1978 

National Cancer Institute 

CARCINOGENESIS 

Technical Report Series 

No. 86
 

BIOASSAY OF 

1,2-DIBROMOETHANE 

FOR POSSIBLE CARCINOGENICITY 

CAS No. 106-93-4 

NCI-CG-TR-86 

US. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE 

Public Health Service 

National Institutes of Health 

BIDASSAY OF
 

1,2-DIBROMOETHANE
 

FOR POSSIBLE CARCINOGENICITY
 

Carcinogenesis Testing Program
 

Division of Cancer Cause and Prevention
 

National Cancer Institute
 

National Institutes of Health
 

Bethesda, Maryland 2001-4
 

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

Public Health Service
 

National Institutes of Health
 

DHEW Publication No. (NIH) 78-1336
 

REPORT ON THE BIOASSAY OF 1,2-DIBROMOETHANE
 

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
 

1,2-dibromoethane 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. Negative
 

results, in which the test animals do not have a significantly
 

greater incidence of cancer than control animals, do not necessarily
 

mean the test chemical is not a carcinogen because the experiments
 

are conducted under a limited set of circumstances. Positive results
 

demonstrate that the test chemical is carcinogenic for animals under
 

the conditions of the test and indicate a potential risk to man. The
 

actual determination of the risk to man from animal carcinogens requires a wider analysis.
 

CONTRIBUTORS: This bioassay of 1,2-dibromoethane was conducted by
 

Hazleton Laboratories America, Inc., Vienna, Virginia, initially
 

under direct contract to the NCI and currently under a subcontract
 

to Tracor Jitco, Inc., prime contractor for the NCI Carcinogenesis
 

Testing Program.
 

The experimental design was determined by the NCI Project Officers, Dr. J. H. Weisburger (1,2) and Dr. E. K. Weisburger (1). The
 

principal investigators for the contract were Dr. M. B. Powers (3),
 

Dr. R. W. Voelker (3), Dr. W. A. Olson (3,4) and Dr. W. M. Weatherholtz (3). Chemical analysis was performed by Dr. C. L. Guyton
 

(3,5) and the analytical results were reviewed by Dr. N. Zimmerman
 

(6); the technical supervisor of animal treatment and observation
 

was Ms. K. J. Petrovics (3).
 

Histopathologic examinations were performed by Dr. D. A. Banas
 

(3) and Dr. R. H. Habermann (3) and reviewed by Dr. R. W. Voelker
 

(3) at the Hazleton Laboratories America, Inc., and the diagnoses
 

included in this report represent the interpretation of these pathologists. Histopathology findings and reports were reviewed by Dr. R.
 

L. Schueler (7).
 

iii 
Compilation of individual animal survival, pathology, and summary tables was performed by EG&G Mason Research Institute (8); the
 

statistical analysis was performed by Mr. W. W. Belew (6) and Dr. J.
 

R. Joiner (7), using methods selected for the Carcinogenesis Testing
 

Program by Dr. J. J. Gart (9).
 

This report was prepared at METREK, a Division of The MITRE Corporation (6) under the direction of the NCI. Those responsible for
 

this report at METREK are the project coordinator, Dr. L. W. Thomas
 

(6), task leader Dr. M. R. Kornreich (6), senior biologist Ms. P.
 

Walker (6), biochemist Dr. B. Fuller (6), and technical editor Ms. P.
 

A. Miller (6). The final report was reviewed by members of the
 

participating organizations.
 

The following other scientists at the National Cancer Institute
 

were responsible for evaluating the bioassay experiment, interpreting
 

the results, and reporting the findings: Dr. K. C. Chu (1), Dr. C.
 

Cueto, Jr. (1), Dr. J. F. Douglas (1), Dr. D. G. Goodman (1), Dr. R.
 

A. Griesemer (1), Dr. H. A. Milman (1), Dr. T. W. Orme (1), Dr. R. A.
 

Squire (1,10), Dr. J. M. Ward (1), and Dr. C. E. Whitmire (1).
 

1.	 Carcinogenesis Testing Program, Division of Cancer Cause and
 

Prevention, National Cancer Institute, National Institutes of
 

Health, Bethesda, Maryland.
 

2.	 No wit w h the Naylor Dana Institute for Disease Prevention, American Health Foundation, Hammon House Road, Valhalla, New York.
 

3.	 Hazleton Laboratories America, Inc., 9200 Leesburg Turnpike,
 

Vienna, Virginia.
 

4.	 Now with the Center for Regulatory Services, 2347 Paddock Lane,
 

Reston, Virginia.
 

5.	 Now with Rhodia, Inc., 23 Belmont Drive, Somerset, New Jersey.
 

6.	 The MITRE Corporation, METREK Division, 1820 Dolley Madison
 

Boulevard, McLean, Virginia.
 

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

Maryland.
 

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

Rockville, Maryland.
 

iv
 
9.	 Mathematical Statistics and Applied Mathematics Section, Biometry
 

Branch, Field Studies and Statistics Program, Division of Cancer
 

Cause and Prevention, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
 

10.	 No wit w h the Division of Comparative Medicine, Johns Hopkins
 

University, School of Medicine, Traylor Building, Baltimore,
 

Maryland.
 

v
 

SUMMARY
 

A bioassay for possible carcinogenicity of technical-grade 1,2­

dibromoethane was conducted using Osborne-Mendel rats and B6C3F1 mice.
 

1,2-Dibromoethane in corn oil was administered by gavage, at either
 

of two dosages, to groups of 50 male and 50 female animals of each
 

species. The time-weighted average high and low doses of 1,2-dibromoethane used in the chronic bioassay were, respectively, 41 and 38 mg/
 

kg/day for male rats, 39 and 37 mg/kg/day for female rats and 107 and
 

62 mg/kg/day for mice of both sexes. For each species 20 animals of
 

each sex were placed on test as vehicle controls. These animals were
 

gavaged with corn oil with the same frequency that dosed animals were
 

gavaged with 1,2-dibromoethane mixtures. Twenty animals of each sex
 

were placed on test as untreated controls for each species. These
 

animals were not intubated.
 

There was a positive association between increased dosage and
 

accelerated mortality in rats and mice of both sexes. All surviving
 

dosed male rats were sacrificed in week 49 and all surviving dosed
 

female rats were sacrificed after 61 weeks of compound administration.
 

All male mice and high dose female mice died or were sacrificed by
 

week 78, while the low dose mice were observed for an additional 37
 

weeks after a 53-week period of chemical administration.
 

In rats squamous-cell carcinomas of the forestomach were observed in 45/50, 33/50, 40/50 and 29/50 of the low dose males, high
 

dose males, low dose females and high dose females, respectively,
 

while none were observed in controls. Each of these incidences was
 

statistically significant. These lesions were seen as early as week
 

12 in rats and week 24 in mice; they invaded locally and eventually
 

metastasized. Increased incidences of hepatocellular carcinomas were
 

observed in dosed rats, but the incidence of this neoplasm was significant only in females. Increased incidences of hemangiosarcomas were
 

observed in each dosed rat group, but was statistically significant
 

only in males, where they appeared as early as week 26.
 

Early development of squamous-cell carcinomas which invaded and
 

metastasized was also observed among mice. Squamous-cell carcinomas
 

were found in 45/50, 29/49, 46/49 and 28/50 of the low dose males,
 

high dose males, low dose females and high dose females, respectively,
 

but none were found in controls. Each of these incidences was statistically significant. Incidences of alveolar/bronchiolar adenomas were
 

significant for male and female dosed mice.
 

Under the conditions of this bioassay, 1,2-dibromoethane was
 

carcinogenic to Osborne-Mendel rats and B6C3F1 mice. The compound
 

vii
 
induced squamous-cell carcinomas of the forestomach in rats of both
 

sexes, hepatocellular carcinomas in female rats, and hemangiosarcomas
 

in male rats. In mice of both sexes the compound induced squamouscell carcinomas of the forestomach and alveolar/bronchiolar adenomas.
 

viii
 
TABLE OF CONTENTS
 

Page
 

I. INTRODUCTION
 

II. MATERIALS AND METHODS
 

A. Chemicals
 

B. Dosage Preparation
 

C. Animals
 

D. Animal Maintenance
 

E. Gastric Intubation
 

F. Selection of Initial Dose Levels
 

G. Experimental Design 10
 

H. Clinical and Histopathologic Examinations 14
 

I. Data Recording and Statistical Analyses 15
 

III. CHRONIC TESTING RESULTS: RATS 20
 

A. Body Weights and Clinical Observations 20
 

B. Survival 20
 

C. Pathology 24
 

D. Statistical Analyses of Results 26
 

IV. CHRONIC TESTING RESULTS: MICE 39
 

A. Body Weights and Clinical Observations 39
 

B. Survival 39
 

C. Pathology 42
 

D. Statistical Analyses of Results 44
 

V. DISCUSSION 58
 

VI. BIBLIOGRAPHY 61
 

APPENDIX A SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

RATS TREATED WITH 1,2-DIBROMOETHANE A-l
 

APPENDIX B SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

MICE TREATED WITH 1,2-DIBROMOETHANE B-l
 

APPENDIX C SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN RATS TREATED WITH 1,2-DIBROMOETHANE C-l
 

APPENDIX D SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN MICE TREATED WITH 1,2-DIBROMOETHANE D-l
 

1 

4 

4

6

6

7

8

8
 

ix
 
LIST OF ILLUSTRATIONS
 

Figure Number
 

1
 

2
 

3
 

4
 

5
 

Table Number
 

1
 

2
 

3
 

4
 

5
 

6
 

CHEMICAL STRUCTURE OF 1,2-DIBROMOETHANE
 

GROWTH CURVES FOR 1,2-DIBROMOETHANE CHRONIC
 

STUDY RATS
 

SURVIVAL COMPARISONS OF 1,2-DIBROMOETHANE
 

CHRONIC STUDY RATS
 

GROWTH CURVES FOR 1,2-DIBROMOETHANE CHRONIC
 

STUDY MICE
 

SURVIVAL COMPARISONS OF 1,2-DIBROMOETHANE
 

CHRONIC STUDY MICE
 

LIST OF TABLES
 

DESIGN SUMMARY FOR OSBORNE-MENDEL RATS—
 

1,2-DIBROMOETHANE GAVAGE EXPERIMENT
 

DESIGN SUMMARY FOR B6C3F1 MICE—1,2-DIBROMOETHANE GAVAGE EXPERIMENT
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS
 

AT SPECIFIC SITES IN MALE RATS TREATED WITH
 

1,2-DIBROMOETHANE
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS
 

AT SPECIFIC SITES IN FEMALE RATS TREATED
 

WITH 1,2-DIBROMOETHANE
 

TIME-ADJUSTED ANALYSES OF THE INCIDENCE OF
 

PRIMARY TUMORS AT SPECIFIC SITES IN MALE RATS
 

TREATED WITH 1,2-DIBROMOETHANE
 

TIME-ADJUSTED ANALYSES OF THE INCIDENCE OF
 

PRIMARY TUMORS AT SPECIFIC SITES IN FEMALE
 

RATS TREATED WITH 1.2-DIBROMOETHANE
 

Page
 

5
 

21
 

22
 

40
 

41
 

Page
 

11
 

12
 

27
 

30
 

34
 

36
 

x
 
Table Number
 

7
 

8
 

9
 

10
 

Al
 

A2
 

Bl
 

B2
 

Cl
 

C2
 

Dl
 

LIST OF TABLES (Continued) 

Page 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN MALE MICE TREATED WITH 

1,2-DIBROMOETHANE 45 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN FEMALE MICE TREATED 

WITH 1,2-DIBROMOETHANE 48 

TIME-ADJUSTED ANALYSES OF THE INCIDENCE OF 

PRIMARY TUMORS AT SPECIFIC SITES IN MALE 

MICE TREATED WITH 1,2-DIBROMOETHANE 54 

TIME-ADJUSTED ANALYSES OF THE INCIDENCE OF 

PRIMARY TUMORS AT SPECIFIC SITES IN FEMALE 

MICE TREATED WITH 1,2-DIBROMOETHANE 56 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

MALE RATS TREATED WITH 1,2-DIBROMOETHANE A-3 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

FEMALE RATS TREATED WITH 1,2-DIBROMOETHANE A-8 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

MALE MICE TREATED WITH 1,2-DIBROMOETHANE B-3 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

FEMALE MICE TREATED WITH 1,2-DIBROMOETHANE B-8 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN MALE RATS TREATED WITH 1,2­

DIBROMOETHANE C-3 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN FEMALE RATS TREATED WITH 1,2­

DIBROMOETHANE C-8 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN MALE MICE TREATED WITH 1,2­

DIBROMOETHANE D-3 

xi
 
LIST OF TABLES (Concluded)
 

Table Number Page 

D2 SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN FEMALE MICE TREATED WITH 1,2­

DIBROMOETHANE D-8 

xii
 
I. INTRODUCTION
 

1,2-Dibromoethane (NCI No. C00522), a volatile saturated brominated hydrocarbon, is used principally as a lead scavenger in tetraalkyl lead gasoline and antiknock preparations (Fishbein, 1976) but
 

also as a soil and grain fumigant, a chemical intermediate, and a
 

solvent (International Agency for Research on Cancer, 1977). This
 

chemical was selected for bioassay by the National Cancer Institute
 

because of the extensive potential for human exposure.
 

The Chemical Abstracts Service (CAS) Ninth Collective Index
 

(1977) name for this compound is 1,2-dibromoethane. It is also
 

called DBE; sym-dibromoethane, ethylene dibromide; EDB; and glycol
 

dibromide.
 

Domestic production figures were first reported for 1,2-dibromoethane in 1923 (U.S. Tariff Commission, 1924) and in 1974 U.S. production was approximately 330 million pounds (U.S. International Trade
 

Commission, 1976). Although more than 200 million pounds of the 1974
 

domestic production were utilized in tetraalkyl lead antiknock formulations, consumption of 1,2-dibromoethane via this application has
 

been declining since the early 1970s in response to the decreased use
 

of leaded fuels (Chemical and Engineering News, 1976). The efficacy
 

of application of the compound as a fumigant was first reported in 1925
 

by Neifert (Spencer, 1973) and it has been used in fumigant mixtures
 

*
 

The CAS registry number is 106-93-4.
 

1
 
for disinfecting fruits, vegetables, grains, tobacco, seeds, mills,
 

and warehouses (Berck, 1974). There have been more than 100 pesticides registered by the U.S. Environmental Protection Agency which
 

include 1,2-dibromoethane as a constituent (U.S. Environmental Protection Agency, 1975). In determining use of 1,2-dibromoethane as
 

a pesticide, it was estimated that 1 million pounds were used by U.S.
 

farmers in 1971 and 230 thousand pounds were used in California in
 

1974 to combat insects (California Department of Food and Agriculture,
 

1975).
 

The most ubiquitous source of potential exposure of the general
 

population to 1,2-dibromoethane is through inhalation of automobile
 

emissions (i.e., evaporation from the fuel tank and carburetor of
 

vehicles using leaded gasoline). Preliminary air monitoring data
 

revealed 1,2-dibromoethane concentrations of approximately 0.01 ppb
 

in the vicinity of gasoline stations on traffic arteries, 0.1 ppb at
 

an oil refinery, and 10 to 15 ppb at 1,2-dibromoethane manufacturing
 

sites (U.S. Environmental Protection Agency, 1975); therefore, it is
 

apparent that employees of these enterprises may be exposed to
 

1,2-dibromoethane. In addition, use of the compound as a fumigant
 

indicates the probable exposure of agricultural workers or those
 

individuals fumigating crops in storage facilities.
 

1,2-Dibromoethane is a severe irritant, inducing blisters subsequent to dermal exposure. Upon inhalation 1,2-dibromoethane causes
 

2
 
delayed pulmonary lesions and mild central nervous system depression
 

(Gosselin et al., 1976).
 

Prior to this study, no evidence for the carcinogenicity of
 

1,2-dibromoethane was found in the literature. The compound has been
 

shown to induce mutations in bacteria, plants, and fruit flies (International Agency for Research on Cancer, 1977).
 

3 
II. MATERIALS AND METHODS
 

A. Chemicals
 

One batch of technical-grade 1,2-dibromoethane (Figure 1) was
 

purchased from Dow Chemical Company by Hazleton Laboratories America,
 

Inc., Vienna, Virginia. The purity of the compound was initially
 

determined at Hazleton Laboratories using gas-liquid chromatography
 

(GLC) internal standard and total-area analyses. GLC analysis, using
 

the internal standard method, revealed the technical-grade compound
 

to be 96.3 percent pure. Using GLC total-area analysis, the 1,2­

dibromoethane peak occupied 88.3 percent of the total area, while a
 

second major peak accounted for 10.1 percent, and ten other peaks
 

each accounted for less than 1 percent of the total area.
 

Second and third purity determinations were performed by Hazleton
 

Laboratories to establish the stability of 1,2-dibromoethane under
 

storage conditions. The second analysis, performed approximately 16
 

months after the initial analysis and using both GLC internal standard
 

and total-area analyses, indicated that the technical-grade compound
 

was 99.1 percent pure. The third analysis, performed approximately
 

5 months after the second analysis and using GLC total-area analysis,
 

indicated that the technical-grade 1,2-dibromoethane was 99.6 percent
 

pure. Infrared spectra from both the second and third chemical
 

characterizations were comparable to the spectrum of the analytical
 

standard.
 

4
 
FIGURE 1

 

CHEMICAL STRUCTURE OF 1,2-DIBROMOETHANE 

5 
Although the results of the first GLC total-area analysis disagreed with the manufacturer's stated minimum purity of 99.5 percent
 

(based on the results of a total-area analysis), subsequent stability
 

tests indicated that the purity was over 99 percent.
 

Throughout this report the term 1,2-dibromoethane is used to
 

represent this technical-grade material.
 

B. Dosage Preparation
 

®


Fresh solutions of 1,2-dibromoethane in Duke's corn oil (S. F.
 

Sauer Company, Richmond, Virginia) were prepared weekly, sealed, and
 

stored in dark bottles at 1°C. These solutions were considered
 

generally stable for 10 days under the indicated storage conditions.
 

The concentrations of 1,2-dibromoethane in corn oil were 4 percent
 

for the rat bioassay and 1 to 2 percent for the mouse bioassay.
 

C. Animals
 

Two animals species, rats and mice, were used in the carcinogenicity bioassay. The Osborne-Mendel rat was selected on the basis of a
 

comparative study of the tumorigenic responsiveness to carbon tetrachloride of five different strains of rats (Reuber and Glover, 1970).
 

The B6C3F1 mouse was selected because it has been used by the NCI for
 

carcinogenesis bioassays and has proved satisfactory in this capacity.
 

Rats and mice of both sexes were obtained through contracts of
 

the Division of Cancer Treatment, National Cancer Institute. The
 

Osborne-Mendel rats and the B6C3F1 mice were obtained from the Charles
 

River Breeding Laboratories, Inc., Wilmington, Massachusetts. Upon
 

6 
receipt, animals were quarantined for at least 10 days, observed for
 

visible signs of disease or parasites, and assigned to the various
 

treated and control groups.
 

D. Animal Maintenance
 

All animals were housed by species in temperature- and humidity-


controlled rooms. The temperature range was 20° to 24°C and the
 

relative humidity was maintained between 45 and 55 percent. The air
 

conditioning system in the laboratory provided filtered air at a
 

rate of 12 to 15 complete changes of room air per hour. Fluorescent
 

lighting was provided on a 12-hour-daily cycle.
 

