
 

8/62 (13)
 

N.S.
 

—
 

2/65 (3)
 

N.S.
 

—
 

Matched Low 

Control Dose 

0/5 (0) 6/42 (14) 

N.S. N.S. 

1.107 

0.339 

3.348 

Infinite 

0.244 

Infinite 

__ 

81 

0/9 (0) 3/39 (8) 

N.S. N.S. 

2.500 

0.299 

28.669 

Infinite 

0.156 

Infinte 

57 — 

High
 

Dose
 

5/46 (11)
 

N.S.
 

0.842
 

0.230
 

2.711
 

Infinite
 

0.176
 

Infinite
 

84
 

1/42 (2)
 

N.S.
 

0.774
 

0.013
 

14.321
 

Infinite
 

0.013
 

Infinite
 

112
 
__ 

(continued) 

Topography: Morphology
 

Thyroid: C-cell Adenoma or
 

Carcinoma^3
 

P Valuesc»d
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Thyroid: Papillary Adenocarcinoma
 

or Follicular-cell Adenoma'3
 

P Valuesc'd
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

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

Fed Photodieldrin in the Dieta 

Pooled Matched
 

Control Control
 

2/65 (3) 0/9 (0)
 

N.S. N.S.
 

—
 

0/65 (0) 0/9 (0)
 

N.S. N.S.
 

Low
 

Dose
 

4/39 (10)
 

N.S.
 

3.333
 

0.499
 

35.249
 

Infinite
 

0.242
 

Infinite
 

57
 

1/39 (3)
 

N.S.
 

Infinite
 

0.089
 

Infinite
 

Infinite
 

0.014
 

Infinite
 

—
 —
 —


High
 

Dose
 

1/42 (2)
 

N.S.
 

0.774
 

0.013
 

14.321
 

Infinite
 

0.013
 

Infinite
 

2/42 (5)
 

N.S.
 

Infinite
 

0.455
 

Infinite
 

Infinite
 

0.071
 

Infinite
 

112 

112 
__ 

__ 

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

Fed Photodieldrin in the Dieta
 

(continued)
 

Topography: Morphology
 

Pancreatic Islets:
 

Islet-cell Adenoma^3
 

P Valuesc»d
 

Departure from Linear Trend6
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)

f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

All Sites: Hemangioma^
 

P Valuesc»d
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)^
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Pooled
 

Control
 

3/72 (4)
 

N.S.
 

0/75 (0)
 

P = 0.021
 

Low
 

Dose
 

0/42 (0)
 

N.S.
 

0.000
 

0.000
 

2.840
 

0.000
 

0.000
 

4.444
 

0/48 (0)
 

N.S.
 

—
 

—
 

—
 

—
 

—
 

—
 —
 

High
 

Dose
 

0/45 (0)
 

N.S.
 

0.000
 

0.000
 

2.659
 

0.000
 

0.000
 

4.155
 

3/50 (6)
 

N.S.
 

Infinite
 

0.895
 

Infinite
 

Infinite
 

0.134
 

Infinite
 

Matched
 

Control
 

1/10 (10)
 

N.S.
 

P = 0.033
 

111
 

0/10 (0)
 

N.S.
 

—
 99 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats
 

Fed Photodieldrin in the Diet3
 

(continued)
 

a

Treated groups received doses of 5 or 10 ppm in feed.
 

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

c

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


Armitage test when P < 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 (*) 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 E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Fed Photodieldrin in the Dieta
 

Topography: Morphology
 

Pituitary: Chromophobe Adenoma*3
 

P Values0'd
 

Relative Risk (Pooled Control)^
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Thyroid: C-cell Adenomab
 

P Valuesc»d
 

Relative Risk (Pooled Control) f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Pooled
 

Control
 

12/62 (19)
 

N.S.
 

—
 

1/66 (2)
 

N.S.
 

—
 

Matched
 

Control
 

0/8 (0)
 

P = 0.038
 

0/9 (0)
 

N.S.
 

—
 

Low
 

Dose
 

4/48 (8)
 

N.S.
 

0.431
 

0.107
 

1.319
 

Infinite
 

0.178
 

Infinite
 

58
 

2/43 (5)
 

N.S.
 

