1979 

National Cancer Institute 

CARCINOGENESIS 

Technical Report Series 

NO. 122 

BIOASSAY OF 

DIBENZO-p-DIOXIN 

FOR POSSIBLE CARCINOGENICITY 

CAS No. 262-12-4 

NCI-CG-TR-122 

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

Public Health Service 

National Institutes of Health 

BIOASSAY OF
 

DIBENZO-p-DIOXIN
 

FOR POSSIBLE CARCINOGENICITY
 

Carcinogenesis Testing Program
 

Division of Cancer Cause and Prevention
 

National Cancer Institute
 

National Institutes of Health
 

Bethesda, Maryland 20014
 

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

Public Health Service
 

National Institutes of Health
 

DHEW Publication No. (NIH) 79-1377
 
ii

 
BIOASSAY OF
 

DIBENZO-p-DIOXIN
 

FOR POSSIBLE CARCINOGENICITY
 

Carcinogenesis Program
 

Division of Cancer Cause and Prevention
 

National Cancer Institute
 

National Institutes of Health
 

FOREWORD; This report presents the results of the bioassay of
 

dibenzo-p-dioxin conducted for the Carcinogenesis Testing
 

Program, Divison of Cancer Cause and Prevention, National Cancer
 

Institute (NCl), Bethesda, Maryland. This is one of a series of
 

experiments designed to determine whether selected chemicals have
 

the capacity to produce cancer in animals. Negative results, in
 

which the test animals do not have a greater incidence of cancer
 

than control animals, do not necessarily mean that the test
 

chemical is not a carcinogen, inasmuch as the experiments are
 

conducted under a limited set of circumstances. Positive results
 

demonstrate that the test chemical is carcinogenic for animals
 

under the conditions of the test and indicate that exposure to
 

the chemical is a potential risk to man. The actual 

determination of the risk to man from chemicals found to be 

carcinogenic for animals requires a wider analysis. 

CONTRIBUTORS; The bioassay of dibenzo-p-dioxin was conducted at
 

the Illinois Institute of Technology Research Institute (lITRl),
 

Chicago, Illinois, initially under direct contract to NCI and
 

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

Maryland, prime contractor for the NCI Carcinogenesis Testing
 

Program.
 

The project director was Mr. A. Shefner (1), Dr. M. E. King (1)
 

was the principal investigator for this study, and Dr. P. Holmes
 

(1) assembled the data. Doses of the test chemical were selected
 

by Dr. King, Mr. Shefner, and Dr. R. R. Bates (2,3). Mr. T.
 

Kruckeberg (1) and Mr. K. Kaltenborn (1) were in charge of animal
 

care.
 

Histopathologic examinations were performed by Dr. A. R. Roesler
 

(1). Tumor diagnoses were reviewed by Dr. R. L. Schueler (4),
 

who also prepared the interpretive pathology summary included in
 

this report. Pathologists at NCI and at Tracor Jitco have
 

reviewed selected slides and concur with the overall pathologic
 

evaluation of the study.
 

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

Mason Research • Institute (5). The statistical analyses were
 

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

methods selected for the bioassay program by Dr. J. J. Gart (6).
 

Chemicals used in this bioassay were synthesized and analyzed
 

under the direction of Dr. A. Gray (1), with the assistance of
 

Mr. S. Cepa (1) and Mr. V. DaPinto (1). Further analyses were
 

conducted under the direction of Dr. E. Murrill (7). The results
 

of the analytical work were reviewed by Dr. S. S. Olin (4).
 

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

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

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

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

Ms. L. A. Waitz, and Mr. W. D. Reichardt, bioscience writers; and
 

Dr. E. W. Gunberg, technical editor, assisted by Ms. Y. E.
 

Presley and Ms. P. J. Graboske.
 

The following scientists at NCI (2) were responsible for
 

evaluating the bioassay experiment, interpreting the results, and
 

reporting the findings: Dr. Kenneth C- Chu, Dr. Cipriano Cueto,
 

Jr., Dr. J. Fielding Douglas, Dr. Richard A. Griesemer, Dr.
 

Thomas E. Hamm, Dr. William V. Hartwell, Dr. Morton H. Levitt,
 

Dr. Harry A. Milman, Dr. Thomas W. Orme, Dr. Sherman F. Stinson,
 

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

(1) IIT Research Institute, 10 West 35th Street, Chicago,
 

Illinois.
 

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

Prevention, National Cancer Institute, National Institutes of
 

Health, Bethesda, Maryland.
 

(3) Now with the National Institutes of Environmental Health
 

Sciences, P.O. Box 12233, Research Triangle Park, North
 

Carolina.
 

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

Maryland.
 

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

Rockville, Maryland.
 

(6) Mathematical Statistics and Applied Mathematics Section,
 

Biometry Branch, Field Studies and Statistics, Division of
 

iv
 
Cancer Cause and Prevention, National Cancer Institute,
 

National Institutes of Health, Bethesda, Maryland.
 

(7) Midwest Research Institute, 425 Volker Boulevard, Kansas City,
 

Missouri.
 

(8) Now with the Division of Comparative Medicine, Johns Hopkins
 

University, School of Medicine, Traylor Building, Baltimore,
 

Maryland.
 
vi

 
SUMMARY
 

A bioassay of dibenzo-p-dioxin (UDD) for possible carcinogenicity
 

was conducted by administering the test chemical in feed to
 

Osborne-Mendel rats and B6C3F1 mice.
 

Groups of 35 rats of each sex were administered UDD at one of two
 

doses, either 5,000 or 10,000 ppm, for 110 weeks. Groups of 50
 

mice of each sex were administered the same doses for 87 or 90
 

weeks. Controls consisted of groups of 35 untreated rats of each
 

sex and 50 untreated mice of each sex. All surviving male rats
 

were killed at 110 weeks, all surviving female rats at 111 to 117
 

weeks, all surviving male mice at 92 to 97 weeks, and all
 

surviving female mice at 91 to 93 weeks.
 

Mean body weights of the dosed male and female rats and mice were
 

lower than those of the corresponding controls; the depression in
 

the amount of weight gained in the dosed male mice was, however,
 

relatively slight. Except for the male rats, survival at the end
 

of the bioassay was lower in the dosed groups of both rats or
 

mice than in the corresponding control groups. At week 90, at
 

least 57% of the rats and 54% of the mice were still alive. 

Because the mean body weights and survival rats of the dosed 

animals were lower than those of corresponding controls and 

because there was an increase in the incidence of hepatotoxic
 

lesions, the 10,000-ppm concentration administered to the rats
 

and mice is considered to be maximum tolerated dose.
 

No tumors were induced in rats or mice of either sex at
 

incidences that were significantly higher in the dosed groups
 

than in the corresponding control groups.
 

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

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

VII
 
viii

 
TABLEOF CONTENTS
 

Page
 

I. Introduction 1
 

II. Materials and Methods 3
 

A. Chemical 3
 

B. Dietary Preparation 3
 

C. AnimaIs 4
 

D. Animal Maintenance 5
 

E. Chronic Studies 7
 

F. Clinical and Pathologic Examinations 7
 

G. Data Recording and Statistical Analyses 10
 

III. Results - Rats 17
 

A. Body Weights and Clinical Signs (Rats) 17
 

B. Survival (Rats) 17
 

C. Pathology (Rats) 20
 

D. Statistical Analyses of Results (Rats) 21
 

IV. Results - Mice 25
 

A. Body Weights and Clinical Signs (Mice) 25
 

B. Survival (Mice) 25
 

C. Pathology (Mice) 28
 

D. Statistical Analyses of Results (Mice) 29
 

V. Discussion 33
 

VI. Bibliography 35
 

APPENDIXES
 

Appendix A
 

Summary of the Incidence of Neoplasms in Rats
 

Administered UDD in the Diet 37
 

Table Al Summary of the Incidence of Neoplasms in Male
 

Rats Administered UDD in the Diet 39
 

Table A2 Summary of the Incidence of Neoplasms in Female
 

Rats Administered UDD in the Diet 43
 

IX
 
Page 

Appendix B Summary of the Incidence of Neoplasms in Mice 

Administered UDD in the Diet 47 

Table Bl Summary of the Incidence of Neoplasms in Male 

Mice Administered UDD in the Diet 49 

Table B2 Summary of the Incidence of Neoplasms in Female 

Mice Administered UDD in the Diet 52 

Appendix C Summary of the Incidence of Nonneoplastic 

Lesions in Rats Administered UDD in the 

Diet 55 

Table Cl Summary of the Incidence of Nonneoplastic 

Lesions in Male Rats Administered UDD 

in the Diet 57 

Table C2 Summary of the Incidence of Nonneoplastic 

Lesions in Female Rats Administered UDD 

in the Diet 63 

Appendix D Summary of the Incidence of Nonneoplastic 

Lesions in Mice Administered UDD in the 

Diet 71 

Table Dl Summary of the Incidence of Nonneoplastic 

Lesions in Male Mice Administered UDD 

in the Diet 73 

Table D2 Summary of the Incidence of Nonneoplastic 

Lesions in Female Mice Administered UDD 

in the Diet 77 

Appendix E Analyses of the Incidence of Primary Tumors 

in Rats Administered UDD in the Diet 81 

Table El Analyses of the Incidence of Primary Tumors 

in Male Rats Administered UDD in the Diet .... 83 

Table E2 Analyses of the Incidence of Primary Tumors 

in Female Rats Administered UDD in the Diet .. 89 

Appendix F Analyses of the Incidence of Primary

in Mice Administered UDD in the Diet

 Tumors 

 95 

x
 
Table Fl Analyses of the Incidence of Primary Tumors 

in Male Mice Administered UDD in the Diet .. 97 

Table F2 Analyses of the Incidence of Primary Tumors 

in Female Mice Administered UDD in the Diet 101 

TABLES 

Table 1 UDD Chronic Feeding Studies in Rats 8 

Table 2 UDD Chronic Feeding Studies in Mice 9 

FIGURES 

Figure 1 Growth Curves for Rats Administered 

UDD in the Diet 18 

Figure 2 Survival Curves for Rats Administered 

UDD in the Diet 19 

Figure 3 Growth Curves for Mice Administered 

UDD in the Diet 26 

Figure 4 Survival Curves for Mice Administered 

UDD in the Diet 27 

XI
 
xii

 
I. INTRODUCTION
 

Unsubstituted dibenzo-p-dioxin,
 

(CAS 262-12-4; NCI C03656) is
 

an analog of a series of
 

chlorinated dibenzo-p-dioxins
 

that were selected for
 

Dibenzo-p-dioxin
 carcinogenesis testing. The
 

synonym for unsubstituted
 

dibenzo-p-dioxin — UDD — is used throughout this report. The
 

chlorinated compounds are formed as unwanted by-products during
 

the synthesis of chlorophenols, and were discovered in the late
 

1960's as contaminants in the industrial microbicide
 

pentachlorophenol, and in a widely used agricultural herbicide,
 

2,4,5-trichloro- phenoxyacetic acid (2,4,5-T) (Crossland and
 

Shea, 1973). Certain members of the chlorinated series were
 

shown to be highly toxic and teratogenic (Sparschu et al., 1971;
 

Schwetz et al., 1973). Chronic carcinogenicity studies were
 

begun with these compounds because of evidence that they were
 

both widely distributed and persistent in the environment
 

(Kearney et al., 1972). The unsubstituted dibenzo-p-dioxin has
 

been reported to be a photodecomposition product of chlorinated
 

dibenzo-p-dioxins (Crosby et al., 1971; Kearney et al., 1972).
 
Except for a preliminary report of the present bioassay (King et
 

al., 1973), no previous information is available on the toxicity
 

of UDD. Studies for the acute and subacute toxicities of the
 

2,7-dichloro-, 2,3,7,8-tetrachloro-, hexachloro-, and octachlorodibenzo-p-dioxin analogs of UDD have shown that the
 

2,3,7,8-tetrachloro analog (TCDD) is the most toxic, having an
 

LD of 0.022 mg/kg in Sherman rats (Schwetz et al., 1973).
 

The principal target organs of TCDD in rats, guinea pigs, and
 

mice are the liver and thymus (International Agency for Research
 

on Cancer, 1977), and evidence has been presented for the
 

induction of carcinomas of the ear duct, kidney, and liver by
 

TCDD administered in the diet to Sprague-Dawley rats (Van Miller
 

et al., 1977).
 

The series of chlorinated dibenzodioxins was selected for
 

carcinogenesis testing because of the wide distribution of some
 

of them in the environment and the possibility of their entrance
 

into the food chain, causing long-term human exposure. UDD was
 

included in the series because of interest in it as the
 

unsubstituted analog.
 
II. MATERIALS AND METHODS
 

A. Chemical
 

The batch of UDD used for this bioassay was synthesized by the
 

IITRI Chemistry Division. Analysis by Midwest Research Institute,
 

Kansas City, Missouri, confirmed the identity of the chemical and
 

indicated a purity of approximately 99.5% by vapor-phase
 

chromatography (vpc). Results of mass spectrometry suggested a
 

phenoxydibenzo-p-dioxin structure for an impurity accounting for
 

0.5% of the total vpc peak area. One other trace impurity (less
 

than 0.0-2%) was detected by vpc, but no chlorinated compounds
 

were detected. Elemental analyses were correct for
 

C.7H_0_, the molecular formula of UDD. The melting point
 

of this white crystalline material was 124.5 to 126.0°C (120 to
 

122°C given in the literature [Oilman and Dietrich, 1957] ).
 

Infrared, ultraviolet, and nuclear magnetic resonance spectra
 

were consistent with the spectra given in Sadtler Standard
 

Spectra (Sadtler Research Laboratories, Philadelphia, Pa.).
 

Hereinafter this materials is referred to as "UDD".
 
B. Dietary Preparation
 

Test diets were prepared by incorporating a known quantity of UDD
 

into a 2-week supply of ground Wayne Lab Blox animal feed
 

(Allied Mills, Inc., Chicago, 111.). Diets were mixed in a
 

Patterson-Kelly twin-shell blender for approximately 1 hour, and
 

were stored in sealed plastic containers at room temperature for
 

no more than 2 weeks.
 