The rats were individually housed in suspended galvanized-steel
 

wire-mesh cages with perforated floors, while mice were housed by
 

sex in groups of 10 in solid-bottom polypropylene cages equipped
 

(R)
 with filter tops. Sanitized cages with fresh bedding (Sanichips ,
 

Pinewood Sawdust Company, Moonachie, New Jersey) were provided once
 

each week for mice. Rats received sanitized cages with no bedding
 

with the same frequency. Food hoppers were changed and heat-


sterilized once a week for the first 10 weeks and. once a month thereafter. Fresh heat-sterilized glass water bottles and sipper tubes
 

were provided three times a week. Food (Wayne Lab-Blox , Allied
 

Mills, Inc., Chicago, Illinois) and water were available ad libitum.
 

Rats treated with 1,2-dibromoethane and the untreated and vehicle control rats were housed in the same room as other rats intubated
 

7 
with* 1,1,2,2-tetrachloroethane (79-34-5); allyl chloride (107-05-1);
 

carbon tetrachloride (56-23-5); and chloroform (67-66-3). The mice
 

treated with 1,2-dibromoethane and their controls were housed in the
 

same room as other mice intubated with 1,1,2,2-tetrachloroethane
 

(79-34-5); chloroform (67-66-3); allyl chloride (107-05-1); chloropicrin (76-06-2); dibromochloropropane (96-12-8); 1,2-dichloroethane
 

(107-06-2); 1,1-dichloroethane (75-34-3); trichloroethylene (79-01-6);
 

3-sulfolene (77-79-2); iodoform (75-47-8); methylchloroform (71-55-6);
 

1,1,2-trichloroethane (79-00-5); tetrachloroethylene (127-18-4); carbon disulfide (75-15-0); hexachloroethane (67-72-1); trichlorofluoromethane (75-69-4); and carbon tetrachloride (56-23-5).
 

E. Gastric Intubation
 

Intubation was performed for five consecutive days per week on
 

a mg/kfe body weight basis utilizing the most recently observed group
 

mean body weight as a guide for determining the dose. Mean body
 

weights for each group were recorded at weekly intervals for the
 

first 10 weeks and at monthly intervals thereafter. All animals of
 

one sex within a treated group received the same dose. Animals were
 

gavaged with test solutions under a hood to minimize extraneous exposure of other animals and laboratory personnel to the chemical.
 

F. Selection of Initial Dose Levels
 

In order to establish the maximum tolerated dosages of 1,2-dibromoethane for administration to treated animals in the chronic studies,
 

subchronic toxicity tests were conducted with both rats and mice.
 

~ft !
 CAS registry numbers are given in parentheses.
 

8
 
Animals of each species were distributed among six groups, each consisting of five males and five females. 1,2-Dibromoethane mixed with
 

corn oil was introduced by gavage to five of the six rat groups and
 

five of the six mouse groups at dosages of 40, 63, 100, 163, and 251
 

mg/kg/day. The sixth group of each species served as a control
 

group, receiving only the corn oil by gavage. Intubation was performed 5 consecutive days per week for 6 weeks, followed by a 2-week
 

observation period to detect any delayed toxicity.
 

A dosage inducing no mortality and resulting in a depression in
 

mean group body weight of approximately 20 percent relative to controls was selected as the initial high dose. When weight gain criteria were not applicable, mortality data alone were utilized.
 

At 63 mg/kg/day none of the rats died during the 8-week period.
 

At dosages of 100 mg/kg/day one male and one female rat died. Mean
 

group body weight of dosed rats at the end of the 8-week period was
 

within 10 percent of that of control rats at dosages of 63 mg/kg/day
 

or less. At dosages of 100 mg/kg/day mean body weight for male rats
 

was 75 percent that of controls, and for female rats, was 82 percent
 

of that for controls. The initial high dose selected for use in the
 

chronic bioassay was 80 mg/kg/day for male and female rats.
 

All the male mice receiving dosages of 159 mg/kg/day or less
 

survived the 8-week study. All female mice survived except one
 

treated with 100 mg/kg/day and two receiving 251 mg/kg/day. At
 

dosages of 159 mg/kg/day or less mean body weight in treated mice
 

9 
was greater than that in control mice, except in males receiving 63
 

and 159 mg/kg/day. Mean body weight was 71 and 91 percent that of
 

controls in males treated with 63 and 159 mg/kg/day, respectively.
 

The initial high dose selected for use in the chronic bioassay was
 

120 mg/kg/day for male and female mice.
 

G. Experimental Design
 

The experimental design parameters for the chronic study (species, sex, group size, dosages administered, duration of treated and
 

untreated observation periods, and the time-weighted average dosages)
 

are summarized in Tables 1 and 2.
 

The treated and vehicle control rats were placed on test simultaneously and were all approximately 8 weeks old at the time the
 

experiment began. The untreated control rats were placed on test 15
 

weeks later at the age of 5 weeks. Intubation was performed 5 consecutive days per week. The initial doses utilized for male and female rats were 80 and 40 mg/kg/day. Throughout this report those rat
 

groups initially receiving the formed dosage are referred to as the
 

high dose groups, while those rat groups initially receiving the
 

latter dosage are referred to as the low dose groups. In week 17
 

intubation of the high dose rats was discontinued as a result of the
 

deaths of 18 high dose males and 20 high dose females during or immediately after intubation in week 15. During the 13 weeks when
 

1,2-dibromoethane dosing was suspended, the high dose rats received
 

no corn oil intubations. In week 30 the high dose rats were again
 

10
 
TABLE 1
 

DESIGN SUMMARY FOR OSBORNE-MENDEL RATS
 

1,2-DIBROMOETHANE GAVAGE EXPERIMENT
 

TIME-WEIGHTED 

INITIAL 1,2-DIBROMO­ OBSERVATION PERIOD AVERAGE DOSAGE 

GROUP ETHANE TREATED UNTREATED OVER WEEKS OF 

SIZE DOSAGE3 (WEEKS) (WEEKS) TEST PERIODb 

MALE
 

UNTREATED CONTROL 20 107
 — —
 —
 VEHICLE CONTROL 20 0 49 14 0
 

LOW DOSE 50 40 41 38
 

40C 6 2
 

HIGH DOSE 50 80 16 41
 

0 13
 

40 12
 

40C 6 2
 

FEMALE
 

UNTREATED CONTROL 20 107
 — —
 —
 VEHICLE CONTROL 20 0 61 2 0
 

LOW DOSE 50 40 41 37
 

40C 16 4
 

HIGH DOSE 50 80 16 39
 

0 13
 

40 12
 

40C 16 4
 

Dosages, given in rag/kg body weight, were administered by gavage 5 consecutive days per week.
 

b . . , , 2 (dosag3 e X weeks received)
 Time-weighted average dosag6e = ^ , r — :—rr
 

 Z (weeks of test period)
 

Male rats were on test for 49 weeks and female rats were on test for 61
 

weeks.
 

These dosages were cyclically administered with a pattern of 1 dosage-


free week followed by 4 weeks (5 days per week) of dosage at the level
 

indicated.
 

11
 

c 
TABLE 2
 

DESIGN SUMMARY FOR B6C3F1 MICE
 

1,2-DIBROMOETHANE GAVAGE EXPERIMENT
 

INITIAL 1 , 2-DIBROMO­ OBSERVATION PERIOD TIME-WEIGHTED 

GROUP E THANE TREATED UNTREATED AVERAGE 

SIZE DOSAGE3 (WEEKS) (WEEKS) DOSAGE 

MALE
 

UNTREATED CONTROL 20	 78
 —
 —
 VEHICLE CONTROL 20 0 53 6 0
 

LOW DOSE 50 60 10 62
 

100 2
 

60 41
 

0 25
 

HIGH DOSE 50	 120 10 107
 

200 2
 

120 27
 

60 14
 

0 24
 

FEMALE
 

UNTREATED CONTROL 20	 — ,
 90
 —
 VEHICLE CONTROL 20 0 53 7 0
 

LOW DOSE 50 60 10 62
 

100 2
 

60 41
 

0 37
 

HIGH DOSE 50	 120 10 107
 

200 2
 

120 27
 

60 14
 n o =;
 

Dosages, given in rag/kg body weight, were administered by gavage 5 consecutive days per week.
 

(dosage X weeks received)
 Time-weighted average dosage
 (weeks receiving chemical)
 

12
 
intubated, but this time at the same dosage that the low dose animals
 

were receiving. In week 42 all intubations of low and high dose rats
 

ceased for 1 week followed by 4 weeks of dose administration. All
 

surviving treated male rats were sacrificed in week 49; all surviving
 

treated females were sacrificed in week 61. For both males and
 

females the surviving vehicle control rats were sacrificed in week
 

63. Corn oil gavage of male vehicle controls was suspended after 49
 

weeks, followed by a 14-week observation period. Gavage of female
 

vehicle controls was suspended after 61 weeks, followed by a 2-week
 

observation period. There were no untreated observation periods for
 

dosed rats.
 

The treated and control mice were all approximately 5 weeks old
 

at the time the bioassay was started. Intubation was performed 5
 

consecutive days per week. The initial dosages utilized for male and
 

female mice were 120 and 60 mg/kg/day. Throughout this report those
 

mice initially receiving the former dosage are referred to as the
 

high dose groups, while those mice initially receiving the latter
 

dosage are referred to as the low dose groups. In week 11 high and
 

low dosages for both sexes were increased to 200 and 100 mg/kg/day,
 

respectively. In week 13 dosages for all mice were decreased to
 

initial levels. In week 40 the dosage administered to the high dose
 

groups was decreased to 60 mg/kg/day, the same dosage being administered to the low dose groups. Compound administration to high and
 

low dose mice and corn oil gavage of vehicle controls were discontinued in week 54. All surviving male mice and high dose female mice
 

13
 
were sacrificed by week 78. Low dose females were observed for 37
 

weeks after intubation ceased.
 

The untreated controls received no 1,2-dibromoethane or corn oil,
 

while the vehicle controls were intubated with corn oil.
 

H. Clinical and Histopathologic Examinations
 

Animals were weighed immediately prior to initiation of the experiment. Body weights, food consumption, and data concerning appearance, behavior, signs of toxic effects, and incidence, size,
 

and location of tissue masses were recorded at weekly intervals for
 

the first 10 weeks and at monthly intervals thereafter. From the
 

first day, all animals were inspected daily for mortality. The
 

presence of tissue masses was determined by observation and palpation
 

of each animal.
 

A necropsy was performed on each animal regardless of whether it
 

died, was killed when moribund, or was sacrificed at the end of the
 

bioassay. The animals were euthanized by exsanguination under sodium
 

pentobarbital anesthesia, and were immediately necropsied. The histopathologic examination consisted of gross and microscopic examination
 

of major tissues, organs, and gross lesions taken from sacrificed
 

animals and, whenever possible, from animals found dead.
 

Tissues were preserved in 10 percent buffered formalin, embedded
 

in paraffin, sectioned, and stained with hematoxylin and eosin prior
 

to microscopic examination. An occasional section was subjected to
 

special staining techniques for more definitive diagnosis.
 

14
 
Slides were prepared from the following tissues: skin, subcutaneous tissue, lungs and bronchi, trachea, bone marrow, spleen, lymph
 

nodes, thymus, heart, salivary gland, liver, gallbladder (mice),
 

pancreas, esophagus, stomach, small intestine, large intestine,
 

kidney, urinary bladder, pituitary, adrenal, thyroid, parathyroid,
 

testis, prostate, seminal vesicle, brain, eye, muscle, uterus,
 

mammary gland, and ovary.
 

A few tissues were not examined for some animals, particularly
 

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

preclude histopathologic interpretation. Thus, the number of animals
 

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

animals that were placed on experiment in each group.
 

I. Data Recording and Statistical Analyses
 

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

(Linhart et al., 1974). The data elements include descriptive information on the chemicals, animals, experimental design, clinical observations, survival, body weight, and individual pathologic results,
 

as recommended by the International Union Against Cancer (Berenblum,
 

1969). Data tables were generated for verification of data transcription and for statistical review.
 

These data were analyzed using the statistical techniques described in this section. Those analyses of the experimental results
 

15
 
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) when testing two groups for
 

equality and used Tarone's (1975) extensions of Cox's methods when
 

testing a dbse-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 was examined (denominator). In most instances, the denominators included only those animals for which that site was examined
 

histologically. However, when macroscopic examination was required
 

to detect lesions prior to histologic sampling (e.g., skin or mammary
 

tumors), or when lesions could have appeared at multiple sites (e.g.,
 

lymphomas), the denominators consist of the numbers of animals necropsied.
 

16
 
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, pp. 48-52) was used to compare the tumor incidence of a control
 

group to that of a group of treated animals at each dose level. When
 

results for a number of treated groups, k, are compared simultaneously
 

with those for a control group, a correction to ensure an overall
 

significance level of 0.05 may be made. The Bonferroni inequality
 

(Miller, 1966, pp. 6-10) 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, pp. 362-365), was also used
 

when appropriate. Under the assumption of a linear trend, this test
 

determined if the slope of the dose-response curve is different from
 

zero at the one-tailed 0.05 level of significance. Unless otherwise
 

noted, the direction of the significant trend was 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
 

17
 
tumor was observed were excluded by basing the statistical tests on
 

animals that survived at least 52 weeks, unless a tumor was found at
 

the anatomic site of interest before week 52. When such an early
 

tumor was found, comparisons were based exclusively on animals that
 

survived at least as long as the animal in which the first tumor was
 

found. Once this reduced set of data was obtained, the standard procedures for analyses of the incidence of tumors (Fisher exact tests,
 

Cochran-Armitage tests, etc.) were followed.
 

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

incidence of tumors. Curves of the proportions surviving without an
 

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

during which animals died naturally or were sacrificed was entered as
 

the time point of tumor observation. Cox's methods of comparing
 

these curves were used for two groups; Tarone'fi extension to testing
 

for linear trend was used for three groups. The statistical tests for
 

the incidence of tumors which used life-table methods were one-tailed
 

and, unless otherwise noted, in the direction of a positive dose
 

relationship. Significant departures from linearity (P < 0.05, two-


tailed test) were also noted.
 

The approximate 95 percent confidence interval for the relative
 

risk of each dosed group compared to 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 treated group of animals
 

18
 
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 treated group
 

and the proportion in a control group corresponds to a relative risk
 

of unity. Values in excess of unity represent the condition of a
 

larger proportion in the treated group than in the control.
 

The lower and upper limits of the confidence interval of the
 

relative risk have been included in the tables of statistical analyses. The interpretation of the limits is that in approximately 95
 

percent of a large number of identical experiments, the true ratio
 

of the risk in a treated group of animals to that in a control group
 

would be within the interval calculated from the experiment. When
 

the lower limit of the confidence interval is greater than one, it
 

can be inferred that a statistically significant result (a P < 0.025
 

one-tailed test when the control incidence is not zero, P < 0.050
 

when the control incidence is zero) has occurred. When the lower
 

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

the lower limit indicates the absence of a significant result while
 

the upper limit indicates that there is a theoretical possibility
 

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

detected under the conditions of this test.
 

19
 
III. CHRONIC TESTING RESULTS: RATS
 

A. Body Weights and Clinical Observations
 

Compound-related mean group body weight depression was apparent
 

in male and female rats after the first 10 weeks of the study (Figure
 

2). Fluctuations in the growth curve may be due to mortality; as the
 

size of the group diminishes, the mean body weight may be subject to
 

wide variations.
 

Reddened ears and a hunched appearance were observed in all
 

treated groups by week 5. Firm distended abdomens and abdominal
 

urine stains were noted in the treated groups by week 38.
 

B. Survival
 

The estimated probabilities of survival for male and female
 

rats in the control and 1,2-dibromoethane-dosed groups are shown in
 

Figure 3.
 

For male rats the Tarone test for positive association between
 

increased dosage and accelerated mortality was significant (P <
 

0.001). Although the study was originally scheduled to last 110
 

weeks, the bioassay of male rats was terminated in week 49 due to
 

excessive deaths among both the high dose and low dose treated
 

groups: the remaining 5 high dose and 19 low dose males were sacrificed at that point. In the vehicle control rats, 9 were sacrificed
 

in week 49 and the remaining 9 were sacrificed in week 63. In the
 

untreated control group, 5 males were sacrificed in week 59 and the
 

remaining 4 in week 107. Of the 18 high dose males that died in week
 

20
 
TIME ON TEST (WEEKS) 

FIGURE 2 

GROWTH CURVES FOR 1,2-DIBROMOETHANE CHRONIC STUDY RATS 

21 
TIME ON TEST (WEEKS)

 

FIGURES 

SURVIVAL COMPARISONSOF 1,2-DIBROMOETHANE CHRONIC STUDY RATS 

22 
15, 11 had both acanthosis and hyperkeratosis of the forestomach.
 

Three rats in the high dose treated group showed evidence of gastric
 

squamous-cell carcinomas as early as week 15. Thirty of the thirty-


one high dose male rats living over 15 weeks developed squamous-cell
 

carcinomas of the stomach. A high incidence of early-developing
 

squamous-cell carcinomas was also observed in the low dose treated
 

group but no squamous-cell carcinomas were detected in the stomachs
 

of any of the rats from either control group. Thus, mortality may
 

have been associated with tumor incidence.
 

For female rats the Tarone test for positive association between
 

increased dosage and accelerated mortality was also significant (P <
 

0.001). In the high dose group, 20/50 females (40 percent) died in
 

week 15 either during intubation or shortly thereafter, suggesting
 

acute toxic reactions. High mortality in both treated groups led to
 

sacrificing all remaining dosed rats in week 61, when the 1 remaining
 

high dose and 2 remaining low dose rats were sacrificed. All of the
 

surviving vehicle control rats were sacrificed in week 63. Five of
 

the untreated control rats were sacrificed in week 59 with the remainder sacrificed in week 107. In the high dose group one rat showed
 

evidence of stomach squamous-cell carcinoma as early as week 12 and
 

two additional high dose rats showed evidence of this tumor in week
 

15. All females that survived beyond week 15 showed evidence of
 

squamous-cell carcinomas. Results were similar in the low dose rats
 

where the first squamous-cell carcinoma was observed in week 12 and
 

23
 
100 percent of those surviving beyond week 15 showed evidence of this
 

tumor; this tumor was absent in the control groups. Thus, mortality
 

may have been associated with tumor incidence.
 

C. Pathology
 

Histopathologic findings on neoplasms in rats are summarized in
 

Appendix A (Tables Al and A2); findings on nonneoplastic lesions are
 

summarized in Appendix C (Tables Cl and C2).
 

Exposure of rats to 1,2-dibromoethane by gavage was associated
 

with a dramatically increased incidence of squamous-cell carcinomas
 

originating in the forestomach in male and female rats. This malignant neoplasm occurred in 45/50 (90 percent) low dose males, 40/50
 

(80 percent) low dose females, 33/50 (66 percent) high dose males,
 

and 29/50 (58 percent) high dose females. None were observed in
 

untreated or vehicle control animals. Microscopically, these tumors
 

were characterized by acanthosis and hyperkeratosis of squamous
 

epithelium, downward growth of basal epithelium in papillary cords,
 

and sequestered nests of anaplastic cells invading the lamina propria, muscularis mucosa, submucosa, tunica muscularis and serosa of
 

the stomach and spreading to the peritoneal cavity. Metastases, by
 

peritoneal seeding or through blood vessels, were widespread and
 

usually multiple, involving nearly every organ of the abdominal
 

cavity in some animals. Several tumors metastasized to the lung.
 

