1979 

National Cancer Institute 

CARCINOGENESIS 

Technical Report Series 

NO. 123 

BIOASSAY OF 

2,7-DICHLORODIBENZO-p-DIOXIN (DCDD) 

FOR POSSIBLE CARCINOGENICITY 

CAS No. 33857-26-0 

NCI-CG-TR-123 

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

Public Health Service 

National Institutes of Health 

BIOASSAY OF
 

2,7-DICHLORODIBENZO-p-DIOXIN (DCDD)
 

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) 79-1378
 

BIOASSAY OF
 

2,7-DICHLORODIBENZO-p-DIOXIN (DCDD)
 

FOR POSSIBLE CARCINOGENICITY
 

Carcinogenesis Testing Program
 

Division of Cancer Cause and Prevention
 

National Cancer Institute
 

National Institutes of Health
 

FOREWORD; This report presents the results of the bioassay of
 

2,7-dichlorodibenzo-p-dioxin (DCDD) conducted for the
 

Carcinogenesis Testing Program, Division of Cancer Cause and
 

Prevention, National Cancer Institute (NCI), National Institutes
 

of Health, Bethesda, Maryland. This is one of a series of
 

experiments designed to determine whether selected chemicals have
 

the capacity to produce cancer in animals. A negative result, in
 

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

than control animals, does not necessarily mean that the test
 

chemical is not a carcinogen, inasmuch as the experiments are
 

conducted under a limited set of circumstances. A positive
 

result demonstrates that the test chemical is carcinogenic for
 

animals under the conditions of the test and indicates that
 

exposure to the chemical is a potential risk to man. The actual
 

determination of the risk to man from chemicals found to be
 

carcinogenic in animals requires a wider analysis.
 

CONTRIBUTORS; This bioassay of 2,7-dichlorodibenzo-p-dioxin
 

(DCDD) wasconducted by the Illinois Institute of Technology
 

Research Institute (lITRl) (1), Chicago, Illinois, initially
 

under direct contract to NCI (2) and currently under a
 

subcontract to Tracer Jitco., Inc. (3), 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.
 

ill
 
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. DePinto (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 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 were responsible for evaluating
 

the bioassay experiment, interpreting the results, and reporting
 

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

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

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

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

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

(1) 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 Environment Health
 

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

Carolina.
 

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

Maryland.
 

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

Rockville, Maryland.
 

iv
 
(6) Mathematical Statistics and Applied Mathematics Section,
 

Biometry Branch, Field Studies and Statistics, Division of
 

Cancer Cause and Prevention, National Cancer Institute,
 

National Institutes of Health, Bethesda, Maryland.
 

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

Missouri.
 

SUMMARY
 

A bioassay of 2,7-dichlorodibenzo-p-dioxin (DCDD) 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 DCDD at one of
 

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

50 mice of each sex were administered these same doses for 90
 

weeks. Controls consisted of 35 untreated rats of each sex and
 

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

killed at 110 to 112 weeks, all surviving female rats at 110 to
 

117 weeks, all surviving male mice at 92 to 101 weeks, and all
 

surviving female mice at 91 to 98 weeks.
 

Mean body weights of most of the dosed groups of rats and mice
 

were lower than those of corresponding controls both when placed
 

on study and for much of the study period; however, survival of
 

any group was not significantly affected by administration of the
 

test chemical. Sufficient numbers of dosed and control rats and
 

mice of each sex were at risk for the development of
 

late-appearing tumors.
 

No tumors were induced in male or female rats or female mice at
 

incidences that were significantly higher in the dosed groups
 

than in the corresponding control groups. Both low- and
 

high-dose rats had toxic hepatic lesions characterized by
 

centrilobular fatty metamorphosis and/or necrosis.
 

In the male mice, hepatocellular adenomas or carcinomas occurred
 

at incidences that were dose related (P = 0.008), and, in direct
 

comparisons, were higher in the low-dose group (P = 0.008) and
 

the high-dose group (P = 0.010) than in the control group
 

(controls 8/49, low-dose 20/50, high-dose 17/42). However, the
 

historical incidence of this lesion in control male B6C3F1 mice
 

at this laboratory does not permit a clear association of the
 

lesion with the administration of the test compound. There were
 

also significant increases in the incidence of combinations of
 

leukemias and lymphomas and of hemangiosarcomas and hemangiomas
 

in the low-dose male mice, but these findings were not supported
 

by the high-dose animals.
 

vii
 
It is concluded that under the conditions of this bioassay, DCDD
 

was not carcinogenic for Osborne-Mendel rats of either sex or for
 

female B6C3F1 mice. The marginal increased incidences of combinations of leukemias and lymphomas, of hemangiosar comas and
 

hemangiomas, and of hepatocellular carcinomas and adenomas in
 

male B3C3F1 mice are, however, considered as suggestive of a
 

carcinogenic effect of 2,7-dichlorodibenzo-p-dioxin in these
 

animals.
 

viii
 
TABLE OF CONTENTS
 

Page
 

I. Introduction 1
 

II. Materials and Methods 3
 

A. Chemical 3
 

B. Dietary Preparation 3
 

C. Animals 4
 

D. Animal Maintenance 5
 

E. Chronic Studies 6
 

F. Clinical and Pathologic Examinations 9
 

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) 21
 

D. Statistical Analyses of Results (Rats) 21
 

IV. Results - Mice 23
 

A. Body Weights and Clinical Signs (Mice) 23
 

B. Survival (Mice) 23
 

C. Pathology (Mice) 27
 

D. Statistical Analyses of Results (Mice) 28
 

V. Discussion 31
 

VI. Bibliography 35
 

APPENDIXES
 

Appendix A Summary of the Incidence of Neoplasms in Rats
 

Administered DCDD in the Diet 37
 

Table Al Summary of the Incidence of Neoplasms in Male
 

Rats Administered DCDD in the Die£ 39
 

Table A2 Summary of the Incidence of Neoplasms in Female
 

Rats Administered DCDD in the Diet 43
 

ix
 
Appendix B Summary of the Incidence of Neoplasms in Mice 

Administered DCDD in the Diet 47 

Table Bl Summary of the Incidence of Neoplasms in Male 

Mice Administered DCDD in the Diet 49 

Table B2 Summary of the Incidence of Neoplasms in Female 

Mice Administered DCDD in the Diet 52 

Appendix C Summary of the Incidence of Nonneoplastic 

Lesions in Rats Administered DCDD in the 

Diet 55 

Table Cl Summary of the Incidence of Nonneoplastic 

Lesions in Male Rats Administered DCDD 

in the Diet 57 

Table C2 Summary of the Incidence of Nonneoplastic 

Lesions in Female Rats Administered DCDD 

in the Diet 63 

Appendix D Summary of the Incidence of Nonneoplastic 

Lesions in Mice Administered DCDD in the 

Diet 69 

Table Dl Summary of the Incidence of Nonneoplastic 

Lesions in Male Mice Administered DCDD 

in the Diet 71 

Table D2 Summary of the Incidence of Nonneoplastic 

Lesions in Female Mice Administered DCDD 

in the Diet 74 

Appendix E Analyses of the Incidence of Primary Tumors 

in Rats Administered DCDD in the Diet 79 

Table El Analyses of the Incidence of Primary Tumors 

in Male Rats Administered DCDD in the Diet 81 

Table E2 Analyses of the Incidence of Primary Tumors 

in Female Rats Administered DCDD in the Diet 87 

Appendix F Analyses of the Incidence of Primary Tumors 

in Mice Administered DCDD in the Diet 93 
Table Fl Analyses of the Incidence of Primary Tumors 

in Male Mice Administered DCDD in the Diet 95 

Table F2 Analyses of the Incidence of Primary Tumors 

in Female Mice Administered DCDD in the Diet « 101 

TABLES 

Table 1 DCDD Chronic Feeding Studies in Rats 7 

Table 2 DCDD Chronic Feeding Studies in Mice 8 

FIGURES 

Figure 1 Growth Curves for Rats Administered 

DCDD in the Diet 18 

Figure 2 Survival Curves for Rats Administered 

DCDD in the Diet 19 

Figure 3 Growth Curves for Mice Administered 

DCDD in the Diet 24 

Figure 4 Survival Curves for Mice Administered 

DCDD in the Diet 26 

xi
 
X TT
I. INTRODUCTION
 

2,7-Dichlorodibenzo-p-dioxin (CAS
 

33857-26-0; NCI C03667), referred to in this report as DCDD, is
 

a chlorinated dibenzodioxin.
 

Chlorinated dibenzodioxins have
 

been found as by-products in the 27 — Dichlorodibenzo-p-dioxin
 

manufacture of pentachlorophenol
 

and in the herbicide 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and its esters. Pentachlorophenol is a microbicidal agent that is used as a wood preservative,
 

for slime control in herbicide formulations, and in the manufacture
 

of paper pulp; 2,4,5-T has been used as a herbicide on national
 

forests, rangelands, pastures, in the agricultural industry, and
 

as a component of Agent Orange, a wartime defoliant (Stecher,
 

1968; EPA, 1971; Crossland and Shea, 1973).
 

As a result of these applications, certain dibenzodioxins have
 

been dispersed in the environment where they are slowly degraded.
 

Laboratory experiments to test photodegradation indicate that
 

2,3,7,8-tetrachlorodibenzodioxin is degraded to 2,3,7-trichlorodibenzodioxin and DCDD; photodegradation occurs in organic
 
solvents, but not in aqueous suspensions or on wet or dry soil
 

(Crosby et al., 1971; Kearney et al., 1972).
 

In acute oral toxicity studies, doses of 1 to 2 g DCDD/kg did not
 

kill female rats (international Agency for Research on Cancer,
 

1977). Except for this information and that in a preliminary
 

report of the present bioassay (King et al., 1973), no other data
 

are available on the toxicity of DCDD. Studies on the acute and
 

subacute toxicities of the 2,3,7,8-tetrachloro-, hexachloro-, and
 

octachlorodibenzo-p-dioxin analogs of DCDD have shown that the
 

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

acute 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 and
 

Allen, 1977).
 

DCDD was selected for the Carcinogenesis Testing Program as one of
 

a series of chlorinated dibenzo-p-dioxins because some of these
 

compounds, due to their dispersion and persistence in the
 

environment, may have entered the food chain, causing long-term
 

human exposure.
 
II. MATERIALS AND METHODS
 

A. Chemical
 

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

Chemistry Division of IITRI. It was prepared by heating sodium
 

2,4-dichlorophenoxide with copper catalyst in bis(2-ethoxyethyl)ether at 180°C (Aniline, 1973).
 

The identity of the chemical was confirmed by mass spectrometry
 

and by comparison of gas chromatographic retention time with that
 

of an authentic sample obtained from Dr. David Firestone of the
 

Food and Drug Administration. Three impurities with peak areas 3
 

to 6% of the major peak were detected, all with longer retention
 

times. One of the impurities was identified by mass spectrome-ry
 

as a trichlorodibenzodioxin. No tetrachlorodibenzodioxin was
 

detected by mass spectrometry.
 

B. Dietary Preparation
 

Test diets were prepared by incorporating a known quantity of
 

DCDD into a 2-week supply of powdered Wayne® Sterilizable 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 in two individual batches of test diet
 

several months after preparation. Ninety percent of the expected
 

concentration was found at the 10,000 ppm level and 110% of the
 

expected concentration at 5,000 ppm.
 

C. Animals
 

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. All animals were obtained from Charles
 

River Breeding Laboratories, Inc., Wilmington, Massachusetts.
 

Rats and mice were received at the laboratory at approximately 4
 

weeks of age. They were placed in quarantine for 1 week. Those
 

animals with no visible signs of disease were earmarked and
 

assigned to dosed or control groups.
 
D. Animal Maintenance
 

The rats and mice were housed in rooms maintained at 22 to
 

23°C; the relative humidity ranged from 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.).
 

Control and dosed rats and mice were housed in groups of 4 and
 

10, respectively, in suspended polypropylene cages (Maryland
 

Plastics, Federalsburg, Maryland), which were covered with a wire
 

mesh screen and a polyester filter (Research Equipment Co., Inc.,
 

Bryan, Tex.). The bedding used in the cages was Absorb-dri
 

hardwood chips (Lab Products, Inc., Garfield, N. J.). Tap water
 

was made available ad 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 dosed animals received the same diets, to which was added the
 

test chemical. The diets were made 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 once per
 

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

Elizabeth, N. J.)
 

The racks were rotated in the test rooms once per month. The
 

rats and the mice were housed in separate rooms. The untreated
 

controls were housed in the same room with the dosed animals*
 

The animals fed DCDD were in the same room with the animals
 

administered the following test compounds:
 

Drinking Water Studies
 

(CAS 123-91-1) 1,4-dioxane
 

Feed Studies
 

(CAS 3268-87-9) 1,2,3,4,6,7,8,9-octachlorodibenzodioxin
 

(CAS 262-12-4) dibenzo-p-dioxin (UDD)
 

E. Chronic Studies
 

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

studies are shown in tables 1 and 2. Dosed and control male rats
 

originally placed on study died, due to a failure of the
 

air-conditioning system. The male groups in this report were
 

placed on study 1 year later than the female rats and male and
 
Table 1. DCDD Chronic Feeding Studies in Rats
 

Sex and
 

Test
 

Group
 

Male
 

Control (b)
 

Low-Dose
 

High-Dose
 

Female
 

Control (b)
 

Low-Dose
 

High-Dose
 

Initial
 

No. of
 

Animals (a)
 

35
 

35
 

35
 

35
 

35
 

35
 

DCDD
 

in Diet
 

(ppm)
 

0
 

5,000
 

10,000
 

0
 

5,000
 

10,000
 

Time on Study
 

Dosed Observed
 

(weeks ) (weeks)
 

110
 

110 1-2
 

110 1
 

116-117
 

110
 

110
 

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

(b) Male controls were started 4 weeks earlier than the dosed
 

male groups; female controls were started 17 weeks earlier
 

than the dosed female groups.
 