Analyses were performed to assess the accuracy of concentrations
 

in two individual batches of test diet. These batches had been
 

stored at room temperature and were analyzed several months after
 

preparation. Ninety-eight percent of the expected concentration
 

was found at the 10,000 ppm level and 80% of the expected
 

concentration at 5,000 ppm.
 

C. An ima1s
 

Osborne-Mendel rats and B6C3F1 mice of each sex, obtained through
 

a contract with the Division of Cancer Treatment, NCI, were used
 

in the chronic study. Animals were obtained at various times
 

from Charles River Breeding Laboratories, Inc., Wilmington,
 

Massachusetts. The rats and mice were received at the laboratory
 
at approximately 4 weeks of age and were placed in quarantine for
 

1 week. Those animals with no visible signs of disease were
 

assigned to dosed or control groups according to a series of
 

random numbers and were earmarked for individual identification.
 

Due to a loss of male rats occasioned by an air-conditioning
 

failure, all groups of male rats were restarted 1 year after the
 

beginning of the first tests, using new groups of 4-week-old
 

animals obtained from Charles River Breeding Laboratories and
 

quarantined for 1 week.
 

D. Animal Maintenance
 

The rats and mice were housed in temperature- and
 

humidity-controlled rooms. The temperature was maintained at 22
 

to 23°C and the relative humidity at 40 to 50%. Fluorescent
 

lighting was provided for 12 hours each day. Air in the animal
 

rooms was changed 15 to 20 times per hour and exchanged through
 

fiberglass filters (Air Filter Equipment Corp., Chicago, 111.).
 

The rats were housed 4 per cage and the mice 10 per cage in
 

suspended polypropylene cages (Maryland Plastics, Federalsburg,
 

Maryland), covered with a wire mesh screen and a polyester filter
 

(Research Equipment Co., Inc., Bryan, Tex.). Bedding used in the
 
cages was Absorb-dri hardwood chips (Lab Products, Inc.,
 

Garfield, N. J.). " Tap water was available aid libitum in glass
 

water bottles with sipper tubes and was replenished twice per
 

week. The control animals were fed Wayne Lab Blox animal meal
 

(Allied Mills, Inc.), and the test animals received the same
 

diets, to which was added the test chemical. The diets were
 

available ad libitum and were replenished as necessary, but at
 

least once per week.
 

The cages, cage lids, and water bottles were sanitized weekly at
 

82 C; the feed hoppers, every 2 weeks at the same temperature.
 

The detergent used was liquid Spearhead (Economics Laboratory,
 

Inc., St. Paul, Minn.). The dishwasher used was a flight-type
 

conveyor belt washer (G. S. Blakeslee & Co., Chicago, 111). The
 

bedding was replaced each week. The racks were washed osice per
 

month in a Metalwash Rack Washer (Metalwash Machinery Corp.,
 

Elizabeth, N. J.) and were also rotated once per month. The rats
 

and the mice were housed in separate rooms. The untreated
 

controls and the UDD-dosed animals were housed in the same room
 

as animals administered the following test compounds:
 

Drinking Water Studies
 

(CAS 12.3-91-1) 1,4-dioxane
 
Feed Studies
 

(CAS 3268-87-9) 1,2,3,4,6,7,8,9-octachlorodibenzo-p-dioxin
 

(CAS 33857-26-0) 2,7-dichlorodibenzo-p-dioxin (DCDD)
 

E. Chronic Studies
 

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

studies are shown in tables 1 and 2. No subchronic studies were
 

conducted. The concentrations of 5,000 and 10,000 ppm were
 

chosen for use in the chronic studies because they were the
 

highest amounts used in the Carcinogenesis Testing Program at the
 

time these studies were initiated.
 

F. Clinical and Pathologic Examinations
 

All animals were observed twice daily. Body weights were
 

measured monthly. Moribund animals and animals that survived to
 

the end of the bioassay were killed using sodium pentobarbitol
 

and necropsied. Necropsies were also performed on all animals
 

found dead, unless precluded by autolysis or severe
 

cannibalLzat ion.
 
Table 1. UDD Chronic Feeding Studies in Rats
 

Sex and Initial UDD Time on Study 

Test No. of in Diet Dosed Observed 

Group Animals (a) (ppm) (weeks) (weeks ) 

Male (b)
 

Control 35 0 110 0
 

Low-Dose 35 5,000 110
 

High-Dose 35 10,000 110
 

Female (c)
 

Control 35 0 110 6-7
 

Low-Dose 35 5,000 110 6-7
 

High-Dose 35 10,000 110 1-2
 

(a) Rats were 5 weeks of age when placed on study.
 

(b) These groups were put on study 1 year after the study began,
 

to replace the original groups of male rats that died during
 

an air conditioning failure. The low-dose group was placed
 

on study 8 weeks after the control group, and the high-dose
 

group was placed on study 6 weeks after the control group.
 

(c) Female controls were started 4 weeks after the female dosed
 

groups.
 
Table 2. UDD Chronic Feeding Studies in Mice
 

Sex and Initial UDD Time on Study 

Test No. of in Diet Dosed Observed 

Group An ima Is (a ) (ppm) (weeks ) (weeks) 

Male
 

Control (b) 50 0 90 2-3
 

Low-Dose 50 5 , 000 90 7
 

High-Dose 50 10,000 87 6-7
 

Female
 

i _'
 Control (b) 50 0 90
 

Low-Dose 50 5,000 90 2-3
 

High-Dose 50 10,000 90 1-2
 

(a) Mice were 5 weeks of age when placed on study.
 

(b) Controls were placed on study 2-1/2 weeks after the dosed groups,
 
The following tissues were taken at necropsy: lung, heart,
 

liver, spleen, kidney, adrenal, gonads, brain, stomach, nasal
 

septum, skin, and tissue masses. Two years after the start of the
 

bioassay, a new necropsy protocol was instituted, and the tissues
 

that were taken therefore included: skin, lymph node (mandibular
 

and mesenteric), salivary gland, mammary gland, bone marrow,
 

thymus, larynx, trachea, lungs and bronchi, heart, thyroid,
 

parathyroids, esophagus, stomach, duodenum, colon, liver, gall
 

bladder (mice), pancreas, spleen, kidney, adrenal, gonads, nasal
 

cavity, brain, pituitary, spinal cord, skeletal muscle, sciatic
 

nerve, and tissue masses. The tissues were preserved in 10%
 

buffered formalin, embedded in paraffin, sectioned, and stained
 

with hematoxylin and eosin. All tissues were examined
 

microscopically by the pathologist, except for some tissues that
 

were lost during necropsy or histologic processing.
 

A few tissues from some animals were not examined, particularly
 

from those animals that may have died early, been missing, or
 

been in advanced states of cannibalization or autolysis. 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.
 

10
 
G. 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 appropriate statistical
 

techniques described in this section. Those analyses of the
 

experimental results that bear on the possibility of
 

carcinogenicity are discussed in the statistical narrative
 

sections.
 

Probabilities of survival were estimated by the product-limit
 

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

report in the form of graphs. Animals were statistically
 

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

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

causes were not statistically censored. Statistical analyses for
 

11
 
a possible dose-related effect on survival used the method of Cox
 

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

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

trend. One-tailed P values have been reported for all tests
 

except the departure from linearity test, which is only reported
 

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

The incidence of neoplastic or nonneoplastic lesions has been
 

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

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

in which that site is examined (denominator). In most instances,
 

the denominators included only those animals for which that site
 

was examined histologically. However, when macroscopic
 

examination was required to detect lesions prior to histologic
 

sampling (e.g., skin or mammary tumors), or when lesions could
 

have appeared at multiple sites (e.g., lymphomas), the
 

denominators consist of the numbers of animals necropsied.
 

The purpose of the statistical analyses of tumor incidence is to
 

determine whether animals receiving the test chemical developed a
 

significantly higher proportion of tumors than did the control
 

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

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

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

12
 
dose level. When results for a number of dosed groups (k) are
 

compared simultaneously with those for a control group, a
 

correction to ensure an overall significance level of 0.05 may be
 

made. The 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
 

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
 

13
 
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 an animal died naturally or was sacrificed
 

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

methods of comparing these curves were used for two groups;
 

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

groups. The statistical tests for the incidence of tumors which
 

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

noted, in the direction of a positive dose relationship.
 

Significant departures from linearity (P less than 0.05,
 

two-tailed test) were also noted.
 

The approximate 95 percent confidence interval for the relative
 

risk of each dosed group compared with its control was calculated
 

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

relative risk is defined as p ,/p where p is the true
 c c c
 

14
 
binomial probability of the incidence of a specific type of tumor
 

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

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

group. The hypothesis of equality between the true proportion of
 

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

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

of unity represent the condition of a larger proportion in the
 

dosed group than in the control.
 

The lower and upper limits of the confidence interval of the
 

relative risk have been included in the tables of statistical
 

analyses. The interpretation of the limits is that in
 

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

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

control group would be within the interval calculated from the
 

experiment. When the lower limit of the confidence interval is
 

greater than one, it can be inferred that a statistically
 

significant result (P less than 0.025 one-tailed test when the
 

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

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

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

limit indicates the absence of a significant result while the
 

upper limit indicates that there is a theoretical possibility of
 

15
 
the induction of tumors by the test chemical, which could not be
 

detected under the conditions of this test.
 

16
 
III. RESULTS - RATS
 

A. Body Weights and Clinical Signs (Rats)
 

Mean body weights of dosed groups of mate and female rats were
 

lower than those of the corresponding control groups (figure 1).
 

Depressions in weight gains were similar in the low- and
 

high-dose groups of both sexes, particularly toward the end of
 

the bioassay. Some fluctuation in the growth curve may be due to
 

mortality; as the size of a group diminishes, the mean body
 

weight may be subject to variation. No clinical signs other than
 

those of lowered body weights were reported.
 

B. Survival (Rats)
 

The Kaplan and Meier curves estimating the probabilities of
 

survival for male and female rats administered UDD in the diet at
 

the doses of this bioassay, together with those of the controls,
 

are shown in figure 2.
 

In male rats, the low-dose group was started on study 8 weeks
 

after the control group, and the high-dose group was started 6
 

17
 
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20 30 40 50 60 70 90 100 

TIME ON STUDY (WEEKS) 

Figure 1. Growth Curves for Rats Administered UOO in the Diet 

18 

 110 
i.oo A 

46 60 75 

TIME ON STUDY (WEEKS) 

0.90­

r

 A--: 

A : 

At »•••: 

A 

f 

3 

CD 

O 

oc 

o. 

0.10­

FEMALE RATS D CONTROL 

O LOW DOSE 

A HIGH DOSE 

n 

i

I

\

6— [ — 

A-: 

A: 

A 

A-: 

A-. 

A 

A-­

TIME ON STUDY (WEEKS) 

Figure 2. Survival Curves for Rats Administered UDO in the Diet 

19 

-

(>4 

^r 

i

o-o AA-. 
weeks after the control group. In females, the two dosed groups
 

were started at the same time, but the controls were started 4
 

weeks after the dosed groups. However, the Tarone test for
 

dose-related trend in mortality is applied as if the different
 

groups were started at the same time. In male rats, the result
 

of the Tarone test is significant (P = 0.011), but in the
 

negative direction. In females, the result of the Tarone test is
 

significant in the positive direction (P = 0.007).
 

In male rats, 29/35 (83%) of each dosed group, and 24/35 (69%) of
 

the control group were still alive at week 90 on study. In
 

females, 20/35 (57%) of the high-dose group, 31/35 (89%) of the
 

low-dose group, and 32/35 (92%) of the control group were still
 

alive at week 90 on study.
 

Sufficient numbers of dosed and control rats of each sex were at
 

risk for the development of late-appearing tumors.
 

C. Pathology (Rats)
 

Histopathologic findings on neoplasms in rats are summarized in
 

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

are summarized in Appendix C, tables Cl and C2.
 

20
 
Neoplasms occurred in a variety of tissues in dosed and control
 

rats and were of the usual types seen in aged Osborne-Mende 1
 

rats. There was no evidence that any neoplasms were induced by
 

administration of UDD in the diet.
 

In some male and more frequently in female rats there was a
 

dose-related increase in incidence of hepatotoxic pathologic
 

alterations characterized by fatty metamorphosis or necrosis.
 

Other nonneoplastic lesions were of the usual types seen in aged
 

Osborne-Mendel rats and were seen in comparable numbers in
 

control and dosed groups of animals.
 

Based on the histopatho logic examination, UDD was not
 

carcinogenic in Osborne-Mendel rats under the conditions of this
 

bioassay.
 

D. Statistical Analyses of Results (Rats)
 

Tables El and E2 in Appendix E contain the statistical analyses
 

of the incidences of those primary tumors that occurred in at
 

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

in one or more than one group.
 

21
 
In male rats, the low-dose group was started on study 8 weeks
 

after the control group, and the high-dose group was started 6
 

weeks after the control group. In females, the two dosed groups
 

were started at the same time, but the controls were started 4
 

weeks after the dosed groups. However, the Cochran-Armitage test
 

for dose-related trend in the incidence of tumors is applied as
 

if the different groups were started at the same time.
 

In each sex, the results of the Cochran-Armitage test and the
 

Fisher exact test are not significant in the positive direction.
 

In male rats, significant results in the negative direction are
 

observed in the incidences of fibroma of the subcutaneous tissue,
 

cortical adenoma and pheochromocytoma of the adrenal, and C-cell
 

adenoma of the thyroid. In female rats, significant results in
 

the negative direction are observed in the incidences of
 

chromophobe adenoma of the pituitary, cortical adenoma or
 

carcinoma of the adrenal, and fibroadenoma of the mammary gland.
 

Significant results in the negative direction in the incidence of
 

tumors in the female rats may have been occasioned by the
 

shortened survival in the high-dose groups compared with that in
 

the controls, but in male rats survival was lowest in the control
 

groups.
 