An increased incidence of hepatic neoplastic nodules and carcinomas also occurred in treated animals. In animals fed high doses,
 

24
 
1/50 (2 percent) males and 1/48 (2 percent) females had neoplastic
 

nodules; and 1/50 (2 percent) males and 5/48 (10 percent) females had
 

hepatocellular carcinomas. In animals fed low doses, 2/50 (4 percent)
 

males had neoplastic nodules and 1/50 (2 percent) males and 1/47
 

(2 percent) females had hepatocellular carcinomas. In untreated animals, 1/20 (5 percent) females had hepatocellular carcinoma, while no
 

hepatic neoplasms were observed in the vehicle control groups. These
 

neoplasms occurred in numbers greater than anticipated for Osborne-


Mendel rats as a group, particularly in the high dose females; consequently, these lesions are considered to be related to the intake of
 

1,2-dibromoethane.
 

An increased incidence of hemangiosarcomas was observed in
 

treated animals. This malignant neoplasm occurred in the spleen of
 

10/50 (20 percent) low dose and 3/49 (6 percent) high dose males and
 

1/49 (2 percent) low dose and 3/48 (6 percent) high dose females. A
 

small number of other primary sites in male rats were involved:
 

liver, 3/50 (6 percent) low dose and 1/50 (2 percent) high dose; pancreas, 2/49 (4 percent) low dose; kidney, 1/50 (2 percent) high dose;
 

and abdominal cavity, 1/50 (2 percent) high dose. Microscopically,
 

most appeared as large cavernous structures although some were small
 

and highly cellular, forming slit-like vascular clefts lined by large
 

anaplastic mesenchymal cells.
 

Induction of nonneoplastic lesions by 1,2-dibromoethane was
 

recognized in several instances. In animals receiving high doses,
 

25
 
hyperkeratosis and acanthosis of the forestomach in 12/50 (24 percent)
 

males and 18/50 (36 percent) females were observed, while 4/50 (8 percent) low dose females and 1/20 (5 percent) untreated females had
 

this change. This is considered to be part of the spectrum of induced
 

lesions of the forestomach. Also, degenerative changes in the liver
 

(peliosis hepatis) and adrenal gland (cortical-cell degeneration) were
 

observed in a small number of treated males and females. Early development of testicular atrophy was observed in dosed rats.
 

Results of this histopathologic examination indicate that administration of 1,2-dibromoethane was carcinogenic in male and female
 

Osborne-Mendel rats, inducing squamous-cell carcinomas of the fore-


stomach in both sexes, hemangiosarcomas (primarily of the spleen) in
 

males and hepatocellular carcinomas in females.
 

D. Statistical Analyses of Results
 

The results of the statistical analyses of tumor incidence in
 

rats are summarized in Tables 3 and 4. The analysis is included for
 

every type of tumor in either sex where at least two such tumors were
 

observed in at least one of the control or 1,2-dibromoethane-dosed
 

groups and where such tumors were observed in at least 5 percent of
 

the group.
 

In both male and female rats significant incidences of stomach
 

squamous-cell carcinomas (often with metastases) were observed. For
 

both sexes the Cochran-Armitage tests indicated significant (P <
 

0.001) positive associations between dosage and tumor incidence.
 

26 
_ __ 

TABLE 3
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN MALE RATS TREATED WITH 1,2-DIBROMOETHANE£
 

TOPOGRAPHY: MORPHOLOGY
 

Circulatory System: Hemangiosarcoma
 

P Values
 

Departure from Linear Trend
 

Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

VEHICLE
 

CONTROL
 

0/20(0.00)
 

N.S.
 

P = 0.006
 

LOW
 

DOSE
 

11/50(0.22)
 

P = 0.017
 

Infinite
 

1.384
 

Infinite
 

31
 

HIGH
 

DOSE
 

4/50(0.08)
 

N.S.
 

Infinite
 

0.386
 

Infinite
 

27

 

Liver: Hepatocellular Carcinoma or
 

Neoplastic Nodule^
 

P Values
 

Relative Risk (Vehicle Control)d
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Stomach: Squamous-Cell Carcinoma
 

P Values0
 

Departure from Linear Trend
 

Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

0/20(0.00)
 

N.S.
 

_—
 

0/20(0.00)
 

P < 0.001
 

P < 0.001
 _
 

3/50(0.06)
 

N.S.
 

Infinite
 

0.250
 

Infinite
 

48
 

45/50(0.90)
 

P < 0.001
 

Infinite
 

6.636
 

Infinite
 

31
 

2/50(0.04)
 

N.S.
 

Infinite
 

0.123
 

Infinite
 

47
 

33/50(0.66)
 

P < 0.001
 

Infinite
 

4.627
 

Infinite
 

15
 

26 
___ 

TOPOGRAPHY: MORPHOLOGY
 

Kidney: Hamartoma* or Mixed Tumor
 

Malignantb
 

P Values
 

Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Thyroid: Follicular-Cell Adenoma or
 

Follicular-Cell Carcinoma*5
 

P Values0
 

Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

TABLE 3 (CONTINUED)
 

VEHICLE
 

CONTROL
 

0/20(0.00)
 

N.S.
 

0/20(0.00)
 

P = 0.042
 

LOW HIGH
 

DOSE DOSE
 

2/49(0.04) 4/50(0.08)
 

N.S. N.S.
 

Infinite Infinite
 

0.125 0.386
 

Infinite Infinite
 

37 41
 

5/50(0.10) 8/49(0.16)
 

N.S. N.S.
 

Infinite Infinite
 

0.525 0.972
 

Infinite Infinite
 

44 15
 

28 

*This is considered to be a benign form of the malignant mixed tumor of the kidney and consists
 

of proliferative lipocj^tes, tubular structures, fibroblasts, and vascular spaces in varying
 

proportions.
 
29

 

TABLE 3 (CONCLUDED)
 

Treated groups received time-weighted average doses of 38 or 41 rag/kg by gavage.
 

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

The probability level for the Cochran-Armitage test is given beneath the incidence of tumors in
 

the control group when P < 0.05; otherwise, not significant (N.S.) is indicated. The probability
 

level for the Fisher exact test for the comparison of a treated group with the control group is
 

given beneath the incidence of tumors in the treated group when P < 0.05; otherwise, not significant (N.S.) is indicated. For both Cochran-Armitage and Fisher exact tests a negative designation (N) indicates a lower incidence in the treated groups(s) than in the control group.
 

The 95% confidence interval on the relative risk of the treated group to the control group.
 Q
 

The probability level of the test for departure from linear trend is given beneath the control
 

group when P < 0.05.
 
TABLE 4
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN FEMALE RATS TREATED WITH 1,2-DIBROMOETHANE£
 

30 

TOPOGRAPHY: MORPHOLOGY
 

Circulatory System: Hemangio sarcoma
 

P Values0
 

Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Liver: Hepatocellular Carcinoma
 

P Values0
 

Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Liver: Hepatocellular Carcinoma or
 

Neoplastic Nodule"
 

P Values0
 

Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

VEHICLE LOW HIGH 

CONTROL DOSE DOSE 

0/20(0.00) 1/49(0.02) 3/48(0.06) 

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

—_ Infinite Infinite 

0.023 0.261 

Infinite Infinite 

38 42 

0/20(0.00) 1/47(0.02) 5/48(0.10) 

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

Infinite Infinite 

0.023 0.547 

Infinite Infinite 

61 33 

0/20(0.00) 1/41(0.02) 6/48(0.13) 

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

Infinite Infinite 

0.027 0.695 

Infinite Infinite 

61 33 
TABLE 4 (CONTINUED) 

TOPOGRAPHY: MORPHOLOGY 

VEHICLE 

CONTROL 

LOW 

DOSE 

HIGH 

DOSE 

Stomach: Squamous-Cell Carcinoma 0/20(0.00) 40/50(0.80) 29/50(0.58) 

P Values 

g

Departure from Linear Trend 

Relative Risk (Vehicle Control) 

Lower Limit 

Upper Limit 

P < 0.001 

P < 0.001 ___ 

P < 0.001 

Infinite 

5.737 

Infinite 

P < 0.001 

Infinite 

4.021 

Infinite 

Weeks to First Observed Tumor 12 12 

u> 

H-1 

Adrenal: Cortical Adenoma or Cortical 

Carcinoma*3 

P Values0 

0/20(0.00) 

N.S. 

0/44(0.00) 

N.S. 

4/45(0.09) 

N.S. 

Relative Risk (Vehicle Control)d 

Lower Limit 

Upper Limit 

Infinite 

0.429 

Infinite 

Weeks to First Observed Tumor 47 

Mammary Gland: Adenoma NOS or Adenocarcinoma NOS^ 1/20(0.05) 0/50(0.00) 2/50(0.04) 

P Values0
 N.S.
 w• <&

N.S.
 

Relative Risk (Vehicle Control) 0.000 0.800 

Lower Limit 0.000 0.045 

Upper Limit 7.475 46.273 

Weeks to First Observed Tumor 33 
_ __ 

32 

TABLE 4 (CONCLUDED)
 

VEHICLE LOW HIGH 

TOPOGRAPHY: MORPHOLOGY CONTROL DOSE DOSE 

Mammary Gland: Adenoma NOS or Fibroadenoma" 0/20(0.00) 0/50(0.00) 3/50(0.06) 

P Values0 N.S. N.S. N.S. ___ 

Relative Risk (Vehicle Control) Infinite
 

Lower Limit 0.250
 

Upper Limit Infinite
 

Weeks to First Observed Tumor 33
 

Treated groups received time-weighted average doses of 37 or 39 rag/kg by gavage.
 

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

The probability level for the Cochran-Armitage test is given beneath the incidence of tumors in
 

the control group when P < 0.05; otherwise, not significant (N.S.) is indicated. The probability
 

level for the Fisher exact test for the comparison of a treated group with the control group is
 

given beneath the incidence of tumors in the treated group when P < 0.05; otherwise, not significant (N.S.) is indicated. For both Cochran-Armitage and Fisher exact tests a negative designation (N) indicates a lower incidence in the preated group(s) than in the control group.
 

The 95% confidence interval on the relative risk of the treated group to the control group.
 

The probability level of the test for departure from linear trend is given beneath the control
 

group when P < 0.05.
 
For both male and female rats the Fisher exact tests supported these
 

findings with significant (P < 0.001) comparisons of both high and
 

low dose to control. Based upon these results, the administration
 

of 1,2-dibromoethane was associated with an increased incidence of
 

squamous-cell carcinomas of the stomach in both male and female rats.
 

Because of the early mortality noted in treated rats, additional,
 

time-adjusted analyses were conducted for selected tumors. These
 

analyses, which included only those rats surviving at least until the
 

time of the appearance of the first tumor of that type, are included
 

in Tables 5 and 6.
 

For females when incidences were combined so that the numerator
 

represented rats with either a hepatocellular carcinoma or a neoplastic
 

nodule of the liver, the Cochran-Armitage test using the time-adjusted
 

incidences showed a significant (P = 0.014) positive association between dosage and tumor incidence. This was supported by a significant
 

(P = 0.022) Fisher exact test comparison of high dose to vehicle control. Based upon these results, the administration of 1,2-dibromoethane was associated with the combined incidence of hepatocellular
 

carcinomas and neoplastic nodules of the liver in female rats.
 

In male rats the incidence of hemangiosarcomas was increased in
 

the low dose group compared to the controls. For the time-adjusted
 

data the Fisher exact test showed a significant (P = 0.018) comparison
 

of the low dose group to the vehicle control. The Cochran-Armitage
 

test, however, was not significant. Although the incidence rate in
 

33
 
TABLE 5
 

TIME-ADJUSTED ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN MALE RATS TREATED WITH l,2-DIBROMOETHANEa
 

34

 

TOPOGRAPHY: MORPHOLOGY 

VEHICLE 

CONTROL 

LOW 

DOSE 

Liver: Hepatocellular Carcinoma or 

Neoplastic Nodule"3'6 0/18(0.00) 3/26(0.12) 

P Values N.S. N.S. 

Relative Risk (Vehicle Control) 

Lower Limit 

Upper Limit 

Infinite 

0.438 

Infinite 

Weeks to First Observed Tumor 48 

Kidney: Hamartoma* or Mixed Tumor 

Malignantb'e 

P Values0 

0/18(0.00) 

N.S. 

2/44(0.05) 

N.S. 

Relative Risk (Vehicle Control) 

Lower Limit 

Upper Limit 

Infinite 

0.126 

Infinite 

Weeks to First Observed Tumor 37 

b e Circulatory System: Hemangiosarcoma ' 0/20(0.00) 11/50(0.22) 

P Values0 N.S. P = 0.018 

Relative Risk (Vehicle Control) 

Lower Limit 

Upper Limit 

Infinite 

1.384 

Infinite 

Weeks to First Observed Tumor 31 

HIGH
 

DOSE
 

2/9(0.22)
 

N.S.
 

Infinite
 

0.627
 

Infinite
 

47
 

4/28(0.14)
 

N.S.
 

Infinite
 

0.628
 

Infinite
 

41
 

4/27(0.15)
 

N.S.
 

Infinite
 

0.718
 

Infinite
 

26
 

*This is considered to be a benign form of the malignant mixed tumor of the kidney and consists
 

of proliferative lipocytes, tubular structures, fibroblasts, and vascular spaces in varying
 

proportions.
 
35 

TABLE 5 (CONCLUDED)
 

TOPOGRAPHY: MORPHOLOGY 

VEHICLE 

CONTROL 

LOW 

DOSE 

HIGH 

DOSE 

Thyroid: Folllcular-Cell Adenoma or 

Follicular-Cell Carcinomab'e 

P Values0 

0/20(0.00) 

P = 0.040 

5/50(0.10) 

N.S. 

8/48(0.17) 

N.S. 

Relative Risk (Vehicle Control) 

Lower Limit 

Upper Limit 

—_ Infinite 

0.525 

Infinite 

Infinite 

0.992 

Infinite 

Weeks to First Observed Tumor 44 15 

Treated groups received time-weighted average doses of 38 or 41 mg/kg by gavage.
 

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

The probability level for the Cochran-Armitage test is given beneath the incidence of tumors
 

in the control group when P < 0.05; otherwise, not significant (N.S.) is indicated. The probability
 

level for the Fisher exact test for the comparison of a treated group with the control group is
 

given beneath the incidence of tumors in the treated group when P < 0.05; otherwise, not significant (N.S.) is indicated. For both Cochran-Armitage and Fisher exact tests a negative designa­ tion (N) indicates a lower incidence in the treated group(s) than in the control group.
 

The 95% confidence interval on the relative risk of the treated group to the control group.
 

e

These analyses were based solely upon animals surviving at least 52 weeks, except for sites
 

where the first tumor of interest was observed earlier than 52 weeks in any group of this sex
 

and species, where the analyses were based upon all animals that survived until or past the
 

date that the first tumor was observed.
 
___ 

TABLE 6
 

TIME-ADJUSTED ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN FEMALE RATS TREATED WITH 1,2-DIBROMOETHANE*
 

36

 

TOPOGRAPHY :MORPHOLOGY
 

Liver: Hepatocellular Carcinoma '
 

P Values0
 

Departure from Linear Trend
 

Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Liver: Hepatocellular Carcinoma or
 

Neoplastic Nodule^»f
 

P Values0
 

Departure from Linear Trend
 

Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Adrenal: Cortical Adenoma or Cortical
 

Carcinoma^ > f
 

P Values0
 

Departure from Linear Trend
 

Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

VEHICLE
 

CONTROL
 

0/20(0.00)
 

P = 0.028
 

P = 0.016
 

«_
 

0/20(0.00)
 

P = 0.014
 

P = 0.006
 

0/20(0.00)
 

N.S.
 

P - 0.008
 

LOW
 

DOSE
 

1/35(0.03)
 

N.S.
 

Infinite
 

0.032
 

Infinite
 

61
 

1/35(0.03)
 

N.S.
 

Infinite
 

0.032
 

Infinite
 

61
 

0/19(0.00)
 

N.S.
 

HIGH
 

DOSE
 

5/25(0.20)
 

P = 0.043
 

Infinite
 

1.058
 

Infinite
 

33
 

6/25(0.24)
 

P = 0.022
 

Infinite
 

1.345
 

Infinite
 

33
 

4/17(0.24)
 

P = 0.036
 

Infinite
 

1.150
 

Infinite
 

47
 
37 

TABLE 6 (CONCLUDED)
 

Treated groups received time-weighted average doses of 37 or 39 mg/kg by gavage.
 

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

The probability level for the Cochran-Armitage test is given beneath the incidence of tumors in
 

the control group when P < 0.05; otherwise, not significant (N.S.) is indicated. The probability
 

level for the Fisher exact test for the comparison of a treated group with the control group is
 

given beneath the incidence of tumors in the treated group when P < 0.05; otherwise, not significant (N.S.) is indicated. For both Cochran-Armitage and Fisher exact tests a negative designation (N) indicates a lower incidence in the treated group(s) than in the control group.
 

The 95% confidence interval on the relative risk of the treated group to the control group.
 

e

The probability level of the test for departure from linear trend is given beneath the control
 

group when P < 0.05.
 

These analyses were based solely upon animals surviving at least 52 weeks, except for sites
 

where the first tumor of interest was observed earlier than 52 weeks in any group of this
 

sex and species, where the analyses were based upon all animals that survived until or past
 

the date that the first tumor was observed.
 
the high dose was 4/27 (15 percent) compared to 0/20 in the control,
 

the high dose to control Fisher exact test was not significant.
 

In female rats increases in the combined incidence of cortical
 

adenomas or cortical carcinomas of the adrenal gland were observed.
 

Neither the Cochran-Armitage test nor the Fisher exact tests, however,
 

were significant under the Bonferroni criterion.
 

In male rats the treated groups showed an increased incidence
 

of thyroid tumors. For the time-adjusted statistical analysis, the
 

Cochran-Armitage test showed a significant (P = 0.040) positive association between dosage and the combined incidence of follicular-cell
 

adenomas or follicular-cell carcinomas of the thyroid.
 

38
 
IV. CHRONIC TESTING RESULTS: MICE
 

A. Body Weights and Clinical Observations
 

Dose-related mean body weight depression was apparent in both
 

male and female mice from week 10 through the remainder of the bioassay (Figure 4). Fluctuations in the growth curve may be due to mortality; as the size of the group diminishes, the mean body weight may
 

be subject to wide variations.
 

In week 7 alopecia was observed among treated animals. Nine high
 

dose males and 13 high dose females died between weeks 12 and 14 and
 

at that time all surviving animals had soft feces, alopecia, and body
 

sores. These observations, as well as a thin, hunched appearance,
 

increased in high dose groups as the study progressed. In week 42
 

small inguinal nodules were observed on some of the low dose males.
 

B. Survival
 

The estimated probabilities of survival for male and female
 

mice in the control and 1,2-dibromoethane-dosed groups are shown in
 

Figure 5.
 