3.070
 

0.166
 

176.825
 

Infinite
 

0.069
 

Infinite
 

106
 

High
 

Dose
 

8/39 (21)
 

N.S.
 

1.060
 

0.409
 

2.534
 

Infinite
 

0.543
 

Infinite
 

95
 

1/39 (3)
 

N..S.
 

1.692
 

0.022
 

129.471
 

Infinite
 

0.014
 

Infinite
 

112
 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats 

(continued) 

Topography: Morphology
 

Thyroid: C-cell Adenoma
 

or Carcinoma"
 

P Valuesc'd
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Thyroid: Papillary Adenoma,
 

Papillary Adenocarcinoma, or
 

Follicular-cell Adenoma*3
 

P Valuesc>d
 

Departure From Linear Trend6
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Fed Photodieldrin in the Dieta 

Pooled Matched Low High
 

Control Control Dose Dose
 

2/66 (3) 0/9 (0) 2/43 (5) 2/39 (5)
 

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

1.535 1.692
 

0.114 0.127
 

20.387	 22.398
 

Infinite Infinite
 

0.069 0.077
 

Infinite Infinite
 

_-.
 106	 112
 —
 

0/66 (0) 0/9 (0) 4/43 (9) 0/39 (0)
 

N.S.	 N.S. P = 0.022** N.S.
 

P = 0.002
 

Infinite
 —
 1.415
 

Infinite
 —


—
 

Infinite
 —
 0.220
 —
 Infinite
 —
 

102
 —	 —
 —
 
__ 

__ 

__ 

E2. Analyse* of the Incidence of Primary Tumors in Female Rats
 

(continued)
 

Topography: Morphology
 

Thyroid: Papillary Adenoma or
 

Papillary Adenocarcinoma^1
 

P Valuesc»d
 

Departure From Linear Trend6
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Pancreatic Islets: Islet-cell
 

Adenoma^
 

P Values0 >d
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)^
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Fed Photodieldrin in the Dieta
 

Pooled Matched
 

Control Control
 

0/66 (0) 0/9 (0)
 

N.S. N.S.
 

P = 0.007
 

—
 

1/69 (1) 0/9 (0)
 

N.S. N.S.
 

Low
 

Dose
 

3/43 (7)
 

N.S.
 

Infinite
 

0.920
 

Infinite
 

Infinite
 

0.142
 

Infinite
 

102
 

0/49 (0)
 

N.S.
 

0.000
 

0.000
 

26.256
 

—
 

—
 

—
 

High
 

Dose
 

0/39 (0)
 

N.S.
 

—
 

—
 

—
 

—
 

—
 

—
 

2/42 (5)
 

N.S.
 

3.286
 

0.176
 

189.114
 

Infinite
 

0.071
 

Infinite
 

—
 —
 100 
__ __ 

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

Fed Photodieldrin in the Dieta
 

(continued)
 

Topography: Morphology
 

Mammary Gland: Adenoma,
 

Fibroadenoma,* i
 or Adenocarcinoma, NOS
 

P Valuesc'd
 

Relative Risk (Pooled Control)^
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Mammary Gland: Adenoma
 

or Fibroadenoma
 

P Values0>d
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Pooled
 

Control
 

9/72 (13)
 

N.S.
 

8/72 (11)
 

N.S.
 

—
 

Matched
 

Control
 

0/9 (0)
 

N.S.
 

0/9 (0)
 

P = 0.039
 

—
 

Low
 

Dose
 

7/50 (14)
 

N.S.
 

1.120
 

0.376
 

3.137
 

Infinite
 

0.396
 

Infinite
 

58
 

5/50 (10)
 

N.S.
 

0.900
 

0.244
 

2.920
 

Infinite
 

0.256
 

Infinite
 

81
 

High
 

Dose
 

10/49 (20)
 

N.S.
 

1.633
 

0.642
 

4.180
 

Infinite
 

0.622
 

Infinite
 

56
 

10/49 (20)
 

N.S.
 