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

22
 
in the tables, the value of one or less than one is included;
 

this indicates the absence of significant positive results. It
 

should also be noted that most of the intervals have upper limits
 

greater than one, indicating the theoretical possibility of the
 

induction of tumors by UDD, which could not be detected under the
 

conditions of this test.
 

23
 
24

 
IV. RESULTS - MICE
 

A. Body Weights and Clinical Signs (Mice)
 

Mean body weights of the dosed male and female mice were
 

generally lower than those of corresponding controls throughout
 

the bioassay, although the effect of the UDD was slight in the
 

males (figure 3). Some fluctuation in the growth curve may be
 

due to mortality; as the size of a group diminishes, the mean
 

body weight may be subject to variation. No clinical signs other
 

than those of lowered body weight were reported.
 

B. Survival (Mice)
 

The Kaplan and Meier curves estimating the probabilities of
 

survival for male and female mice administered UDD in the diet at
 

the doses of this bioassay, together with those of the controls,
 

are shown in figure 4.
 

In each sex, the control group was started on study 2-1/2 weeks
 

after the dosed groups; however, the Tarone test for dose-related
 

trend in mortality is applied as if the dosed and control groups
 

25
 
D D D s O A3 O a A3 IU 

A AD O >

a

o 

ca 

2

°M 

MALE MICE 

D CONTROL 

O LOW DOSE 

A HIGH DOSE 

40 50 60

TIME ON STUDY (WEEKS) 

 70 

2

iQ

O 

m 8

A 

8 

D

D 

O 

O 

A A O A 

o 

A 

D

O

A

 D 

O 

A 

D 

O 

11 

10­

FEMALE MICE D CONTROL 

O LOW DOSE 

A HIGH DOSE 

TIME ON STUDY (WEEKS) 

Figure 3. Growth Curves for Mice Administered UOD in the Diet 

26 
PROBABILITY OF SURVIVAL PROBABILITY OF SURVIVAL 

f> c3 <= c 

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3 C3 C3 CS f» «3 c5 <= «» f5 f3 C3 3 3 

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were started at the same time. In male mice, the result of the
 

Tarone test is not significant. In females, the result of the
 

Tarone test is significant (P less than 0.001). A departure from
 

linear trend is observed (P = 0.006), because of the steep
 

decrease in survival of the dosed animals.
 

In male mice, 46/50 (92%) of the high-dose group, all 50 of the
 

low-dose group, and 48/50 (96%) of the controls were still alive
 

at week 90 on study. In females, 27/50 (54%) of the high-dose
 

group, 44/50 (88%) of the low-dose group, and 44/50 (88%) of the
 

control group were still alive at week 90 on study.
 

Sufficient numbers of dosed and control mice of each sex were at
 

risk for the development of late-appearing tumors.
 

C. Pathology (Mice)
 

Histopathologic findings on neoplasms in mice are summarized in
 

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

are summarized in Appendix D, tables Dl and D2.
 

Neoplasms which occurred in a variety of tissues of dosed and
 

28
 
control mice were of the usual types and incidences seen in aged
 

B6C3F1 mice.
 

Toxic hepatic lesions including liver degeneration, necrosis,
 

fibrosis, and/or cirrhosis were observed in slightly increased
 

numbers in several of the dosed mice, mainly in the high-dose
 

females. Other nonneoplastic lesions were of the usual types
 

seen in aged B6C3F1 mice.
 

Based on the histopathologic evaluation, there was no evidence
 

that UDD was carcinogenic in B6C3F1 mice under the conditions of
 

this bioassay.
 

D. Statistical Analyses of Results (Mice)
 

Tables Fl and F2 in Appendix F contain the statistical analyses
 

of the incidences of those primary tumors that occurred in at
 

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

in one or more than one group.
 

In each sex, the control group was started on study 2-1/2 weeks
 

after the dosed groups; however, the Cochran-Armitage test for
 

29
 
dose-related trend in the incidence of tumors is applied as if
 

the dosed and control groups were started at the same time.
 

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

alveolar/bronchiolar carcinomas between the low-dose and control
 

groups indicates a P value of 0.027, which is above the 0.025
 

level required for significance when the Bonferroni inequality
 

criterion is used for multiple comparison. The result of the
 

Cochran-Armitage test for dose-related trend in this incidence of
 

tumors and that of the Fisher exact test comparing the incidence
 

in the high-dose group with that in the control group are not
 

significant.
 

Tn females, the results of the statistical tests on the
 

incidences of tumors are not significant.
 

A significant dose-related trend in the negative direction is
 

observed in the incidence of squamous-cell papillomas of the
 

stomach in male mice, in which the incidence in the control group
 

is 5/49 (10%), but no such tumor is observed in either of the
 

dosed groups.
 

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

in the tables (except for the incidence of alveolar/bronchiolar
 

30
 
carcinomas in the low-dose male mice), the value of one or less
 

than one is included; this indicates the absence of significant
 

positive results. It should also be noted that each of the
 

intervals (except that for the incidence of squamous-cell
 

papilloma of the stomach in male mice) has an upper limit greater
 

than one, indicating the theoretical possibility of the induction
 

of tumors by UDD, which could not be detected under the
 

conditions of this bioassay.
 

31
 
32

 
V. DISCUSSION
 

Toxicity of UDD for rats and mice at the doses of 5,000 and
 

10,000 ppm administered in the diet in this bioassay was
 

indicated by lowered mean body weights and survivals of most of
 

the dosed groups when compared with control groups. The mean
 

body weights of the dosed male and female rats and the dosed
 

female mice were lower than those of the corresponding controls;
 

the depression in the amount of weight gained in the dosed male
 

mice was, however, relatively slight. Survivals of the high-dose
 

groups of female rats and male and female mice at the end of the
 

bioassay were lower than those of the corresponding control
 

groups; the survivals of the dosed groups of male rats were
 

higher than that of the corresponding control group, but the
 

survival of the control male rats may have been abnormally low.
 

At week 90, at least 57% of the rats and 54% of the mice were
 

still alive. In some male and, more frequently, female rats
 

there was a dose-related increase in the incidence of hepatotoxic
 

alterations characterized by fatty metamorphosis or necrosis.
 

Also, in mice, toxic hepatic lesions including liver
 

degeneration, necrosis, fibrosis and/or cirrhosis were observed
 

in slightly increased numbers in the dosed mice — particularly
 

in the high-dose females. Thus the 10,000-ppm concentration
 

33
 
administered to the rats and mice is considered to be the maximum 

tolerated dose. 

No tumors were induced in rats or mice of either sex at 

incidences that were significantly higher in the dosed groups 

than in the corresponding control groups. 

Unlike 2,3,7,8-tetrachlorodibenzo-p-dioxin, which has been 

reported to be highly toxic in Sherman rats (Schwetz et al., 

1973) and to be carcinogenic in Sprague-Dawley rats (Van Miller 

et al., 1977), UDD, the unsubstituted analog, was observed in the 

present bioassay to have a very low toxicity for Osborne-Mendel 

rats and B6C3F1 mice, and to be noncarcinogenic for both 

species. However, the degeneration and necrosis of the liver 

observed in the rats and mice administered UDD is similar to the 

liver damage observed in rats and mice administered TCDD 

(international Agency for Research on Cancer, 1977). 

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

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

34 
VI. BIBLIOGRAPHY
 

Arraitage, P., Statistical Methods in Medical Research, J. Wiley &
 

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

Berenblura. I., ed., Care inogen ic i ty Testing; A Report of the
 

Panel of Carcinogenicity of the Cancer Research Commission o_f the
 

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

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

Soc. B: 187-220, 1972.
 

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

London, 1970, pp. 48-52.
 

Crosby, D. G., Wong, A. S., Plimmer, J. R., and Woolson, E.A.,
 

Photodecomposition of chlorinated dibenzo-p-dioxins. Science 1731
 

748-749, 1971.
 

Crossland, J. and Shea, K. P., The hazards of impurities,
 

Environment 15 (5); 35-38, 1973.
 

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

significance . j.te.sts,,- confidence limits and adjustments for 

stratification. Rev. Int. Stat. Inst. 39; 148-169, 1971. 

Gilman, H. and Dietrich, J. J., Halogen derivatives of dibenzop-dioxin. J. Amer. Ch.em. Soc. 7JJ: 1439-1441, 1957.
 

International Agency for. Research on Cancer, Chlorinated dibenzodioxins. In: IARC Monographs on the Evaluation of the Carcinogenic
 

Risk of Chemicals .to Man; Some Fumigants, the Herbicides 2,470
 

and 2,4,5-T, Chlorinated Diberizodioxins and Miscellaneous Industrial Chemicals, Vol. 15, IARC Working Group on the Evaluation of
 

the Carcinogenic Risk of Chemicals to Man, Lyon, France, 1977,
 

pp. 41-101.
 

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

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

1958.
 

Kearney, P. C., Woolson, E. A., and Ellington, C. P., Jr.,
 

Persistence and metabolism of chlorodioxins in soils. Environ.
 

Sci. & Tech. 6 (12): 1017 -1019, 1972.
 

35
 
King, M. E., Shefner, A. M., and Bates, R. R., Carcinogenesis
 

bioassay of chlorinated dibenzodioxins and related chemicals. In:
 

Environmental Health Perspectives, National Institute of
 

Environmental Health Sciences, Research Triangle Park, N.C. 1973,
 

pp. 163-170.
 

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

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

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

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


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

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

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.
 

Schwetz, B. A., Norris, J. M., Sparschu, G. L., Rowe, V. K.,
 

Gehring, P. J., Emerson, J. L., and Gerbig, C. G., Toxicology of
 

chlorinated dibenzo-p-dioxins. In: Environmental Health Perspectives , National Institute of Environmental Health Science,
 

Research Triangle Park, N.C., 1973, pp. 87-99.
 

Sparschu, G. L., Dunn, F. L., and Rowe, V. K., Study of the
 

teratogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the rat.
 

Fd. Cosmet. Toxicol. 9^: 405-412, 1971.
 

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

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

Van Miller, J. P., Lalich, J. J., and Allen, J. R., Increased
 

incidence of neoplasms in rats exposed to low levels of 

2,3,7,8-tetrachlorodibenzo-p-dioxin. Chemosphere £:537-544, 

1977. 

36
 
APPENDIX A
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

RATS ADMINISTERED UDD IN THE DIET
 

37
 
38

 
TABLE A1.

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE RATS 

ADMINISTERED UDD IN THE DIET 

CONTROL LOW DOSE HIGH DOSE 

ANIMAL S INITIALL Y IN STUDY 35 35 35 

ANIMAL S NECROPSIE D 3H 33 35 

ANIMAL S EXAMINE D HISTOPATHOLOGICALLY 33 33 35 

INTEGUMENTAR Y SYSTEM 

*SKIN {34) (33) (35)
 

T8ICHOEPITHELIOMA 1 (3%)
 

*SUBCUT TISSUE (34) (33) (35)
 

FIBROMA 3 (9%)
 

FIBSOSARCOMA 1 (3«) 1 (3%)
 

LIPOMA 1 (3%)
 

RESPIRATORY SYSTEM
 

*LONG (30) (33) (35)
 

ALVEOLAR/BRONCHIOLAR ADENOHA 1 (3%)
 

ALVEOLAS/BRONCHIOLAB CARCINOMA 1 (3%)
 

HEMATOPOIETIC SYSTEM
 

*MULTIPL E ORGAN S (3U) (33) (35) 

MALIG.LYMPHOMA , LYMPHOCYTIC TYPE 1 (3X) 

#SPLEEN (31 ) (33) (35) 

SARCOMA , NOS 1 (3X) 

CIRCULATOR Y SYSTEM 

NONE 

DIGESTIVE SYSTEM 

ILIVER (31) (32) (35)
 

HIPATOCELI,ULAR_i£ENOMA. 1
 

t NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

39
 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

tSTOMACH (31) (33) (33) 

PAPILLOMA, NOS 2 (6«) 

URINAR Y SYSTEM 

tKIDNE Y (31) (33) (35)

 

LIPOSARCOM A 1 (3%)

 

MIXE D TUMOR , MALIGNAN T 1 (3X)

 

IURINAR Y BLADDE R (28) (31) (30) 

TRANSITIONAL-CEL L CARCINOM A 1 (3S) 

ENDOCRIN E SYSTEM 

#PITUITAR Y (16) (21) (16) 

ADENOMA , NO S 2 (13*) 

CHHOBOPHOB E ADENOM A 1 (6«) 1 (6«) 

*ADRENA L (31) (30) (34) 

CORTICA L ADENOM A 7 (23S) 4 (13X) 2 (6K) 

PHEOCHROMOCYTOM A 6 (19%) 2 (6%) 

tTHYROID (29) (33) (33) 

FOLLICULAR-CEL L ADENOH A 2 (7%) 

FOLLICULAR-CELL CARCINOM A 1 (3%) 1 (3%) 

C-CELL ADENOM A 3 (10%) 

CYSTADENOMA , NO S 2 (6X) 

#PARATHYROI D (25) (27) (27)

 

ADENOMA , NO S 2 (8%)

 

#PANCREATI C ISLETS (24) (33) (31) 

ISLET-CELL ADENOM A 1 (H%) 2 (6«) 1 (3X) 

REPRODUCTIV E SYSTEM 

*MAMMAR Y GLAN D (34) (33) (35) 

ADENOMA , NO S 1 (3%) 

NERVOU S SYSTEM 

#BRAI N (31) (30) (35)

 

ASTROCYTOM A - -i--» 1 (3*)

 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

40
 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

SPECIAL SENSE ORGANS 

NONE 

HUSOJLOSKELETAL SYSTEM 

NONE 

BODY CAVITIES 

*TUNICA VAGINALI S

MESOTHELIOMA , NOS

 (3U )

 2 (6%) 

 (33) (35) 