For male mice the Tarone test for positive association between
 

increased dosage and accelerated mortality was significant (P <
 

0.001). Due to excessive deaths among the treated animals, the study
 

was terminated in week 78: only 20 percent (10/50) of the high dose
 

and 40 percent (20/50) of the low dose mice survived for at least 58
 

weeks. The 18/20 vehicle control mice (90 percent) surviving to week
 

59 were sacrificed at that time. Mortality was somewhat higher than
 

39
 
FIGURE 4

 

GROWTH CURVES FOR 1,2-DIBROMOETHANE CHRONIC STUDY MICE 

40 
TIME ON TEST (WEEKS) 

FIGURES 

SURVIVAL COMPARISONS OF 1,2-DIBROMOETHANE CHRONIC STUDY MICE 

41 
expected among the untreated controls, with only 70 percent (14/20)
 

remaining alive by week 58. Seventy-eight percent (31/40) of the
 

high dose males and 92 percent (42/46) of the low dose males surviving at least 26 weeks developed a squamous-cell carcinoma of the
 

forestomach. This tumor was not observed in male mice of either
 

control group.
 

For female mice the Tarone test showed a significant (P < 0.001)
 

positive association between dosage and mortality. The high dose
 

group was terminated in week 78, while the low dose group was not
 

terminated until week 90. Sixteen percent (8/50) of the high dose,
 

56 percent (28/50) of the low dose, and 95 percent (19/20) of the
 

untreated control animals survived at least 70 weeks. The 18 vehicle
 

controls (90 percent) remaining alive in week 58 were sacrificed in
 

weeks 59 and 60. Seventy-six percent (28/37) of the high dose female
 

mice alive in week 14 developed a squamous-cell carcinoma of the
 

forestomach. In the low dose group, all mice surviving longer than
 

week 18 for which tissues were available for examination developed a
 

forestomach squamous-cell carcinoma. No control mice developed this
 

tumor.
 

C. Pathology
 

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).
 

42
 
Exposure of mice to 1,2-dibromoethane by gavage was associated
 

with a dramatically increased incidence of squamous-cell carcinomas
 

of the forestomach of male and female mice. This malignant gastric
 

neoplasm was observed in 29/49 (59 percent) high dose males, 28/50
 

(56 percent) high dose females, 45/50 (90 percent) low dose males,
 

and 46/49 (94 percent) low dose females; none were observed in the
 

untreated or vehicle controls. The microscopic appearance and distribution of metastases of this neoplasm to the peritoneal cavity and
 

lung were similar to those described in rats. In addition, squamouscell papillomas of the forestomach were recognized in 2/49 (4 percent)
 

high dose males and 1/49 (2 percent) low dose females that did not
 

have carcinomas. These are considered to be part of the spectrum of
 

induced gastric lesions.
 

Increased numbers of primary lung neoplasms were also noted in
 

treated animals. Alveolar/bronchiolar adenomas occurred in 10/47 (21
 

percent) high dose males, 6/46 (13 percent) high dose females, 4/45
 

(9 percent) low dose males, and 10/43 (23 percent) low dose females.
 

Additionally, an alveolar/bronchiolar carcinoma occurred in 1/43 (2
 

percent) low dose females. No pulmonary neoplasms were observed in
 

control mice; consequently, the tumors are considered to be compound-


related.
 

Nonneoplastic lesions related to intake of 1,2-dibromoethane were
 

observed in several instances. In the forestomach, acanthosis was recognized in 5/49 (10 percent) high dose males, 9/50 (18 percent) high
 

43
 
dose females, and 1/50 (2 percent) low dose males. Hyperkeratosis
 

occurred in the stomach of 13/49 (27 percent) high dose males, 12/50
 

(24 percent) high dose females, and 1/49 (2 percent) low dose females.
 

These two related changes are considered to be part of the spectrum
 

of gastric lesions induced by 1,2-dibromoethane.
 

Additionally, testicular atrophy related to compound administration occurred in males receiving high doses.
 

The histopathologic examination indicated that under the conditions of this experiment administration of 1,2-dibromoethane was
 

carcinogenic in male and female B6C3F1 mice, inducing squamous-cell
 

carcinomas of the forestomach and pulmonary adenomas.
 

D. Statistical Analyses of Results
 

The results of the statistical analyses of tumor incidence in
 

mice are summarized in Tables 7 and 8. The analysis is included for
 

every type of tumor in either sex where at least two such tumors were
 

observed in at least one of the control or 1,2-dibromoethane-dosed
 

groups and where such tumors were observed in at least 5 percent of
 

the group.
 

In both male and female mice significant incidences of stomach
 

squamous-cell carcinomas (often with metastases) were observed. For
 

both sexes the Cochran-Armitage tests indicated significant (P <
 

0.011) positive associations between dosage and tumor incidence using
 

either the untreated or the vehicle controls. The Fisher exact tests
 

confirmed these findings with significant (P < 0.001) comparisons of
 

44
 
___

___

TABLE 7
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN MALE MICE TREATED WITH 1,2-DIBROMOETHANE3
 

TOPOGRAPHY :MORPHOLOGY
 

Hematopoietic System: Leukemia or
 

Malignant Lymphoma'3
 

P Values
 

Departure from Linear Trend
 

Relative Risk (Untreated Control)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Vehicle Control)d
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Lung: Alveolar/Bronchiolar Adenoma
 

P Values0
 

Relative Risk (Untreated Control)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

UNTREATED


CONTROL


3/20(0.15)


N.S.


P = 0.025
 

76
 

0/18(0.00)


P = 0.011


 VEHICLE
 

 CONTROL
 

 0/20(0.00)
 

 N.S.
 

___
 

 0/20(0.00)
 

P = 0.009
 

___
 

LOW
 

DOSE
 

1/50(0.02)
 

N.S.
 

0.133
 

0.003
 

1.568
 

Infinite
 

0.022
 

Infinite
 

72
 

4/45(0.09)
 

N.S.
 

Infinite
 

0.389
 

Infinite
 

Infinite
 

0.429
 

Infinite
 

58
 

HIGH
 

DOSE
 

2/49(0.04)
 

N.S.
 

0.272
 

0.025
 

2.233
 

Infinite
 

0.125
 

Infinite
 

59
 

10/47(0.21)
 

P = 0.029*
 

P = 0.021**
 

Infinite
 

1.197
 

Infinite
 

Infinite
 

1.320
 

Infinite
 

26
 

45

 
46

 

TABLE 7 (CONTINUED) 

TOPOGRAPHY : MORPHOLOGY 

UNTREATED 

CONTROL 

VEHICLE 

CONTROL 

LOW 

DOSE 

HIGH 

DOSE 

Stomach: Squamous-Cell

P Values0 

 Carcinoma 0/20(0.00) 

P = 0.003 

0/20(0.00) 

P = 0.003 

45/50(0.90) 

P < 0.001* 

P < 0.001** 

29/49(0.59) 

P < 0.001* 

P < 0.001** 

Departure from Linear Trend P < 0.001 P < 0.001 

Relative Risk (Untreated Control) 

Lower Limit 

Upper Limit 

Relative Risk (Vehicle Control)

d 

Lower Limit 

Upper Limit 

Infinite 

6.638 

Infinite 

Infinite 

6.638 

Infinite 

Infinite 

4.108 

Infinite 

Infinite 

4.108 

Infinite 

Weeks to First Observed Tumor 24 26 

Stomach: Squamous-Cell Papilloma

Squamous-Cell Carcinoma*' 

P Values0 

 or 

0/20(0.00) 

P = 0.001 

0/20(0.00) 

P = 0.001 

45/50(0.90) 

P < 0.001* 

P < 0.001** 

31/49(0.63) 

P < 0.001* 

P < 0.001** 

Departure from Linear Trend P < 0.001 P < 0.001 

Relative Risk (Untreated Control) 

Lower Limit 

Upper Limit 

Relative Risk (Vehicle Control)

d 

Lower Limit 

Upper Limit 

_ 

Infinite 

6.636 

Infinite 

Infinite 

6.636 

Infinite 

Infinite 

4.411 

Infinite 

Infinite 

4.411 

Infinite 

Weeks to First Observed Tumor 24 26 
TABLE 7 (CONCLUDED)
 

treated groups received time-weighted average doses of 62 or 107 mg/kg by gavage.
 

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

c,
The probability level for the Cochran-Armitage tes6 is given beneath the incidence of tumors
 

in the corresponding control group when P < 0.05; otherwise, not significant (N.S.) is indicated. The probability level for the Fisher exact test for the comparison of a treated
 

group with the untreated control group (*) or the vehicle control group (**) is given beneath
 

the incidence of tumors in that treated group when P < 0.05; otherwise, not significant (N.S.)
 

is indicated. For both Cochran-Armitage and Fisher exact tests a negative designation (N)
 

indicates a lower incidence in the treated group(s) than in the control group.
 

The 95% confidence interval on the relative risk of the treated group to the control group.
 

£

The probability level of the test for departure from linear trend is given beneath the control
 

group when P < 0.05.
 47 
TABLE 8
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN FEMALE MICE TREATED WITH 1,2-DIBROMOETHANE£
 

TOPOGRAPHY : MORPHOLOGY
 

Hematopoietic System: Malignant
 

Lymphoma'-'
 

P Values0
 

Departure from Linear Trend
 

Relative Risk (Untreated Control)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Lung: Alveolar/Bronchiolar Adenoma
 

P Values0
 

Departure from Linear Trend
 

Relative Risk (Untreated Control)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

UNTREATED
 

CONTROL
 

5/20(0.25)
 

P < 0.001
 

P = 0.123
 

90
 

0/20(0.00)
 

N.S.
 

P = 0.020
 

VEHICLE LOW 

CONTROL DOSE 

0/20(0.00) 1/48(0.02) 

N.S. P = 0.007*(N) 

P = 0.226 

0.083 

0.002 

0.690 

0.417 

0.006 

32.057 

85 

0/20(0.00) 10/43(0.23) 

N.S. P = 0.015* 

P = 0.015** 

P = 0.020 

Infinite 

1.445 

Infinite 

Infinite 

1.445 

Infinite 

50 

HIGH
 

DOSE
 

0/50(0.00)
 

P < 0.001*(N)
 

0.000
 

0.000
 

0.313
 

0.000
 

0.000
 

7.475
 

6/46(0.13)
 

N.S.
 

Infinite
 

0.725
 

Infinite
 

Infinite
 

0.725
 

Infinite
 

49
 

48

 
TABLE 8 (CONTINUED)
 

49

 

TOPOGRAPHY : MORPHOLOGY 

UNTREATED 

CONTROL 

VEHICLE 

CONTROL 

LOW 

DOSE 

HIGH 

DOSE 

Lung: Alveolar/ Bronchiolar Adenoma

Carcinoma^ 

 or 

0/20(0.00) 0/20(0.00) 11/43(0.26) 6/46(0.13) 

P Values N.S. N.S. P

P

 =

 =

 0.009* 

 0.009** 

N.S. 

Departure from Linear Trend P = 0.010 P = 0.010 

Relative Risk (Untreated Control) 

Lower Limit 

Upper Limit 

_ _— Infinite 

1.614 

Infinite 

Infinite 

0.725 

Infinite 

Relative Risk (Vehicle Control) 

Lower Limit 

Upper Limit 

Infinite 

1.614 

Infinite 

Infinite 

0.725 

Infinite 

Weeks to First Observed Tumor 50 49 

Stomach: Squamous-Cell Carcinoma 0/20(0.00) 0/20(0.00) 46/49(0.94) 28/50(0.56) 

P Values P = 0.011 P = 0.011 P

P

 < 0.001* 

< 0.001** 

P

P

 < 0.001* 

< 0.001** 

Departure from Linear Trend6 P < 0.001 P < 0.001 

Relative Risk

Relative Risk

 (Untreated Control) 

Lower Limit 

Upper Limit 

 (Vehicle Control)

d 

Lower Limit 

Upper Limit 

Infinite 

7.101 

Infinite 

Infinite 

7.101 

Infinite 

Infinite 

3.880 

Infinite 

Infinite 

3.880 

Infinite 

Weleks to First Observed Tumor 40 34 
TOPOGRAPHY :MORPHOLOGY 

Mammary Gland: Adenocarcinoma,NOS 

P Values 

Relative Risk (Untreated Control) 

Lower Limit 

Upper Limit 

Relative Risk (Vehicle Control) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 

TABLE 8 (CONTINUED) 

UNTREATED 

CONTROL 

0/20(0.00) 

N.S. 

VEHICLE 

CONTROL 

0/20(0.00) 

N.S. 

LOW 

DOSE 

3/48(0.06) 

N.S. 

Infinite 

0.261 

Infinite 

Infinite 

0.261 

Infinite 

82 

HIGH 

DOSE 

1/50(0.02) 

N.S. 

Infinite 

0.022 

Infinite 

Infinite 

0.022 

Infinite 

50 

Uterus: Endometrial Stromal Polyp 

P Values0 

Relative Risk (Untreated Control) 

Lower Limit 

Upper Limit 

Relative Risk (Vehicle Control)

d 

Lower Limit 

Upper Limit 

Weleks to First Observed Tumor 

1/20(0.05) 0/20(0.00) 1/38(0.03) 3/44(0.07) 

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

0.526 1.364 

0.007 0.120 

40.260 69.919 

Infinite Infinite 

0.029 0.284 

Infinite Infinite 

90 90 67 

54 
51

 

TABLE 8 (CONCLUDED) 

Treated groups received time-weighted average doses of 62 or 107 mg/kg by gavage. 

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

The probability level for the Cochran-Armitage test is given beneath the incidence of tumors 

in the corresponding control group when P < 0.05; otherwise, not significant (N.S.) is indicated. The probability level for the Fisher exact test for the compa rison of a treated 

group with the untreated control group (*) or the vehicle control group (**) is given beneath 

the incidence of tumors in that treated group when P < 0.05; otherwise, not significant (N.S.) 

is indicated. For both Cochran-Armitage and Fisher exact tests a negative designation (N) 

indicates a lower incidence in the treated group(s) than in the control group. 

The 95% confidence interval on the relative risk of the treated group to the control group, g

The probability level of the test for departure from linear trend is given beneath the control 

group when P < 0.05. 
both high and low dose to each control for both male and female mice.
 

A significant (P < 0.001) departure from linearity was also observed
 

for both sexes since there was a sharp increase in this tumor incidence in the dosed mice. Based upon these results, the administration of 1,2-dibromoethane was associated with the incidence of
 

squamous-cell carcinomas of the stomach in both male and female mice.
 

In female mice, the Cochran-Armitage and Fisher exact tests
 

indicated a negative association between dosage and the incidence of
 

malignant lymphomas. This result appears related to the shorter
 

survival of dosed mice.
 

Because of the poor survival noted in the treated mice and because of the sacrifice of all male and female vehicle control mice
 

(the controls of choice) in weeks 59 and 60, additional, time-adjusted
 

analyses were conducted. In performing these time-adjusted analyses,
 

it was necessary first to adjust for the numerous deaths before the
 

mice had been at risk of developing neoplasms for an adequate period.
 

This was done by including only those mice which survived at least 52
 

weeks or, if the tumor of interest occurred earlier, at least until
 

the first tumor of that type was observed. Due to the sacrifice of
 

the vehicle controls it was also necessary to adjust for those dosed
 

mice which survived longer than (and hence were at risk longer than)
 

the vehicle controls. When the vehicle controls were sacrificed it
 

was principally because these mice were approaching a moribund stage.
 

To adjust for this problem, only those mice surviving less than 64
 

52
 
weeks were used in these analyses. The results of these analyses are
 

presented in Tables 9 and 10 for selected tumors.
 

In both male and female mice the incidence of alveolar/bronchiolar
 

adenomas was increased in the treated groups compared to the control
 

groups. Using the time-adjusted analysis for males, the Cochran-


Armitage test showed a significant (P = 0.004) positive association
 

between dosage and incidence. This was supported by a significant
 

Fisher exact test result in comparing the high dose to the vehicle
 

control (P = 0.020). For females, using the time-adjusted analysis,
 

the Cochran-Armitage test was also significant (P = 0.018). The
 

Fisher exact test was significant for the comparisons of the high
 

dose to vehicle control (P = 0.024). Historically, corn oil vehicle
 

control B6C3F1 mice at Hazelton Laboratories used in the NCI Carcinogenesis Testing Progam showed incidence levels of 7/180 (4 percent)
 

alveolar/bronchiolar adenomas in males and 6/180 (3 percent) in
 

females. Based on these results, the administration of 1,2-dibromoethane was associated with the incidence of alveolar/bronchiolar
 

adenomas in both male and female B6C3F1 mice.
 

53
 
TABLE 9
 

TIME-ADJUSTED ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT SPECIFIC
 

SITES IN MALE MICE TREATED WITH 1,2-DIBROMOETHANEa

>f
 

TOPOGRAPHY: MORPHOLOGY
 

Lung: Alveolar/Bronchiolar Adenoma
 

P Values
 

Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Stomach: Squamous-Cell Carcinoma
 

P Values0
 

Departure from Linear Trend
 

Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

VEHICLE LOW HIGH 

CONTROL DOSE DOSE 

0/19(0.00) 1/30(0.03) 8/34(0.24) 

P = 0.004 N.S. P = 0.020 ___ Infinite Infinite 

0.035 1.341 

Infinite Infinite 

58 26 

0/19(0.00) 29/31(0.94) 24/34(0.71) 

P < 0.001 P < 0.001 P < 0.001 

P < 0.001 

Infinite Infinite 

6.743 4.690 

Infinite Infinite 

24 26 

54

 
55 

TABLE 9 (CONCLUDED)
 

Treated groups received time-weighted average doses of 62 or 107 mg/kg by gavage.
 

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

The probability level for the Cochran-Armitage test is given beneath the incidence of tumors in
 

the control group when P < 0.05; otherwise, not significant (N.S.) is indicated. The probability
 

level for the Fisher exact test for the comparison of a treated group with the control group is
 

given beneath the incidence of tumors in the treated group when P < 0.05; otherwise, not significant (N.S.) is indicated. For both Cochran-Armitage and Fisher exact tests a negative designation (N) indicates a lower incidence in the treated group(s) than in the control group.
 

The 95% confidence interval on the relative risk of the treated group to the control group.
 Q
 

The probability level of the test for departure from linear trend is given beneath the control
 

group when P < 0.05.
 

These time-adjusted analyses include those mice surviving less than 64 weeks but surviving at
 

least as long as the earliest time at which the tumor of interest was observed in any of the
 

groups.
 
TABLE 10
 

TIME-ADJUSTED ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT SPECIFIC
 

SITES IN FEMALE MICE TREATED WITH l,2-DIBROMOETHANEa>f
 

56

 

TOPOGRAPHY: MORPHOLOGY
 

Lung: Alveolar/Bronchiolar Adenoma
 

P Values0
 

Relative Risk (Vehicle Control)d
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Stomach: Squamous-Cell Carcinoma
 

P Values0
 

Departure from Linear Trend
 

Relative Risk (Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

VEHICLE LOW HIGH 

CONTROL DOSE DOSE 

0/19(0.00) 2/10(0.20) 4/14(0.29) 

P ­ 0.018 N.S. P = 0.024 

_—_ Infinite Infinite 

0.592 1.338 

Infinite Infinite 

50 49 

0/19(0.00) 9/10(0.90) 11/14(0.79) 

P < 0.001 P < 0.001 P < 0.001 

P = 0.004 ___ 

Infinite Infinite 

5.914 5.051 

Infinite Infinite 

40 34 
57 

TABLE 10 (CONCLUDED)
 

treated groups received time-weighted average doses of 62 or 107 mg/kg by gavage.
 