1.837
 

0.700
 

4.945
 

Infinite
 

0.622
 

Infinite
 

56
 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Fed Photodieldrin in the Dieta
 

(continued)
 

Pooled Matched Low High
 

Topography: Morphology Control Control Dose Dose
 

Uterus: Endometrial Stromal
 

Polypb 7/67 (10) 1/6 (17) 5/42 (12) 6/37 (16)
 

P Valuesc»d N.S. N.S. N.S. N.S.
 

Relative Risk (Pooled Control)f 1.139 1.552
 

Lower Limit 0.303 0.459
 

Upper Limit 3.868 4.940
 

Relative Risk (Matched Control)f 0.714 0.973
 

Lower Limit 0.116 0.171
 

Upper Limit 32.973 43.453
 

Weeks to First Observed Tumor Ill 81 112
 —
 

a

Treated groups received time-weighted average doses of 3.4 or 7.5 ppm in feed.
 

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

c

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


Armitage test when P < 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 (*) 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.
 
APPENDIX F
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS
 

IN MICE FED PHOTODIELDRIN IN THE DIET
 

87
 

Table Fl. Analyses of the Incidence of Primary

Fed Photodieldrin in the Qieta 

Pooled Matched
 

Topography: Morphology Control Control
 

Lung: Alveolar/Bronchiolar
 

Adenoma^5 5/77 (6) 0/20 (0)
 

P Valuesc»d N.S. N.S.
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 —
 

Hematopoietic System: Lymphoma" 0/78 (0) 0/20 (0)
 

P Valuesc»d N.S. N.S.
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 —
 —
 

 Tumors in Male Mice 

Low
 

Dose
 

1/47 (2)
 

N.S.
 

0.328
 

0.007
 

2.792
 

Infinite
 

0.023
 

Infinite
 

93
 

1/47 (2)
 

N.S.
 

Infinite
 

0.088
 

Infinite
 

Infinite
 

0.023
 

Infinite
 

93
 

High
 

Dose
 

4/49 (8)
 

N.S.
 

1.257
 

0.260
 

5.529
 

Infinite
 

0.393
 

Infinite
 

0/49 (0)
 

N.S.
 

—
 

—
 

—
 

—
 

—
 

—
 

—
 

81 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice 

Fed Photodieldrin in the Dieta 

(continued) 

Pooled Matched Low High 

Topography: Morphology Control Control Dose Dose 

Liver: Hepatocellular 

Carcinoma" 11/76 (14) 3/18 (17) 10/47 (21) 9/47 (19) 

P Valuesc'd N.S. N.S. N.S. N.S. 

Relative Risk (Pooled Control)f 1.470 1.323 

Lower Limit 0.603 0.520 

Upper Limit 3.484 3.219 

Relative Risk (Matched Control)f 1.277 1.149 

Lower Limit 0.388 0.336 

Upper Limit 6.657 6.094 

__ 

Weeks to First Observed Tumor 93 74 68 

Liver: Neoplastic Nodule or 

Hepatocellular Carcinoma'3 14/76 (18) 3/18 (17) 10/47 (21) 10/47 (21) 

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

Relative Risk (Pooled Control)f 1.155 1.155 

Lower Limit 0.497 0.497 

Upper Limit 2.540 2.540 

Relative Risk (Matched Control)f 1.277 1.277 

Lower Limit 0.388 0.388 

Upper Limit 6.657 6.657 

Weeks to First Observed Tumor 93 74 68 — 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice
 

Fed Photodieldrin in the Diet3
 

(continued)
 

a

Treated groups received doses of 0.32 or 0.64 ppm in feed.
 

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

G

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


Armitage test when P < 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 (*) 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 F2. Analyses of the Incidence of Primary Tumors in Female Mice
 

Fea Photodieldrin in the Dieta
 

Pooled Matched Low High
 

Topography: Morphology Control Control Dose Dose
 

Lung: Alveolar/Bronchiolar
 

Adenoma'3 2/78 (3) 1/20 (5) 0/48 (0) 2/48 (4)
 

P Valuesc»d N.S. N.S. N.S. N.S.
 