A LL OTHER SYSTEMS 

ADIPOSE TISSUE 

LIPOM A 1 

ANIMAL DISPOSITION SUMMARY 

ANIMALS INITIALLY IN STUDY 

NATURAL DEATHS 

MORIBUND SACRIFICE 

SCHEDULED SACRIFICE 

ACCIDENTALLY KILLED 

TERMINAL SACRIFICE 

ANIMAL MISSING 

35 

20 

1 

m 

35 

9 

1 

25 

35 

25 

l_OCiUDJ|S_AUTOL_YZED_A8IMALl 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED

* NUMBER OF ANIMALS NECROPSIED 

 MICROSCOPICALLY 

41
 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE
 

TUMOR SUMMAR Y
 

TOTAL ANIMALS WITH PRIMARY TUMORS* 21 11 11
 

TOTAL PRIMARY TUMORS 37 11 1<»
 

TOTAL ANIMALS WITH BENIGN TUMORS 17 8 8
 

TOTAL BENIGN TUMORS 30 8 11
 

TOTAL ANIMALS WITH MALIGNANT TOHORS 5 3 3
 

TOTAL MALIGNANT TUMORS 5 3 3
 

TOTAL ANIMALS WITH SECONDARY TUMORSt
 

TOTAL SECONDARY TUMORS
 

TOTAL ANIMALS WITH TUMORS UNCERTAIN­ BENIGN OR MALIGNANT 2
 

TOTAL UNCERTAIN TUMORS 2
 

TOTAL ANIMALS WITH TUMORS UNCERTAIN­ PRIMARY 03 METASTATIC
 

TOTAL UNCERTAIN TUMORS
 

PRIMAR Y TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 

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

42
 
TABLE A2. 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS 

ADMINISTERED UDD IN THE DIET 

CONTROL LOW DOSE HIGH DOSE 

ANIMAL S

ANIMAL S

ANIMAL S

 INITIALL Y IN STUDY

 NECROPSIED

 EXAMINE D HISTOPATHOLOGICALL Y

 35

 35

 31

 35

 33

 33

 35 

 33 

 33 

INTEGUMENTAR Y SYSTEM 

*SUBCUT TISSUE

FIBROM A

FIBROSARCOM A

 (35)

 1

 1

 (355) 

 (3«) 

 (33) (33) 

RESPIRATORY SYSTEM 

NONE 

HEMATOPOIETIC SYSTEM 

#RENAL LYMPH NODE

ADENOCARCINOMA, NOS, METASTATIC

 (25) (23)

 1 (UX) 

 (14) 

CIRCULATORY SYSTEM 

NONE 

IIGESTIVE SYSTEM 

#LIVER

NEOPLASTIC NODULE

HEPATOCELLULAR CARCINOMA

 (31) (32) (32) 

1 (3«) 

1 (3%) 

URINAR Y SYSTEM 

#KIDNEY (31) (32)

FIBROS ARCQMA. METASTATIC 1 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBFR OF ANIMALS NECROPSIED 

 (32) 

43
 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED) 

ENDOCRINE SYSTEM 

#PITUITAR Y 

ADENOMA , NOS 

CHROMOPHOB E ADENOM A 

*ADRENAL 

CORTICAL ADENOMA 

CORTICAL CARCINOMA 

tADRENA L CORTEX 

CYSTADENOMA, NOS 

tTHYROID 

FOLLICOLAR-CELL CARCINOM A 

C-CELL ADENOM A 

C-CELL CARCINOM A 

tTHYROID FOLLICLE 

CYSTADENOMA, NOS 

IPANCREATIC ISLETS 

ISLET-CELL ADENOM A 

REPRODUCTIVE SYSTEM 

*«AMMAR Y GLAN D 

ADENOMA , NOS 

ADENOCARCINOHA , NO S 

FIBROM A 

FIBROADENOMA 

tUTEROS 

ADENOCARCINOMA, NOS 

PAPILLARY CYSTADENOMA, NOS 

LEIOMYONA 

ENDOMETRIAL STROM AL POLYP 

tUTERUS/ENDOMETRIUM 

ADENOCARCINOMA , NOS 

tO VAR Y 

GRANULOSA-CELL TUMOR 

# NUMBER OF ANIMALS WITH TISSUE

* NUMBER OF ANIMALS NECROPSIED 

CONTROL LOW DOSE HIGH DOSE 

(18) (19) (11) 1 (5%) 4

 (22%) 1 (5%) 

(30) (31)

(30) 

11 (37%) 8 (26%) 3 (10%) 

1 (3%) 

(30) (31) (30) 

2 (7%) 

(28) (28) (24) 

1 (4%) 

4 (14%) 1 (4%) 

1 (4%) 

(28) (28) (24) 

2 (7%) 

(29) (28) (21) 

1 (3%) 

(35) (33) (33) 

3 (9%) 1 (3%) 

1 (3%) 

1 (3%) 1 (3%) 

13 (37%) 8 (24%) 5 (15%) 

(30) (30) (27) 

1 (3%) 1 (3%) 1 (4%) 

1 (3%) 

1 (4%) 

1 (3%) 1 (4%) 

(30) (30) (27) 

1 (3%) 

(26) (29) (21) 

1 f5%) 

 EXAMINED MICROSCOPICALLY 

44 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE
 

TUBULAR ADENOMA 1 (US)
 

NERVOUS SYSTEM
 

NONE
 

SPECIAL SENSE ORGANS
 

*HARDERIAN GLAND (35) (33) (33)
 

ADENOCARCINOHA, NOS 1 (3%)
 

MUSCULOSKEL3TAL SYSTEM
 

NONE
 

BODY CAVITIES
 

"ABDOMINAL HALL (35) (33) (33)
 

FIBROSARCOMA 1 (3%)
 

ALL OTHER SYSTEMS
 

NONE
 

ANIMAL DISPOSITION SUMMARY
 

ANIMALS INITIALLY IN STUDY 35 35 35
 

NATURAL DEATHS 15 19
 

MORIBUND SACRIFICE 5
 

SCHEDULED SACRIFICE 13
 

ACCIDENTALLY KILLED
 

TERMINAL SACRIFICE 17 16
 

ANIMAL MISSING
 

3 INCLUDES
 

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

45
 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

TUMOR SUMMARY
 

TOTAL ANIMALS WITH PRIMARY TUHORS* 26 19 13
 

TOTAL PRIMARY TUMORS 147 24 19
 

TOTAL ANIMALS WITH BSSIGN TUMORS 2U 17 12
 

TOTAL BENIGN TUMORS 42 20 14
 

TOTAL ANIMALS WITH MALIGNANT TUMORS 5 4 2
 

TOTAL MALIGNANT TUMORS 5 4 3
 

TOTAL ANIMALS WITH SECONDARY TUMORS* 1 1
 

TOTAL SECONDARY TUHORS 1 1
 

TOTAL ANIMALS WITH TUMORS UNCERTAIN­ BENIGN OR MALIGNANT 2
 

TOTAL UNCERTAIN TUMORS 2
 

TOTAL ANIMAL S WITH TUMORS UNCERTAIN ­

PRIMAR Y OS METASTATIC 

TOTAL UNCERTAIN TUMORS 

* PRIMARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUHOHS
 

# SECONDARY TOMORS: METASTATIC TOSORS OR TUMORS INVASIVE INTO AN ADJACENT ORGAN
 
APPENDIX B
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

MICE ADMINISTERED UDD IN TOE DIET
 

47
 
48

 
TABLE B1.

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE MICE 

ADMINISTERED UDD IN THE DIET

 

CONTROL LOW DOSE HIGH DOSE
 

ANIMALS INITIALLY IN STUDY 50 50 50
 

ANIMALS NECROPSIED 50 50 48
 

ANIMALS EXAMINED HISTOPATHOLOGICALLY 49 50 48
 

INTEGUMENTARY SYSTEM
 

*SKIN (50) (50) (1*8)
 

PAPILLOMA, NOS 1 (2%)
 

FIBROSARCOMA 1 (2%)
 

*SUBCUT TISSUE (50) (50) (48)
 

SEBACEOUS ADENOMA 1 (2S)
 

LEIOMYOSARCOMA 1 (2«)
 

RESPIRATORY SYSTEM
 

*NASAL SEPTUM (50) (50) (48)
 

MENINGIOMA, METASTATIC 1 (2%)
 

#LUN G (49) (48) (48 ) 

ALVEOLAR/BRONCHIOLA R ADENOM A 8 (16S) 6 (13%) 5 (10%) 

ALVKOLAR/BRONCHIOLA R CARCINOM A 5 (10«) 1 (2%) 

HEMATOPOIETIC SYSTEM 

MULTIPLE ORGAN S (50) (50) (48) 

MALIG. LYMPHOMA , HISTIOCYTIC TYPE 2 (4%) 

ISPLEEN (48) (48) (44 ) 

HEMANGIOM A 3 (6%) 1 (2%) 

CIRCULATOR Y SYSTEM 

NON E 

DIGESTIV E SYSTEM 

#LIVER (19) (50) (48) 

HEPATOCSLLULAR ADENOM A 4 (8X1 1 (2S1 2 <4%) 

# NUMBER OF ANIMALS HITH TISSUE EXAHINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

49
 
TABLE B1. MALE MICE: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

HEPATOCELLULA R CARCINOM A

*BILE DUCT

BILE DUCT CARCINOMA

tSTOMACH

SQUAMOUS CELL PAPILLOHA

 4

 (50)

 1

 (49)

 5

 (8S)

 (2%) 

 (10X) 

7

 (50)

 (49)

 (14X) 3 (6X) 

 (48) 

 (45) 

URINAR Y

NONE 

 SYSTEM 

ENDOCRINE SYSTEM 

tTHYROI D

PAPILLAR Y CYSTADENOMA , NOS

 (39)

 1 (3X) 

 (37) (31 ) 

REPRODUCTIVE SYSTEM 

NONE 

NEPVOUS SYSTEM 

IBRAIN

MENINGIOMA

 (48) (49) (42) 

1 (2X) 

SPECIAL

NONE 

 SENSE ORGANS 

MUSCULOSKELETAL

NON E 

 SYSTEM 

BODY CAVITIES 

NONE 

A LL OTHER SYSTEMS 

* NUMBER

* NUMBE H

 OF

 OF

 ANIMAL S

 ANIMALS

 VtTTH TISSUE

 NECROPSIED 

 EXAMINE D MICROSCOPICALLY 

50 
TABLE B1. MALE MICE: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

NIMAL DISPOSITION SUMMARY 

ANIMALS INITIALLY IN STUDY 50 50 50
 

NATURA L DEATH* 5
 

MORIBUND SACRIFICE 50 45
 

SCHEDULED SACRIFICE 

ACCIDENTALLY KILLED 

TERMINAL SACRIFICE 

ANIMAL MISSING 

INCLUDES AUTOLYZED ANIHALS 

UMOR SUMMARY
 

TOTAL ANIMALS HITH PRIMARY TUMORS* 19 19 16
 

TOTAL PRIMARY TUMORS 26 22 16
 

TOTAL ANIMALS HITH BENIGN TUMORS 17 10 8
 

TOTAL BENIGN TUMORS 20 10 8
 

TOTAL ANIMALS HITH MALIGNANT TUMORS 5 11 8
 

TOTAL MALIGNANT TUMORS 6 12 8
 

TOTAL ANIMALS HITH SECONDARY TUMORSt 1
 

TOTAL SECONDARY TUMORS 1
 

TOTAL ANIMALS HITH TUMORS UNCERTAINBENIGN OR MALIGNANT
 

TOTAL UNCERTAIN TUMORS
 

TOTAL ANIMALS HITH TUMORS UNCERTAINPRIMARY OR METASTATIC
 

TOTAL UNCERTAIN TUMORS
 

PRIMARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 

SECONDARY TUMORS: METASTATIC TUMORS OB TUMORS INVASI?E INTO AM ADJACENT ORGAN
 

51 
TABLE 82.

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE MICE 

ADMINISTERED

ANIMALS INITIALLY IN STUDY

ANIMALS HISSING

ANIMAL S NEGROPSIED

ANIMALS EXAMINE D HISTOPATHOLOGICALLY

INTEGUMENTARY SYSTEM 

*SKIN

FIBROSARCOMA

*SUBCUT TISSUE

FIBROSARCOMA

RESPIRATORY SYSTEM 

*LUNG

HEPATOCELLULAH CARCINOMA. METAST

ALVEOLA3/BRONCHIOLAR ADENOMA

HEMATOPOIETIC SYSTEM 

*HULTIPLE ORGANS

MALIGNANT LYMPHOMA, NOS

MALIG.LYMPHOMA, UNDIFFEP-TYPE

MALIG.LYMPHOMA, LYMPHOCYTIC TYPE

MALIG.LYMPHOMA , HISTIOCYTIC TYPE

GRANOLOCYTIC LEUKEMI A

*SPLEEN
 HEMANGIOHA


#LYMPH NODE


HF,MANGIOSARCOMA, METASTATIC


CIRCULATORY SYSTEM
 

HONE
 

 UDD IN THE DIET 

CONTROL LOW DOSE

 50 50

 50 49

 50 49

 (50) (H9)

 1 (2%) 

 (50) (49)

 1 (2%) 

 (50) (1*7)

 1 (2%) 

3 (6«) 2 (4%)

 (50) (U9)

 U (8%) 1 (2%) 

1 (2%) 

1 (2%) 

2 (4%) 3 (6%)

 (50) (46)


 (5)	 (11)


 1 (20%)
 

 HIGH DOSE 

 50 

1 

 40 

 39 

 (HO ) 

 (40) 

 (37) 

5 (14%) 

 (40) 

1 (3%) 

1 (3%) 

 (39)
 

1 (3%)
 

 (6)
 

#	 NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

*	 NUMBER OF ANIMALS NECROPSIED
 

52
 
TABLE B2. FEMALE MICE: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE
 

DIGESTIVE SYSTEM
 

ILIVE8 (50) (47) (38)
 