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

The probability level for the Cochran-Armitage test is given beneath the incidence of tumors in
 

the control group when P < 0.05; otherwise, not significant (N.S.) is indicated. The probability
 

level for the Fisher exact test for the comparison of a treated group with the control group is
 

given beneath the incidence of tumors in the treated group when P < 0.05; otherwise, not significant (N.S.) is indicated. For both Cochran-Armitage and Fisher exact tests a negative designa­ tion (N) indicates a lower incidence in the treated group(s) than in the control group.
 

The 95% confidence interval on the relative risk of the treated group to the control group.
 

The probability level of the test for departure from linear trend is given beneath the control
 

group when P < 0.05.
 

These time-adjusted analyses include those mice surviving less than 64 weeks but surviving at
 

least as long as the earliest time at which the tumor of interest was observed in any of the
 

groups.
 
V. DISCUSSION
 

Under the conditions of this bioassay there was a significant
 

positive association between increased dosage and accelerated mortality in rats and mice of both sexes. Although the study was originally
 

designed to last 110 weeks for rats and 90 weeks for mice, these bioassays were terminated early due to poor survival and the early onset
 

of cancer. The accelerated mortality in both species appeared to be
 

associated with cancer of the forestomach. A preliminary report of
 

some of these findings from the same study reported here has already
 

been published (Olson et al., 1973).
 

In both species there were dramatically increased incidences of
 

squamous-cell carcinomas of the forestomach. These tumors appeared
 

early, invaded locally, and eventually metastasized throughout the
 

abdominal cavity. In addition, hyperkeratosis and acanthosis, considered to be components of the spectrum of chemically induced gastric
 

lesions, were present in many of the high dose rats and mice. In rats
 

squamous-cell carcinomas of the forestomach occurred in 45/50 (90 percent), 33/50 (66 percent), 40/50 (80 percent), and 29/50 (58 percent)
 

of the low dose males, high dose males, low dose females, and high
 

dose females, respectively, and in mice they were detected in 45/50
 

(90 percent), 29/49 (59 percent), 46/49 (94 percent), and 28/50 (56
 

percent) of the low dose males, high dose males, low dose females,
 

and high dose females. These lesions were seen as early as week 12
 

in rats and week 24 in mice. None were observed in untreated or
 

58
 
vehicle control rats or mice. For each sex of both species the
 

Cochran-Armitage tests indicated a significant positive association
 

between dosage and tumor incidence. These associations were substantiated in each case by Fisher exact comparisons of the high and low
 

dose group to both types of controls.
 

Increased incidences of hepatic lesions (i.e., neoplastic nodules and hepatocellular carcinomas) were observed in dosed rats,
 

particularly among high dose females. When the incidences of hepatocellular carcinoma in females were adjusted to include only those
 

surviving at least until the first hepatocellular carcinoma was observed (33 weeks), the Cochran-Armitage test indicated a significant
 

positive association between dosage and incidence, and this association was substantiated by the high dose to control Fisher exact comparison. Increased incidences of hemangiosarcomas were observed in
 

all dosed rat groups, but the incidence was statistically significant
 

only for low dose males. These lesions appeared as early as week 26
 

in male rats. That the incidence in the low dose group exceeded that
 

in the high dose group may be due to the higher rate of early deaths
 

among high dose rats.
 

The incidences of alveolar/bronchiolar adenomas in mice dosed
 

with 1,2-dibromoethane were elevated relative to controls. These
 

pulmonary neoplasms were detected in 4/45 (9 percent) low dose and
 

10/47 (21 percent) high dose males and in 10/43 (23 percent) low dose
 

and 6/46 (13 percent) high dose females, but in no controls of either
 

59
 
sex. The Cochran-Armitage test indicated significant positive associations between dosage and incidence for male and female mice.
 

These associations were supported by the high dose to control Fisher
 

exact comparisons for both sexes.
 

Under the conditions of this bioassay 1,2-dibromoethane was
 

carcinogenic to Osborne-Mendel rats and B6C3F1 mice. The compound
 

induced squamous-cell carcinomas of the forestomach in rats of both
 

sexes, hepatocellular carcinomas in female rats and hemangiosarcomas
 

in male rats. In mice of both sexes the compound induced squamouscell carcinomas of the forestomach and alveolar/bronchiolar adenomas.
 

60
 
VI. BIBLIOGRAPHY
 

Armitage, P., Statistical Methods in Medical Research, Chapter 14.
 

J. Wiley & Sons, New York, 1971.
 

Berck, B., "Fumigant Residues of Carbon Tetrachloride, Ethylene Bichloride, and Ethylene Dibromide in Wheat, Flour, Bran, Middlings and
 

Bread." Journal of Agricultural Food Chemistry 22:977-984, 1974.
 

Berenblum, I., editor, Carcinogenicity Testing. International Union
 

Against Cancer, Technical Report Series, Vol. 2. International
 

Union Against Cancer, Geneva, 1969.
 

Berg, G.L., editor, Farm Chemicals Handbook, 1976. Meister Publishing
 

Company, Willoughby, Ohio, p. Dill, 1976.
 

California Department of Food and Agriculture, Pesticide Use Report,
 

1974. Sacramento, California, pp. 77-78, 1975; as cited in IARC,
 

1977.
 

Chemical Abstracts Service, The Chemical Abstracts Service (CAS) Ninth
 

Collective Index, Volumes 76-85, 1972-1976. American Chemical
 

Society, Washington, D.C., 1977.
 

Chemical and Engineering News. "Industry/Business," Vol. 54, p. 9,
 

1976.
 

Cox, D.R., Analysis of Binary Data, Chapters 4 and 5. Methuen and
 

Co., Ltd., London, 1970.
 

Cox, D.R., "Regression Models and Life-Tables." Journal of the Royal
 

Statistical Society, Series "B" 34:187-220, 1972.
 

Fishbein, L., "Industrial Mutagens and Potential Mutagens: I. Halogenated Aliphatic Derivatives." Mutation Research 32:267-308,
 

1976.
 

Gart, J.J.. "The Comparison of Proportions: A Review of Significance
 

Tests, Confidence Limits, and Adjustments for Stratification."
 

International Statistical Institute Review 39:148-169, 1971.
 

Gosslin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason, Clinical
 

Toxicology of Commercial Products, 4th edition. The Williams
 

and Wilkins Company, Baltimore, Maryland, 1976.
 

International Agency for Research on Cancer (IARC), IARC Monographs
 

on the Evaluation of Carcinogenic Risk of Chemicals to Man.
 

Volume 15: Some Fumigants, the Herbicides 2,4-D and 2,4,5-T,
 

61
 
Chlorinated Dibenzodioxins and Miscellaneous Industrial Chemicals.
 

United Nations World Health Organization, Geneva, Switzerland, pp.
 

195-209, August 1977.
 

Kaplan, E.L., and P. Meier, "Nonparametrie Estimation from Incomplete
 

Observations." Journal of the American Statistical Association
 

_53_:457-481, 1958.
 

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

"Carcinogenesis Bioassay Data System." Computers and Biomedical
 

Research 7:230-248, 1974.
 

Miller, R.G., Simultaneous Statistical Inference. McGraw-Hill Book
 

Co., New York, 1966.
 

Olson, W.A., R.T. Habermann, E.K. Weisburger, J.M. Ward, and J.H.
 

Weisburger, "Induction of Stomach Cancer in Rats and Mice by Halogenated Aliphatic Fumigants." Journal of the National Cancer Institute 51(6):1993-1995, December 1973.
 

Reuber, M.D.j and E.L. Glover, "Cirrhosis and Carcinoma of the Liver
 

in Male Rats Given Subcutaneous Carbon Tetrachloride." Journal
 

of the National Cancer Institute 44:419-423. 1970.
 

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

Kaufman, "Respiratory Tract Carcinogenesis in Hamsters Induced
 

by Different Numbers of Administration of Benzo (a) Pyrene and
 

Ferric Oxide." Cancer Research 32:1073-1079. 1972.
 

Spencer, E.Y., Guide to the Chemicals Used in Crop Protection, 6th
 

edition. University of Western Ontario, Research Branch, Agriculture Canada, Publication 1093. London, Ontario, p. 263,
 

1973.
 

Tarone, R.E., "Tests for Trend in Life-Table Analysis." Biometrika
 

^.•679-682, 1975.
 

U.S. Environmental Protection Agency, Sampling and Analysis of
 

Selected Toxic Substances, Task II: Ethylene Dibromide, Final
 

Report. Office of Toxic Substances, Washington, D.C., September
 

1975.
 

U.S.	 International Trade Commissin, Synthetic Organic Chemicals, U.S.
 

Production and Sales, 1974. USITC Publication 776, Washington,
 

D.C., 1976.
 

U.S.	 Tariff Commission, Censu os f Dyes and Other Synthetic Organic
 

Chemicals, 1923. Tariff Information Series, No. 32, Washington,
 

D.C., 1924.
 

62
 
APPENDIX A
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS
 

IN RATS TREATED WITH 1,2-DIBROMOETHANE
 

TABLE A1 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE RATS TREATED WITH 1,2-DIBROMOETHANE (EDB) 

CONTROL (U»TR) 

01-031H 

CONTROL (VEH) 

01-061M 

ANIBALS INITIALLY IN STODY 

ANIRALS SECROPSIED 

ANIBALS FXABINED HISTOPATHOLOGICALLY** 

20 

20 

20 

20 

20 

20 

INTEGUMENTARY SYSTEM
 

*SUBCDT TISSOE (20) (20)
 FIBROSARCOBA 1 (5X)
 

RESPIRATORY SYSTEB
 

• LUNG (20) (20)
 SOOABODS CELL CARCINOMA, BETASTA
 

BIXED TOBOR, BETASTATIC
 

HEBATOPOIETIC SYSTFM
 

*BULTIPLE ORGANS (20) (20)
 LYBtHOCITIC LEUKEBIA 1 (5X)
 GRAKULOCYTIC LEDKEBIA
 

fSPLEEN (20) (20)
 SODArOUS CELL CARCINOMA, BETASTA
 

HEBANGIOEARCOBA
 

tBESENTEHIC L. NODE (19) (20)
 SODA SODS CELL CARCINOMA, BLTASTA
 

tThYflOS	 (13) (6)
 SOUACOOE CELL CARCINOMA, BETASTA
 

THYBOBA
 

BIXED TDHOR, BETASTATIC
 

CIRCULATORY SYSTEM
 

»HEART (20) (20)
 SOUABOUS CELL CARCINOMA, HETASTA
 

i NUMBER OP ANIMALS 1IITB TISSUE KXAHIKED BICROSCOPICAL1J 

* N0HBEH OP ANIMALS KECROPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

LOW DOSE
 

01-062M
 

50
 

50
 

50
 

(50)
 

(50)
 

5 (10X)
 

{50)
 

(50)
 

4 (8*)
 

10 (20%)
 

(«7)
 

2 (1*)
 

(32)
 

1 (3X)
 

(50)
 

1 (2*)
 

HIGH DOSE
 

01-063H
 

50
 

50
 

50
 

(50)
 

(50)
 

1 (2X)
 

1 (2%)
 

(50)
 

1 <2X>
 

(49)
 

10	 (20*)
 

3 (6X)
 

(46)
 

2 (KX)
 

(20)
 

1 (5X)
 

1 (5*)
 

(50)
 

A-3 
TABLE A1 (CONTINUED) 

CONTROL (UNTR) CONTROL (VEH) LOW DOSE HIGH DOSE 

01-031H 01-061H 01-062B 01-063H 

DIGESTIVE S7STFB 

• SALIVAR Y GLAN1) (1U) (1) 

CARCINOBA.liOS 1 (7%) 

*LIVEH (20) (20) (50) (50) 

S.JUAWOUS CELL CARCIUOBA, BE1ASTA 18 (36X) 1H (28X) NEOPLASTIC MODULE 2 (IX) 1 (2X) 

HEPA10CFLLUIAR CARCItlOBA 1 (2S) 1 (2%) B1XED TOUOh, MPTASTAT1C 1 (2%) HEBAS.GIOSARCOBA 2 («*) 1 (2X) HEMA^GIOSARCOBA , BETASTATIC 1 (2X) 

• PANCREAS (20) (20) (149) (16) 

SQUAfOUS CELL CARC1NORA, BE1ASTA 10 (20X) 9 (20%) 

MIXED TUHOR, RPIASTATIC 1 (2%) HEflANGlOSARCOB A 1 (2%) HERAhGIOSARCOBA , RETASTATIC 1 (2%) 

fES-OPHAGDE (15) (16) (46) (11) 

SQOArOUK CELL CARCIHOBA, BL7AS1A 2 <«X ) 1 (2%) 

• STOHAC1 (20) (20) (50) (50) 

£?UA!"ODE CELL CARCISORA 15 (90%) 33 (66*) KIXEP TUPOR, BiTASTATIC 1 (2%) 

• SHALL INTESTINE (20) (20) (»5) («3) SCUA'OUS CELL CARCINOHA, ME1ASTA 2 (1%) AOEHOCARCII1OBA, SOS 1 (2%) PIBROSARCOBA 1 (5X) 

»I)UODE»OB (20) (20) (15) (13) 

SQDABOUS CELL CARCINOBA, HETASTA 1 (2*) 1 (2%) 

*COLOII (19) (20) (18) (18) SOOA.1OUS CELL CARCINOBA , BETASTA 1 (2%) 

DRIKAR K 'YSTEB 

• KIDRE Y (20) (20) (»9) (50) 

SQBABOUS CELL CAECIBOBA, HETASTA 3 (6%) 1 (2%) B1XEU 1UBOR, BALIGNAH T 1 (2%) 1 (8%) HEKANGIOSARCOBA 1 (2%) HABA^TOBA- 1

- 1 (2%) 

» BOBBER Of ASI*ALS WIT H TISSUE EXAKIKED BICROSCOPICALLY 

* NUMBER OF ANIBAI •> NECROPS1ED 

+ THIS IS CONSIDERED TO BE A BENIGN FORM OF THE MALIGNANT MIXED TUMOR OF THE KIDNEY AND CONSISTS OF PROLIFERATIVE 

IIPOCYTES, TUBULAR STRUCTURES, FIBROBLASTS, AND VASCULAR SPACES IN VARYING PROPORTIONS. 

A-4
 
TABLE A1 (CONTINUED)
 

COBTROL (UHTR) COWTSOL (TEH 

01-031B 01-061B 

KURINAR Y BLADDFR (19) (20)

 

S^OAflOUS CELL CARCI80HA, BETASTA 

ENDOCRIN^ SYSTEM 

fPITUITARl (20) (20)

 CKRO"OPFOBE ADBNOBA 2 (10%)

 

tADRENJl (20) (20) SQUA*-OOS CELL CARCIBOHA, BKTASTA CORTICAL ADPNOBA

 

CORTICAL CA1C1NOBA 2 (10%)

 BIXEn TDflOR, KtlASTATIC

 

f'PHiROln (19) (20)

 POLLICULAR-CELL ADEROMi

 

POLLICDLAR-CEL1. CARCINOnA 1 (5%)

 

REPRODUCTIV E SISTER 

*MAMMART GLAND (20) (20)

 ADENOCARCI11OBA, ffOS 1 <5X)

 FIBROADENOBA 1 (5X)

 

*PROSTA1E (20) (11) SOUA"OUS CELL CARCINOBA, BETASTi 

KlhSTIS (20) (20)

 

SQCA W OUS CELL C1HCINOHA, BETASTA 

INTfSTITIAL-CTLL TUBOR 

*EI'IDID<"IS (20) (20)

 

SQUA'OOS CELL CARCINOMA, BETASTA 

NERVOU S SYS1EB 

NOSE 

SPECIAL 'ENSE ORGANS 

NONE 

* NUBBEk OP ANIMALS BIIH TISSUE EXABINED BICBOSCOPICALLT
 

* NUrBfH OF ART1AIS K1CEOISIED
 

) LOU DOSE 

01-062H 

(H9) 

(50) 

(*8) 

1 (2X) 

1 (2X) 

1 (2X) 

(50) 

1 (8X) 

1 (2X) 

(50) 

(30) 

(49) 

1 (2%) 

1 (2X) 

(50) 

1 (2%) 

HIGH DOSE 

01-063H 

(II) 

1 (2*) 

(»6) 

(17) 

2 (t%) 

1 (2X) 

(49) 

7 (1««) 

1 (2%) 

(50) 

(20) 

1 (5*) 

(50) 

1 (2X) 

(50) 

A-5
 
TABLE Al (CONTINUED)
 

CONTROL (DHTR ) CONTROL (VEH )
 

01-031H 01-0618
 

HUSCULOSKELETAL	 SI STEM
 

•SKELETAL BOSCLB (20) (20)
 

SQOABODE CELL CARCIHOBA, BETASTA
 

BODI CAVITIES
 

•BEDIASTIHDB	 (20) (20)
 

SODAKOUS CELL CARCIKOBA, BETASTA
 

*ABDOHINAL CAVITY (20) (20)
 

SOOAfOUS CELL CARCIHOBA
 

HEBAHGIOSABCOBA
 

"HESENTFBt (20) (20)
 

SOU4BOU£ CELL CASCISOBA. BETASTA
 

ALL OTHER SYSTEHS
 

»OHE
 

ABIBAL DISPOSITIOK SUBHARi
 

ANIBALS IIHTIALLY I» STUDI 20 20
 NATDRAL DEATHin 11 2
 

BOEIBOND SACRIFICE
 

SCHEDULED SACRIFICE 5 9
 ACCIDENTALLY KILLED
 

TERBINAL SACRIFICE 4 9
 

ASIBAL BISSIB6
 

« INCLODRS AOTOLYZED ANIHALS
 

t	 NOBBER OF ABIBALS HITK TISSUE EXAMINED BICROSCOPICALLI
 

* NUBBER OF AHI1ALS NECROPSIED
 

A-6
 

LOW DOSE HIGH DOSE
 

01-062B 01-063B
 

(50)	 (50)
 

1 (2*) 1 (2*)
 

(50)	 (50)
 

1 (2*)
 

(50) (50)
 1	 (2X)
 

1 (2*)
 

(50)	 (50)
 

1 (2*)
 

50 50
 28 tU
 

3 1
 

19 f.
 