Table 2. DCDD Chronic Feeding Studies in Mice
 

Sex and
 

Test
 

Group
 

Male
 

Control (b)
 

Low-Dose
 

High-Dose
 

Female
 

Control (b)
 

Low-Dose
 

High-Dose
 

Initial DCDD
 

No. of in Diet
 

Animals (a) (ppm)
 

50 0
 

50 5,000
 

50 10,000
 

50 0
 

50 5,000
 

50 10,000
 

Time on Study
 

Dosed Observed
 

(weeks) (weeks)
 

90 2-3
 

90 10-11
 

90 9
 

90 1-2
 

90 2-3
 

90 8
 

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

(b) Controls were placed on study 16 weeks before the
 

dosed groups.
 
female mice. The doses were set at 5,000 and 10,000 ppm for both
 

species, based on the maximum dose levels permitted by NCI
 

protocols for administration of materials presumed to be
 

nontoxic. A subchronic study was not conducted. In an acute
 

oral LD study, DCDD in doses of 1 to 2 g/kg did not kill
 

female rats (IARC, 1977).
 

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 pentobarbital
 

and necropsied.
 

The tissues taken at necropsy 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.
 

Necropsies were also performed on all animals found dead, unless
 

precluded in whole or in part by autolysis or cannibalization.
 

Thus, the number of animals from which particular organs or
 

tissues were examined microscopically varies and does not
 

necessarily represent the number of animals that were placed on
 

study in each group.
 

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
 

10
 
techniques described in this section. Those analyses of the
 

experimental results that bear on the possibility of
 

carcinogenicity are discussed in the statistical narrative
 

sections.
 

Probabilities of survival were estimated by the product-limit
 

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

report in the form of graphs. Animals were statistically
 

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

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

causes were not statistically censored. Statistical analyses for
 

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

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

extensions of Cox'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
 

11
 
examination was required to detect lesions prior to histologic
 

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

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

denominators consist of the numbers of animals necropsied.
 

The purpose of the statistical analyses of tumor incidence is to
 

determine whether animals receiving the test chemical developed a
 

significantly higher proportion of tumors than did the control
 

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

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

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

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

compared simultaneously with those for a control group, a
 

correction to ensure an overall significance level of 0.05 may be
 

made. The 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
 

12
 
one-tailed 0.05 level of significance. Unless otherwise noted,
 

the direction of the significant trend is a positive dose
 

relationship. This method also provides a two-tailed test of
 

departure from linear trend.
 

A time-adjusted analysis was applied when numerous early deaths
 

resulted from causes that were not associated with the formation
 

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

first tumor was observed were excluded by basing the statistical
 

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

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

such an early tumor was found, comparisons were based exclusively
 

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

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

obtained, the standard procedures for analyses of the incidence
 

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;
 

13
 
Tarone's extension to testing for linear trend was used for three
 

groups. The statistical tests for the incidence of tumors which
 

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

noted, in the direction of a positive dose relationship.
 

Significant departures from linearity (P less than 0.05,
 

two-tailed test) were also noted.
 

The approximate 95 percent confidence interval for the relative
 

risk of each dosed group compared with its control was calculated
 

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

relative risk is defined as P../P where p is the true
 

binomial probability of the incidence of a specific type of tumor
 

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

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

group. The hypothesis of equality between the true proportion of
 

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
 

14
 
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
 

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

detected under the conditions of this test.
 

15
 
16

 
III. RESULTS - RATS
 

A. Body Weights and Clinical Signs (Rats)
 

Among male rats the mean body weights of both dosed groups were
 

lower than those of the corresponding controls at the time the
 

animals were placed on study and throughout the test period.
 

After week 50, mean body weights of dosed groups of female rats
 

were also lower than those of controls and were dose related
 

(figure 1). Fluctuation in the growth curves may be due to
 

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

weight may be subject to variation. 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 DCDD in the diet
 

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

controls, are shown in figure 2. In male rats, the dosed groups
 

were started on study 4 weeks after the control group, and in
 

females, the dosed groups were started 17 weeks after the
 

17
 
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500­ ° 0 D AAA 0°°°A A A^ A 

5 *

 A A A A

a < ° A A 

A A H 0 A Z a 0 400­ Ul

D °A A 5 

> 

O a OA 

§ 300­

Z A

Ul O 5 200 | MALE RATS 3

 A 

a CONTROL 

& o LOW DOSE j k 100­ A HIGH DOSE 

C 10 20 30 40 50 60 70 80 90 100 11 

TIME ON STUDY (WEEKS) 

700­

600­

500­

3 

tX 

2

Ul 400­ a 

a D ° D D a i 

5 to cP cf o o o 0 0 0 0 ( 

> 

O A Q /fl

D ^^

 $ A 

A A A X 2S ** AA A A A ^ 

g 300­

Z 

< n jo S] O 7\ *•** A " 

Ul 

S 

200­

(P A 

8 A 

FEMALE RATS 

[ I D CONTROL 

< t O LOW DOSE 

100­ A HIGH DOSE 

100 110 

TIME ON STUDY (WEEKS) 

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

18 
PROBABILITY OF SURVIVAL PROBABILITY OF SURVIVAL 

p p p p p 

I 

-> O D 

I o m N> a § s i 

8 i % 30 

..>"= 

O-J » I

CD 2! 

2 3 n. en ^ 

O 

o 

o 

3' 

<D 

p 

a 
controls; however, the Tarone test for dose-related trend in
 

mortality is applied as if the three groups of each sex were
 

started at the same time. The control and high-dose male rats
 

were terminated at 110 weeks while the low-dose males were
 

terminated at 112 weeks. In female rats, the differences in time
 

on study were more pronounced; the controls were terminated at
 

116 to 117 weeks, whereas the dosed groups were terminated at 110
 

weeks. All animals were censored at 110 weeks in the application
 

of the Cox and Tarone tests. The results of the Tarone tests are
 

not significant in either sex, although substantial mortality
 

occurred in the high-dose group from weeks 36 to 40 compared with
 

the other groups. The results of the Cox test comparing the
 

mortality of the control group with that of each dosed group also
 

are not significant in either sex.
 

In male rats, 29/35 (83%) of the high-dose animals, 26/35 (74%)
 

of the low-dose animals, and 30/35 (86%) of the controls were
 

still alive at week 78 on study. In females, 28/35 (80%) of the
 

high-dose animals, 30/35 (86%) of the low-dose animals, and 33/35
 

(94%) of the controls were still alive at week 78 on study.
 

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

risk for the development of late-appearing tumors.
 

20
 
C. Pathology (Rats)
 

Histopathologic findings on neoplasms in rats are summarized in
 

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

are summarized in Appendix C, tables Cl and C2.
 

A variety of tumors were observed in both the control and dosed
 

rats, each of which has been previously seen in untreated aging
 

Osborne-Mendel rats.
 

Both low- and high-dose rats had toxic hepatic lesions
 

characterized by centribolular fatty metamorphosis (33-48%)
 

and/or necrosis (6-20%). Other nonneoplastic lesions were of the
 

types usually seen in aged Osborne-Mendel rats.
 

Based on the histopathologic examination, DCDD was not
 

carcinogenic in Osborne-Mendel rats of each sex 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
 

21
 
least two animals of one group and at an incidence of at least 5%
 

in one or more than one group. In male rats, the control group
 

was started on study 4 weeks before the dosed groups, and in
 

females, the control group was started 17 weeks before the dosed
 

groups; however, the Cochran-Armitage test for dose-related trend
 

in the incidence of tumors is applied as if the three groups of
 

each sex were started at the same time.
 

The results of the Cochran-Armitage test and those of the Fisher
 

exact test are not significant in the positive direction in
 

either sex. Several significant results in the negative
 

direction are observed in each sex; in females, this may be due
 

to the earlier termination of the dosed groups compared with the
 

control group.
 

In all of the intervals shown in the tables, the value of one or
 

less than one is included; this indicates the absence of
 

significant positive results. It should also be noted that most
 

of the intervals have upper limits greater than one, indicating
 

the theoretical possibility of the induction of tumors by DCDD,
 

which could not be detected under the conditions of this test.
 

22
 
IV. RESULTS - MICE
 

A. Body Weights and Clinical Signs (Mice)
 

Among both male and female mice the mean body weights of both
 

dosed groups were lower than those of the corresponding controls
 

at the time the animals were placed on study. During the study,
 

mean body weights of dosed female mice were lower than those of
 

corresponding controls and were essentially the same in the low-


and high-dose groups (figure 3). Mean body weights of the male
 

mice were unaffected by administration of the test chemical.
 

Some fluctuation in the growth curves may be due to mortality; as
 

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

subject to variation. No clinical signs other than those of
 

lowered body weights in the dosed females were reported.
 

B. Survival (Mice)
 

The Kaplan and Meier curves estimating the probabilities of
 

survival for male and female mice administered DCDD in the diet
 

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

23
 
O D AA 8

o: an a o 

I 30 • D n 

Q D 

Q

O 

m 

2

°i, 

A

O A 

D

O

A

MALE MICE 

 CONTROL 

 LOW DOSE 

 HIGH DOSE 

40 50 60 70 

TIME ON STUDY (WEEKS) 

100 110 

Q D 

D D 

o a £ 

A 

A

O 

D D D D a D 

a

o

m D A

O 

o 

10­

FEMALE MICE 

O CONTROL 

O LOW DOSE 

A HIGH DOSE 

TIME ON STUDY (WEEKS) 

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

100 no 

24 
controls, are shown in figure 4. In each sex, the control group
 

was started on study 16 weeks before the dosed groups; however,
 

the Tarone test for dose-related trend in mortality is applied as
 

if the three groups of each sex were started at the same time.
 

There are substantial differences in the time on study for both
 

male and female groups. Control males were terminated at 92 to
 

93 weeks, while dosed males were terminated at 99 to 101 weeks.
 

Control and low-dose females were terminated at 91 to 93 weeks,
 

whereas the high-dose females were terminated at week 98. The
 

Cox and Tarone tests are applied only to the first 91 weeks on
 

study. The results of the Tarone test are not significant in
 

male mice but indicate a probability trend of P less than 0.001
 

in female mice.
 

In male mice, 38/50 (76%) of the high-dose animals, 36/50 (72%)
 

of the low-dose animals, and 48/50 (96%) of the controls lived to
 

the end of the study. In females, 28/50 (56%) of the high-dose
 

animals, 46/50 (92%) of the low-dose animals, and 45/50 (90%) of
 

the controls lived to the end of the study. Sufficient numbers
 

of dosed and control mice of each sex were at risk for the
 

development of late-appearing tumors.
 

25
 
PROBABILITY OF SURVIVAL

 PROBABILITY OF SURVIVAL 

S S S S S S S S S S S

 8

S 8 8 S S S S 

o • 1 o • 

j

rf 

(5* tn ' [> 0 C] — tn ' [

> 0 C —

 

to i

i

 s- o m 5 5 S S

 *» i 1 | S s 5 >

 o 5 am

 E </» 1

 0 g

 m

 0

m 2 

... . s . < 0 -

S- o— 

S 0

m m 

0 

c »• 

1i a ' 1 ._:m m

m 

S o O 

M 5' Z Z 

ON » 0) (O 

^^ O) 

i" 5 o

 

11 m

CD m m 

CA 

(ji ' i. s J

o 

,J 

0 

•r

0 

CK

1 T ?J 

=9 OJ

1 o•8J

 

CD 

0 

o^" 

S *

 g

01 
C. Pathology (Mice)
 

Histopathologic findings on neoplasms in mice are summarized in
 

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

are summarized in Appendix D, tables Dl and D2.
 

A variety of tumors were observed in both the control and dosed
 

mice, each of which has been previously seen in untreated aging
 

B6C3F1 mice.
 

The incidence of hepatocellular carcinomas in male mice was 4/49
 

(8%) in the controls, 5/50 (10%) in the low-dose group, and 5/42
 

(12%) in the high-dose group; the incidence of hepatocellular
 

adenomas was 4/49 (8%) in the controls, 15/50 (30%) in the
 

low-dose group, and 12/42 (29%) in the high-dose group. In
 

contrast, the female mice administered DCDD in the diet did not
 

respond with an increased incidence of either hepatocellular
 

neoplasm. Both male and female mice, however, showed increased
 

incidences of focal necrosis of the liver in the dosed groups.
 

Based on the pathology examination, exposure to DCDD may have
 

been associated with an increased incidence of liver tumors in
 

male B6C3F1 mice under the conditions of this bioassay.
 

27
 
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 16 weeks
 

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

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

the three groups of each sex were started at the same time.
 

In male mice, the result of the Cochran-Armitage test for the
 

incidence of animals with either hepatocellular adenomas or
 

carcinomas is significant (P = 0.008). The Fisher exact
 

comparisons of the incidence in the control group with those in
 

the low- and high-dose groups show P values of 0.008 and 0.010,
 

respectively. In the current historical records at this
 

laboratory the incidence of such liver tumors in control groups
 

is 32/125 (26%), with individual group incidences of 8/49 (16%),
 

9/25(36%), and two groups with 7/25 (28%), compared with 17/42
 

(40%) in the high-dose group and 20/50 (40%) in the low-dose
 

group of this study.
 