HEPATOCELLULAR CARCINOMA 1 (2%)
 

ANGIOSARCOMA 1 (2%)
 

•STOMACH	 (48) (47) (33}
 

SQUABOUS CELL PAPILLOMA 1 (2%) 1 (2%)
 

URINARY SYSTEM
 

•URINARY BLADDER (2) (2)
 

PAPILLONATOSIS 2 (100X)
 

ENDOCRINE SYSTEM
 

NONE
 

. •^ » • ••<•••«. _——••«__•.»•_«»<» .v.v^4B ••_. ^^•••^^^••^• BV-V^flB.* 0 «WW«_W.I.» «••» «.^«— ^ ^^^^«. «^ «.«< 

REPRODUCTIV E SYSTEM 

*VAGINA

HEMANGIOSARCOMA

 (50)

 1 (2%) 

(H9) (40) 

#OVAR Y

GRANULOSA-CELL ^ TOMOR —

 (20) (33)

 1 (3X) —

 (21) 

_ __

NERVOUS SYSTEM
 

NONE
 

SPECIAL SENSE ORGANS
 

NONE
 

HOSCOLOSKELETAL SYSTEM
 

_NONE
 

t NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

53
 
TABLE B2. FEMALE MICE: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

BODY CAVITIES 

*PERITONEUM (50) (49 )

 

LYMPHANGIOM A 1 (2% )

 

*MESENTER Y (50) (49 ) (UO) 

HEMANGIOSARCOM A 1 (3%) 

A LL OTHER SYSTEMS 

NON E 

ANIMA L DISPOSITION SUMMAR Y 

ANIMAL S INITIALL Y IN STUDY 50 50 50 

NATURA L DEATHS 6 22 

MORIBUN D SACRIFICE 44 27

 

SCHEDULE D SACRIFICE 

ACCIDENTALL Y KILLE D 

TERMINA L SACRIFICE 

ANIMA L MISSING 

INCLUDES AfJTOLYZED ANIMALS 

TUMOR SUMMAR Y
 

TOTAL ANIMALS HITH PRIMARY TUMORS* 14 12 9
 

TOTAL PRIMARY TUMORS 15 13 9
 

TOTAL ANIMALS WITH BENIGN TUMOPS
 

TOTAL BENIGN TUMORS
 

TOTAL ANIMALS WITH MALIGNANT TUMORS
 

TOTAL MALIGNANT TUMORS
 

TOTAL ANIMALS WITH SECONDARY TUMORS*
 

TOTAL SECONDARY TUMORS
 

TOTAL ANIMALS WITH TUMORS UNCERTAIN­ BENIGN OP. MALIGNANT
 

TOTAL UNCERTAIN TUMORS
 

TOTAL ANIMALS HITH TUMORS UNCERTAIN­ PRIMARY 09 METASTATIC
 

TOTAL UNCERTAIN TUMORS
 

* PRIMAR Y TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 * SECONDARY TUMORS: METASTATIC TUMORS OR TUMORS INVASIVE INTO AN ADJACENT ORGAN
 
APPENDIX C
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS
 

IN RATS ADMINISTERED UDD IN THE DIET
 

55
 
56

 
TABLE C1.

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE RATS 

ADMINISTERED UDD IN THE DIET 

CONTROL LOW DOSE HIGH DOSE
 

ANIMALS INITIALLY IN STUDY 35 35 35
 

ANIMALS NECROPSIED 34 33 35
 

ANIMALS EXAMINED HI STO PATHOLOGIC ALLY 33 33 35
 

INTEGUMENTARY SYSTEM
 

*SKIN (34) (33) (35)
 

EPIDERMAL INCLUSION CYST 2 (6X)
 

*SUBCUT TISSUE (34) (33) (35)
 

5RANULOMA, NOS 1 (3X)
 

RESPIRATORY SYSTEM
 

*NASAL CAVITY (34) (33) (35)
 

INFLAMMATION, CHRONIC 1 (3X) 3 (9X)
 

*NASAL TURBINATE (34) (33) (35)
 

INFLAMMATION, ACUTE 5 (15X)
 

INFLAMMATION, ACUTE SUPPURATIVE 6 (18%)
 

INFLAMMATION, CHRONIC 2 (6X)
 

#TRACHEA (30) (33) (35)
 

INFLAMMATION, ACUTE SUPPURATIVE 1 (3X)
 

INFLAMMATION, CHRONIC 7 (23X) 2 (6X) 3 (9X)
 

INFLAMMATION, CHRONIC SUPPURATIV 2 (7X)
 

#LUNG (30) (33) (35)
 

CONGESTION, NOS 1 (3X) 3 (9%)
 

EDEMA, NOS 1 (3X)
 

PNEUMONIA, ASPIRATION 1 (3X)
 

BEONCHOPNEUMONIA, ACOTE 1 (3X)
 

PNEUMONIA, CHRONIC MURINE 8 (27X) 7 (21X) 21 (60X)
 

#LUNG/ALVEOLI (30) (33) (35)
 

HEMORRHAGE 1 (3X)
 

HEHATOPOIETIC SYSTEM 

IBONE MARRO W (31) (33) (35)
 

HYPERPLASIA, HEHATOPOIETIC C13S)
 

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

57 
TABLE C1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE
 

#SPLEEN (31) (33) (35)
 

HEBOSIDEROSIS 3 (10%) 1 (3%)
 

ATROPHY, NOS 1 (3%)
 

LYHPHOID DEPLETION 1 (3%)
 

HYPERPLASIA, HEHATOPOIETIC 2 (6%)
 

HEMATOPOIESIS 3 (10%) 1 (3%)
 

tSPLENIC FOLLICLES (31) (33) (35)
 

ATROPHY, NOS 1 (3%)
 

tSPLENIC RED PULP (31) (33) (35)
 

HEMOSIDEROSIS 1 (3%) 4 (11%)
 

HYPERPLASIA, NOS 1 (3%)
 

#MANDIBULA3 L. NODE (22) (29) (30)
 

HYPSRPLASIA, LYMPHOID 5 (23%)
 

#CERVICAL LYMPH NODE (22) (29) (30)
 

HEMORRHAGE 1 (3%)
 

INFLAMMATION, CHRONIC 1 (3%)
 

tBRONCHIAL LYMPH NODS (22) (29) (30)
 

HEMORRHAGE 1 (5%)
 

INFLAMMATION, CHRONIC 1 (3%)
 

*LUMBAR LYMPH NODE (22) (29) (30)
 

INFLAMMATION, CHRONIC 1 (3%)
 

#NESENTERIC L. NODE (22) (29) (30)
 

HYPERPLASIA, LYMPHOID 1 (3%)
 

•RENAL LYMPH NODE (22) (29) (30)
 

INFLAMMATION, CHRONIC 1 (3%)
 

iTHYMOS (3) (25) (20)
 

ATROPHY, NOS 3 (100%)
 

CIRCULATORY SYSTEM
 

#MYOCARDIUM (30) (33) (35)
 

INFLAMMATION, CHRONIC a (13%) 1 (3%)
 

INFLAMMATION, CHRONIC FOCAL 1 (3%)
 

INFLAMMATION^ CHRONIC DIFFUSE 1 (3%)_
 —
 

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

58
 
TABLE C1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

DEGENERATION , NOS 

tENDOCARDIUM 

DEGENERATION , HUCOID 

METAPLASIA , OSSEOUS 

* A08TA 

MINERALIZATIO N 

^ABDOMINA L AORTA 

PERIARTERITI S 

*PULMONAS Y ARTER Y 

CALCIFICATION, DYSTROPHIC 

DIGESTIVE SYSTEM 

SLIVER 

CYST, NOS 

CONGESTION, CHRONIC PASSIVE 

ABSCESS, NOS 

CIRRHOSIS, CARDIAC 

METAMORPHOSI S FATTY 

FOCAL CELLOLAP CHANGE 

CLEAR-CELL CHANG E 

HYPERPLASIA , NO S 

ANGIECTASI S 

HEMATOPOIESIS 

#LIVER/CENTRILOBULA H 

NECROSIS, NOS 

METAMORPHOSI S FATTY 

*BILE DUCT 

HYPERPLASIA , NOS 

tPANCREA S 

PERIARTERITI S 

• PANCREATIC ACINUS 

ATROPHY, FOCAL 

fGASTRIC MUSCULARI S 

MINERALIZATIO N .. 

# NUMBE R OF ANIMALS HITH TISSUE

* NUMBER OF ANIHALS NECROPSIED 

CONTROL LOW DOSE HIGH DOSE 

1 (3*) 

(30) (33) (35) 

1 (3X) 1 (3X) 

1 (3X) 

(34) (33) (35) 

1 (3X) 

(34) (33) (35) 

1 (3X) 

(34) (33) (35) 

1 (3X) 

(31) (32) (35) 

1 (3X) 

1 (3X) 

1 (3X) 

1 (3X) 

2 (6%) 1 (3X) 

1 (3X) 2

 (6X) 

6 (17X) 

5 (16X) 

1 (3X) 

1 (3X) 1

 (3X) 

(31) (32) (35) 

1 (3X) 1 (3X) 

2 (6X) 11 (31X) 

(34) (33) (35) 

8 (24X) 

(24) (33) (31) 

1 (4X) 1 (3X) 

(24) (33) (31)

1 (3X) 

(31) (33) (33) 

1 131} 

 EXAMINED MICROSCOPICALLY 

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

UHINAH Y SYSTEM 

IKIDNE Y 

HYDRONEPHROSI S 

CYST, NOS 

MULTIPL E CYSTS 

PYELONEPHRITIS, NOS 

INFLAMMATION , INTERSTITIAL 

INFLAMMATION , CHRONIC 

PYELONEPHRITIS , CHRONIC 

NEPHROPATH Y 

NECROSIS, MEDULLAR Y 

#URINAR Y BLADDER 

INFLAMMATION,

INFLAMMATION ,

HYPERPLASIA ,

ENDOCRIN E SYSTEM 

tPITUITAR Y 

CYST, NOS 

tADRENA L 

ECTOPIA 

HYPERPLASIA ,

ANGIECTASI S 

tADRENA L CORTEX 

LIPOIDOSIS 

tTHYROI D 

HYPEPPLASIA,

#PARATHYROI D 

HYPERPLASIA ,

 CHRONIC 

 CHRONIC SUPPURfcTIV 

 EPITHELIAL 

 FOCAL 

 C-CELL 

 NOS 

REPRODUCTIV E SYSTEM 

*NAMMAR Y GLAN D 

HYPERPLASIA, NOS 

HYPEHPLASIA^ . CYSTIC _ _ __ 

CONTROL LOW DOSE HIGH DOSE 

(31) (33) 

2 (6X) 

(35) 

2 (6X) 

1 (3X) 

1 (3%) 

2 (6X) 

2 (6%) 

23 (7ttX) 

1 (3*) 

17 (52%) 21 (60X) 

1 <3X) 

(28) (31) (30) 

2 (7%) 

1 (3%) 

1 (3X) 

(16) (21) (16) 

2 (13X) 

(31) (30) (3<0 

1 (3%) 

1 (3X) 

1 (3%) 

(3D 

11 (35%) 

(30) 

2 (7%) 

(3<») 

(29) (33) (33) 

1 <3X) 2 (6X) 

(25) 

U (16X) 

(27) 

1 OUt) 

(27) 

2 (7X) 

(34) (33) (35) 

1 (3X) 

1 (3X) 

# NUHBEH OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

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

CONTROL LOW DOSE


#PBOSTATE (29) (31)


INFLAMMATION, ACUTE 2 (7%)
 

INFLAMMATION, CHRONIC H (T»%)
 

INFLAMMATION, CHRONIC SUPPURATIV 1 (3%)


*SEMINAL VESICLE (3I») (33)


DILATATION, NOS 1 (3X)
 

INFLAMMATION, CHRONIC 1 (3X)
 

INFLAMMATION, CHRONIC SOPPORATIV 1 (3%)
 

#TESTIS (32) (33)


ABSCESS, NOS 1 (3X)
 

PF.RIARTERITIS 2 (6%)
 

ATROPHY, NOS 9 (28*) 8 (2«X)


ATROPHY, FOCAL 1 (3S)
 

ASPERHATOGENESIS 1 (3X)
 

HYPERPLASIA, INTERSTITIAL CELL


NERVOUS SYSTEM
 

NONE
 

SPECIAL SENSE ORGANS
 

NONE
 

MUSCOLOSKELETAL SYSTEM
 

NONE
 

BODY CAVITIES
 

*ABDOMINAL CAVITY (3t) (33)


INFARCT, NOS 1 (3X)
 

*MESENTEPY (3U) (33)


PEPIARTERITIS 1 (3X) 1 (3X)
 

ALL OTHER SYSTEMS
 

NONE
 

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

 HIGH DOSE
 

 (30)
 

3 (10%)
 

 (35)
 

 (34)
 

 13 (38X)
 

1 (3X)
 

 (35)
 

 (35)
 

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

CONTROL LOW DOSE HIGH DOSE 

SPECIA L MORPHOLOG Y SU8HARY 

NO LESION REPORTED 1

 

IVOTO/NECROPSY/HISTO PERF 1 1

 

AUTO/NECEOPSY/NO HISTO \ 

AUTOLYSIS/NO NECROPSY 1 2 

# NUMBEB OF ANIMAL S KITH TISSUE EXAMINE D HICSOSCOPICALLY 

* NUMBE R OF ANIMAL S NECROPSIED 

62 
TABLE C2.

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE RATS 

ADMINISTERED UDD IN THE DIET 

CONTROL LOW DOSE HIGH DOSE 

ANIMALS INITIALLY IN STUDY 35 35 35
 

ANIMALS NECROPSIED 35 33 33
 

ANIMALS EXAMINED HI STOPATHOLOGICALLY 31 33 33
 

INTEGUMENTAR Y SYSTEM 

*SKIN (35) (33) (33)
 

ULCER, NOS 1 (3X)
 

*SUBCUT TISSUE (35) (33) (33)
 