TABLE Al (CONCLUDED)
 

COHTROL (UHTR) COSTROL (VEH) LOW DOSE HIGH DOSE
 01-03111 01-061F! 01-062H 01-063B
 

TUBOR SUflBAEY
 

TOTAL AHIKALS WITH PRIBARY TUBORS* 6 46 35
 TOTAL PPIBAFY TUBORS 11 72 56
 

TOTAL ANIM1LS WITh BEHIGH TUMORS 2 6 8
 TOTAL BBNIGH TDBORS 3 7 8
 

TOTAL ANIBALS WITH BALIGSANT TOBORS 6 15 3U
 TOTAL BALIGSAHT TUBORS 8 63 U7
 

TOTAL ANIBAL? WITH SECONDARY TUBORS* 25 19
 

TOTAL SECOKDARY TUBORS 57 52
 

TOTAL ANIBALE KITH TUBORS UBCERTAIHBEHIGS OR BALIGBAHT 2 1
 

TOTAL DKCERTAIN TUBORS 2 1
 

TOTAL ANIBALS KITH TUBORS UNCEHTAIN­ PFIKAR* OP BETAS1AT1C
 

TOTAL UNCERTAIN TOBORS
 

* PRIBARt TUBORS: ALL TUBORS EXCEPT SECONDiRI TDBORS
 

t SECOHLARY TOBORS: BETASTATIC TUBORS OR TDBORS INVASIVE INTO AH ADJACBHT ORGAN
 

A-7
 
TABLE A2

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS TREATED WITH 1,2-DIBROMOETHANE (hDB) 

CONTROL (DHTF) COHIBOL (VEH) 

01-031F 01-061P 

aNlBALS INITIALL Y IN STUDY 20 20 

AMBALS t-ECROPSIED 20 20 

AM«ALS IXAPINt D H1STOPATUOLOGICALLY ** 20 20 

1NTEGUBE1TARY SKSl^M 

*SDBCUT TISfU E (20) (20) 

EyUA-OUS CEL1 CARCINOMA , METASTA 

RLSHRATuRI SYSTEM 

*LU1G (20) (20) 

CARCINOMA , tiOS, METASTATIC 

SOUA»OUE CELL CARCIKOMA , ME1ASTA 

HEPAIOCT'LLULAR CARCISOM1, BETAS! 

HLKA1OPOIETIC SYSTLM 

tSPLEPN (20) (20) 

SwUA"OD S CELL CAECINOBA, BE1ASTA 

HiHA l b!06ARCOI"A 

• LYflP" TODL (20) (20) 

SOUA"OUS CEIL CARCINOBA, BETASTA 

tflFSENT^RIC L. MODE (20) (20) 

ECUAt'ODS CELL CAhClNOBA, BETASTA 

CIRCOLATOH Y SYSTiM 

»»IAH (20) (20) PIXEr TUrCP , PL1AS1ATIC 1 (5») 

DlGtSlIVp SYSTE M 

•LIVER (20) (20) 

S2l)A»ODJ CELL CARCINOMA, HETASTA 

» NDtBI R OF ANIMAL S HIT h TISSUE MABIRED MICROSCOPICALLY 

* NUflfcrR OF ANIMAL S UECROPSIiD 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

LOW DOSE 

01-06 "IP 

50 

50 

50 

(50) 

1 (2*) 

(50) 

H (8%) 

(19) 11 (22X) 

1 (2*) 

(i9) 

3 (8%) 

(39) 

(SO) 

(47) 

21 C45X) 

HIGH DOSE 

01-065P 

50 

50 

50 

(50) 

(18) 

1 (2*) 

« (8%) 

1 (2X) 

(18) 

» (8*) 

3 (6%) 

(39) 

(30) 

1 (3*) 

(17) 

(18) 

12 f25») 

A-8 
TABLE A2 (CONTINUED) 

COBTSOL (USTR) CONTROL (VEH) LOB DOSE HIGF DOSE 

01-031P 01-061P 01-06tP 01-065P 

8EOPLASTIC MODULE 1 (2%) HEPATOCPLLULAR CARCIROBA 1 (5%) 1 (2%) 5 (10») 

HEBA1GIOSAHCOBA, BETASTATIC 1 (2%) 

*BILE DUCT (20) (20) (50) (50) 

CARCIHOBA.SOE 1 (2*) 

*PA1<CREJS (20) (20) (45) (U7) 

CARCIROBA, NOS, BETASTATIC 1 (2%) 

SQUAfOUS CELL CARCIKOBA, BETASTA 11 (21%) B (17%) 

•ESOPHAGUS (1S) (111) (1(3) (11) 

SQUAIJOUS CELL CARCINOMA, BETASTA 1 (2%) 1 (2X) 

• STORAC11 

SQUA^ODS CELL CARCINOHA 

(20) (20) (50) 

10 (80*) 

ro) 29 (5t)%) 

*S«ALL IBTESTIRE (20) (20) («7) (Hb) 

SQUA PIOUS CELL CARCINOBA, RETAETA 1 (2*) 

URINARY SYSTEM
 

•KIDNEY	 (20) (20) («7) (KB)
 

SQU4.-OUS CELL CARtlNORA, BETASTA H (9%) t («%)
 

MIXEI. TUHOR, KALIGKANT 1 (5%) 2 <U%) 1 (2%)
 

HABA'TOPIA + 2 (10X) 1 (2X) 1 (2*)
 

L'NDOCHINF SYSTEM
 

•PITUITARY	 (19) (20) (39) (KO)
 

CHBOPOPHOBE ADENOBA 6 (32*) 1 (5%)
 

• ADRESAI. (20) (20) (4H) (15)
 

SOUAP'OUS CELL CARCIKIBA, BETASTA 1 (2*) 3 (7%)
 

COR1ICAL ADENORA 2 (1%)
 

CORTICAL CARCINOMA 2 (M%)
 

ITPYROIt' (20) (20) (U3) 0*3)
 

FOLLICOLAR-CELI ADEFOBA 1 (2%)
 

FOLLJCULAR-CELL CARCIKOBA 1 (2*)
 C-CELL SDENOBA 2 (10%)
 

C-CELL CARCINORA 2 (10%)
 

•PANCRESTIC ISLETS (20) (20) («5) <H7)
 

ISLET-CELL ADE^OfiA 1 <5S) _ .
 

t BOBBER OF ASIHALS HITP TISSUE EXAB1NED BICROSCOPICALLJ 

* SUBBER OF ANIMALS RECFOPS1ED 

+ THIS IS CONSIDERED TO BE A BENIGN FORM OF THE MALIGNANT MIXED TUMOR OF THE KIDNEY AND CONSISTS OF PROLIFERATIVE 

LIPOCYTES, TUBULAR STRUCTURES, FIBROBLASTS, AND VASCULAR SPACES IN VARYING PROPORTIONS. 

A-9 
TABLE A2 (CONTINUED) 

CONTROL (DNTR)

01-031F

 CONTROL (TEH)

 01-061F

 LOU DOSE 

 01-064F 

KEPRODUCIIVt SYSTEM 

*MAHBARY GLAND

ADEH^HA, HOS 

ADEHnCARCISOHA, KOS

FI6ROADESOBA

tUIERUS

SQUA.-OOS CELL CARCINOMA, HETASTA 

ENDO"FTtIAL STPOHAL POLJP

HE.1AVGIOBA

1OVARY/OVII.DCT

SOUA'OUS CELL CARCINOMA, HETASTA

fOVAR?

SPUAMQUS CELL CARCIKOBA, BETASTA

CYSl'.DRNOCAECINOKA, NOS

 (20)

 2 (10%)

 2 (10*) 

 (20)

 1 (5X) 

 (20)

 (20)

 1 (5%) 

 (20)

 1 (5X) 

 (20)

 1 (5X)

 (20)

 (20)

 (50) 

 (15) 

2 (1*) 

 (15) 

1 (2X) 

 (17) 

1 (2*) 

JitFVOUS SJSTEK 

NONE 

SH.CIAL EEUSE OP6AWS 

NONt 

CUSCULOSKELETAL SJ ETEB 

KOBE 

bODJ CAV1TIPS 

*PlESESTIKY

SQDA-OUS CELL CARCII.OBA, BETASTA 

 (20) (20) (50) 

ALL OTHLt SYSTitlS 

AEIPOS^ TISSDE 

SODA»OUS CELL CAFCINOHA, BETASTA 

» NUMBES OF AKI.-SALS WITH TISSDE EXABINED BICHOSCOPICALLY 

* SUMBER OF AWIHALS KECSOPSIED 

HIGH DOSB
 

01-065?
 

(50)
 

1 (2X)
 

1 (2X)
 

2 («%)
 

(45)
 

1 (2X)
 1 (2*)
 

(15)
 

(«8)
 

(50)
 

2 (1X>
 

A-10
 

2 
ANIBAL DISPOSITIOH SUHSARY
 

ANIMALS INITIALLY IS STUDY


NATURAL DEATBol


BORIUUND SACRIFICE


SCHEDULED SACRIFICE


ACCIDENTALLY KILLED
 

TERMINAL SACRIFICE


ANIMAL HISSINt
 

a INCLUDES AUTOLYZBD ANIMALS
 

TDHOR SUKMiRY
 

TOTAL ANIMALS KITH PRIHAKY TUdORS*


TOTAL tRIHARY TUMORS


TO1AL AHIPALS IIIIH BEKIGII TUMORS


TOTAL BEhlGR TUBORS


TABLE A2 (CONCLUDED)
 

CONTROL (UNTR)


01-031F


 20


 2


 5
 

 13


 It
 21


 12


 1H


TOTAL ANIHALS WI1H HALIGKANT TUHOHS

TOTAL MALIGNANT TUMORS

 6

 7

TOTAL ANIMALS HITH SECO8DARY TUMORSd

TOTAI SECONDARY TDMORS

 1

 1

TOTAL ANIHALS HITh TUMORS ONCERTAINBENIUB OR MALIGNANT 

TOTAL UNCERTAIS TUMORS 

TOTAL ARIBALS WITH TUMORS UNCERTAIIT­ PRII1ART OR BETASTA1IC TOTAI UNCERTAIN TUBOPE
 

* PK1MARY TDBORS: ALL TDBORS EXCEP1 SICONDARY TOBORS
 

 CONTROL (VEH)


 01-061P


 20


 1


 19


 2


 3


 2


 2


 1


 1


 LOU DOSE
 

 01-06HF
 

 50
 

 15
 

3
 

2
 

 UO
 17
 

3
 

3
 

 HO
 

 114
 

 29
 

 59
 

* SiCONDSRY TDBORS: METAS1A1IC TUMORS OR TUBORS INVASIVE INTO AN ADJACENT ORGAN
 

A-ll
 

BIGP DOSE
 01-065F
 

50
 

nt
 

1
 

29
 

52
 

6
 

8
 

29
 

U3
 

18
 

«7
 

1
 

1
 

APPENDIX B
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS
 

IN MICE TREATED WITH 1,2-DIBROMOETHANE
 

TABLE Bl

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE MICE TREATED WITH 1,2-DIBROMOETHANE (EDB) 

CONTROL (UNTR) CONTROL (VEH ) LOU DOSE HIGH DOSB 

02-B061 02-B051 02-H062 02-B063 

ANIBALS INITIALLY IN STUDY 20 20 50 50 

ANIBALS "ISSING 1 

ANIBALS XECROPSIED 19 20 50 19 

ANIBALS KSABINED HIS10PATHOLOGICALLK ** 19 20 50 19 

INTEGUBFKTAK Y SYSTFB 

*SKIN (19) (20) (50) (19) 

SOUA'OUS CELL CAECIHOBA, BETASTA 1 <2X) 

*SUBCDT TISSUE (19) (20) (50) (119) 

SOUA'ODS CELL CARCINOMA, BETASTA 2 (1») 1 (2X) 

FIBROSARCOMA 1 (5X) 

RESPIRATORY SYSTEB 

ILDNG/bPONCHDS (18) (20) (15) (17) SOUATODS CELL CARCINOMA, BETASTA 1 (2X) 

ILUNG (1H ) (20) (*5) (17) 

SQDAr.OUS CELL CARCINOMA, BETASTA 3 (7*) 1 (2X) 

ALVEOLAP/BROHCHIOLAR ADENOMA 1 (9X) 10 (21X) 

HEBATOPOIETIC SYSTEM 

*BULTIPLE ORGANS (19) (20) (50) (19) BALIG.LYBPHOHA, UNDIJ'FER-TY t-E 1 (5*) 

BALId.LYRPHOBA , LYBPHOCYTIC TYPE 1 (5X) 

MALIG.LYBPHOMA , HISTIOCYTIC TYPE 1 (2X) GRANHLOCYTIC LfUKEBIA 1 (5X) 1 (2*) 

HSPLEE1I (19) (20) (15) (33) 

SQUAMDS CELL CAHCINOHA, METASTA 18 (40*) 16 (48X) 

»BROHCHIAL LYBPH NODE (18) (18) (11) (32) 

SpUA-ODS CELI CAFCINOBA, BE1ASTA 5 (12*) l» (13X) 

*BEEEl»TrRIC L. NODE (18) (18) (11) (32) SOUA.-OUS CELL CAECINOBA, BETASJA 12 (29*) 7 I22X) 

• NUBBER OP ANIBALE HITH TISSUE EXABINEI) BICPOSCOPICALLY 

* NUKBER OF ANI»ALS RECBOPSIED 

**EXCLODES PARTIALLY AUTOLYZED ANIMALS 

B-3 
TABLE Bl (CONTINUED) 

COKTROL(UN!TE) COSTBOL (VEH)
 

02-H061 02-H051
 

*STONACL1 (20) (20)
 

fULIb.LYHPKOnA, HISTIOCYTIC TYPE
 

»THKBUS (12) (19)
 SOOA»OUS CELL CARCINOMA, RLTASTA
 

CIRCULATORY SYSTEB
 

NOHi
 

LICiFSTIV SYSTEB
 

*LIVER (19) (20)
 

SQDA-ODS CELL CAPCI&OBA, BETASTA
 NKOP1ASTIC KODUIE 1 (5X)
 HEPAtOCELLULAB CARCINOBA 1 (5*)
 

*GALLbI.1DDEH (19) (20)
 

SQUAHOUS CT.I.L CARCINOBA, BFTASTA
 

•PANCREAS	 (19) (19)
 SOOAttOUS CELL LARCISOBA, METASTA
 

•ESOPHAGUS	 (18)
 

SOUA'OUS CKLL CAF.CISOBA, BETASTA
 

*STOMACh (20) (20)
 

EyUAIODS CELL PAPI1.LOBA
 

SCUArODS CELL CARCIKORA
 

*SBALL INTESTINE (18) (19)
 

SyUA"OUS- CEIL CAHCINOMA, BETASTA
 

•DUODEBUR	 (18) (19)
 

SyDA^ODS CELL CARCINOKA, RETASTA
 

JLARGL' INTESTINE (19) (19)
 

SOUA»OLS CELL CARCINORA, BEIASTA
 

URINAHY ?YSTEf
 

•KIDNEY	 (19) (20)
 

S^UAKODS CELL CARCINOMA, HETASTA
 

» NUKiE R OP ASISALS KITH TISSUE EXABISED SICSOSCOPICALLY 

* NUMBE R OF ANIMALS NECROPSIHi 

LOU DOSE
 

02-H062
 

(50)
 

(37)
 

1 (3X)
 

(US)
 18 (110%)
 

1 <2X)
 

(50)
 

a (8X>
 

(•»«)


23 (52%)
 

(10)
 

1 (3X)
 

(50)
 

45 (90%)
 

(12)
 

9 (21%)
 

(«2)
 

(12)
 

4 (10%)
 

(15)
 

10 (22%)
 

HIGH DOSB
 

02-H063
 

(19)
 

1 (2%)
 

<31)
 

(18)
 

20 (12%)
 

1 (2%)
 

(19)
 

1 (8%)
 

(36)
 

21 (67%)
 

(15)
 

2 (1%)
 

(19)
 

2 (1%)
 29 (59%)
 

(12)
 

1 (10%)
 

(12)
 

7 (17%)
 

(«0)
 

3 (8%)
 

(17)
 

5 (11%)
 

B-4 
TABLE Bl (CONTINUED) 

CONTROL (ONTR) 

02-B061 

CONTROL (VBH) 

02-B051 

LOB DOSE 

02-B062 

HIG1J DOSE 

02-B063 

»ORINAR Y BLADDER

SQUA irons CELL CARCINOMA, BETASTA 

 (17) (19) (HO) 

3 (8X) 

(45)

6 (13*) 

ENDOCRINE STSTEB 

• ADRENAL

SQBArOUS CELL CARCIHOBA, BETASTA 

#THYROID

FOLLICDLAE-CBLL ADEHOBA 

 (19) 

 (18) 

(20) 

(20) 

(43) 

13 (30*) 

(34) 

(46) 

16 (35X) 

(35) 

1 (3*) 

HEPRODOCTIVE SYSTEH 

fPROSTATE

SQUAPOUS CELL CARCISORA, BEIASTA 

*SEBI»AL VESICLE

S(;UAHOUS CELL CARCINOBA, BETASTA 

•TFSIIS

SQUAHODS CELL CABCIKOMA, BETASTA 

*EP1DIDYBIS

SQOAfODS CELL CABCINOBA, BETASTA 

 (18) 

 (19) 

 (19) 

 (19) 

(20) 

(20) 

(20) 

(20) 

(37) 

5 (14X) 

(50) 

1 (2X) 

(45) 

8 (18*) 

(50) 

10 (20*) 

(35) 

6 (17*) 

(1*0 

<U7) 

14 (30X) 

(49) 

10 (20X) 

NERVOUS &YSTEB 

NOHE 

SPECIAL TENSE ORGANS 

*EYE

BALIGHANT BELAKOBA

 (19) 

1 (5X) 

(20) (50) (49) 

BDSCOLOEKELETAL SYSTEB 

*RIB (19) 

SQDArOUS CELL CARCINOMA, BETASTA 

*BUSCLE OF BACK (19) 

SOBABODS CELL CARCINOBA. BEIASTA 

(20) 

(20) 

» SUBBBR OF A1IIBALS »ITB TISSUE FXABINED BICROSCOPICALLT 

» SDBBER OF ANIBALS NECSOPEIEE 

(50) 

2 (4X) 

(50) 

1 (2X» 

(49) 

(49) 

B-5 
TABLE Bl (CONTINUED) 

CONTROL (0»TR) COIT! SOL (VEH) LOU DOSE HIGH DOSE
 

02-HObl 02-H051 02-M062 02-R063
 

*AbDOHISAL MUSCLE (19) (20) (50) («9)
 

SQUAROUS CfcLL CARCIBOEA, BE1ASTA 7 (14X) 2 (<t%)
 

BOD? CAVITIES
 

•MESENTERY	 (19) (20) (50) («9)
 

EQOArOUS CELL CAECIHOBA, HETASTA 1 (8*)
 

ALL OTHER SYSTEHb
 

DIAPHRAGM
 

synABons CELL CARCIHOBA, BETASTA	 » i
 

ANIHAL DISPOSITIOS SOMBARS
 

A1JIBALL IKITIALLY IR ETUDT 20 20 50 50
 

HATDRAL DEATHffi 16 2 '16 41
 

HORI1DHD SACRIFICE 2
 

SCHEDULED SACRIFICE
 

ACCIDENTALLY KILLED
 

TERB1NAL SACRIFICE 1 18 2
 

AHIBAL MISSING 1
 

o> IKCLDD1TS AUTOLYZED AKIHALS
 

* NUBBER OF ARIBALS «ITH T1SSDE EXABINED BICSOSCOPICAL1I
 

» NOBBER OF ANIHALE NECROPSIED
 

B-6
 
TABLE Bl (CONCLUDED)
 

COFTPOL(UHTB)