Relative Risk (Pooled Control)f 0.000 1.625
 

Lower Limit 0.000 0.120
 

Upper Limit 5.493 21.678
 

Relative Risk (Matched Control)f 0.000 0.833
 

Lower Limit 0.000 0.047
 

Upper Limit 7.780 48.155
 

Weeks to First Observed Tumor —
 93 81
 ——
 

Hematopoietic System: Lymphoma'3 3/79 (4) 2/20 (10) 1/49 (2) 4/49 (8)
 

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

Relative Risk (Pooled Control)f 0.537 2.150
 

Lower Limit 0.010 0.379
 

Upper Limit 6.442 14.050
 

Relative Risk (Matched Control)f 0.204 0.816
 

Lower Limit 0.004 0.130
 

Upper Limit 3.754 8.603
 

Weeks to First Observed Tumor —
 92 93 88
 
Table F2. Analyses of the Incidence of Primary Tumors in Female Mice
 

Fed Photodieldrin in the Diet3
 

(continued)
 

Pooled Matched Low High
 

Topography: Morphology Control Control Dose Dose
 

Liver: Hepatocellular
 

Carcinoma 2/76 (3) 0/19 (0) 0/43 (0) 1/47 (2)
 

P Values0 'd N.S. N.S. N.S. N.S.
 

Relative Risk (Pooled Control)f 0.000 0.809
 

Lower Limit 0.000 0.014
 

Upper Limit 5.958 15.027
 

Relative Risk (Matched Control)f »_ Infinite
 

Lower Limit 0.022
 

Upper Limit —
 Infinite
 —
 

Weeks to First Observed Tumor
 —
 — —
 

a

Treated groups received doses of 0.32 or 0.64 ppm in feed.
 

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

c

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


Armitage test when P < 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 (*) 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.
 

93 

APPENDIX G
 

ANALYSIS OF FORMULATED DIETS FOR
 

CONCENTRATIONS OF PHOTODIELDRIN
 

95
 

APPENDIX G
 

Analysis of Formulated Diets for
 

Concentrations of Photodieldrin
 

A 10-g sample of the diet mixture was shaken with 125 ml benzene
 

for 16 hours, then filtered through Celite with benzene washes.
 

The combined extracts were reduced in volume and analyzed for
 

photodieldrin by gas-liquid chromatography (electron capture
 

detector, 10% DC-200 on Gas Chrom Q column). Recoveries were
 

checked with spiked samples, and external standards were used for
 

calibrations.
 

Theoretical No. of Sample Coefficient of Range (ppm) 

Concentrations Samples Analytical Variation (%) 

in Diet (ppm) Mean (ppm) 

0.32 10 0.32(1) 5.8% 0.29-0.35
 

0.64 10 0.63(8) 3.7% 0.61-0.68
 

2.50 9 2.51 4.2% 2.36-2.70
 

5.00 23 5.08 3.2% 4.80-5.50
 

10.00 22 9.98 4.6% 9.20-10.90
 

A U.S. GOVERNMENT PRINTING OFFICE: 1977—260-899:3138 

97 



DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE
 

National Institutes of Health
 

REPORT ON BIOASSAY OF PHOTODIELDRIN FOR POSSIBLE CARCINOGENICITY
 

Availability
 

Photodieldrin has been tested for cancer-causing activity with
 

rats and mice in the Carcinogenesis Program, Division of Cancer Cause
 

and Prevention, National Cancer Institute. A report is available to
 

the public.
 

Summary: A bioassay of dieldrin-free photodieldrin (synthesized
 

by Gulf South Research Institute) for possible carcinogenicity was
 

conducted by administering the test material in feed to Osborne-Mendel
 

rats and B6C3F1 mice.
 

Groups of 50 rats of each sex were initially administered photo-


dieldrin at one of two doses, either 5 or 10 ppm. Because of neurotoxic
 

signs, doses in the females were reduced after 30 weeks. Total periods
 

of treatment for low- and high-dose males and low-dose females were 80
 

weeks, followed by periods of 31 or 32 weeks of additional observation;
 

the total period of treatment for the high-dose females was 59 weeks,
 

followed by a period of additional observation of 53 weeks. The time-


weighted average doses for the females were 3.4 or 7.5 ppm. Matched-


controls consisted of 10 untreated rats of each sex; pooled controls,
 

used for statistical evaluation, consisted of the matched controls
 

combined with 65 untreated male and 65 untreated female rats from similarly performed bioassays of six other test chemicals. All surviving
 

rats were killed at 111-112 weeks.
 