INFLAMMATION, CHRONIC 1 (3%)
 

GRANULOMA, FOREIGN BODY 1 (3X)
 

RESPIRATORY SYSTEM
 

*NASAL CAVITY (35 ) (33) (33) 

INFLAMMATION, NOS 1 (3X) 

INFLAMMATION, ACUTE 1 (3X) 

INFLAMMATION, CHRONIC 3 (9%) 

INFLAMMATION, CHRONIC DIFFDSE 1 (3X) 

INFLAMMATION, CHRONIC NECROTIZIN 1 PX) 

HYPERPLASIA, NOS 1 (3X) 

*NASAL SEPTUB (35) (33) (33) 

INFLAMMATION, CHRONIC 3 (9X) 

INFLAMMATION, CHRONIC DIFFUSE 1 PX) 

*NASAL TURBINATE (35) (33) (33)

 

INFLAMMATION, ACUTE 1 (3%)

 

INFLAMMATION, ACUTE SUPPURATIVE 1 (3X)

 

tTSACHEA (29) (31) (28) 

INFLAMMATION, NOS 5 (17%) 

INFLAMMATION, ACUTE SUPPURATIVE 1 (3X) 

INFLAMMATION, CHRONIC 3 (10%) 

INFLAMMATION, CHRONIC DIFFUSE 1 <3X) 

HYPERPLASIA, EPITHELIAL 1 OX) 

METAPLASIA. SQUAMQUS 1 (3XL 1 UX> 

I NUMBER OF ANIMAL S WITH TISSUE EXAMINE D MICROSCOPICALLY * NUMBER OF ANIMAL S NECROPSIED 

63 
TABLE C2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE 

*LUNG (30) (33) 

EMPHYSEMA , NOS 1 (3%) 

ATELECTASIS 7 (21%) 

CONGESTION, NOS 2 (7%) 

BRONCHOPNEUMONIA , NOS 1 (3S) 

INFLAMMATION , ACUTE SUPPURATIV E 1 (3X) 

PNEUMONIA , CHRONIC flURIN E 6 (20*) 25 (76*) 

BRONCHOPNEUMONI A CHRONIC SUPPURA 1 (3*) 

GRANULOHA , NOS 1 (3%) 

FIBROSIS 1 (3%) 

HYPERPLASIA , ADENOMATOU S 3 (9% ) 

HEMATOPOIETIC SYSTEM
 

IBONE MARROW (31) (27)
 

HYPERPLASIA , HEMATOPOIETTC 4 (13*)
 

#SPLEEN (30) (30) 

INFLAMMATION , ACUTE 4 (13*) 

INFLAMMATION , CHRONIC 1 (3*) 

HEMOSIDEROSI S 2 (7%) 

ATROPHY, NOS 1 (3*) 

LYMPHOI D DEPLETION 2 (7%) 

HYPERPLASIA , HEMATOPOIETIC 1 (3*) 

HEMATOPOIESIS 6 (20*) 5 (17*) 

GPANULOPOIESI S 1 (3X) 

#MANDIBULA R L. NOD E (25) (23)
 

HEMORRHAGIC CYST 1 (4X)
 

INFLAMMATION , ACUTE 1 (1**)
 

PLASMA-CELL INFILTRATE 3 (12*)
 

HYPERPLASIA , LYMPHOI D 5 (20*)
 

fCERVICAL LYMP H NODE (25) (23) 

INFLAMMATION , NOS 1 (<**) 

#BRONCHIAL LYMP H NODE (25) (23) 

INFLAMMATION , CHRONIC 1 (UX) 

•MESENTE8IC L. NODE (25) (23)
 

HYPERPLASIA , LYMPHOI D 1 (4X)
 

ITHYMUS (9)
 

____CYST. NOS 2 (22*1
 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIBD
 

HIGH DOSE 

(33) 

1 (3X) 

1 (3*) 

19 (58*) 

(27)
 

(29)
 

1 (3X)
 

5	 (17X)
 

2 (7X)
 

(14)
 

(14)
 

(14)
 

(14)
 

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

CONTROL LOW DOSE 

ATROPHY, NOS 9 (100%) 

CIRCULATORY SYSTEM 

#HEART (31) (30)

 

CALCIFICATION , DYSTROPHIC 1 (3%)

 

tENDOCARDIU M (31) (30)

 

INFLAMMATION , CHRONIC 

FI3ROSIS, FOCAL 

*MESENTEBIC ARTERY (35) (33)

 

THROMBOSIS , NO S 1 (3%)

 

INFLAMMATION , CHRONIC 1 (3%)

 

DIGESTIVE SYSTEM 

tLIVER (31) (32) 

CYST, NOS 

CONGESTION, NOS 1 (3%) 

ABSCESS, NOS 1 (3%) 

HEPATITIS , TOXIC 

NECROSIS, NOS 1 (3%) 

NECROSIS, FOCAL 1 (3%) 1 (13%) 

NECROSIS, DIFFUSE 1 (3%) 

METAMORPHOSIS FATTY 16 (50%) 

LIPOIDOSIS 2 (6%) 

MEGALOCYTOSIS 

HYPERPLASIA , NOS 7 (23%) 

ANISOCYTOSIS 1 (3%) 

HEMATOPOIESIS 1 (3%) 3 (9%) 

#LIVER/CENTRILOBULAR (31) (32) 

NECROSIS, NOS 2 (6%) 

METAMOEPHOSIS FATTY 1 (3%) 3 (9%) 

ANGIECTASIS 1 (3%) 

#LIVER/PERIPORTAL (31) (32)

 

FIBROSIS 

HETAM08PHOSIS FATTY 

*BILE DUCT (35) (33)

 

DILATATION, NOS .. _ _ . _ _ 1 J3%)

 

I NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

HIG H DOSE 

(32) 

(32) 

1 (3%) 

1 (3%) 

(33) 

(32) 

2 (6%) 

1 (3%) 

1 (3%) 

1 (3X) 

1 (3%) 

18 (56%) 

1 (3X) 

1 (3%) 

(32) 

3 (9%) 

7 (22%) 

(32) 

3 (9%) 

1 (3%) 

(33) 

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

CONTROL LOW DOSE 

MULTIPL E CYSTS 

INFLAMMATION, CHRONIC 1 (3K) 

HYPERPLASIA , NO S 13 (31%) 

HYPERPLASIA, FOCAL 1 (3%) 

• PANCREA S (29) (28) 

INFLAMMATIO N WITH FIBROSIS 1 (3*) 

*P AN CHEAT 1C DUCT (29) (28) 

HYPERPLASIA , NO S 3 (10*) 

#PANCREATI C ACINUS (29) (28) 

ATSOPHY , NOS 2 (7*) 

AT?OPHY, FOCAL 2 (7*) 

#STOMACH (31) (31) 

CALCIFICATION, DYSTROPHIC 1 (3X) 

HYPERKF.RATOSI S 

URINAR Y SYSTEM 

#KIDNE Y 

MINERALIZATIO N 

(31) 

17 (55*) 

(32) 

CAST, NOS 

PYELONEPHRITIS, NOS 

INFLAMMATION , INTERSTITIAL 

1 (3*) 

1 (3*) 

PYELONEPHRITIS , ACUTE 1 OX) 

INFLAMMATION , ACUTE 

INFLAMMATION , CHRONIC 5 (16%) 

INFLAMMATION , CHRONIC FOCAL 

GLOMERULOSCLEROSIS, NOS 

NECROSIS, MEDULLARY 

1

2

2

 (3*) (6*) 

 (6*) 

HYPERPLASIA , EPITHELIAL 1 (3*) 

*KIDNEY/MEDULL A (31) (32) 

MINERALIZATIO N 1 (3X) 

•KIDNEY/TUBUL E 

DILATATION , NOS 

CAST, NOS 

(31) (32) 

3 (9*) 

10 (31X) 

CYST, NOS H (13*) 

tURINAR Y BLADDER (25) (15) 

INFLAMMATION , NOS _ ) I<*X1 

# NUMBER OF ANIMALS WITH TISSUE EXAHINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

HIGH DOSE 

1 (3%) 

1 (3X) 

U (12*) 

(21) 

(21) 

(21) 

1 (5*) 

1 (5*) 

(28) 

1 (UX ) 

(32) 

3 (9X) 

3 (9*) 

1 (3X) 

1 (3*) 

5 (16*) 

(32) 

(32) 

t (13*) 

<* (13*) 

(8) 

66
 
TABLE C2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

INFLAMMATION , ACUTE 1 (US) 

ENDOCRIN E SYSTEM 

tPITUITA R Y (18) (19) (11)

 

CYST, NOS 3 (17%)

 

#ADRENA L (30) (31) (30) 

ANGIECTASI S 8 (27%)

 

#ADFENA L CORTEX (30) (31) (30) 

HSHORRHAGI C CYST 1 (3%) 

LIPOIDOSIS 9 (30%) 

HYPERPLASIA , NO S 1 (395) 

tTHYROI D (28) (28) (24)

 

CYSTIC FOLLICLES 1 (455) 

FOLLICULA B CYST, NOS 1 (ttX) 1 (<•»)

 

HYPERPLASIA , C-CELL 3 (11%) 

REPRODUCTIV E SYSTEM 

*MAMMAR Y GLAN D (35) (33) (33)

 

CYST, NOS 1 (3*)

 

#UTERUS (30) (30) (27) 

PYOMETR A 1 (4X) 

INFLAMMATION , ACUTE 2 (7%) 

ABSCESS, NOS 1 («»%) 

ATROPHY , NOS 2 (7%) 

f UTERUS/ENDOMETRIU M (30) (30) (27) 

CYST, NOS 2 (7%) 

INFLAMMATION , ACUTE 2 (7%) 

HYPERPLASIA , NOS 1 (3%) 

HYPERPLASIA , CYSTIC 2 (7%) 

#OVARY (26) (29) (21) 

CYSTIC FOLLICLES 1 (4%) 

FOLLICULAR CYST, NOS 1 (<*%) 1 (3%) 1 (5%) 

NERVOU S SYSTEM 

NONE 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICBOSCOPICALLT
 * NUMBER OF ANIMALS NECROPSIED
 

67
 
TABLE C2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

SPECIAL SENSE ORGAN S 

*EYE (35) (33) (33) 

INFLAHHATION, ACUTE 2 (6X) 

CATARACT 1 (3%) 

*EYE/CORNEA (35) (33) (33) 

INFLAMMATION, ACUTE 1 (3X) 

*EYE/RETINA (35) (33) (33) 

INFLAMMATION , NOS 21 (60%) 

*2YE/LACRIMAL GLAND (35) (33) (33) 

INFLAMMATION , ACUTE SUPPORATIVE 1 (3%) 

*HARDBRIA N GLAN D (35) (33) (33) 

ABSCESS, NOS 1 (3%) 

INFLAMMATION, CHRONIC 1 (3%) 1 (3X) 

INFLAMMATION , CHRONIC SUPPURATIV 1 (3%) 

MUSCULOSKSLETAL SYSTEM 

*SKELETAL MUSCLE (35) (33) (33) 

GRANULOMA , FOREIGN BODY 1 (3X) 

BOD Y CAVITISS 

"•ABDOMINAL WAL L (35) (33) (33) 

INFLAMMATION , CHRONIC 1 (3%) 

*PERITONEAL CAVITY (35) (33) (33) 

INFLAMMATION , CHRONIC DIFFUSE 1 (3S) 

*PLEURA (35) (33) (33) 

INFLAMMATION, CHRONIC 1 (3%) 

A LL OTHER SYSTEMS 

NONE _ __•_ _ ^*_.._.._____ _ _____ _ ___ •_ _^ __• __^^__.._____._^_~_«~__ _ ___^_^_^^^~ ___ _ •____ _ _^_. 

SPECIAL MORPHOLOGY SUMMARY
 

AUTOZNECRQPSY/NQ_HISTfl 

t NUMBE R OF ANIMAL S WITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBE R 0? ANIMAL S NECROPSIE D 

68 
TABLE C2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

AUTOLYSIS/NO NECROPSY 2 2 

* NOMBSR OF ANIMAL S WITH TISSUE EXAMINE D MICKOSCOPICALLY 

* NUHBER OF ANIMAL S NBCROPSIED 

69 
70

 
APPENDIX D
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS
 

IN MICE ADMINISTERED UDD IN THE DIET
 

71
 
72

 
TABLE D1.