28
 
The result of the Fisher exact test comparing the incidence of 

animals with either lymphoma or leukemia of the hematopoietic 

system in the low-dose male mice with that of the control group 

is significant (P = 0.006), but a significant incidence is not 

indicated in the high-dose group. The result of the 

Cochran-Armitage test for this incidence of tumors is not 

significant. 

In the incidence of male mice with either hemangiosarcomas or 

hemangiomas of all sites, the Fisher exact comparison of the 

incidences in the low-dose and control groups shows a P value of 

0.028, which is above the 0.025 level required for significance 

when the Bonferroni inequality criterion is used for multiple 

comparison. The high-dose group does not have a significant 

incidence. The result of the Cochran-Armitage test for this 

incidence of tumors is not significant. 

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

those of the Fisher exact test for tumor incidence at any site 

are not significant. A significant trend in the negative 

direction is observed in the incidence of squamous-cell 

papillomas of the stomach in male mice. 

29 
In some of the intervals shown in the tables, the value of one or
 

less than one is included; this indicates the absence of
 

significant positive results. It should also be noted that each
 

of the intervals (except that for the incidence of 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 DCDD, which could not be detected under the
 

conditions of this test.
 

30
 
V. DISCUSSION
 

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

mice were lower than those of the corresponding controls at the
 

time the animals were placed on study. While the mean body
 

weights of the dosed male rats remained lower than those of their
 

corresponding controls throughout the study, the mean body
 

weights of the dosed female rats were lower than their
 

corresponding controls only after week 50. Mean body weights of
 

the dosed female, but not the male, mice were lowered throughout
 

the study. The survival in any of the dosed groups, however, was
 

not significantly affected by administration of the test
 

chemical. In the mice the tests for difference in survival were
 

applied only to the first 91 weeks on study since control males
 

were terminated at 92 to 93 weeks, while dosed males were
 

terminated at 99 to 101 weeks. Control and low-dose females were
 

terminated at 91 to 93 weeks, whereas the high-dose females were
 

terminated at week 98.
 

No tumors were induced in male or female rats or female mice at
 

incidences that were significantly higher in the dosed groups
 

than in the corresponding control groups.
 

31
 
In the male mice, hepatocellular adenomas or carcinomas occurred
 

at incidences that in direct comparisons were higher in the
 

low-dose group (P = 0.008) and the high-dose group (P = 0.010)
 

than in the control group (controls 8/49, low-dose 20/50,
 

high-dose 17/42). In recent findings at this laboratory the
 

incidence of such liver tumors in control groups is 32/125 (26%),
 

with individual group incidences of 8/49 (16%), 9/25 (36%), and
 

two groups with 7/25 (28%), compared with 17/42 (40%) in the
 

high-dose group and 20/50 (40%) in the low-dose group in this
 

study. The occurrence of increased incidences of hepatocellular
 

adenomas or carcinomas in the dosed groups of male mice cannot,
 

therefore, be clearly related to the administration of the test
 

chemical.
 

Leukemias or lymphomas occurred in the male mice at incidences
 

that were significant (P = 0.006) in a direct comparison of the
 

low-dose and control groups. Similarly, hemangiosarcomas or
 

hemangiomas at all sites occurred in male mice at incidences that
 

were significant (P = 0.028) in a direct comparison of the
 

low-dose and control groups. However, the incidences of these
 

hematopoietic tumors or vascular tumors did not show dose-related
 

trends and were not higher in high-dose groups than in
 

corresponding control groups. Thus, the occurrence of these
 

32
 
tumors in the dosed groups of male mice cannot be clearly related
 

to administration of the test chemical.
 

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

reported to be highly toxic when tested in Sherman rats (Schwetz
 

et al., 1973) and to be carcinogenic in Sprague-Dawley rats (Van
 

Miller et al., 1977), DCDD was observed in the present bioassay
 

to have a relatively low toxicity for Osborne-Mendel rats and
 

B6C3F1 mice. The necrosis observed in both rats and mice and the
 

fatty metamorphosis observed in the rats administered DCDD is
 

similar, however, 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 DCDD
 

was not carcinogenic for Osborne-Mendel rats of either sex or for
 

female B6C3F1 mice. The marginal increased incidences of
 

combinations of leukemias and lymphomas, of hemangiosarcomas and
 

hemangiomas, and of hepatocellular carcinomas and adenomas in
 

male B6C3F1 mice is considered as suggestive of a carcinogenic
 

effect of 2,7-dichlorodibenzo-p-dioxin in these animals.
 

33
 
34

 
VI. BIBLIOGRAPHY
 

Aniline, 0., Preparation of chlorodibenzo-p-dioxins for
 

toxicological evaluation. In: Chlorodioxins - Origin and Fate,
 

Advances vn Chemistry Series 120, Blair, E., ed., American
 

Chemical Society, Washington, D.C., 1973, pp. 126-135.
 

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

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

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

Panel £f_ Carcinogenicity o_f the Cancer Research Commission of 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 o£ 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 173;
 

748-749, 1971.
 

Cross land, J. and Shea, K. P., The hazards of impurities,
 

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

Environmental Protection Agency, EPA Compendium £f Registered
 

Pesticides, Environmental Protection Agency, Washington, D.C.,
 

1971, pp. I-T-28, I-D-29.1, I-D-29.7.
 

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

significance tests, confidence limits and adjustments for
 

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

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

Risk o£ Chemicals to Man; Some Fumigants, the Herbicides 2,4-D
 

and 2,4,5-T, Chlorinated Dibenzodioxins 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. ~
 

35
 
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.
 

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_:230-2U8, 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.
 

Stecher, P. G., ed., The Merck Index, Merck & Co., Inc., Rahway,
 

N.J., 1968, p. 792.
 

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

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

Van Miller, J. P. and Allen, J. R., Chronic toxicity of 2,3,7,8­

tetrachlorodibenzo-p-dioxin in rats. Fed. Proc. 36(3); 396, 1977.
 

36
 
APPENDIX A
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

RATS ADMINISTERED DCDD IN THE DIET
 

37
 
38

 
TABLE A1. 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE RATS 

ADMINISTERED DCDD IN THE DIET 

CONTROL LOW DOSE HIGH DOSE 

ANIMALS

ANIMAL S

ANIMALS

 INITIALLY IN STUEY

 NECROPSIED

 EXAMINED HISIOPATHOLOGICALLY

 35

 34

 33

 35

 35

 34

 35 

 34 

 33 

INTEGUMENTAR Y SYSTEM 

*SUBCUT TISSUE

FIBROM A

FIEROSAFCOM A

LIFOMA

 (34)

 3

 1

 (9») 

(3%) 

 (35)

 1 (3X) 

 (34) 

RESPIRATOR Y SYSTEM 

*LUNG

ALVECLAR/BRONCHIOLA R JDENOM A

ALVF.OLAR/BRONCHIOLAR CARCINCMA

CORTIOL CARCINOMA , METASTATIC

 (30)

 1 (3%) 

 (34)

 1 (3X) 

 (33) 

1 (3*) 

HEHATOPOIETIC SYSTEM 

*BRAIN

MALIGNAN T RETICULOSIS

 (31) (34)

 1 (3X) 

 (31) 

*MULTI£LE ORGAN S

MALIG.LYBPHOMA ,

 (34)

 tfNDIFFER-TYPE

 (35)

 1 (3X) 

 (34) 

tSPLEEN

SARCCMA, NOS

HEMANGIOSARCOMA

 (31)

 1 (3«) 

 (34)

 2 (6X) 

 (32) 

CIRCULATOR Y SYSTEM 

NCNE 

DIGESTIVE SYSTEM 

tLIVER

HEFATOCgLLULAE ADENOM A

 (31)

 L_L3X1 

 (34) (33) 

» NUMBER

* NUMBER

 OF ANIMAL S

 OF ANIMALS

 KITH TISSUE

 NECROPSIED 

 EXAMINE D MICROSCOPICALLY 

39 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

HEFATOCELLULA R CARCINOM A 

*STCMACH 

LEICKYCSARCOM A 

URINAR Y SYSTEM 

&KIDNE Y 

LIFCSAFCOMA 

MIXE D TUMOR , MALIGNAN T 

ENDOCFIN E SYSTEM 

frPITUITAP Y 

ADINCMA , NOS 

CHROMOPHOBE ADENOM A 

tAERENA L 

COFTICAL ADENOM A 

CORTICAL CARCINOMA 

PHECCHFOMOCYTOM A 

tTHYRCI E 

FAFILLAF Y ADENOCARCINO M A 

FOLIICULAR-CELL ADENOMA 

FOLLICULAR-CEL L CARCINOM A 

C-CELL ADENOM A 

IPARATHYROI D 

ADENCMA , NOS 

tFANCFEATI C ISLETS 

ISLEt-CELL ADENOM A 

REPRODUCTIV E SYSTE M 

NON E 

NERVCU S SYSTEM 

NONE 

SPECIAL SENSE ORGAN S 

_NCNE 

t NUMBE R OF ANIMAL S WITH TISSUE

* NUMBE R OF ANIMALS NECROPSIED 

CONTROL LOW DOSE 

(31) (34) 

(31) (34) 

1 (3X> 

1 (3S) 

(16) (22) 

2 (13%) 

1 (6%) 

(31) (34) 

7 (23%) 4 (12%) 

1 (3») 

6 (19%) 2 ((>%) 

(29) (34) 

2 (7*) 

1 (3%) 1 (3«) 

3 (10S) 3 (9*) 

(25) (24) 

2 (8%) 

(24) (33) 

1 (4%) 1 (3«) 

 EXAMINE D MICROSCOPICALLY 

HIGH DOSE 

1 (3%) 

(33) 

1 (3% ) 

(33) 

(17) 

1 (6«) 

(32) 

2 (6%) 

1 (3%) 

(32) 

1 (3«) 

(26) 

(29) 

40 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

MUSCULOSKELETAL SYSTEM 

NON E 

BOCY CAVITIES 

*ABDOHINAL CAVITY (34) (35) (34)

 

FIBFCSAFCOMA , HETASTATIC 1 (3%) 

*TUNICA VAGINALIS (34) (35) (34)

 

MESCTHELIOHA, NOS 2 (6X)

 

A LL OTHER SYSTEMS 

ADIPOSE TISSUE 

LIECM A 

ANIMAI EISPCSITION SUMMARY
 

ANIMAIS INITIALLY IN STUDY 35 35 35
 

NA1UFAI DEATHS 20 20 26
 

MOFIBUND SACRIFICE 3 1
 

**SCHEDUIED SACRIFICE 1
 

ACCIDENTALLY KILLEC
 

TEFMINAL SACRIFICE 11
 

ANIHAl MISSING
 

* NUMBER OF ANIMALS HITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 **
 

Animals are in fact early terminal sacrifices, but appear
 

as scheduled sacrifices due to system interpretation.
 

41
 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE
 

TUMOR SUMMARY
 

ICIAL ANIMALS WZTH PRIMARY TUMORS* 21 14 6
 

TOTAL PRIMARY TOMOES 37 18 7
 

TOTA1 ANIHALS WITH BENIGN TUMORS 17 10 3
 

TOTAL BFNIGN TUMORS 30 11 3
 

TOTAL ANIBALS WITH MALIGNAN3 TUBORS 5 7 4
 

TOTAL MALIGNANT TUMORS 5 7 4
 

TOTAL ANIMALS WITH SECONDARY TUHORS* 1 1
 

TOTAL SECONDARY TUMORS 1 1
 

TOTAL ANIMALS KITH TUMORS UNCERTAINBENIGN OE MALIGNANT 2
 

TOTAL UNCERTAIN TUMORS 2
 

TOTAL ANIMALS WITH TUMORS UNCERTAINEBIBABY OP METASTATIC
 

TOTAL UNCERTAIN TUMORS
 

* PFIMARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 

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

42
 
TABLE A2. 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS 

ADMINISTERED DCDD IN THE DIET 

CONTROL LOW DOSE HIGH DOSE 

ANIMAL S

ANIMALS

ANIMAL S

 INITIALLY IN STUDY

 KECFOPSIED

 EXAMINE D HISTOPATHOLOGICALLY

 35

 35

 31

 35

 33

 33

 35 

 33 

 30 

INTEGUMENTARY SYSTEM 

*SK1N


FIBEOMA


LEIOMYOSARCOMA. METASTATIC


*SUBCUT TISSUE

F1EROMA

FIBROSARCOMA

RESPIRATOR Y SYSTEM 

*NASA L CAVITY

SQOtMOUS CELL CARCINOMA


HEMATOPOIETIC SYSTEM
 

ISPLEEN

HEMANGIOMA

CIRCULA1CPY SYSTEM 

NONE 

DIGESTIVE SYSTEM 

#EANCBEA S 

LEICMYOSARCOMA, INVASIVE
 

#S10MACK
 

PAPILLOBA, NOS
 

 (35)

 (35)

 1 (3%) 

1 (3X) 

 (33)

 1

 (33)

 (3X) 

 (33) 

1 (3X) 

 (33) 

 (35) (33) (33) 

1 (3%) 

 (30) (33) (29) 

1 (3%) 

(29) 

(31) 

(32) 

(33) 