02-H061


TUBOR SD1BARY
 

•tO-Hl.	 ANIHALS WITH PRIMARY TOHOHS* 5


TOTAL PRIMARY TUMORS 5


TOTAL ANIMALS WITfc BEKIGN TUBORS
 

TOTAL BENIGS TUHORS
 

TOISL ANIfALS WITH HALIGNANT TUBOHS 5


TOTAL KJILIGMAKT TUMORS 5


TOTAL ANIMALS KITH SECONDARY TU.1ORS*
 

TOTAL SECONDARY TUBORS
 

TOTAL HNIHALS WITH TUBORS ONCERTA1NBEBIGS OR RALI6NANT


TOTAL UNCERTAIK TUMORS


TOTAL ANIBALS WI1B TUBORS BNCERTAIK-


PRlBAHf OR HETASTATIC
 

*	 PRIBAR* TUBORS: ALL TUBORS EXCEPT SECONDARS 1UBORS
 

 CONTROL (VEH) LOW DOSE HIGH DOSE
 

 02-S051 02-B062 02-H063
 

2 US 33
 

2 51 Hf>
 

n 13
 

i> 13
 

1 15 30
 

1 U7 32
 

29 26
 

165 158
 

1
 

1
 

» SECONDARY TUKORS: KETASTATIC TUBORS OR TOMORS INVASIVE 1«TO AN ADJACENT ORGAN
 

B-7
 
TABLE B2

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE MICE TREATED WITH 1,2-DIBROMOETHANE (EDB) 

CONTROL (UHTR) CONTROL (VEH) 

02-F061 02-P051 

ANIBALS IHITIALLY IS STDD1 20 20 

ANIHALS MISSING 

AHIHAXS "IECROPSIED 20 20 

ANIMALS EXAMINED H1STOPATHOLOUICALLY ** 20 20
 

INTEGUMENTARY SYSTEM
 

*SKIN (20) (20)
 

SOHAPOOS CELL CARCINOBA, BETASTA
 

*SOBCUT TISSUE (20) (20)
 

SODA«OUE CELL CARCINOBA, RETASTA
 FIBROSARCOBA
 

RESPIRATORY SYSTEM
 

»LUNG (20) (20)
 

CARCISOHA, BOS, BETASTATIC 1 (5*)
 

SQUAHOOS CELL CARCINOBA, HETASTA
 

AIVPOLAE/BRONCHIOLAR ADENOMA
 

ALVEOLAR/BROSCflOLAR CARCIHOBA
 

HEBATOPOTETIC SYSTEB
 

*MULTIPLE ORGASS (20) (20)
 

BALIb.LYMPHOMA, LYMPHOCYTIC TYPE U (20*)
 

MALIGNANT LYMPHOBA, BIXED TYPE 1 (5*)
 

*SPLEEN (20) (20)
 

SQUA.100S CELL CARCISOBA, HETASTA
 

tHRONCHlAL LYBPH BODE (20) (19)
 

SQUABOOS CELL CARCIHOBA, BETASTA
 

*BESESTFRIC L. NODE (20) (19)
 

SQUAflODS CELL CARCINOMA, BETASTA
 

HTKYBUS (20) (20)
 

SQUA^OUS CELL CARCINOMA, HETASTA
 

CIRCOLATORY SYSTEM
 

NONE
 

* KUMBES OF ANIMAL S WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIHALS RECROPSIED 

**EXCLUDES PARTIALLY ADTOLYZED ANIMALS 

LOB DOSE
 

02-E06H
 

50
 

1
 

48
 

US
 

0»8)
 

(U8)
 

1 (2*)
 

1 (2*)
 

(«3)
 

3 (7»)
 

10 (23%)
 

1 (2*)
 

(18)
 

1 (2X)
 

(«2)
 

21 (57X)
 

(13)
 

8 (19*)
 

(13)
 

18 (12*)
 

(38)
 

2 (5X)
 

HIGH DOSE
 

02-F065
 

50
 

50
 

50
 

(50)
 

1 (2*)
 

(50)
 

1 (2*)
 

(16)
 

6 (13*)
 

(50)
 

(12)
 

11 (26S)
 

(29)
 

2 (7X)
 

(29)
 

8 (28X)
 

(19)
 

B-8 
TABLE B2 (CONTINUED)
 

CONTROL (DBTB) COHTROL(VEB)
 02-P061 02-F051


DIGESTIVi SYSTEM
 

•SALIVAPY	 GLAND (19)
 PISPOSARCOMA , KETASTAflC
 

•LIVER	 (20) (20)
 

SQUA!«OnS CEIL CARCINOMA, HETASTA
 

HKPATOCELLU1AR CARCIHOM9
 

*tfALLBLADDE8 (20) (20)
 

EQUA»OUS CEL1 CARCINOMA, BETASTA
 

•PANCREAS	 (19) (20)
 CARCINOMA, J!OS, BETASTATIC 1 (5X)
 SCUA»ODS CELL CARCINOMA, BETASTA
 

•ESOPHAGUS	 (20)
 SCUAr'OUS CELL CARCINOMA, HETASTA
 

•STOfAC"	 (20) (20)
 

SQBAPOUS CELL PAPILLOSA
 

SQUA"IOUS CELL CARCINOMA
 

*SMALL INTESTINE (20) (20)
 

b(,OA»OUS CELL CARCIROMA, FETASTA
 

•DUODEHUM	 (20) (20)
 

SQOAfOUS CELL CARCINOMA, BETASTA
 

•LARGE IITESTIHE (19) (20)
 

SQOAMODS C£LL CASCINOBA, M£T»STA
 

URINARY SJS1EM
 

•KIDNEY	 (20) (20)
 

SQDAriODE CELL CARCINOMA, HETASTA
 

TUBULAR-CELL ADENOBA
 

tURISARY BLADDER (18) (19)
 

SQUAHOUS CELL CARCINOHA, BETASTA
 

EMDOCPIltf SYSTEM
 

tADRESAl	 d")
 (19)
 

SQUA»-Oi]S CELL CARCINOMA,, METAETi
 

» NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPblED
 

B-9
 

 LOW DOSE
 02-F06I*
 

(31)
 

1 <3X)
 

(44)
 

26	 (59X)
 

1 (2%)
 

(48)
 

7 (15X)
 

(43)
 

31	 (72*)
 

(42)
 

1 (2%)
 

(49)
 

1 <2X)
 46 (94%)
 

(41)
 

2 (5%)
 

(41)
 

6 (15*)
 

(40)
 

2 (5*)
 

(43)
 

7 (16*)
 

(37)
 

3 (8*)
 

<t1>
 12	 (29X)
 

HIGH DOSE
 02-F065
 

(34)
 

(47)
 

12 (26*)
 

(50)
 

2 (4*)
 

(39)
 

13	 (33*)
 

(44)
 

(50)
 

28 (56*)
 

(42)
 

(42)
 

5 (12S)
 

(42)
 

2 (5%)
 

(46)
 

1 (2X)
 

1 (2*)
 

(41)
 

(45)
 

4 (9*)
 
TABLE B2 (CONTINUED) 

CONTROL (USTR) CONTROL (VEH) 

02-F061 02-F051 

• THYROID (20) (20) 

FOLLICULAR-CELL CARCINOMA 1 (5%) 

• PANCREATIC ISLETF (19) (20) 

ISLET-CELL ADENOMA 

REPRODDCT1VE SYSTEM 

*BABBARY GLAND (20) (20) 

ADENOCARC1NOHA, SOS 

• UTERUS (20) (20) 

EQUAMOUS CELL CARCINOBA, BETASTA 

ESDOPETRIAL STROMAL POLYP 1 (5%) 

• OVART/OVIDUCT (20) (20) 

SOUAHOUS CELL CARCINOBA, BETASTA 

• OVAR Y (20) (20) 

CARCINOBA, NOE 1 (5X) 

SQDA»OUS CELL CARCINOBA, BETASTA 

GRANULOSA-CELL TUBOR 

NERVOUS SYSTEM 

NONE 

SPECIAL SENSE ORGANS 

NONE 

BUSCOLOSKELETAL SYSTEM 

*ABDOBI1AL MUSCLE (20) (20) 

SQUAHODS CELL CARCINOMA , BETAS1A 

BODY CAVITIES 

*ABDOMIRAL WALL (20) (20) 

SUUABODS CELL CARCINOBA, BETASTA 

» HUBBER OF ANIBALS WIT H TISSDE EXABIHED MICROSCOPICALLY 

» NUMBER OF A8IBALS NECROPSIFD 

LOU DOSE 

02-F06H 

(39) 

(13) 

1 (2%) 

(18) 

3 (6%) 

(38) 

8 (21%) 

1 (3S) 

(38) 

3 (8X) 

<37> 

10 (27X) 

1 (3%) 

<t8) 

2 (»%) 

(US) 

1 (2%} 

HIGH DOSE 

02-F065 

(38) 

(39) 

(50) 

1 (2%) 

(44) 

1 (2%) 3 (7%) 

({1 (I \ 

/ n i\ 

2 (5%) 

(50) 

1 (2%) 

(50) 

B-10 
*BESENTERY


SCOAfOUS CELL CARCIHOBA, BETAST&
 

ALL OTHEP SYSTE1S
 

SOHE
 

A1UBAL DISPOSITION SUBBARY
 

ANIBALf INITIALLY IB STUDK


HATUPAL DEATEdl


MOPlbUltD SACRIFICE
 

SCHEDULED SACRIFICE
 

ACCIDEHTALLY KILLED
 

TERBI8AL SACRIFICE


AI»IBJSL KISSIH6
 

a INCLDDtS AOTOLYZED ANIHALb
 

TDBOH SUHHARI
 

TOTAL ANIBALE WITH PRIBARt TOBOES*


TOTAL PKIBARY TUBORS


IO1AL ARIBALS WITH 6EHIGN IUBOBS


TOTAL BEHIGN TDBORS


TABLE B2 (CONCLUDED)
 

CONTROL (UNTR) CONTROL (VEH)
 

02-F061 02-F051
 

 (20) (20)
 

 20 20
 

1 2
 

 19 18
 

6
 

8
 

1
 

1
 

TOTAL ASIBALS WITH BALIGKANT THBOHS

TOTAL BALIGNAST TUBORS

 6 

7 

TOTAL ANIMALS HITH SECOHDARY lOBORSf

TOTAL SECONDAS? TUBORS

 1 

2 

TOTAL AMIBALS WITH TUMORS UHCERTAIDBENIGH OR KALIGBANT 

TOTAL UNCERTAIN TUBORS 

TOTAL f.HIMALS KITH TUBORS UKCERTAIJIPRinAHY OR BETASTATIC 

TOTAL ONCERTA1N TUBORS
 

* PRIBARY 1UHORS: ALL TUBORS EXCEPT SECONDARY TOHORS
 

LOO DOSE HIGH DOSE
 

02-F06U 02-F065
 

(«8) (50)
 

8 (17X) 1 (2»)
 

50 50
 

40 17
 

2
 

7 3
 

1
 

17 31
 

67 HO
 

12 8
 

13 10
 

17 29
 

53 30
 

31 16
 

186 66
 

1
 

1
 

* SECOHDARY TUBORS: BETASTATIC TUBORS OR TUMORS IHVASIVE INTO AN ADJACE1T ORGAH
 

B-ll
 

APPENDIX C
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN RATS TREATED WITH 1,2-DIBROMOETHANE
 

TABLE Cl

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE RATS 

TREATED WITH 1,2-DIBROMOETHANE (EDB) 

COIITROI (DHTR) CONTROL (VEH) LOW DOSE HIGH DOSE
 

01-031H 01-061B 01-062M 01-063B
 

AHIBALS INITIALLY IN STDDY 20 20 50 50
 

ANIBALS NECROPSIED 20 20 50 50
 

ASIHALS EXAMINED HISTOPATHOLOGICALLY** 20 20 50 50
 

INTEGOHENTARY SYSTEM
 

*SKIN (20) (20) (50) (50)
 

INFLAMMATION, NOS 1 (5X)
 

RESHRATCRY SYSTER
 

*TRACHEA (15) (17) (50) (t«)
 INFLABBATION, KOS 1 (2*)
 

• LONG (20) (20) (50) (50)
 

PNEUMONIA, CHRONIC HURI8E 16 (80%) 4 (20*) 16 (32X) 8 (16X)
 CALCIDH DEPOSIT 1 (5*)
 

HEBATOPOIETIC SYSTEB
 

1SPLEES (20) (20) (50) (49)
 

HEHORBHA6IC CYST 1 <2X) 2 (4%)
 

INFLAMMATION, ROS 1 (2X) 1 (2%)
 P1BBOSIS, FOCAL 1 (2X)
 HEHATOPOIESIS 1 (5*) 1 (2X)
 

tCERYICU. 1YBPH NODE (19) (20) (47) («6)
 INF1AHBATIOII, SOS 1 (5*)
 

*PU1.BOJH1RY LYBPH MODE (19) (20) (17) (16)
 HEBOHBHA6E 1 (2*)
 

tTHTHOS (13) (*>) (32) (20)
 

CYST, NOS 1 (3X)
 HEMORRHAGE 1 <5X)
 INF1AHBATION, *OS 1 (5X)
 AUGIECTASIS 1 (5X)
 

» NUMBER OF ANIKALE IIITH TISSUE EXAMINED MICROSCOPICALLY 

* HUHBEB OF ANIMALS HECROPSIED 

"EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

C-3 
TABLECl (CONTINUED)
 

COHTEOL(UNTR) COHTHOL (VEH)
 

01-031B 01-061B
 

CIRCULATORY SYSTEM 

•HEART 

FIBROSIS 

ARTERIOSCLEROSIS, SOS 

CALCIUM DEPOSIT 

CALCIFICATION, SOS 

(20)

1 (5%) 

 (20) 

1 (5*) 

*BYOCARDIUR 

ISFLAHBATION, TOS 

DIGB1.ERATIOS, dOS 

CALCTDB DEPOSIT 

(20)

2

1

 (10X) 

 (5%)

 (20) 

1 (5*) 

»EHDOCA~<DIUB 

bYPEcPHSIA, SOS 

(20)

1 (5%) 

 (20) 

*AORTA 

ANED^YSK 

PtRIJFTEFITIS 

I-FDISL CALCIFICATION 

(20)

2 (10%) 

 (20) 

*AORIIC TONICA BE^IA CALCIFICATION, KOS 

(20) (20) 

*PUL-\O!iAHY ARTERY 

HYPERTROPHY, SOS 

(20) (20) 

*BESENTERIC ARTERY 

r£DI»L CALCIFICATION 

(20)

1 (5%) 

 (20) 

CIGESTIVI SYSTE1
 

»LIVER (20) (20)
 CYST, !-OS
 

THRO-BDS, ORGANIZED
 

hFHO'iRFAGE
 

HEBO'm»AGlC CYST
 

ISPLBPI1ATION, HOE 1 (5*)
 PFLIOEIE CFPAIIE
 

NiCtOSIS, FOCAL
 

HETA^ORPBOSIS FATTY 2 (10*)
 FOCAI CELLULAR CHANGE
 

PEPAIOCY1OBEGALY
 

HfPf<PLASlA. KOS
 

* NUMbE-! Of ARIMA1S WITH TISSUE EXJB1SED BICEOSCOPICALLY
 

* KUKBLR OF ANIIALS NECFOPSIED
 

C-4
 

LOW DOSE
 

01-062B
 

(50)
 

1 (2%)
 

(50)
 

1 (2%)
 

(50)
 

(50)
 

1 (2%)
 

(50)
 

1 (2%)
 

(50)
 

(50)
 

(50)
 

1 (2%)
 4 (8%)
 

10 (20%)
 

1 (2%)
 

1 (2%)
 

1 12*)
 

HIGH DOSE
 

01-063B
 

(50)
 

1 (2*)
 

1 (2%)
 

(50)
 

1 (2%)
 

1 (2%)
 1 (2*)
 

(50)
 

(50)
 

1 (2%)
 

1 (2%)
 

(50)
 

1 (2%)
 

(50)
 

1 (2%)
 

(50)
 

1 (2%)
 

(50)
 

1 (2%)
 

1 (2%)
 2 (t%)
 

5 (10*)
 

9 (18%)
 

3 (6%)
 

1 (2%)
 

1 (2%)
 
TABLE Cl (CONTINUED) 

CONTR9L(OUTR) CONT80L (VEH) LOB POSE HIGH DOSE 

01-931* 61-061B 81-062* 01-063H 

ANGIfCTASI S 3 (15X) 1 (2*) 

*BILE 0PCT 

IHFLABBAT101I, UOS 

HYPERPLASIA, DOS 

(28) 

4 (20%) 

(20) (5«) (50) 

1 (2*) 

•PANCRBAS (2») (29) (U9) (16) 

IXFLSBMATION,

PERIAITERITIS 

 XOS 

H (20X) 

2 (»%} 

»E£OPHAbUS 

1NFLABHATIOS, MOS 

(15) (16) (**) (11)

1 (2*) 

•STOBACP (20) (20) (50) (50) 

ULCE*>, NOS 

CALCIDB DEPOSIT 2 (10*) 

1 <2X) 

HYPEBKEPATOSIS 12 (2t*) 

ACAHTHOSIS 12 (2«X) 

•COLON (19) (28) (*8) (U8) 

UfiiUTODIASIS 

PARASITISM 

1 (5*) 1 (2*) 

dCECUB 

1NFLAB8A1ION, ACUTE 

(19) (28) (48) (18) 

1 (2*) 

URINAR Y SYSTEB 

« KID* BY 

PTELOBEPERITIS, SOS 

INFLAMMATION, 10S 

ABSCISS, 1»OS 

IHFLABHATIOII, CHEONIC 

CALCIUB DEPOEIT 

HYPEPPLASIA, SOS 

(20) 

1 (5X) 

15 (75X) 

1 (5*) 

(20) 

11 (55*) 

(»9)

1 (2*) 

1 (2X)

8 (16*)

5 (10X)

1 (2X) 

 (50) 

1 <2X) 

1 (2*) 

 10 (20X) 

B (16X) 

•KIDNEY /PELVIS 

IIIPLAIIIIATIOF, NOE 

CALC1UB DEPOSIT 

(20) (20) (*9)

1 (2X) 

 (SO) 

1 (2*) 

»URI»AR Y BLADDER 

miaAflnATioii, »os (19) 

1 (5*) 

(20) (MS) (114) 

CALCIHB DEPOSIT 

HYPJRPLASIA^ EPITHELIAL _. _, 1

 1

 (21) 

 12*) 

t HUHBE8 OF AWIftALS KITK TISSUE LXABIiED RICHOSCOPICALLY 

» liUHBEP OF ANIMALS BECKOPSIiD 

C-5 
TABLE Cl (CONTINUED)
 

CONTROL (DNTR) CONTROL (TEH )


01-031H 01-061H
 

ENDOCRINE SISTBB
 

•PITUITARY	 (20) (20)
 CYST, NOS
 

ABGI1CTASIS 1 (SX)
 

tADREKAl (20) (20)
 DEGENERATION, SOS
 

HECSOSIS, BOS
 ASGIRCTASIS
 

tADREHAL CORTEX (20) (20)
 DEGENERATION, NOS
 

NECROSIS, NOE
 

ANGIECTASIS 1 (5%)
 

tTHYBOID (19) (20)
 DLTIBOBRANCHIAL CIST 2 (11%)
 HTPERPLASIA, C-CELL 1 (5*)
 HYPEItPLASIA, FOLLICULAR-CELL 1 (5*)
 

•PARATHYROID	 (3) (11)
 HYPBRPLASIA, NOS 2 (67X)
 

REPRODUCTIVE SISTEH
 

•PROSTATE	 (20) (1»)
 

IBPIA'TIIATIOII, NOS 5 (25*)
 