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE MICE 

ADMINISTERED UDD IN THE DIET 

CONTROL LOW DOSE 

ANIMALS INITIALLY IN STUDY 50 50
 

ANIMALS NECROPSIED 50 50
 

ANIMALS EXAMINED HISTOPATHOLOGIC ALLY 49 50
 

INTEGUMENTARY SYSTEM 

*SKIN (50) (50)


ULCER, FOCAL
 

INFLAMMATION, ACUTE/CHRONIC
 

INFLAMMATION, CHRONIC DIFFUSE
 

ACANTHOSIS
 

RESPIRATOR Y SYSTEM 

ITRACHEA (45) (46)
 

HYPERPLASIA, EPITHELIAL
 

tLUNG (49) (48)
 

INFLAMMATION, NOS 1 (2%)
 

INFLAMMATION, INTERSTITIAL
 

PNEUMONIA, CHRONIC HURINE 1 (2%)
 

PNEUMONIA INTERSTITIAL CHRONIC 6 (13%)
 

HYPERPLASIA, ADENOMATOUS 2 (4%)
 

HYPERPLASIA, ALVEOLAR EPITHELIUM 1 (2%)
 

HEMATOPOIETIC SYSTEM
 

ISPLEEN (48) (48)
 

ATROPHY , FOCAL 

LYMPHOI D DEPLETION 1 (2%) 

HYPERPLASIA, LYMPHOID 2 (4%) 

#LUMBAR LYMP H NODE (1) (31)
 

INFLAMMATION , CHRONIC 

#MESENTERIC L. NODE (1) (31) 

# NUMBER OF ANIMAL S WIT H TISSUE EXAHINE D MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

HIGH DOSE 

50
 

48
 

48
 

 (1*8)
 

1 (2%)
 

1 (2%)
 

1 (2%)
 

6 (13%)
 

(41)
 

2 (5%)
 

(48)
 

1 (2%)
 

2 (4%)
 

(44) 

1 (2X) 

2 (5%) 

3 (7%) 

(25) 

1 (4S) 

(25 ) 

73 
•AXILLARY	 LYMPH NODE
 

INFLAMMATION, CHRONIC
 

•INGUINAL	 LYMPH NODE
 

INFLAMMATION, CHRONIC
 

CIRCULATORY SYSTEM
 

•HEART
 

PERIARTEFITIS
 

•MYOCARDIUM
 

INFLAMMATION, CHRONIC FOCAL
 

DIGESTIVE SYSTEM
 

•LIVER
 

HEMORRHAGE
 

INFLAMMATION, ACUTE/CHRONIC
 

INFLAMMATION, CHRONIC
 

HEPATITIS, TOXIC
 

NECROSIS, FOCAL
 

HETAMORPHOSIS FATTY
 

BASOPHILIC CYTO CHANGE
 

•STOMACH
 

HYPERPLASIA, EPITHELIAL
 

ilYFERKERATOSIS
 

ACANTHOSIS
 

•GASTRIC MUSCULARIS
 

NECROSIS, DIFFUSE
 

URINAR Y SYSTEM
 

•KIDNEY
 

INFLAMMATION, INTERSTITIAL
 

GLOMERULOSCLEROSIS, NOS
 

•URINARY	 BLADDER
 

CALCULUS, NOS
 

TABLE D1. MALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

HIGH DOSE
 

(25)
 

1 (4S)
 

(25)
 

2 (8X)
 

(46)
 

1 (2%)
 

(46)
 

1 (2%)
 

(48)
 

1	 (2%)
 

1 (2%)
 

1	 (2%)
 

(45)
 

1 (2%)
 

(45)
 

1 (2%)
 

(48)
 

2 (4%)
 

1 (2%)
 

CONTROL LOWD
 

d)	 (31)
 

d)	 (31)
 

(49)	 (50)
 

(49)	 (50)
 

(49)	 (50)
 

1
 

5
 

1
 

1
 

2
 

1
 

(49)	 (49)
 

1
 

1
 

(49)	 (49)
 

(49)	 (50)
 

(9)


1
 

OSE
 

(2%)
 

(10%)
 

(2X)
 

(2%)
 

(4%)
 

(2%)
 

(2%)
 

(2%)
 

(11*)
 

NUMBE R OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

::;::• •:•'• ANIMALS NBCROPSIED
 

74
 
TABLE D1. MALE MICE: NQNNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

INFLAMMATION , CHRONIC DIFFUSE 1 (11%) 

ENDOCRINE SYSTEM 

tTHYROID

ATROPHY , FOCAL

tPAHATHYROI D

CYST, NOS

 (39)

 (15)

 (37)

 (10)

 (31) 

1 (3%) 

 (17) 

1 (6%) 

REPRODUCTIVE SYSTEM 

*PREPUTIAL GLAND

DILATATION, NOS

INFLAMMATION, CHRONIC SUPPURATIV

*TESTIS

3RANULOMA, SPERMATIC

ATROPHY, NOS

 (50)

 1 (2%) 

1 (2%)

 (49)

 1 (2%) 

 (50)

 (49)

 1 (2%) 

 (48) 

1 (2%) 

 (45) 

NERVOUS SYSTEM 

NONE 

SPECIAL SENSE ORGANS 

HONE 

MUSCULOSKELETAL SYSTEM 

NONE 

BODY CAVITIES 

*PERITONEOM

INFLAMMATION, CHRONIC

 (50) (50) (48) 

1 (2X) 

ALL OTHER SYSTEMS 

NONE

# NUMBER OF ANIMAL S WITH TISSUE

* NUMBER OF ANIMALS NECROPSIED 

 EXAMINE D HICROSCOPICALLY 

_. 

75
 
TABLE D1. MALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

SPECIAL MORPHOLOGY SUMMARY
 

NO LESION REPORTED 26 18 16
 

AUTO/NECROPSY/NO HISTO 1
 

AUTOLYSIS/NO NECROPSY


* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

76
 

 2 
TABLE D2. 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE MICE 

ADMINISTERED UDD IN THE DIET 

CONTROL LOW DOSE HIGH DOSE 

ANIMAL S INITIALLY IN STUDY 50 50 50 

ANIMAL S HISSING 1 

ANIMALS NECROPSIED 50 49 40 

ANIMAL S EXAMINE D HI STOPATHOLOGICALL Y 50 49 39 

INTEGUMENTAR Y SYSTEM 

*SKIN (50) (49) (40) 

ACARIASI S 2 (5*) 

RESPIRATOR Y SYSTEM 

tTRACHE A (45) (44) (24) 

HYPERPLASIA , EPITHELIAL 1 (4%) 

*LUNG/BRONCHIOLE (50) (47) (37) 

HYPERPLASIA , EPITHELIAL 1 (3S) 

tLONG (50) (47) (37) 

CONGESTION, NOS 1 (2%) 1 (3%) 

INFLAMMATION , NOS 2 (4%) 

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

BHONCHOPNEONONIA, ACUTE 2 (5*) 

LOBAR PNEUMONIA , ACUTE 1 (3*) 

PNEUMONIA , CHRONIC ttURIH E 2 (4%) 3 (8X) 

PNEUMONIA INTERSTITIAL CHRONIC 6 (16%) 

HYPSRPLASIA , ALVEOLA R EPITHELIUM 1 (2%) 

HEMATOPOIETIC SYSTEM 

• BONE MAEHOH (l»8) (43) (24) 

HYPERPLASIA , HEMATOPOIETIC 3 (7%) 

tSPLEEN (50) (46) (39) 

LYMPHOI D DEPLETION 2 (5%) 

HYPERPLASIA,

HYPERPLASIA ,

HEMATOPOIESIS 

 HEMATOPOIETIC 

 LYMPHOI D 6 (12*) 

1 (2%) 

7 (15*) 

1 (2%) 

2 (5X) 

5 (13%) 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

77
 
TABLE D2. FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

#LYMPH NODE


HYPERPLASIA, LYMPHOID


#BRONCHIAL LYMPH NODE


INFLAMMATION, NOS
 

•LUMBAR	 LYMPH NODE


INFLAMMATION, CHRONIC
 

#RENAL LYMPH NODE


INFLAMMATION, CHRONIC
 

HYPERPLASIA, LYMPHOID
 

CIRCULATORY SYSTEM
 

NONE
 

DIGESTIVE SYSTEM
 

fLIVER


ABSCESS, NOS
 

INFLAMMATION, ACUTE/CHBONIC
 

INFLAMMATION, CHRONIC
 

FIBROSIS
 

CIRRHOSIS, NOS
 

HEPATITIS, TOXIC
 

NECROSIS, NOS
 

BEGALOCYTOSIS
 

HYPERPLASIA, NOS


HYPERPLASIA, HEMATOPOIETIC
 

HEMATOPOIESIS
 

GRANULOPOIESIS
 

#LIVER/HEPATOCYTES


NECROSIS, NOS


*BILE DUCT


HYPERPLASIA, NOS
 

IPANCREAS


DILATATION/DUCTS


INFLAMMATION. CHRONIC SOPPURATIV
 

CONTROL
 

 (5)
 

1 (20%)
 

 (5)
 

 (5)
 

 (5)
 

 (50)
 

1 (2%)
 

 (50)
 

1 (2%)
 

 (50)
 

 (26)
 

1 (4X)
 

LOW DOSE
 

(11)
 

(11)


1 (9X)
 

(11)


1 (9%)
 

(11)
 

1 (9%)
 

1 (9%)
 

(47)
 

2 (4%)
 

3 (6X)
 

2 (4%)
 

(H7)
 

(49)
 

(45)
 

1 (2%)
 

HIGH DOSE
 

(6)
 

(6)
 

(6)
 

1


(6)
 

1


(38)
 

1


1


3


2


5


3


1


1


(38)
 

(40)
 

1


(25)
 

1


 (17%)
 

 (17%)
 

 (3%)
 

 (3%)
 

 (8%)
 

 (5%)
 

 (13%)
 

 (8%)
 

 (3%)
 

 (3%)
 

 (3%)
 

 (4%)
 

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

78
 
TABLE D2. FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE
 

tPANCREATIC ACINUS (26) (45)
 

ATROPHY, NOS 1 (2%)
 

URINARY SYSTEM
 

iKIDNEY 

LYMPHOCYTIC INFLAMMATORY INFILT

INFLAMMATION, INTERSTITIAL 

GLOMERULOSCLEROSIS, NOS 

R 

(50) 

2 (4X) 

(47) 

7

2

 (15%) 

 {!*%) 

#KIDNEY/GLOMERULUS 

AMYLOIDOSIS 

(50) 

1 (2%) 

(47) 

#KIDNEY/TUBULE 

NECROSIS, NOS 

HYPOPLASIA, NOS 

(50) (47) 

ENDOCRINE SYSTEM
 

#ADRENAL MEDULLA (43) (29)
 

CYST, NOS 1 (3%)
 

REPRODUCTIVE SYSTEM
 

#UTERUS (i*9) (48)
 

HYDROMETRA 4 (8%)
 

PYOMETRA 1 (2«)
 

ATROPHY, NOS 1 (2%)
 

IUTERUS/ENDOMETRIUM (49) (48)
 

INFLAMMATION, SUPPURATIVE 6 (13%)
 

HYPERPLASIA, DIFFUSE 1 (2%)
 

HYPERPLASIA, CYSTIC 48 (98%) 37 (77%)
 

tUTERUS/MYOMETRIUM (49) (48)
 

INFLAMMATION, ACUTE/CHRONIC 1 (2%)
 

#OVARY/OVIDUCT (<*9) (48)
 

PUS 1 (2%)
 

PUS
 

#OVARY (20) (33)
 

CYST, NOS 5 (25?)
 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

HIGH D'OSE
 

(25)
 

(39)
 

5 (13%)
 

(39)
 

(39)
 

1 (3«)
 

1 (3%)
 

(35)
 

(26)
 

(26)
 

3 (12%)
 

18 (69%)
 

(26)
 

(26)
 

1 (4%)
 

1 (4%)
 

(21)
 

79
 
TABLE 02. FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

FOLLICULA R CYST, NOS

HEMORRHAGI C CYST

ABSCESS, NOS

ABSCESS, CHRONIC

 5 (25%) 2

 1

 (6«)

 (3«) 

2

 2

 1

 (10*) 

 (10X) 

 (5X) 

NERVOU S SYSTEM 

#BRAIN/MENINGE S

INFLAMMATION , CHRONIC FOCAL

 (47) (44)

 1 (2X) 

 (27) 

SPECIA L SENSE ORGAN S 

NON E 

MUSCULOSKELETA L SYSTE M 

NON E 

BODY CAVITIES 

'PERITONEUM

INFLAMMATION, CHRONIC

INFLAMMATION, CHRONIC FOCAL

INFLAMMATION, CHRONIC SOPPURATIV

 (50) (49)

 4 (8%) 

 (40) 

1 (3X) 

1 (3X) 

ALL OTHER SYSTEMS 

ADIPOSE TISSUE 

LIPOGRANULOHA 1 

SPECIAL MORPHOLOGY SUMMARY 

NO LESION REPORTED

ANIMAL MISSING/NO NECROPSY

AUTO/NECROPSY/HISTO PESF

AUTO/NECROPSY/NO HISTO

AUTOLYSIS/NO NECROPSY

# NUMBER OF ANIMALS WITH TISSOI EXAMINED

* NUMBER OF ANIMALS NECROPSTED 

1

 MICROSCOPICALLY 

3

 1

 2 

1 

2 

1 

9 

80
 
APPENDIX E
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS
 

IN RATS ADMINISTERED UDD IN THE DIET
 

31
 
82

 
Tabl,2 El. Analyses of the Incidence of Primary

Administere d UDD in the Diet

 Tumors

 (a) 

 in Male Rats 

Topography: Morphology Control 

Low 

Dose 

High 

Dose 

Integumentary System: Fibroma of 

the Subcutaneous Tissue (b) 3/34 (9) 0/33 (0) 0/35 (0) 

P Values (c,d) P = 0.036 (N ) N.S. N.S. 

Relative Risk (f) 

Lower Limit 

Upper Limit 

0.000 

0.000 

1.687 

0.000 

0.000 

1.594 

oc 

us 

Weeks to First Observed Tumor 96 — — 

Stomach: Papilloma, NOS (b) 0/31 (0) 0/33 (0) 2/33 (6) 

P Values <c,d ) N.S. — N.S. 

Relative Risk (f) 

Lower Limit 

Upper Limit 

— 

— 

— 

Infinite 

0.282 

Infinit e 

Weeks to First Observed Tumor 110 
00 

Table El. Analyses of the Incidence of Primarv Tumors in Hal? Rats
 

Administered HDD in the Diet (a)
 

(continued)
 

Low
 

Topography; Morphology Control Dose
 

Pituitary: Adenoma, NOS (b) 2/16 (13) 0/21 (0)
 

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

Relative Risk (f) 0.000
 

Lower Limit 0.000
 

Upper Limit 2.475
 

Weeks to First Observed Tumor 110
 

Adrenal: Cortical Adenoma (b) 7/31 (23) 4/30 (13)
 

P Values (c,d) P = 0.039 (N) .M.S.
 

Relative Risk (f) 0.590
 

Lower Limit 0.141
 

Upper Limit 2.068
 

Weeks to First Observed Tumor 91 110
 

High
 

Dose
 

0/16 (0)
 

N.S.
 

0.000
 

0.000
 

3.190
 

—
 

2/34 (6)
 

N.S.
 