(26) 

1 (H%) 

* NUMBEE OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBEE OF ANIMALS NECEOPSIED
 

43
 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

LEICKYCSA&COMA 

USINAP , Y SYSTEM 

#K1DNE Y 

FIBFCSAFCOMA, METASTATIC 

ENDOCRIN E SYSTEM 

#FIT(JITAB Y 

ChFCMOPHOB E ADENOM A 

#ADHENA L 

COETICA L ADENOM A 

(flhYFOI D 

FOIIICULAE-CELL CAECINOM A 

C-CEIL ADENOM A 

CYSTADENOMA , NOS 

#THYPCir FOLLICLE 

CYS1ADENOMA , NOS 

#FANCBEATIC'ISLET S 

ISLIT-CELL ADENOM A 

ISLIT-CFLL CAPCJNOM A 

RtPEODUCTIV E SYSIEM 

*MAMMAR Y GLAN D 

ADENCMA , NO S 

ADENCCARCINOMA , NO S 

FIEFC M A 

FIEFOADENOM A 

tUTIEU S 

ADENCCAPCINOMA , NOS 

PAPIILAF Y CYSTADENCMA , NO S 

LEICMYOSAECOMA 

#OVAE Y 

GEANULOSA-CEL L TUBO F 

* NUM6EF , OF ANIMAL S BITH TISSUE

* NUMBE F OF ANIMALS NECEOPSIED 

(12*) 

(21*) 

(6*) 

(38) 

(3%) 

(15%) 

(3X) 

(3*) 

(21*) 

<6*) 

1 

(30) 

(20) 

7 

(29)

9 

(25) 

2 

(25) 

(26) 

(33) 

4 

(30) 

1 

(26) 

(«*) 

(358) 

(318) 

(88) 

(128) 

(38) 

(31) 

1 (3%) 

(18) 

H

(30) 

11

(28) 

4

(28) 

2

(29) 

1

(35) 

(22%) 

(31%) 

 (148) 

 (7*) 

 (3*) 

3 (9%) 

1 (3*) 

1 (3S) 

13 (37%) 

(30) 

1 (3%) 

1 (3*) 

(26) 

(33) 

(25) 

3 

(33; 

7 

(32) 

2 

1 

(32) 

(32) 

1 

(33) 

5 

1 

1 

7 

(32) 

(31) 

2 

 EXAMINE D MJCEOSCOPJCALLY 

44 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED) 

TUEOLA R ADENOM A

NERVOU S SYSTEM 

NCN E 

SPECIAL SENSE ORGAN S 

*HARDERIA N GLAN D

ADENCCARCINOHA , NOS

BUSCULOSKELETA L SYSTEM 

NONE 

BODY CAVITIES 

*ABDO«INA L WALL

FIBF.OSAECOBA

ALL OTHER SYSTEMS 

NON E 

ANIMA L E1SP05ITION S'lMKAR Y 

ANIMAL S INITIALLY IN STUD Y

NATURA L DEATHS

NORIEUN D SACRIFICE 

**SCHEEULED SACRIFICE

ACCIDENTALLY KILLED 

TERMINA L SACRIFICE

ANIC.AL MISSING 

a>_IKCLUDES AUIQLYZED_ANIHAL £ 

CONTROL LOW DOSE HIGH DOSE 

1 (4S) 1 (3») 

 (35) (33) (33) 

1 (3X ) 

 (35) (33) (33) 

1 (3%) 

 35 35 35 

 14 10 14 

1 

4 1 

 17 25 19 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

Animals are in fact early terminal sacrifices, but appear
 

as scheduled sacrifices due to system interpretation.
 

45
 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

TUMOR SUMMARY
 

TOTAL ANIMALS WITH PRIMARY TUMORS* 26 22 16
 

TOTAL FPIMAEY TUMOES i*7 32 27
 

TOTAL ANIMALS HITH BENIGN TUMCES 2« 19 15
 

TOTAL BENIGN TUMORS U2 26 22
 

TOTAL ANIMALS HITH MALIGNANT TUMORS 5 U 5
 

TOTJL MALIGNANT TUMORS 5 U 5
 

TOTAL ANIMALS HITH SECONDARY TUMORS* 1 2
 

TOTAL SECONDARY TUM08S 1 2
 

TOTAL ANIHALS HITH TUMORS UNCERTAINBENIGN OR MALIGNANT 2
 

TOTAL UNCERTAIN TUMOFS 2
 

TOTAL ANIMALS HITH TUMOES UNCERTAINFKIHAEY OR METASTATIC
 

TOTAL UNCERTAIN TUMORS
 

* PRIMARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 

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

46 
APPENDIX B
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

MICE ADMINISTERED DCDD IN THE DIET
 

47
 

TABLE B1. 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE MICE 

ADMINISTERED DCDD IN THE DIET 

CONTROL LOW DOSE HIGH DOSE 

ANIMAL S INITIAL!! IN STCDY 50 50 50 

ANIMALS NECROPSIED 50 50 45 

ANIMAL S EXAMINE D HISTOPATHOLOGICALLY 4 9 50 45 

INIEGUMENTRF Y SYSTEM 

*SKIN (50) (50) (45) 

PAPILLOMA, NOS 1 (2%) 

HEMANGIOSARCOMA, METASTATIC 1 (2%) 

*SUBCUI TISSUE (50) (50) (45)
 

SEEACEOUS ADENOMA 1 (2*)
 

LEICMYOSAECOMA 1 (2%)
 

RESPIRATORY SYSTEM
 

»LUNG (49) (49 ) (44) 

ALVEOLAR/BRONCHIOLAR ADENOMA 8 (16S) 2 (4%) 5 (11%) 

ALVECLAE/BRONCHIOLAR CARCINOMA 3 (6X) 

tiEKATOPOIETIC SYSTEM 

*MULTIFLE ORGANS (50) (50) (45) 

MALIG.LYMPHOMA , ON EIFF ER-1YPE 1 (2%) 

MALIG.IYMPHOMA, HISTIOCYTIC TYPE 2 (4S) 2 (4%) 

UNDIFFERENTIATE D LEUKEMI A 1 (2%) 1 (2% ) 

MONOCYTI C LEUKEHI A 1 (2%) 

MAST-CEIL LEUKEMI A 1 (2X) 

#SPLEE N (48) (48) (43) 

HEUANGIOM A 1 (2%) 

hEMANGIOSARCOM A 4 (8X) 1 (2*) 

tMESENTEPIC L. NODE (1) (42) (36)

 

MALIG.LYMPhOMA , HISTIOCYTIC TYPE 1 (2% )

 

CIBCULA1CF Y SYSTEM 

NON E 

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

* NUMBE F OJ ANIMAL S NECROPSIED 

49 
TABLE B1. MALE MICE: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

DIGESTIV E SYSTEM 

#L1VEF (50) (U2) 

HEFATOCELLULAR ADENOHA 4 (8X) 15 (30*) 12 (29%) 

HEPATOCELLULAR CARCINOMA 4 (8*) 5 (1C*) 5 (12X) 

HEMANGIOSARCOMA 1 (2%) 

HEMJNGIOSARCOMA, METASTATIC 1 (2*) 

*EILE DUCT (49) (50) (<J2) 

BILi DUCT CARCINOMA 1 (2%)

 

#STCMACH (49) (47) (43)

 

SQUAMCUS CELL PAPILIOMA 5 (1C*)

 

ICCLON (37) (36) 

ADENCCAECINOMA , NOS 1 (3*) 

URINAR Y SYSTEM 

NON E 

ENECCRIN S SYSTEM 

#IHYEOIC (39) (43) (43)
 

PAFILLABY ADENOMA 1 (2*)
 

PAPILLARY CYSTADENCMA, NOS 1 (3X)
 

HEPRODUCTIVE SYSTEM
 

NONE
 

NEBVCUS SYSTEM
 

NONE
 

SPECIAL SENSE ORGANS
 

*HARDERIAN Gi-ANl) (50) (50) (45)
 

PAFILLAFY ADENOMA 1 (2X)
 

MUSCULCSKELETAL SYSTEM
 

_NONE
 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUBBEE OF ANIMALS NECROPSIED
 

50
 
TABLE B1. MALE MICE: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

BOCY CAVITIES 

NONE 

ALL OTHER SYSTEMS 

NCN E 

ANIMAL riSPOSITION SUMMARY
 

ANIMALS INITIALLY IN STUDY 50 50 50 

NATURAL DEATHS 5 11 

MORIEUND SACRIFICE 9 1 

SCHEDULED SACRIFICE 

ACCIDENTALLY KILLED 

TERMINAL SACRIFICE 36 38 

ANIMAL MISSING 

d INCLUDES AUTOLYZED ANIMALS
 

TUMCF SUHMAFY 

TOTAL ANIMALS WITH PRIMARY TU

TOTAL PRIMARY TUMORS 

MORS* 19 

26 

30 

HO 

25 

27 

TOTAL ANIMALS WITH BENIGN TUM

TOTAL BENIGN TUMORS 

ORS 17 

20 

19 

19 

17 

18 

TOTAL ANIMALS WITH MALIGNANT 

TOTAL MALIGNANT TUMORS 

UMORS 17 

21 

TOTAL ANIMALS WITH SECONDARY TUMORS* 1
 

TOTAL SECONDARY TUMORS 2
 

TOTA1 ANIMALS WITH TUMORS UNCERTAINBENIGN OR MALIGNANT
 

TOTAL UNCERTAIN TUMORS
 

TOTAL ANIMALS WITH TUMORS UNCHBTAISEFIMAEY OF METASTATIC
 

TOTA1 UNCERTAIN TUMORS
 

* PRIMARY TUMOHS: ALL TUMORS EXCEPT SECONDARY TUMORS
 

f SECONDARY TUMORS: METASTA1IC TUMORS OK TUMORS INVASIVE INTO AN ADJACENT ORGAN
 

51
 
TABLE B2.

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE MICE 

ADMINISTERED DCDD IN THE DIET 

CONTROL LOW DOSE HIGH DOSE 

ANIMAL S INITIALLY IN SIUDY 50 50 50 

ANIMALS NECPOPSIED 50 49 48 

ANIMALS EXAMINED HISTOFATHOIOGICALLY 50 49 48 

INTEGUMENTAR Y SYSTEM 

*SKIN (50) (49) (48)
 

SQDABOUS CELL CARCINOMA 1 (2%)
 

FIERCSARCOMA 1 (2*)
 

FIBROUS HISTIOCYTOMA, MALIGNANT 1 (2%)
 

HEM8NGIOMA 1 (2%)
 

*SOBCUT TISSUE (50) (49) (48)
 

FIEROSARCOMA 1 (2%)
 

RESPIRATORY SYSTEM
 

tLUNG (50) (47) (47) 

ALVECLAR/BfiONCHIOLAE ADENOM A 3 (6X) 2 (U%) 

HEHATOFCIETIC SYSTEM 

*MUITIF1E ORGAN S (50) (49) (48) 

BALIGNANT LYMPHOMA , NOS 4 (8X) 1 (2%) 

MALIG.LYBPHOBA, LYMPHOCYTIC TYPE 1 (2*) 

MALIG.LYMPHOMA , HISTIOCYTIC TYPE 2 (4S) 7 (14%) 3 (6%) 

LYMPHOCYTIC LEUKEMI A 2 (4*) 

GRANULOCYTIC LEUKEMIA 1 (2%) 

*SPIEF.N (50) (48) (46) 

HEBANGIOSAECOMA 1 <2X ) 

tLYBP H NODE (5) (37) (37)

 

HEMANGIOSARCOMA , METASTA1IC 1 (20«)

 

CIRCULATOR Y SYSTEM 

NOJE 

# NUMBE R OF ANIMALS WIT H TISSUE EXAMINE D MICROSCOPICALLY * NUMBE B Of ANIMALS NECEOPSIED 

52 
TABLE B2. FEMALE MICE: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

DIGESTIVE SYSTEM 

tLIVER (50) (48) (HI) 

HEEATOCFLLULAB CARCINOM A 1 (2%) 

• S1CHACH (48) (48) (39)
 

EAPIILCBA, NOS 2 (4X) 1 (3*)
 

PAPIILCMATOSIS 1 (2%)
 

SQUAHOOS CELL PAPILLOMA 1 (2*)
 

URINARY SYSTEM
 

tUF.INARY BLADDER (2) (36) (34)
 

PAPIILCHATOSIS 2 (100%)
 

iNDOCRINE SYSTEM
 

•PARATHYROID	 (20) (25) (29)
 

ADENOCAECINOMA, NOS 1 (3%)
 ____.____*—_____ _ — _ -. ——-».^^.^_ _ ___ ^^.^-^-~^^.~.^ __^.w.^^^.^_^ ^^___ _^_ .^^^_^_.^^-_^ ^._^ _-.-^^ _...-• 

REPFODOC1IVE SYSTEM 

*VAGIN A (50) (49) (48) 

HEMANGIOSARCOM A 1 (2X) 

tDlEROS (49) (46) (45) 

IEICMYCKA 1 (2X) 

tCVAR Y (20) (43) (41) 

LUTECM A 1 (2X) 

NERVOU S SYSTEM 

NONE 

SPECIAL SENSE ORGAN S 

NOSE 

BUSCULOSKEIFTA L SYSTEM 

NCN E 

* NUMBEF OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 * NUMBEF OF ANIMALS NECFOPSIED
 

53
 
TABLE B2. FEMALE MICE: NEOPLASMS (CONTINUEO) 