- 2 ­

Groups of 50 mice of each sex were administered photodieldrin at
 

one of two doses, either 0.32 or 0.64 ppm, for 80 weeks, then observed
 

for an additional 13 weeks. Matched controls consisted of groups of
 

10 untreated mice of each sex at each dose; pooled controls, used for
 

statistical evaluation, consisted of the matched controls combined with
 

60 untreated male and 60 untreated female mice from similarly performed
 

bioassays of six other test chemicals. All surviving mice were killed
 

at 93 weeks.
 

Mean body weights attained by low- and high-dose male and female
 

rats and mice were essentially unaffected by photodieldrin. Convulsions
 

and hyperactivity were noted in treated male and female rats and in male
 

mice. Mortality rates of either sex or either species were not affected
 

by treatment.
 

In rats, benign tumors (adenoma and fibroadenoma) of the mammary
 

gland in females showed a dose-related trend (P - 0.039) compared with
 

matched, but not pooled, controls (8/72 pooled controls, 0/9 matched
 

controls, 5/50 low-dose, 10/49 high-dose). Adenocarcinoma of the mammary
 

gland occurred in two additional low-dose females. The incidences of
 

these tumors in either of the treated groups were not significantly higher
 

than those in the control groups using either matched or pooled controls.
 

Three papillary and follicular-cell adenomas and one papillary adenocarcinoma of the thyroid occurred in the low-dose females, giving a statistically significant increase over the pooled controls (P = 0.022), but
 

these thyroid tumors did not occur in the high-dose animals. The dose-


related trend was not statistically significant using either pooled or
 
- 3 ­

matched controls, and the incidence in the low-dose group is not greater
 

than that in the historical controls. In male rats, the incidence of
 

hemangiomas showed a statistically significant dose-related trend (P =
 

0.021) using pooled controls, but the direct comparison of the three
 

hemangiomas in the high-dose group with the pooled-control group was not
 

statistically significant. Furthermore, three hemangiomas is a small
 

number, and the tumors occurred in more than one anatomic site (two in
 

the spleen, one in subcutaneous tissue). The occurrence of these tumors
 

cannot clearly be associated with treatment.
 

In mice, there were no tumors that were statistically significant
 

in treated groups of either sex.
 

It is concluded that under the conditions of this bioassay, photo-


dieldrin was not carcinogenic for Osborne-Mendel rats or B6C3F1 mice.
 

Single copies of the report are available from the Office of Cancer
 

Communications, National Cancer Institute, Building 31, Room 10A21,
 

National' Institutes of Health, Bethesda, Maryland 20014.
 

Dated: December 2, 1977
 

Director
 

National Institutes of Health
 

(Catalogue of Federal Domestic Assistance Program Number 13.393, Cancer
 

Cause and Prevention Research)
 
U. S. DEPARTMENT OF HEALTH. EDUCATION. AND WELFARE 

FOR RELEASE IN A.M. PAPERS National Institutes of Health 

Friday, December 2, 1977 Office of Cancer Communications 

(301) 496-6641 

Availability of a report on animal tests of photodieldrin for
 

cancer-causing activity (carcinogenicity) was announced by HEW's
 

National Cancer Institute in today's Federal Register.
 

Dieldrin-free photodieldrin, a breakdown product of the pesticides
 

aldrin and dieldrin, was given to rats and mice for periods ranging
 

from 59 to 80 weeks. According to a summary of the report included in
 

the announcement, photodieldrin was not carcinogenic for rats or mice
 

under the bioassay conditions.
 

The tests are part of the Institute's Carcinogenesis Bioassay
 

Program. Copies of the report, Bioassay of Photodieldrin for Possible
 

Carcinogenicity, are available from the Office of Cancer Communications,
 

National Cancer Institute, Bethesda, Maryland 20014.
 

# # # #
 
DHEW Publication No. (NIH) 77-817