0.261
 

0.028
 

1.245
 

110 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats
 

Administered UDD in the Diet (a)
 

(continued) 

Topography: Morphology Control 

Low 

Dose 

High 

Dose 

Adrenal: Pheochromocvtoma (b) 6/31 (19) 0/30 (0) 2/34 (6) 

P Values (c,d) P = 0.047 (N) P = 0.013 (N) N.S. 

Departure from Linear Trend (e) P = 0.038 

Relative Risk ( f ) 

Lower Limit 

Upper Limit 

0.000 

0.000 

0.631 

0.304 

0.032 

1.554 

Weeks to First Observed Tumor 86 — 110 

Thyroid: Follicular-cell Adenoma
 

or Carcinoma (b) 3/29 (10) 0/33 (0) 1/33 (3)
 

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

Relative Risk (f) 0.000 0.293
 

Lower Limit 0.000 0.006
 

Upper Limit 1.437 3.417
 

Weeks to First Observed Tumor 97
 110 
__ 

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

Administered UDD in the Diet (a)
 

(continued)
 

Low 

Topography; Morphology Control Dose 

Thyroid: Cystadenoma, NOS (b) 0/29 (0) 2/33 (6) 

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

Relative Risk (f) Infinit e 

Lower Limit

 r 0.265 

^Upper Limit •Infinit e 

WHeks to First Observed. Tumor 110 

oo
 

Thyroid: C-cell Adenoma (b) 3/29 (10) 0/33 (0) 

P Values (c,d ) P = 0.029 (N) N.S. 

Relative Risk, (f) 0.000

 

Lower Limit 0.000

 

Upper Limit 1.437

 

Weeks to First Observed Tumor 110
 

High 

Dose 

0/33 (0) 

— 

— 

.— . . 

— 

0/33 (0) 

N.S. 

0.000 

0.000 

1.437 
00 

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

Administered ODD in the Diet (a)
 

(continued)
 

Low
 

Topography : Morpjiology Control Dose
 

Parathyroid: Adenoma, NOS (b) 2/25 (8) 0/27 (0)
 

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

Relative Risk (f) 0.000
 

Lower Limit 0.000
 

Upper Limit 3.057
 

Weeks to First Observed. Tumor 110
 —
 

Pancreatic Islets: Islet-cell
 

Adenoma (b) 1/24 (4) 2/33 (6)
 

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

Relative Risk (f) 1.455
 

Lower Limit 0.081
 

Upper Limit 83.169
 

Weeks to First Observed Tumor 97 110
 

High
 

Dose
 

0/27 (0)
 

N.S.
 

0.000
 

0.000
 

3.057
 

—
 

1/31 (3)
 

N.S.
 

0.774
 

0.010
 

58.826
 

110 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats
 

Administered UDD in the Diet (a)
 

(continued)
 

Low High
 

Topography ; Morphology Control Dose Dose
 

Tunica Vaginalis: Mesothelioma,
 

NOS (b) 2/34 (6) 0/33 (0) 0/35 (0)
 

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

Relative Risk (f) 0.000 0.000
 

Lower Limit 0.000 0.000
 

Upper Limit 3.435 3.246
 

oo Weeks to First Observed Tumor 31
 00 —
 

(a) Dosed groups received 5,000 or 10,000 ppm.
 

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

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

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

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

for th'e cotnparison of that dosed group with the control group when P is less than . •/-.
 

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

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

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

any comparison.
 

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

HIM) in the Dist (a)
 

Topography; Morphology Control 

Pituitary: Chromophobe Adenoma (b) 4/!8 (22) 

P Values (c,d) P = 0.045 (N) 

Relative Risk (f) 

Lower Limit 

Upper Limit 

oo 

Weeks to Tirst Observed Tumor 116 

Adrenal: Cortical Adenoma (b) 11/30 (37) 

P Values (c,d) P = 0.012 (N) 

Relative Risk (f) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tutnor 115

Low 

Dose 

1/19 (5) 

N.S, 

0.237 

0.005 

2.106 

116 

8/31 (26) 

N.S. 

0.704 

0.289 

1.643 

 95

High 

Dose 

0/11 (0) 

N,3. 

0.000 

0.000 

1.589 

— 

3/30 (10) 

P = 0.015 (N) 

0.273 

0.055 

0.909 

 67 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Administered UDD in the Diet (a)
 

(continued)
 

Low High
 

Topography: Morphology Control Dose Dose
 

Adrenal: Cortical Adenoma or
 

Carcinoma (b) 11/30 (37) 8/31 (26) 4/30 (13)
 

P Values (c,d) P = 0.027 (N) N.S. P = 0.036 (N)
 

Relative Risk (f) 0.704 0.364
 

Lower Limit 0.289 0.096
 

Upper Limit 1.643 1.072
 

VO Weeks to First Observed Tumor 115 95 67
 O
 

Adrenal Cortex: Cystadenoma, NOS (b) 0/30 (0) 0/31 (0) 2/30 (7)
 

P Values (c,d) N.S. N.S.
 —
 

Relative Risk (f) Infinite
 —
 Lower Limit 0.301
 —
 Upper Limit Infinite
 —
 

Weeks to First Observed Tumor 111
 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats 

Administered UDD in the Diet (a) 

(continued) 

Low High
 

Topography ; Morphology Control Dose Dose
 

Thyroid: C-cell Adenoma or
 

Carcinoma (b) 4/28 (14) 1/28 (4) 1/24 (4)
 

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

Relative Risk (f) 0.250 0.292
 

Lower Limit 0.005 0.006
 

Upper Limit 2.322 2.680
 

Weeks to First Observed Tumor 115 114 111
 

Thyroid Follicle:

NOS (b)

 Cystadenoma, 

 2/28 (7) 0/28 (0) 0/24 (0) 

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

Relative Risk (f) 

Lower Limit 

Upper Limit 

0.000 

0.000 

3.310 

0.000 

0.000 

3.834 

Weeks to First Observed Tumor 116 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats 

Administered UDD in the Diet (a) 

(continued) 

Low 

Topography: Morphology Control Dose 

Mammary Gland: Adenoma, NOS (b) 3/35 (9) 0/33 (0)
 

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

Relative Risk (f) 0.000
 

Lower Limit 0.000
 

Upper Limit 1.737
 

Voeks to First Observed Tumor 113 . — .
 

Mammary Gland: Fibroadenoma fb) 13/35 C37) 8/33 (24)
 

P Values (c,cO P = 0.027 (N) N.S.
 

R-slative Risk ( f ) 0.653
 

Lower Limit 0.272
 

Upper Limit 1.466
 

Weeks to First Observed Tuner 107 95
 

High
 

Dose
 

1/33 (3)
 

N.S.
 

0.354
 

0.007
 

4.136
 

- HI
 

5/33 (15)
 

P = 0.037 (N)
 

0.408
 

0.129
 

1.069
 

111
 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Administered UDD in the Diet (a)
 

(continued)
 

(a) Dosed groups received 5,000 or 10,000 ppm.
 

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

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


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

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

for the comparison of that dosed group with the control group when P is less than
 

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

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

VD
 

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

comparison.
 

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

APPENDIX F
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS
 

IN MICE ADMINISTERED UDD IN THE DIET
 

95
 
96

 
Table Fl. Analyses of the Incidence of Primary Tumors in Malt? Mice

 

Administered UDD in the Diet (a) 

Low High 

Topography; Morphology Control Dose Dose 

Lung: Alveo lar /Bronch io lar 

Carcinoma (b) >L' 0/49 (0) 5/48 (10) 1/48 (2) 

P Values (c,d) N.S. P = 0.027 N.S. 

Departure from Linear Trend (e) P = 0.008 

Relative-Risk (f) ' Infinite Infinite 

Lower Limit . . 1.289 0,055 

Upper Limit Inf in ite Infinite 

Weeks to First Observed Tumor 97 93 

Lung ; Alveo lar /Bronch io lar
 

Adenoma or Carcinoma (b) 8/49 (16) 11/48 (23) 6/48 (13)
 

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

Relative Risk (f) 1.404 0.766
 

Lower Limit 0.565 0.236
 

Upper Limit 3.665 2.322
 

Weeks to First Observed Tumor 92 97 93 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice
 

Administered UDD in the Diet (a)
 

(continued)
 

Low 

Topography: Morphology Control Dose 

Spleen: Hemangioma (b) 0/48 (0) 3/48 (6) 

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

Relative Risk (f) Infinite 

Lower Limit 0.601 

Upper Limit Infinite 

Weeks to First Observed Tumor — 97 

OB
 

Liver: Hepatocellular Carcinoma (b) 4/49 (8) 7/50 (14> 

F Values (c,d) N.S. N;S. 

Relative Risk (f) K715

 •-. , L • .Lower Limit 0.467

 

Upper Limit 7.525 

Ueeks to First Observed Tumor 93
 

High 

Dose 

1/44 (2) 

N.S. 

Infinite 

0.059 

Infinite 

93 

3/48 <6> 

"'•»&".- . 

0.764 oais 

4.285 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice
 

Administered UDD in the Diet (a)
 

(continued)
 

• • . . , . .

Topography: Morphology

 ­

 Control 

...., ' 

Liver: Hepatocellular 

Adenoma or Carcinoma (b) 8/49 (16) 

P Values (c,d) N.S. 

Relative

.

 Risk (f) 

 Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 92 

Stomach: Squamous-ce 11

• 

 Papilloma (b) 5/49 (10) 

P Val-ies (c,d ) ? = Q.007 (N) 

Relative Risk (f) 

Lower Limit 

Upper Limit 

Week? to First Observed Tumor 

Lew 

Dose 

8/50 (16) 

N.S. 

0.980 

0.349 

2.757 

97 

0/49 (0) 

P = 0.028 (N> 

0.000 

O.QOO 

0.792 

High -

Doyg 

5/48 HO) 

N.S, 

0.636 

0.176 

2.047 

93 

6/45 ' (-0) 

P - 0.035 (N) 

0.000 

0.000 . 

0.861 

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

Topography: Morphology


Lung: Alveolar ,/Bronchi.olar
 

Adenoma (b)


P Value? (c,d)


Relative Risk (f)
 

Lower Limit
 

[Jpper Limit
 

Weeks to First Observed Tumor


Hematopo iet ic System:
 

Lymphoma or Leukemia (b)


P Values Cc,d)


Relative Risk ( f )
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Administered UDD in the Diet (a)
 

Low
 

 Control Dose
 

 3/50 (6) 2/47 (4)
 

 N.S. N.S.
 

0.709
 

0.061
 

5.91.3
 

 91 92
 

 6/50 (12) 6/49 (12)
 

 N.S. N.S.
 

1.020
 

0.293
 

3.556
 

76 87
 

High
 

Dose
 

5/37 (14)
 

N.S.
 

2.252
 

0.467
 

13.614
 

2/40 (5)
 

N.S.
 

0.417
 

0.043
 

2.176
 

9L
 

91 
Table F2. Analyses of the Incidence of Primary Tumors in Female Mice
 

Administered UDD in the Diet (a)
 

(continued)
 

(a) Dosed groups received 5,000 or 10,000 ppra.
 

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

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


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

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

for the comparison of that dosed group with the control group when P is less than
 

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

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

o	 (e) Th probabilit e y level for departure from linear trend is given when P is less than 0.05 for any
 

comparison.
 

(f) The 95% confidence interval of the relative risk between each dosed group and the control group.
 
Review of the Bioassay of Dibenzo-p-Dioxin* for Carcinogenicity
 

by the Data Evaluation/Risk Assessment Subgroup
 

of the Clearinghouse on Environmental Carcinogens
 

August 31, 1978
 

The Clearinghouse on Environmental Carcinogens was established in
 

May, 1976, in compliance with DHEW Committee Regulations and the Provisions of the Federal Advisory Committee Act. The purpose of the
 

Clearinghouse is to advise the Director of the National Cancer Institute
 

(NCI) on its bioassay program to identify and to evaluate chemical
 

carcinogens in the environment to which humans may be exposed. The
 

members of the Clearinghouse have been drawn from academia, industry,
 

organized labor, public interest groups, State health officials, and
 

quasi-public health and research organizations. Members have been
 

selected on the basis of their experience in carcinogenesis or related
 

fields and, collectively, provide expertise in chemistry, biochemistry,
 

biostatistics, toxicology, pathology, and epidemiology. Representatives
 

of various Governmental agencies participate as ad hoc members. The
 

Data Evaluation/Risk Assessment Subgroup of the Clearinghouse is charged
 

with the responsibility of providing a peer review of reports prepared
 

on NCI-sponsored bioassays of chemicals studied for carcinogenicity. It
 

is in this .context that the below critique is given on the bioassay of
 

Dibenzo-p-Dioxin for carcinogenicity.
 

The primary reviewer agreed with the conclusion in the report that
 

Dibenzo-p-Dioxin was not carcinogenic in rats or mice, under the conditions
 

of test. After a brief description of the experimental design, he noted
 

the inadequate procedure by which the chronic dose levels were selected
 

and the poor survival among high dose treated female mice. Despite the
 

shortcomings, the primary reviewer said that the study still appeared to
 

be valid. Based on the results of the bioassay, he said that Dibenzo-p-
 Dioxin would not appear to pose a carcinogenic, risk to man.
 

The secondary reviewer agreed with the primary reviewer's critique.
 

A motion was approved unanimously that the report on the bioassay
 

of Dibenzo-p-Dioxin be accepted as written.
 

Members present were;
 

Arnold Brown (Chairman), University of Wisconsin School of Medicine
 

Joseph Highland, Environmental Defense Fund
 

.M-'~hael Shimkin, University of California at San Diego
 

Louise Strong, University of Texas Health Sciences Center
 

103
 
Subsequent to this review, changes may have been made in the bioassay
 

report either as a result of the review or other reasons. Thus,
 

certain comments and criticisms reflected in the review may no longer
 

be appropriate.
 

.S. GOVERNMEN T PRINTIN G OFFICE : 1978-281-217/3268
 

104
 

DHEW Publication No. (NIH) 79-1377