CONTROL LOW DOSE HIGH DOSE 

BODY CAVITIES 

*FERITCNEUM (50) (49) (48)

 

LYNFHANGIOM A 1 12%)

 

*ABEOMINA L VISCERA (50) (49) (48) 

NEOPIASM, NOS 1 12%)

 

ALL OTHER SYSTEMS 

NON E 

ANIMAL DISPOSITION SUMMARY
 

ANIHALS INITIALLY IN STUDY 50 50 50
 

NATURAL DEATH3) 5 4 10
 

MORIEUND SACRIFICE 12
 

SCHEDULED SACRIFICE 

ACCIDENTALLY KILLED 

TERMINA L SACRIFICE 45 46 28 

ANIMAL MISSING 

INCLUDES AUTOLYZE D ANIMAL S 

TUMCB SUMMARY
 

10TAL ANIMALS WITH PRIMARY TUMORS* 14 18 9
 

TOTAL PRIMARY TUMORS 15 19 12
 

TOTAL ANIMALS WITH BENIGN TUMORS 7 6 3
 

TOTAL BENIGN TUMORS 7 6 3
 

TOTAL ANIMALS WITH MALIGNANT TUMORS 8 12 8
 

TOTAL MALIGNANT TUMORS 8 12 9
 

TOTAL ANIMALS WITH SECONDARY TUMORSt 1
 

TOTAL SECONDARY TUMORS 1
 

TOTAL ANIMALS WITH TUMORS UNC1RTAINBENIGN OF MALIGNANT 1
 

TOTAL UNCERTAIN TUMORS 1
 

TOTAL ANIMALS WITH TUMORS UNCIRTAINEFIMAFY OR METASTATIC
 

TOTAL UNCERTAIN TUMORS
 

* PRIMARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 

# SECONDARY TUMORS: ME1ASTATIC TUMORS OR TUMORS INVASIVE INTO AN ADJACENT ORGAN
 

54
 
APPENDIX C
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS
 

IN RATS ADMINISTERED DCDD IN THE DIET
 

55
 
56

 
TABLE C1.

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE RATS 

ADMINISTERED DCDD IN THE DIET 

CONTROL LOW DOSE HIGH DOSE 

ANIMALS INITIALLY IN STUDY 35 35 35
 

ANIMALS NECEOPSIED 34 35 34
 

ANIMALS EXAMINED HISTOPATHOLOGICALLY 33 34 33
 

INTEGUMENTAR Y SYSTEM 

*SKIN (34) (35) C34)
 

SEEACEOOS CYST 1 (3X)
 

*SUBCUI TISSUE (34) (35) (34)
 

GRANULOMA , NOS 1 (3X)
 

EESPIRATORY SYSTEM
 

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

INFLAMMATION, CHRONIC 7 (20%) 1C (29X) 

INFLAMMATION, CHRONIC SUPP0BATIV 3 (9X) 

*NASAL TUFBINATE (34) (35) (34)

 

INFIAHMATION, ACUTE 5 (15X)
 

INFL4HMATION, ACUTE SUPPURATIVE 6 (18X)
 

INFLAMMATION, CHRONIC 2 (6X)
 

tTRACHEA (30) (34) (33) 

INFLAMMATION , ACUTE- SUFFURATIVE 1 (3X) 

INFLAMMATION, CHRONIC 7 (23X) 10 (29X) 9 (27X) 

INFLAHMATION , CHRONIC SUPPURATIV 2 (7X) 1 (3X) 1 (3X) 

ILUNG/BPONCHIOLE (30) (34) (33) 

HYPEEPLASIA, FOCAL 1 (3X) 

*LUNG (30) (34) (33) 

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

EDEMA, NOS 1 (3X) 

EEONCHOPNEUHONIA, NOS 1 (3X) 1 (3X) 

PNEUMONIA, CHRONIC MURIN E 8 (21%) 22 (65X) 21 (64X) 

INFLAMMATION,. CHRONIC 1 t3X) 

« NUMBER OF ANIHALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBE F OF ANIMALS NECROPSIED 

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

HIGH DOSE
 

(31)
 

(32)
 

1 (3X)
 

3 (9*)
 

2 (6*)
 

3 (9*)
 

2 (6X)
 

3 (9*)
 

(32)
 

(28)
 

(28)
 

(28)
 

2 (7*)
 

(28)
 

(25)
 

(33)
 

1 (3*)
 

1 (3*)
 

(33)
 

l_J3*i_
 

HEMATOECIETIC SYSTEM
 

*BONE HARROW
 

ATRCEHY, NOS
 

HYPEPPLAiilA, HEMATOPOIETIC
 

tSPLEEK
 

INFAFCT HEHORRHAGIC
 

HEKOSIDFROSIS
 

ATPOPHY, NOS
 

EEPLH1ION
 

LYMPHOID DEPLETIOH
 

HYPEEPIASXA, HEMATOPOIETIC
 

HYPF.EPLASIA, ERYTHROID
 

HEMATOPOIESIS
 

*SPLENIC FOLLICLES
 

ATFCEHY, NOS
 

•LYMPH	 NODE
 

INFLAMMATION, CHPONIC
 

tMANDIBULAR L. NODE
 

HYFEEPLASIA, LYBPHOID
 

*CEEVICAL LYMPH NODE
 

INFIAHKATION, CHRONIC
 

HYPEFPLASIA, NOS
 

•BRONCHIAL LYMPH NOD!
 

HEMCEEHAGE
 

t TH YB D £
 

ATRCPHY, NOS
 

CIBCOLA1CEY SYSTEM
 

tMYOCAEDIUH
 

INF1AHMATION, CHRONIC
 

INFLAMMATION, CHRONIC FOCAL
 

INFIAHBATION. CHRONIC DIFFUSE
 

•ENDOCARDIUM
 

DEGENERATION. MDCOID
 

CONTROL
 

(31)
 

a (13*)
 

(31)
 

3 (10%)
 

3 (10X)
 

(31)
 

1 (3*)
 

(22}
 

(22)
 

5 (23%)
 

(22)
 

(22)
 

1 (5»)
 

0)
 

3 (100*)
 

(30)
 

H (13*)
 

(30)
 

LOW DOSE
 

(34)
 

1 (3*)
 

(34)
 

2 (6*)
 

« (12*)
 

1 (3*)
 

1 (3*)
 

(34)
 

(22)
 

1 (5*)
 

(22)
 

(22)
 

1 (5*)
 

(22)
 

(")
 

(34)
 

4 (12*)
 

1 (3*)
 

(34)
 

1 (3*)
 

* NOMBEE OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBE F OF ANIMAL S NECROPSIED 

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

 

CONTROL LOW DOSE HIGH DOSE
 

* AORTA (34) (35) (34)
 

MINERALIZATION 1 (3%) 2 (6»)
 

*PULMCKARY ABTERY (34) (35) (34)
 

CALCIFICATION, DYSTROPHIC 1 (3%)
 

DIGESTIVE SYSTEM
 

#LIVER (31) (34) (33)
 

CYST. NOS 1 (3X)
 

CONGESTION, CHRONIC PASSIVE 1 (3X)
 

ABSCESS, NOS 1 (3X)
 

CIRRHOSIS, CARDIAC 1 (3*)
 

METAMORPHOSIS FATTY 2 (6X)
 

FOCAL CELLULAR CHANGE 1 (3X) 1 (3X)
 

HYPEEPLASIA, NOS 5 (16*)
 

ANGIECTASIS 1 (3X)
 

*LIVEP/CENTRILOBULAR (31) (34) (33)
 

CONGESTION, NOS 1 (3*) 1 (3*)
 

NECROSIS, NOS 2 (6X) 2 (6%)
 

METAMORPHOSIS FATTY 13 (38X) 16 (48X)
 

#BILE CUCl (31) (34) (33)
 

CYST, NOS 2 (6X)
 

HYPERPLASIA, NOS 8 (26X)
 

* PANCREAS (24) (33) (29)
 

FEEIARTERITIS 1 (4S) 4 (12*) 1 (3X)
 

#EANCFEATIC ACINUS (24) (33) (29)
 

ATRCEHY, NOS 1 (3X)
 

ATROPHY, FOCAL 2 (7X)
 

tSTCMACH (31) (34) (33)
 

DIVEETICULUH 1 (3X)
 

INFLAMMATION, CHRONIC 1 (3X)
 

ACANTHOSiS 1 (3%)
 

IGASTRIC SUBMUCOSA (31) (34) (33)
 

MINERALIZATION 1 (3X)
 

*ANUS (34) (35) (34)
 

INFLAMMATION. NECROTIZING 1 (3*)
 

* BOMBER OF ANIMALS HI1H TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NFCROPSIED
 

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

CONTROL LOW DOSE 

URINAE Y SYSTEM 

• KIDNE Y (31) (34) 

CAST, NOS 

HYDFONEPHfiOSIS 1 (3X) 

PYELONEPHRITIS , NOS 

INFLAMMATION , INTERSTITIAL 2 (6X) 

INFLAMMATION , CHRONIC 23 (74X) 

PYELONEPHRITIS, CHRONIC 1 (3X) 

NEPHROPATH Y 21 (62X) 

#KIDNEY/TUBOL E (31) (34) 

DILATATION, NOS 1 (3*) 

CAST, NOS 1 (3X) 

HEMORRHAG E 

#KIDNEY/FELVIS (31) (34)

 

HEMCERHAG E 

HYPZRPLfSIA , EPITHELIAL 

#UEINAB Y BLADDER (28) (32) 

INFLJMKATION, SUPFUBATIVE 

INFLAMMATION , CHRONIC 2 (7X) 

INFLAMMATION , CHRONIC SOPPORATIV 1 (3X) 

HYPEPPLASIA, EPITHELIAL 

ENDOCRIN E SYSTEM 

*P1TUITAR Y (16) (22)

 

CYST, NOS 2 (13X)

 

tADEENA L (31) (34) 

CONGESTION, NOS 1 (3X) 

LIPOIDOSIS 2 (6X) 

HYPERPLASIA, FOCAL 1 (3X) 

ANGIECTASIS 1 (3X) 

tACRENA L CORTEX (31) (34)

 

LIFCIDOSIS 11 (35X)

 

tTHYRCID (29) (34)

 

CYST, NOS 

GOITER COLLOID 

# NOMBEP OF ANIMALS WITH TISSUE EXAHINED BICHOSCOPICALLI 

* NUMBE E OF ANIMAL S NECROPSIED 

HIGH DOSE 

(33) 

1 (3X) 

1 (3X) 

5 (15X) 

1 (3%) 

2 (6X) 

(33) 

2 (6%) 

2 (6X) 

1 (3X) 

(33) 

1 (3X) 

3 (9X) 

(27) 

1 (4X) 

1 (4X) 

1 (4X) 

(17) 

(32) 

3 (9X) 

1 (3X) 

(32) 

(32) 

1 (3X) 

1 (3X) 

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

CONTROL LOW DOSE
 

HYEIFFLASIA, FOCAL
 

tEARAThYPOID (25) (24)
 

HYFEKPLASIA, NOS 4 (16X) 1 (4%)
 

REPKODUCTIVE SYSTEM 

*EENIS 

INFLAMMATION, CHROUIC SOPPURATIV 

(34) (35) 

1 (3%) 

IEHOSTATE 

INFLAMMATION, SUPPURATIVE 

INFLAMMATION, ACUTE 

INFLAMMATION, CHRONIC 

INFLAMMATION, CHRONIC SOPFORATIV 

(29) 

2

t

 (7X) 

 (T**) 

(31) 

1

1

 (3*) 

 (3X) 

*SEMINAL VESICLE 

DILATATION, NOS 

INFLAMMATION, SUPPOPATIVE 

ABSCESS, NOS 

INFLAMMATION, CHRONIC 

INFLAMMATION, CHRONIC SUPPORATIV 

ATROPHY, NOS 

HYPERPLASIA, EPITHELIAL 

(3>4) 

1

1

 (3%) 

 (3%) 

(35) 

1

1

1

 (3%) 

 (3X) 

 (3%) 

#TESTIS 

ABSCISS, NOS 

PERIARTEKITIS 

ATPCPHY, NOS 

ATROPHY, FOCAL 

ASP J.FMJTOGENESIS 

(32) 

1

2

9

1

 (3X) 

 (6X) 

 (28X) 

 (3%) 

(33) 

9 (27%) 

ITESTIS/TUBULE 

MINERALIZATION 

(32) (33) 

1 (3%) 

tSEERMAlOGENIC EPITHE 

ATPCEHY, NOS 

(32) (33) 

*£PIDICYMIS 

GRANULOMA, SPERMATIC 

(3<«) (35) 

1 (3%) 

*MUSCULAPIS OF VAS DE 

MINERALIZATION 

(34) (35) 

1 (3X) 

NERVOUS SYSTEM
 

. . NOKE ... „ _ „. _ .
 

* NUMEE5 OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBIE OF ANIMALS NECROPSIEE
 

HIGH DOSE
 

1 (3X)
 

(26)
 

(34)
 

(27)
 

1 (4S)
 

(34)
 

1 (3X)
 

1 (3%)
 

(33)
 

10	 (3C%)
 

1 (3%)
 

(33)
 

1 (3«)
 

(33)
 

1 (3»)
 

(34)
 

(34)
 

61
 
TABLE C1. MALE RATS: NONNEOPLASTIC

SPECIA L SENSi ORGAN S 

*ZYMBAI' S GLAN D

HiPEFPLASIA, CYSTIC

MUSCCJLOSKELEXA L SYSTEM 

"JOINT OF SRISI

INFLAMMATION , CHRONIC

BODY CAVITIES 

*AEDOHINA L CAVIT Y

FEBIAETFRITI S

*MESENTFPY

PEEIAETERITIS

ALL OTHEF SYSTEMS 

NCN E 

SPECIAL COPPHOLOGY SUMBAtY 

AUTO/NECEOtSY/HISTO PE8F

AUTC/NECROPSY/NO HISTO

ADTCLYSIS/NO NECROPSY

 LESIONS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

 (34) (35) (34) 

1 (3*) 

 (34) (35) (34) 

1 (3%) 

 (34) (35) (34) 

1 (38) 

 (34) (35) (34) 

1 (3X) 

1 

1 1 1 

1 1 

62 
TABLE C2.

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE RATS 

ADMINISTERED DCDD IN THE DIET 

CONTROL LOW DOSE 

ANIHALS INITIALLY IB STUDY 35 35
 

ANIMALS NECROPSIED 35 33
 ANIHALS EXAMINED HI STO PATHOLOGIC ALLY 31 33
 

INTEGUMENTAF Y SYSTEM 

*SKIN (35) (33) 

ULCER, NOS 1 (3*) 

HYPERKEPATOSIS 

ACANTHOSIS 

*SUBCUT TISSUE (35) (33) 

GPANDLOMA , FOREIGN BODY 1 (3X) 

RESPIRATORY SYSTEM 

*NASAL CAVITY

INFLAMMATION. SUPPURATIVE 

INFLAMMATION, HEMOREHAGIC 

INFLAMMATION, CHRONIC 

INFLAMMATION, CHRONIC DIFFUSE 

INFLAMMATION, CHRONIC SUPPURATIV 

INFLAMMATION PROLIFE8ATIVE 

 (35) (33) 

1

1

2

1

3

 (3X) 

 (3X) 

 (6X) 

 (3») 

 (9X) 

*NASAL TUEBINATE

INFLAMMATION, ACUTE

INFLAMMATION, ACUTE SUPPURATIVE

 (35) 

1 (3*) 

1 (3«) 

(33) 

tTRACHEA

INFLAMMATION, NOS

INFLAMMATION, SUPPUEAIIVE 

INFLJHHATION, ACUTE SUPPUEiTIVE

INFLAMMATION, CHRONIC 

INFLAMMATION PROLIFERATIVE 

 (29) 

5 (17«) 

1 (3») 

(33) 

1

9

3

 (3%) 

 (27%) 

 (9X) 

•LUN G

CONGESTION, NOS

EPQNCHOPNEUMQNIA , N9S 

 (30) 

2 (7%) 

(33) 

3 (9%) 

t NUMBER OF ANIMALS HITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

HIGH DOSE 

35
 

33
 

30
 

(33)
 

3 (9X)
 

3 (9X)
 

(33)
 

(33)
 

1 (3X)
 

1 (3%)
 

(33)
 

(29)
 

1 (3X)
 

6 (21X)
 

(28)
 

3
 

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

CONTROL LOW DOSE HIGH D 

INFLAMMATION, INTERSTITIAL 1 (3«) 

INFLABMATION, ACUTE SUPPURATIVF. 1 (3*) 

ABSCESS, NOS 1 (3X) 2 

PNEUMONIA , CHRONIC BURIN E 6 (20X) M4 («2X) 10 

PNEUMONIA INTERSTITIAL CHRONIC 1 

GEANULOMA , NOS 1 (3X) 

HEMATOPCIETIC SYSTEM 

#EONE MARROW (31) (32) (26) 

HYFIRPIASIA, HEMATOPOIETIC <* (13X) 

#SFLEEN (30) (33) (29) 

INFLAMMATION , ACUTE 1* (13X) 

INFLAMMATION , CHRONIC 1 (3X) 

HEMOSIDEROSIS 2 <7X) 5 (15*) 2 

ATROPHY, NOS 1 (3X) 

DEPLETION 2 

LYMPHOID DEPLETION 3 (9*) 

HEBATOPOIESIS 6 (20X) 3 (9X) 3 

#MANDIEULA R L. NODE (25) (25) (25) 

HEBCFRHAGIC CYST 1 («*) INFLAMMATION, ACUTE 1 («) 

PLASMA-CELL INFILTRATE 3 (12*) 

HYPERPLASIA, LYHPHOID 5 (20X) 

•CERVICAL LYMPH NODE (25) (25) (25) 

INFLAMMATION, CHRONIC 3 (12X) 

HYPERPLASIA , LYMPHOI D 1 (4X) 

#MESENTFRIC L. NODE (25) (25) (25) 

HYFJRPIASIA, LYMPHOID 1 (IX) 

f THYMUE (9) (D

 

CYS1, NOS 2 (22X)

 

ATROPHY, NOS 9 (100X)

 

CIRCULATOR Y SYSTEM 

tHEART (31) (29) (30) 

CALCIFICATION, DYSTSOPHIC 1 (3X) 

IMYOCABDIUM (31) (29) (30) 

FIDEOSIS, FOCAL 1 (3X) 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECFOPSIED
 

OSE 

(7X)

(36*) 

(«*) 

(7*) 

(7*) 

(10X) 

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

CONTROL LOW DOSE HIGH DOSE 

#ENDOCAPDIUM (31) (29) (30)
 

INFLAMMATION WITH FIBROSIS 1 (3%)
 

DEGENERATION, MUCOID 1 (3%)
 

*AORTA (35) (33) (33)
 

MEDIAL CALCIFICATION 1 (3%)
 

*MESENTEPIC ARTERY (35) (33) (33)
 

THROMBOSIS, NOS 1 (3%)
 

INFLAMMATION, CHRONIC 1 (3%)
 

DIGESTIVE SYSTEM
 

*IIV2R (31) (33) (30)
 

CONGESTION, NOS 1 (3%)
 

CIRRHOSIS, NOS 1 (3%)
 

NECROSIS, NOS 1 (3%) 1 (3%)
 

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

METAMOPFHOSIS FATTY 6 (18%) 10 (33%)
 

L1PCIDOSIS 2 16%)
 

HYPERPLASIA, NODULAR 1 (3%)
 

HYPIRPLASIA, NOS 7 (23%)
 

HEMATOPOIESIS 1 (3%) 2 (6%) 1 (3%)
 

*LIVER/CENTRILOBULAR (31) (33) (30)
 

NECFCSIS, NOS 2 (6%) 6 (20%)
 

METAMORPHOSIS FATTY 1 (3%) 13 (39%) 10 (33%)
 

»BILE EOCT (31) (33) (30)
 

DILATATION, NOS 1 (3%)
 

CYSI, NOS 2 (6%) 1 (3%)
 

INFLAMMATION, CHRONIC 1 (3%)
 

HYPERPLJSIA, NOS 13 (42%)
 

tFANCRHAS (29) (32) (26)
 

INFLAMMATION WITH FIBROSIS 1 (3%)
 

PERIART58ITIS 2 (8%)
 

tPANCFEATIC DUCT (29) (32) (26)
 

HYPERPLASIA, NOS 3 (10%)
 

#EANCEEATIC ACINUS (29) (32) (26)
 

ATROPHY, NOS 1 (3%) 1 (4%)
 

* NUMBE R OF ANIMALS WIT H TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBER OF ANIMALS NECPOPSIED 

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

HIGH DOSE 

(27) 

(27) 

(25) 

1 <««> 

(30) 

7 (23 X) 

1 (3X) 

1 (3X) 

9 (30*) 

1 (3X) 

(30) 

(30) 

7 (23X) 

(23) 

(20) 

(29) 

#STCflACH 

CALCIFICATION,

IGASTEIC MUCOSA 

CALCIFICATION,

tCECOH 

ULCER, NOS 

U8INAKY SYSTEM 

*KIDNEY 

MI NEFA LIZ ATI ON 

CAST, NOS 

CYST, NOS 

HEMOEEBAGE 

PYELONEPHRITIS,

 DJSTROPHIC 

 NOS 

 HOSINFLAMHATION, INTERSTITIAI 

PYELONEPHRITIS, ACUTE 

INFLAMMATION, CHRONIC 

NEPHROPATHY 

*KIDNEY/MFDULLA 

HINEPAIIZATION 

#KIENEY/TOBOt£ 

CIIATATION, NOS 

CAST, NOS 

CYST, NOS 

tURINAF Y BLADDER 

INFLAMMATION, NOS 

INFLAMMATION, HEHOfiRHAGIC 

INFLAMMATION, ACHTF. 

ENDOCRINE SYSTifl 

#PITUITAKY 

CYS1, NOS 

COLLOID CYST 

HEMOFPHAGIC CYST 

tADRENAL 

HEMCFRHAGIC CYST 

# NUMBEF OF ANIMALS BITE TISSUE

* NUMBEE OF ANIMALS NECEOPSIED 

CONTROL 

(31) 

1 (3*) 

(31) 

(19) 

(31) 

17 (55%) 

1 <3X) 

1 (3*) 

5 (16X) 

(31) 

1 <3X) 

(31) 

4 (13*) 

(25) 

1 («X) 

1 (i»X) 

(18) 

3 (17X) 

(30) 

LOW DOSE 

(33) 

(33) 

1 (3X) 

(27) 

(33) 

9 (27X) 

5 (15X) 

(33) 

(33) 

12 (36X) 

3 (9X) 

(29) 

1 (3X) 

(25) 

1 (<*X) 

1 (4X) 

(33) 

1 f3XJ 

 EXAMINED MICROSCOPICALLY 

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

CONTROL LOW DOSE HIGH DOSE 

LIFCIDOSIS 2 (6X) 

ANGIECTASIS 8 (27X) 

tADBENAL COBTEX (30) (33) (29)

 

LIPCIDCSIS 9 (30%)

 

HYPERPLASIA, NOS 1 (3X) 

*THYPCIC (28) (32) (25) 

CYSTIC FOLLICLES 1 (4%) 

FOL1ICHLAR CYST, NOS 1 C*X) HYPERPLASIi, C-CELL 3 (11X) 1 (OX) 

EEPRODOCTIVE SYSTEM 0 

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

ABSCISS, NOS 1 (3X) 

tOTERUS (30) (32) (30) 

EYCMFTB A 1 (3X) 1 (3X) 

INFLAMMATION, ACUTE 2 (7X) 

IUTERUS/ENDONETRIUM (30) (32) (30) 

CYS1, NOS 2 (7X) 

INFLAMMATION, ACUTE 2 (7X) 

HYPF.RPLASIA, NOS 1 (3X) 

IOVAR Y (26) (31) (26)

 

CYSTIC FOLLICLES 1 (US) 

FOL1ICULAS CYST. NOS 1 (4X) 1 (3X)

 

NERVOU S SYSTEM 

NON E 

SPECIAL SENSE ORGANS 

*EYE (35) (33) (33)

 

INFLAMMATION , ACUTE 2 (6X)

 

CATARACT 1 (3X)

 

*EYE/CCRNEA (35) (33) (33) 

INFLAMMATION , ACUTE 1 <3X) 

# NUMBER OF ANIMALS WIIH TISSUE EXAMINED MICROSCOPICALLY
 * NUKBEB OF ANIMALS NECPOPSIED
 

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

*EYE/RETINA
 

INFLAMMATION, NOS
 

*EYE/LACEIMAL GLAND
 

INFLAMMATION, ACUTE SUPFURA1IVE
 

*HARDF.EIAN GLAND
 

ABSCESS, NOS
 

MUSCULOSKELETAL SYSTEM
 

*SKELETAL MUSCLE
 

GEANULOMA, FOPEIGN BODY
 

BODY CAVITIES
 

*ABDOMINAI WALL
 

INFLAMMATION, CHRONIC
 

*PEEITCNEUPl 

INFLAMMATION , CHRONIC 

*«ESENTEFY 

PEEIAETEEITIS 

ALL OTHIP SY3TEHS 

NONE 

SPECIAL HOFPHOLOGY SDMMAEY 

CONTROL LOW DOSE HIGH DOSE 

(35) (33) (33) 

21 (60S) 

(35) (33) (33) 

1 (3X) 

(35) (33) (33) 

1 (3*) 

(35) (33) (33) 

(35) (33) (33) 

1 <3X) 

(35) (33) (33) 

1 (3*) 

(35) (33) (33) 

1 (3») 

68 
APPENDIX D
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS
 

IN MICE ADMINISTERED DCDD IN THE DIET
 

69
 
70

 
TABLE 01.

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE MICE 

ADMINISTERED

ANIBALS INITIALLY IN STOEY

4NIBALS NECROPSISD

ANIMALS EXAHINED HISTOPATHOLOGICALLY

INTEGUMENTAR Y SYSTEM 

NONE 

RESPIRATORY SYSTEM 

tLUNG

CONGESTION, NOS

INFLAMMATION , NOS

INF OHM AT ION, INTERSTITIAL 

HYPIRPLASIA, ALVEOLAR EPITHELIU M

HEBATOPOIETIC SYSTEM 

*ELOOD CFLLS

LEOKCCYTOSIS, NOS 

•BONE MAFRCW

HYPERPLASIA , GKANOLOCYTIC 

tSfLEE N

DEPLETION 

HYPEPPLASIA, LYMPHOI D 

HEMJTOP01ESIS 

fMESENTERIC L. NODE

HYPJRPLJSIA , NOS

HYPEEPLASIA , LYMPHOI D

CIRCULATOR Y SYSTEM 

*AORTA

INPLABMAIION, CHRONIC 

 DCDD IN THE DIET 

CONTROL

 50

 50

 49

 (49)

 1 (2%) 

1 (2X)

 (50)

 (48)

 (48)

 (1)

 (50)

 LOW DOSE HI6H D 

 50 50 

 50 45 

 50 45 

 (49) (44) 

1 (2*) 1 

2 

1 (2%) 

 (50) (45) 

1 

 (43) (39) 

1 

 (48) (43) 

2 

2 

1 

 (42) (36) 

2 (5X) 

2 (5X) 5 

 (50) (45) 

1 

OSE 

(2%) 

(5X) 

(2X) 

(3«) 

(5*) 

<5X ) 

(2X) 

(14%) 

12X1 

f	 NUMBER OF ANIMALS HITH TISSOE EXAMINED MICROSCOPICALLY
 * NUMBER OF ANIMALS NECECFSIED
 

71
 
TABLE 01. MALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

*CORONAF Y ?RTEK Y

INFLAMMATION , CHRONIC

 (50) (50) (45) 

1 (2%) 

DIGESTIVE SYSTEM 

#L1VEK

NECFCSIS, FOCAL

HYPEPPLASIA , NODULAR

HEMATOP01BSIS

 (US) (50)

 1 (2*)

 (42) 

2

 2

 1

 (5*) 

 (5«) 

(2%) 

#EANCBEA S

ABSCESS, NOS

 (42) (48) (40) 

1 (3») 

*EEYEE£ PATCH

HYEEFPUSIA , LYMPHOI D

 (5) (45)

 1 (2X)

 (39) 

2 (5X) 

URINAR Y SYSTEM 

tKIDNEY

INF1AHKATION, INTE8STITIAL

PYELONEPHRITIS SUPPURATIVE

 (49) (48)

 1 (2J) 

 (42) 

1 (2%) 

4UR1NAFY BLADDER

INFLAMMATION, CHRONIC

 (47)

 1 (2X)

 (37) 

1 (3X) 

ENDOCRINE SYSTEM 

NONE 

REFECDDCTIVE SYSTEM 

*EEEPD1IAL GLAND

DILATATION, NOS

CYST, NOS

INFLAMMATION, CHRONIC SUPPURATIV

 (50)

 1 (2S) 

1 (2%)

 (50)

 1 (2*)

 (45) 

1 (2%) 

1 (2X) 

tIESTIS

GRANULOMA, SPERMATIC

ATROPHY, FOCAL

 (49)

 1 (2X) 

 (49)

 1 (2%) 

 (44) 

NERVOUS SYSTEM 

NCNE , 

* NUMBEF OF ANIMALS WI1H TISSUE EXAMINED MICROSCOPICALLY 

* NUMBEF OF ANIMALS NECROPSIED 

72
 
TABLE 01. MALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

SPECIAL SENSE ORGAN S 

*HARDEBIA N GLAN D

HYPERPIASIA, PAPILLARY

 (50) (50)

 1 (2«) 

 (45) 

HUSCULOSKELETAL SYSTEM 

NONE 

BODY CAVITIES 

*PERITCNEUM

INFIAMBflTION ,

INFLAHMATION,

 CHRONIC

 CHRONIC

 FOCAL

 DIFFUSE

 (50J (50)

 1 (2%) 

 (45) 

1 (2%) 

ALL OTHER

NONE 

 SYSTEMS 

SPECIAL MORPHOLOGY SUBHAR Y 

NO LESION REPORTE D

AUTC/NECROPSY/HISTO PERF

 26 15 8 

1 

73 
TABLE 02. 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE MICE 

ADMINISTERED DCDD IN THE DIET 

CONTROL LOW DOSE HIGH DOSE 

ANIHAL S INITIALLY IN STODY 50 50 50 

ANIMAL S NECFOPSIED 50 49 48 

ANIMALS EXAMINED HISTOPATHOLOGICALLY 50 49 48 

INTEGUMENTAP Y SYSTEM 

NONE 

RESFIRATCPY SYSTEM 

#LUNG (50) (47) (47) 

INFLAMMATION , NOS 2 (4X) 

INFLAMMATION , INTERSTITIAL 1 (2%) 

INFLAMMATION , ACUTE/CHRCNIC 1 (2S) 

HYPEBPLASIA, ALVEOLAE EPITHELIUM 1 (2%) 1 (2%) 

HEMATOPCIETIC SYSTEM 

#£ONE MAKRO H (48) (47) (38)
 

HYFEEPLAS1A , HEMATOPOIETIC 

»SPLEFN (50) (48) (46) 

HEWCSIDEBOSIS 3 (7*) 

LYMPHOID DEPLETION 

HYPERPLASIA, LYMPHOID 6 (12*) 5 (11X) 

MASTCCYTOSIS 1 (2«) 

HEMATOPOJESIS 1 (2%) 1 (2%) 

#1YMPH NODE (5) (37) (37)
 

HYFEEPLASIA, LYMPHOID 1 (20X)
 

#MESENirKIC L. NODE (5) (37) (37) 

EDF.KA, NOS 1 (3S) 1 (3X) 

INFLAMMATION , ACUTE/CHRONIC 1 (3%) 

HYPERPIASIA, LYHPHOID 2 (5*) 3 (8X) 

flTHYMUS (5) d)

 

H YF JFP LA SI A.__ LYMPHOID 3 f60XJ

 

# NUMBEE OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBEE OF AN1HALS NECPOPSIED
 
TABLE 02. FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

CIRC0LATORY SYSTEM 

NONE 

DIGESTIVE SYSTEM 

#SALIVm GLAN D (43) 

INFLAMMATION, CHRONIC FOCAL 1 (2X) 

*LIVEE (50) (48) 

HEHATOMA, NOS 

INFLAMMATION, DIFFUSE 

HEPATITIS, TOXIC 

PELIOSIS HEPATIS 

NECROSIS, FOCAL 

METAMORPHOSIS FATTY 

CALCIFICATION, FOCAL 1 (2X) 

HEGALOCYTOSIS 

HYPEFPLASIA, NOS 1 (2%) 

HEMATOPOIESIS 5 (10X) 

•LIVER/HEPATOCYTES (50) (48) 

NECBCSIS, NOS 1 (2X) 

*FANCBEAS (26) (45) 

DILATATION/DUCTS 1 (4X) 1 (2X) 

f STOMACH

INFIAHBATION, CHRONIC

HIPEFPLASIA, FOCAL 

 FOCAL 

 (48) (48) 

1 (2%) 

2 (4X) 

tEEYERS PATCH (1) (44) 

HYFEBPIASIA, LYMPHOID 2 (5X) 

URINAR Y SYSTEM 

iKIDNEY (50) (47) 

LYMEHOCYTIC INFLAMMATORY INFILTR 2 (4X) 

INFLAMMATION , INTERSTITIAL 

tKIDNEY/GLOMEEULOS (50) (47) 

AHYICIDOSIS 1 (2%) 

ENDOCRIN E SYSTEM 

NONE 

* NUMBE R OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBEf i OF ANIMALS NECROPSIEE 

(38) 

(47) 

1

1

1

1

10

1

1

5

(47) 

(44) 

1

(39) 

(36) 

2

(47) 

6

(47) 

 (2*) 

 (2X) 

 (2X) 

 (2X) 

 (21X) 

 (2X) 

 (2X) 

 (11X) 

 (2X) 

 (6X) 

 (13X) 

75 
TABLE 02. FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE

REPFGDUCTIVF SYSTEM 

*CLJTCFIS (50) (49)


INFLAMMATION, CHRONIC SUPPUR4IIV


#U1ERUS (49) (46)


HYCECHETRA 4 (8%)
 

ATRCPHY, NQS


*UTERUS/ENDOMETRIDM (49) (46)


HYPEFPLASIA, DIFFUSE 1 (2%)
 

HYPERP1ASIA, CYSTIC 48 (9855) 20 (43X)


#07ARY (20) (43)


CYST, NOS 5 (25%)
 

FOLIIC0LAR CYST, NOS 5 (25X) 1 (2%)


ABSCFSS, NOS 2 (5X)


NERVOUS SYSTEM
 

NCNE
 

SPECIAL SENSE ORGANS
 

NONE
 

MUSCULCSKELETAL SYSTEM
 

NONE
 

BODY CAVITIES
 

*PERITCNEOM (50) (49)


JNFLAMHATION, CBRONIC


INFLAMMATION, CHRONIC FOCAL


ALL OTHER SYSTEMS
 

ADIPOSE TISSUE
 

LIfCGEANOLOMA 1
 

t NOMBEf OF ANIMALS KITH TISSUE EXAMINED MICROSCOPICALLY
 * NUBBEE OF ANIMALS NECROPSIED
 

 HIGH DOSE 

 (48)
 

1 (2%)
 

 (45)
 

1 (2%)
 

 (45)
 

 10 (22%)
 

 (41)
 

6 (1531)
 

3 (7«)
 

 (48)
 

1 (2%)
 

1 (2%)
 

76
 
TABLE D2. FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

SPECIAL MORPHOLOG Y SUMMAR Y 

NO IF.SION REPORTE D

AUTC/NFCROPSY/HISTO PEBF

AUICLYSIS/JiO NECROPSY

 1 10

 1

 10 

1 

2 

t SUHBE B OF ANIMAL S WIT H TISSUE

* NUBBEE OF ANIMALS NECROPSIED 

 EXAMINE D MICROSCOPICALL Y 

77 
78

 
APPENDIX E
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS
 

IN RATS ADMINISTERED DCDD IN THE DIET
 

79
 
80

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

Administered DCDD in the Diet (a)
 

Low
 

Topography; Morphology Control Dose
 

Integumentary System: Fibroma
 

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

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

Relative Risk (f) 0.000
 

Lower Limit 0.000
 

Upper Limit 1.594
 

Weeks to First Observed Tumor 96
 

oo
 

Spleen: Hemangios arcoma (b) 0/31 (0) 2/34 (6) 

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

Relative Risk (f) Infinite

 

Lower Limit 0.274 

Upper Limit Infinite

 

Weeks to First Observed Tumor 112
 

High
 

Dose
 

0/34 (0)
 

N.S.
 

0.000
 

0.000
 

1.639
 

0/32 (0) 

— 

— 

— 

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

Administered DCDD in the Diet (a)
 

(continued)
 

Low
 

Topography; Morphology Control Dose
 

Adrenal: Cortical Adenoma or
 

Carcinoma (b) 7/31 (23) 5/34 (15)
 

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

Relative Risk (f) 0.651
 

Lower Limit 0.182
 

Upper Limit 2.133
 

Weeks to First Observed Tumor 91 104
 

oo
 

Adrenal: Pheo ch romo cy toma (b) 6/31 (19) 2/34 (6)
 

P Values (c,d) P = 0.006 (N) N.S.
 

Relative Risk (f) 0.304
 

Lower Limit 0.032
 

Upper Limit 1.554
 

Weeks to First Observed Tumor 86 104
 

High
 

Dose
 

3/32 (9)
 

N.S.
 

0.415
 

0.076
 

1.638
 

109
 

0/32 (0)
 

P = 0.011 (N)
 

0.000
 

0.000
 

0.593
 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats
 

Administered DCDD in the Diet (a)
 

(continued)
 

Topography: Morphology


Thyroid: Follicular-cell Adenoma
 

or Carcinoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


oo
 

Thryoid: Papillary Adenocarcinoma,
 

Follicular-cell Adenoma, or
 

Follicular-cell Carcinoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


 Control
 

 3/29 (10)
 

P = 0.048 (N)
 

 97
 

 3/29 (10)
 

 N.S.
 

 97


Low
 

Dose
 

1/34 (3)
 

N.S.
 

0.284
 

0.006
 

3.321
 

77
 

1/34 (3)
 

N.S.
 

0.284
 

0.006
 

3.321
 

 77


High
 

Dose
 

0/32 (0)
 

N.S.
 

0.000
 

0.000
 

1.480
 

—
 

1/32 (3)
 

N.S.
 

0.302
 

0.006
 

3.518
 

 101 
00 

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

Administered DCDD in the Diet (a)
 

(continued)
 

Low
 

Topography: Morphology Control Dose
 

Thyroid: C-cell Adenoma (b) 3/29 (10) 3/34 (9)
 

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

Relative Risk (f) 0.853
 

Lower Limit 0.124
 

Upper Limit 5.927
 

Weeks to First Observed Tumor 110 95
 

Parathyroid: Adenoma, NOS (b) 2/25 (8) 0/24 (0)
 

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

Relative Risk (f) 0.000
 

Lower Limit 0.000
 

Upper Limit 3.421
 

Weeks to First Observed Tumor 110
 

High
 

Dose
 

0/32 (0)
 

N.S.
 

0.000
 

0.000
 

1.480
 

—
 

0/26 (0)
 

N.S.
 

0.000
 

0.000
 

3.170
 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats
 

Administered DCDD in the Diet (a)
 

(continued)
 

Low
 

Topography: Morphology Control Dose
 

Pituitary: Adenoma, NOS, or
 

Chromophobe Adenoma (b) 3/16 (19) 0/22 (0)
 

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

Relative Risk (f) 0.000
 

Lower Limit 0.000
 

Upper Limit 1.157
 

Weeks to First Observed Tumor 110
 —
 

OO
 

Tunica Vaginalis: Mesothelioma,
 

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

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

Relative Risk (f) 0.000
 

Lower Limit 0.000
 

Upper Limit 3.246
 

Weeks to First Observed Tumor 81
 

High
 

Dose
 

1/17 (6)
 

N.S.
 

0.314
 

0.006
 

3.436
 

0/34 (0)
 

N.S.
 

0.000
 

0.000
 

3.338
 

111 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats
 

Administered DCDD 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.
 

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

any comparison,
 oo
 

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

Administered DCDD in the Diet (a)
 

Low High
 

Topography: Morphology Control Dose Dose
 

Pituitary: Chromophobe Adenoma (b) 4/18 (22) 3/25 (12) 7/20 (35)
 

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

Relative Risk (f) 0.540 1.575
 

Lower Limit 0.091 0.488
 

Upper Limit 2.825 6.098
 

Weeks to First Observed Tumor 116 110 103
 

oo
 

Adrenal: Cortical Adenoma (b) 11/30 (37) 7/33 (21) 9/29 (31)
 

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

Relative Risk (f) 0.579 0.846
 

Lower Limit 0.222 0.368
 

Upper Limit 1.415 1.894
 

Weeks to First Observed Tumor 115 110 90
 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Administered DCDD in the Diet (a)
 

(continued)
 

Low High
 

Topography: Morphology Control Dose Dose
 

Thyroid: Follicular-cell Carcinoma (b) 0/28 (0) 2/32 (6) 2/25 (8)
 

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

Relative Risk (f) Infinite Infinite
 

Lower Limit 0.264 0.339
 

Upper Limit Infinite Infinite
 

Weeks to First Observed Tumor 110 108
 CO
 

00
 

Thyroid: C-cell Adenoma (b) 4/28 (14) 0/32 (0) 0/25 (0)
 

P Values (c,d) P = 0.015 (N) P = 0.042 (N) N.S.
 

Relative Risk (f) 0.000 0.000
 

Lower Limit 0.000 0.000
 

Upper Limit 0.925 1.171
 

Weeks to First Observed Tumor 115
 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Administered DCDD in the Diet (a)
 

(continued)
 

Low
 

Topography: Morphology Control Dose
 

Thyroid or Thyroid Follicle:
 

Cystadenoma, NOS (b) 2/28 (7) 1/32 (3)
 

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

Relative Risk (f) 0.437
 

Lower Limit 0.008
 

Upper Limit 7.961
 

oo
 

VO
 

Weeks to First Observed Tumor 116 110
 

Thyroid or Thyroid Follicle:
 

Follicular-cell Carcinoma or
 

Cystadenoma, NOS (b) 2/28 (7) 3/32 (9)
 

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

Relative Risk (f) 1.312
 

Lower Limit 0.163
 

Upper Limit 14.810
 

Weeks to First Observed Tumor 116 110
 

High
 

Dose
 

0/25 (0)
 

N.S.
 

0.000
 

0.000
 

3.688
 

—
 

2/25 (8)
 

N.S.
 

1.120
 

0.087
 

14.392
 

106 
Table E2. Analyses of the 'Incidence of Primary Tumors in Female Rats
 

(continued)
 

Topography; Morphology
 

Mammary Gland: Adenoma, NOS (b)
 

P Values (c,d)
 

Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 \o
 

o
 

Mammary Gland: Fib road enoma (b)
 

P Values (c,d)
 

Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Administered DCDD in the Diet (a) 

Low High 

Control Dose Dose 

3/35 (9) 5/33 (15) 0/33 (0) 

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

1.768 0.000 

0.375 0.000 

10.552 1.737 

113 110 — 

13/35 (37) 7/33 (21) 4/33 (12) 

P = 0.011 (N) N.S. P = 0.017 (N) 

0.571 0.326 

0.222 0.087 

1.336 0.932 

107 110 103 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Administered DCDD in the Diet (a)
 

(continued)
 

Topography: Morphology


Mammary Gland: Adenoma, NOS, or
 

Fibroadenoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

VO
 

Weeks to First Observed Tumor


Mammary Gland: Adenoma, NOS,
 

Fibroadenoma, or Adenocarcinoma,
 

NOS (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Low 

 Control Dose 

 14/35 (40) 12/33 (36) 

P = 0.009 (N) N.S. 

0.909 

0.455 

1.783 

 107 110 

 15/35 (43) 12/33 (36) 

P = 0.005 (N) N.S. 

0.848 

0.432 

1.630 

High
 

Dose
 

4/33 (12)
 

P = 0.009 (N)
 

0.303
 

0.082
 

0.849
 

103
 

4/33 (12)
 

P = 0.005 (N)
 

0.283
 

0.077
 

0.779
 

Weeks to First Observed Tumor 93 110 103
 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Administered DCDD in the Diet (a)
 

(continued)
 

Low High 

Topography: Morphology Control Dose Dose 

Ovary: Granules a-ce 11 Tumor (b) 0/26 (0) 2/31 (6) 0/26 (0) 

P Values (c,d) N.S. N.S. — 

Relative Risk (f) Infinite — Lower Limit 0.254 — Upper Limit Infinite — 

Weeks to First Observed Tumor 110 

(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.
 

(e) The probability level for the 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 DCDD IN THE DIET
 

93
 
94

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

Administered DCDD in the Diet (a)
 

Low
 

Topography! Morphology Control Dose
 

Lung: Alveolar/Bronchiolar
 

Carcinoma (b) 0/49 (0) 3/49 (6)
 

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

Departure from Linear Trend (e) P = 0.016
 

Relative Risk (f) Infinite
 

Lower Limit 0.602
 

Upper Limit Infinite
 

vo
 

Ui Weeks to First Observed Tumor 97
 

Lung: Alveolar/Bronchiolar Adenoma
 

or Carcinoma (b) 8/49 (16) 5/49 (10)
 

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

Relative Risk (f) 0.625
 

Lower Limit 0.172
 

Upper Limit 2.007
 

Weeks to First Observed Tumor 92 97
 

High
 

Dose
 

0/44 (0)
 

5/44 (11)
 

N.S.
 

0.696
 

0.192
 

2.222
 

97 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice
 

Administered DCDD in the Diet (a)
 

(continued)
 

Low High
 

Topography: Morphology Control Dose Dose
 

Hematopoietic System:
 

Leukemia (b) 0/50 (0) 3/50 (6) 1/45 (2)
 

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

Relative Risk (f) Infinite Infinite
 

Lower Limit 0.601 0.060
 

Upper Limit Infinite Infinite
 

Weeks to First Observed Tumor — 98 94
 

Hematopoietic System: Lymphoma (b) 0/50 (0) 4/50 (8) 2/45 (4) 

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

Relative Risk (f) 

Lower Limit 

Upper Limit 

Infinite 

0.927 

Infinite 

Infinite 

0.329 

Infinite 

Weeks to First Observed Tumor 99 99 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice
 

Administered DCDD in the Diet (a)
 

(continued)
 

Low
 

Topography: Morphology Control Dose
 

Hematopoietic System: Leukemia
 

or Lymphoma (b) 0/50 (0) 7/50 (14)
 

P Values(c,d) N.S. P = 0.006
 

Departure from Linear Trend (e) P = 0.016
 

Relative Risk (f) Infinite
 

Lower Limit 1.941
 

Upper Limit Infinite
 

VO
 

Weeks to First Observed Tumor — 98
 

All Sites: Hemangiosarcoma (b) 0/50 (0) 4/50 (8)
 

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

Departure from Linear Trend (e) P=0.031
 

Relative Risk (f) Infinite
 

Lower Limit 0.927
 

Upper Limit Infinite
 

Weeks to First Observed Tumor 97
 

High
 

Dose
 

3/45 (7)
 

N.S.
 

Infinite
 

0.669
 

Infinite
 

94
 

1/45 (2)
 

N.S.
 

Infinite
 

0.060
 

Infinite
 

99
 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice
 

Administered DCDD in the Diet (a)
 

(continued)
 

Low
 

Topography: Morphology Control Dose
 

All Sites: Hemangiosarcoma or
 

Hemangioma (b) 0/50 (0) 5/50 (10)
 

P Values(c,d) N.S. P = 0.028
 

Departure from Linear Trend (e) P = 0.011
 

Relative Risk (f) Infinite
 

Lower Limit 1.261
 

Upper Limit Infinite
 

VD
 

OO Weeks to First Observed Tumor 97
 

Liver: Hepatocellular Carcinoma (b) 4/49 (8) 5/50 (10)
 

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

Relative Risk (f) 1.225
 

Lower Limit 0.280
 

Upper Limit 5.833
 

Weeks to First Observed Tumor 93 99
 

High
 

Dose
 

1/45 (2)
 

N.S.
 

Infinite
 

0.060
 

Infinite
 

99
 

5/42 (12)
 

N.S.
 

1.458
 

0.335
 

6.884
 

99
 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice
 

Administered DCDD in the Diet (a)
 

(continued)
 

Low
 

Topography: Morphology Control Dose
 

Liver: Hepatocellular Carcinoma or
 

Adenoma (b) 8/49 (16) 20/50 (40)
 

P Values (c,d) P = 0.008 P = 0.008
 

Relative Risk (f) 2.450
 

Lower Limit 1.156
 

Upper Limit 5.757
 

Weeks to First Observed Tumor 92 97
 VO
 

vo
 

Stomach: Squamous-cell Papilloma (b) 5/49 (10) 0/47 (0)
 

P Values(c,d) P = 0.008 (N) P = 0.031 (N)
 

Relative Risk (f) 0.000
 

Lower Limit 0.000
 

Upper Limit 0.825
 

Weeks to First Observed Tumor 92 

High
 

Dose
 

17/42 (40)
 

P = 0.010
 

2.479
 

1.138
 

5.862
 

99
 

0/43 (0)
 

P = 0.039 (N)
 

0.000
 

0.000
 

0.900
 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice
 

Administered DCDD 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.
 

(e) The probability level for the 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 F2. Analyses of the Incidence of Primary Tumors in Female Mice
 

Administered DCDD in the Diet (a)
 

Topography: Morphology


Lung: Alveo lar /Bronch io lar
 

Adenoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


Stomach: Papilloma, NOS,
 

Papillomatosis, or Squamouscell Papilloma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

-Weeks to First Observed Tumor
 

 Control
 

 3/50 (6)
 

 N.S.
 

 91
 

 1/48 (2)
 

 N.S.
 

91
 

Low
 

Dose
 

2/47 (4)
 

N.S.
 

0.709
 

0.061
 

5.913
 

92
 

3/48 (6)
 

N.S.
 

3.000
 

0.252
 

154.112
 

92
 

High
 

Dose
 

0/47 (0)
 

N.S.
 

0.000
 

0.000
 

1.766
 

—
 

1/39 (3)
 

N.S.
 

1.231
 

0.016
 

94.143
 

93 
Table F2. Analyses of the Incidence of Primary Tumors in Female Mice
 

Administered DCDD in the Diet (a)
 

(continued)
 

Topography: Morphology Control 

Low 

Dose 

High 

Dose 

Hematopoietic System: 

Leukemia or Lymphoma (b) 6/50 (12) 11/49 (22) 4/48 (8) 

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

Departure from Linear Trend (e) P = 0.044 

Relative Risk (f) 

Lower Limit 

Upper Limit 

1.871 

0.692 

5.683 

0.694 

0.153 

2.739 

Weeks to First Observed Tumor 76 88 93 

(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.
 

(e) The probability level for the 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 2,7-Dichlorodibenzo-p-Dioxin (DCDD)*
 

for Carcinogenicity by the Data Evaluation/Risk Assessment Subgroup
 

of the Clearinghouse on Environmental Carcinogens
 

October 25, 1978
 

The Clearinghouse on Environmental Carcinogens was established in
 

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

Clearinghouse is to advise the Director of the National Cancer Institute
 

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

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

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

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

Members have been selected on the basis of their experience in carcinogenesis or related fields and, collectively, provide expertise in
 

chemistry, biochemistry, biostatistics, toxicology, pathology, and
 

epidemiology. Representatives of various Governmental agencies participate as ad hoc members. The Data Evaluation/Risk Assessment Subgroup
 

of the Clearinghouse is charged with the responsibility of providing a
 

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

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

critique is given on the bioassay of 2,7-Dichlorodibenzo-p-Dioxin (DCDD)
 

for carcinogenicity.
 

The reviewer for the report on the bioassay of DCDD said that,
 

under the conditions of test, the compound was not carcinogenic in
 

either sex of treated rats or female mice. An increased incidence
 

of a variety of tumors, including hepatocellular neoplasms and
 

leukemias, were observed among treated male mice. These findings led
 

the Program staff to conclude that the evidence was suggestive of a
 

carcinogenic effect in male mice. There was no objection to a recommendation that the report on the bioassay of DCDD be accepted as written.
 

Clearinghouse Members present;
 

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

Joseph Highland, Environmental Defense Fund
 

William Lijinsky, Frederick Cancer Research Center
 

Henry Pitot, University of Wisconsin Medical Center
 

Verne A. Ray, Pfizer Medical Research Laboratory
 

Kenneth Wilcox, Michigan State Health Department
 

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

bioassay report either as a result of the review or other
 

reasons. Thus, certain comments and criticisms reflected in
 

the review may no longer be appropriate.
 

103
 

fcU.S . GOVERNMEN T PRINTIN G OFFICE : 1978-281-217/3299
 


DHEW Publication No. (NIH) 79-1378