*SEBIIIA1, VKSICLE (20) (20)
 

ISFLAHBATION. SOS 1 (5*)
 DEGENERATION, NOS
 

ATROPHT, NOS
 

tTESTIS (20) (20)
 GRANULOMA, SPERMATIC 1 (5%)
 DEGEKEBATIOH, NOS
 CALCIFICATION, NOS
 

ATROPHT, NOE 11 (55*)
 

*EP1DIDYRIS	 (20) (20)
 

GRABDLOHA, SPERHAT1C
 

NECROSIS, FAT 1 (5*)
 ATROPHY, NOS 3 (15*)
 

NERVOUS SYSTEB
 

NONE
 

* SOBBEH OF ANIMALS WITH TISEDE EXAH1NED BICBOSCOPICALLJ
 » NUMBER OF ANIBALS NECROPSIED
 

C-6
 

 LOW DOSE
 

01-06 2H
 

(50)
 

2 (U%)
 

0*8)
 

(UB)
 

13 (27*)
 

(50)
 

(26)
 

(30)
 

3 (10*)
 

(50)
 

1 (2X)
 

(U9)
 

11	 (29*)
 

(50)
 

2 («*)
 

HIGH DOSE
 

01-063B
 

(»6)
 

(17)
 

1 (2*)
 

1 (2%)
 

1 (2*)
 

(87)
 

9 (19X)
 

1 (2*)
 

(M9)
 

(25)
 

(20)
 

(50)
 

2 («*)
 

1 (2*>
 1 <2*>
 

(50)
 

1 (2*)
 

1 (2*)
 

1f> (36X)
 

(50)
 

3 (6*)
 
TABLE Cl (CONCLUDED) 

 LOW DOSE HIGH DOSE 

 01-062B 01-063B 

 (50) (50) 

 (50) (50) 

 (50) (50) 

1 (2X) 1 (2X) 

 (50) (50) 

1 (2X) 

 (50) (50) 

1 1 

SPECIAL SKKSE ORGANS 

»EYE/LACRIBAL S1AHD 

IHPLABBATIOH, SOS 

*HARDERIAN GLAND 

I tin, AH H ATI OH, HOS 

BUSCULOSKELETAL SYSTEB 

NODE 

BODY CAVITIES 

*PEHlTO]iEUR 

IRPLABBATION, DOS 

*H,RICA?DIUI« 

INPLABBATION, NOi, 

*BESE»TERY 

PEBIAHTERITIS 

ALL OTHER SYSTEBS 

XOHF 

SPECIAL ilORPKOLOGY SUMMAR Y 

NO 1ESI01I REPORTED 

CO»T!iOL(D»TR) COSTROL {VEH)

01-031B 01-061B

(20) (20)

1 (5%) 

(20) (20)

1 (5*) 

(20) (20)

1 (5»)

(20) (20)

2 (10X)

(20) (20)

1 (20S) 

8 

i	 NUBBER OF ANIBALS WITH TISSUE EXABIHED BICROSCOPICALLY
 

*	 KUBBES OF ANIBALb KECROPSIBD
 

C-7 
TABLE C2

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE RATS 

TREATED WITH 1,2-DIBROMOETHANE (EDB) 

COHTFOL (DUTR) CO»TROL(»EH) LOU DOSE HIGH DOSE 

01-031F 01-061F 01-064F 01-065P 

AM.1ALS INITIALLY III STDDY 20 20 50 50 

A^IBALS I'ECROPSIED 20 20 50 50 

AN1BALS 1XAKIHED BISIOPATHOLOGICALLY ** 20 20 50 50 

IMEGDflENTARY SYSTER 

*SUBCUT TISEDJE (20) (20) (50) (50) 

AfcSCESS, BOS 1 (5*) 

RESPIRATORY SYSTEM 

»LUSG (20) (20) (50) (18)

PSEB'OMIA, 1SHPATION 1 (2%) 

PNEUMONIA , CHROBIC BtJSItlE 18 (90*) 10 (50%) 11 (22%) 9 (19*) 

Hi'BATOPO^ETIC SYSTEB 

*SPLEE» (20) (20) (49) (48) 

CYST, SOS 1 (5%) 

BEBOPSHA61C CYFT 1 (2*) 

IKFLABBATIOK , NOS 3 (6X> 1 (2%) 

LFUKFHOIIi KBACTIOW 1 (2X) 

BEBATOPOIESIS 1 (2*) 

•CERVICAL LTHPP FOEE (20) (20) (39) (33) 

INFLAHnATIOH, KOS t (3*) 

tbROBCHIAL LYBPH I1ODE (28) (20) (39) (39)

 

KYPERPLASIA, HOS 1 (3*) 

CIRCULATORY SYSTEH 

•HEART (20) (20) (50) (47)

 

CALCIUI* DEPOSIT 2 (4%)

 

•BYOCARDIDfl (20) (20) (50) (47)

 

INFLABBATIOK. WOE 1 (2*1

 

» NUMBER OF ANIMALS WITH TISSUE EXARIIED BICROSCOPICALL1 

* RUBBER OF AKIBALS HECHOPSIED **EXCLDDES PARTIALLY AUTOLYZED ANIMALS 

C-8 
TABLE C2 (CONTINUED)
 

COHTROL (U8TR) 

01-031F 

COBTROL (VEH) 

01-061F 

IHFLiHBATION,

FIBROSIS 

DEGENEfcATIOS,

 CHROHIC 

 HOi 

1 (5X) 

1EBDOCARDIUB 

HYPESPLASIA, NOS 

(20) (20) 

1 (5%) 

•AORTA 

BEDIAL CALCIFICAIIOK 

(20) 

1 (5X) 

(20) 

DIGESTIVE SYSTErt 

*LIVER (20) (20) 

CYST, HOS 

HEWOBRRAGE 

HERATOHA, KOS 

IHFLABBATION, NOS 

PEL10SIS HEPATIS 

NECROSIS, FOCAL 

BETAfORPliOSIE FATTY 1 (5S) 1 (5X) 

CYTOFLAS81C VACOOLIZAT1OH 

FOCAI, CELLULAR CHANGE 

HBPATOCYTOHEGALY 

*LIVER/CENTRI10BULAR (20) (20) 

NECROSIS, ROS 1 (5X) 

*h>lLE DDCT (20) (20) 

IKFLirtBATIOlI, SOS 

RYPBRPLASIA , HOS 

IPARCRES S (20) (20) 

IFFLABKATIOF, NOS 

#STOBACl- (20) (20) 

IITPIABIIATIOS, KOS 1 (5%) ULCER, NOS 

ULCFh, FOCAL 

HYi-ERKERATOSIS 1 (5*) ACiHTHOSIS 1 (5X) 

tCOLOS (19) (20) 

PARASITISM 1 (5X) 

UF^ARY SYSTEB 

*KID»EY (20) (20) 

__HYDRONEPHROSIE . „ _ . . ,L .. M. 

* NOMBEE OF ANIRALS KITH TISSUE EXAMINED HICROSCOPICALLY
 

* NUMBER OF AHIHALS NECROPSIED
 

C-9
 

LOW DOSF 

01-061F 

1 (2*) 

1 (2%) 

(50) 

(50) 

(K7) 

1 (2%) 

4 (9%) 

1 (2%) 

1 (2X) 

(17) 

(50) 

1 <2X) 

1 (2*) 

(U5) 

1 (2%) 

(50) 

2 (4%) 

1 (2%) 

H (8*) « (8%) 

(H5) 

(17) 

EIGE DOSE 

01-065F 

(17) 

(50) 

(18)

2 (a*) 

2 (H*) 

1 (2*) 

2 (IX) 

5 (10X) 

a (8«) 

1 (8X) 

1 (8X) 

1 12%} 

(KB) 

1 (2») 

(50) 

1 (2S) 

(«7) 

(50) 

1 (2X) 

1 (2*) 

18 (36*) 

18 (36X) 

(17) 

1 (2X) 

(18) 

1 (2X) 
TABLE C2 (CONTINUED) 

CONTROL (ONT8) CONTROL (VEH) 

01-031F 01-061? 

PYELONEPHRITIS, KOS 1SFLABBATION, CHRONIC 9 (U5X) 7 (35X) 

NEPHPOPATHY CALCIUM DEPOSIT 1 (5%) HYPEKPLASIA, NOS 

F8DOCRIHE SYSTEH
 

tADRENAL (20) (20)
 

ANGIFCTASI5
 

»ADREHAl COPTEX (20) (20)
 THKOrBOSIS, NOi
 DEGEKERATIOF, MS 1 (5*)
 ANGI"CTASIS 3 (15*)
 

1THYROID (20) (20)
 HYPEKPLASIA, C-CELL 4 (20*)
 

PYPERPL4SIA, POLLICULAR-CELL
 

»PARATPYEOID (D (12)
 HJPEFPLASIA, SOS 1 (100%)
 

EEPEODOCTIVE SYSTEB
 

*VAG1BA (20) (20)
 

INFLABHATIOf, KOS 1 (5*)
 

•BTERUS	 (20) (20)
 HYDRCBETRA 1 (20%) 6 (30%)
 

IBFLAHtlATION, UO£ 1 (5*)
 

tUlERUS/EHDOHETRlUM (20) (20)
 IKPLABMATIOK, kOS 1 (5*)
 

HYPEr(PLASIA, CYSTIC 1 (5*) 1 (5*)
 

»OVAR1 (20) (20)
 CYST, SOS 1 (5X)
 

NERVOOS ?YSTEH
 

SOUE
 

SPtCIAL SENSE ORGANS
 

HONE
 

t HUB8ER OF ANIMALS WITH TISSUE EXAMINED BICHOSCOP1CALLY
 * MURBF.R OF ANISAlb NECROPSIED
 

C-10
 

LOW DOSE
 01-06UF
 

3 (6*)
 

1 (2%)
 

it (9%)
 

1 (2*)
 

(UK)
 

(UU)
 

1 (2*)
 

3 (7%)
 

(43)
 

(33)
 

(50)
 

(45)
 

1 (2X)
 

(45)
 

(47)
 

HIGH DOSE
 

01-065F
 

1 <2X)
 

7 (15X)
 

1 <2X)
 

(15)
 

4 (9%)
 

(45)
 

P (18X)
 

(43)
 

2 (5X)
 

(26)
 

(50)
 

(45)
 

1 <9X>
 

(4E.)
 

(48)
 
TABLE C2 (CONCLUDED)
 

COHTPOL (DHT8) COHTROL (VEH) LOW DOSE HIGH DOSE
 

01-031F 01-061F 01-064F 01-065F
 

HUSCOLOSHELETAL SYSTEM
 

NONE
 

bODY CAVITITS
 

'PERITOREDM (20) (20) (50) (50)
 INFLAMMATION, DOS 5 (10%] 3 (6X)
 

*PESICASDIUB (20) (20) (50) (50)
 

INFLAMMATION, NOS 2 (»*)
 

*EPICARt>IBM (20) (20) (50) (50)
 

INFLABMAT10B, SOS 1 (2X)
 

1RFLSBMATION WITH FIBROSIS 1 (2X)
 

ALL OTHER SYSTEMS
 

THOBAI
 

ABSCESS, NOS 1
 

SPECIAL "ORPHOLOGY SUKHABY
 

NO LrSION F'IPORTFD 4 1
 

* NUMBER OP AHIMALS WITH TISSUE EXAMINED HICBOSCOPICALL*
 * NUMBER OF ANIMALS NECROPSIED
 

C-ll 

APPENDIX D
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN MICE TREATED WITH 1,2-DIBROMOETHANE
 

TABLE Dl

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE MICE 

TREATED WITH 1,2-DIBROMOETHANE (EDB) 

(:OSTHOL(OHT8)

02-H061

 CONTROL

 02-R051 

 (VEH 

ANIMALS INITIALLY IN STUDI 

ANIMALS HISSING 

ANIHALS 1ECROPSIED 

ANIMALS EXAMINED H1STOPATHOLOGICALL! ** 

20

19

19

 20 

 20 

 20 

INTEGUMENTARY SYSTEM
 

*SUBCOT TISSUE (19) (20)
 

ABSCESS, SOS 2 (11*)
 

HESHRATORY SYSTEM
 

•TRACHEA	 (19)
 INFLAMMATION, NOS
 

tLUNG/BHONCHUS (18) (20)
 IHPLAMHATION, SOS
 

EMPYltHA
 

»LUNG	 (1C) (20)
 CONGKSTION, NOS
 

EDPMB, HOE	 1 (6%)
 HEKOKRHAGE
 

INFLZMRATIOR, NOS	 1 (6%)
 INFLAMMATION, SUPPURATIVE 1 (b*)
 PNEUMONIA, CHRONIC BURIHE 1 (6X)
 

HEMATOPOIETIC SYSTEM
 

tBONE BARROW (17) (2)
 NECROSIS, NOS 1 (6X)
 

tSPLEBN	 (19) (20)
 COHT'iACTURE
 

AHYLO1DOSIS	 12 (63X)
 

HPMOSIDEROSIS
 

ATROPHY, NOS	 2 (11%)
 LEUKIHOID REACTION
 

HYPEBPLASIA, LYBPROID
 

« NUHEER Of ANIMALS WITH TISSUE EXASIHED MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

"EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

) LOW DOSE
 

02-H062
 

50
 

50
 

50
 

(50)
 

1 (2X)
 

(39)
 

(15)
 

1 (2*)
 

(«5)
 

1 (2*1
 

1 <2X)
 

1 (2*)
 

15 (33%)
 

<«2)
 

(15)
 

1 (2%)
 

21 (tVX)
 

HIGH DOSE
 

02-H063
 

50
 

1
 

49
 

1)9
 

(19)
 

(13)


1 (2*)
 

(17)
 

1 (2%)
 

(17)


1 (2X)
 

11 (3016)
 

1 (M)
 

(16)
 

(33)
 

5 (15*)
 

2 (6X)
 

1 (3*)
 1 (3*)
 

6 (18*)
 

3 C9»)
 

D-3 
TABLED! (CONTINUED)
 

____~—.—— — ~­ i— -T--T­ — T m. _—_._—r-m-t­ . _­ — 

CONTROL (UBTK) COHTROL (VEH )

02-B061 02-B051 

EEBSTOPOIBSIS 

•CEEV3CAL LY!*PP SODE (18) (18) UFLBT.ATION, NOS 

•BRONCHIAL LTHPP NODE (18) (18) 

IHFLJ.flHATION, NOS 

tBESENTCRIC L. SODE (18) (IB) 

INFLinnATION, KOS 

HYPERPLAS1A, LYHPHOID 

fTHYROS (12) (19) AMTLOIDOSIS 

CIRCULATORK SYSTEM
 

KHtART (19) (20)
 

HIWERALIZATION
 

EBBOLUS, SEPTIC
 

ABSCESS, NOS 1 (5%)
 CALCIFICATION, fcOE 3 (16X)
 CALCIFICATION, DYSTEOPHIC
 

tMJOCAPDIUB (19) (20)
 

INFLABBAT3ON, NOS
 

1NFLAKKATIOB, FOCAL
 

INFLAHRATION, SUPPDRATHIE 1 (5%)
 

DE6EKERATIOS, DOS 1 (5%)
 

•BESESU'RIC ARTERY (19) (20)
 PERIAHTEEITIS
 

DIGES1IVF SYSTER
 

SLIVER (19) (20)
 

THRO1BDS, ORGANIZED 1 (5X)
 IHFLS.HBATIOK, KOS
 

INPLABBATI08, iDl>PURATIVE
 INFUflMATIOS, ACDTE SUtPDSATlVE
 ABSCFSS, KOS
 

NECROSIS, POCAI 1 (5%)
 INFAPCT, NOS
 

ARKLOIDOSIS 12 (63%)
 

NDBBKR OF AHIBALS WITH TISSUE EXABISEB HICROSCOPICALLY
 NUBBER Ol ANlfALS NECROPSIED
 

D-4
 

 LOU DOSE
 

02-B062
 

5 (11%)
 

(11)
 

1 (2*)
 

(»1)
 

1 (10*)
 

(HI)
 

1 (2X)
 

(37)
 

1 (3%)
 

(45)
 

1 (2X)
 

1 (2%)
 

(45)
 

» (»*)
 

6 (13S)
 

(50)
 

1 (2%)
 

(i»5)
 

7 (16%)
 

17 (38%)
 

HIGH DOSE
 

02-P063
 

1 (3%)
 

(32)
 

(32)
 

3 (9%)
 

(32)
 

3 (y»)
 

(31)
 

(17)
 

1 (2%)
 

1 (2X)
 

1 (2%)
 

(147)
 

1 (2%)
 

3 (6%)
 

3 (6%)
 

(K9)
 

(48)
 

» (8*)
 

1 (2%)
 1 (2%)
 

2 (KX)
 

1 (2%)
 10 (21%)
 
TABLE Dl (CONTINUED) 

COSTHOL(DSTR)

02-S061

 CONTROL (VEH) 

 02-H051 

CALCIFICATION, NOS 1 (5X) 

tLlVKR/CENTRILOBDLAR 

DEGFFERATION, NOS 

NECROSIS, NOS 

(19)

3 (16*) 

1 (5*) 

 (20) 

IPANCREA S 

ISiFL/.BMATION, NOS 

INKL.1BMATIOX , CHRONIC 

AflfLPIDOSIS 

ATROPHY, HOE 

(19)

6 (32*) 

 (19) 

•STOMAC H 

INFLAMMATION , NOE 

INFLAMMATION , FOCAL 

INFLAMMATION , SUPPUhATHE 

CALCIFICATION, HOS 

HYPE':KERATOS1S 

ACANTHOSI S 

(20)

1

3

 (5*1 

 (15*) 

 (20) 

•GAS1RIC SEROSA 

MINERALIZATIO N 

(20) (20) 

•bRAL L INTESTINE 

NEKAIOMASIS 

(18)

1 (6*) 

 (19) 

•LARG E IKTHST1NR 

NEMATODIASI S 

PARASITISM 

(19)

1 (5*) 

 (19) 

URINAR Y .'YSTEK 

»KIDf>E X (19) (20) 

CONGESTION, KOS 

PYELONEPHRITIS , NOS 

1NFLABNATION , SUP1-URATIVE 

PYELONEPHRITI S SUPPLRATIVE 1 (5*) 

ABSC'-'SS, NOS 

INFLAHKATIOH, ChRONIC 15 (79X) 2 (10*) 

A»JL?,IDOS1S 6 (32*) 

CALCIFICATION, BOS 1 (5X) 

•K1DKEY/TUBOLE (19) (20) 

CALC3FICATIOK, NOS 

fURINAP ? BLADDER (17) (19) 

INFLAMMATION, NOS 

• KBMBEF OP ANIMAL S KITH TISSUE EXABHIED 9ICROSCOPICALLY » FUHBER OF ANIMAL S NECROPSIED 

D-5 

LOW DOSE 

02-B062 

(15) 

a (9X) 

(IK) 

1 (2X) 

1 <2X) 

(50) 

2 (1*) 

1 (2*) 

1 (2*) 

(50) 

1 (2%) 

(12) 

(12) 

3 (7X) 

(»5) 

1 (2X) 

« (9*) 

1 (2%) 12 (27*) 

1 (9*1 

2 (4*) 

(15) 

(00)

3 (8*) 

HIGH DOSE 

02-H063 

(KB) 

7 (15X) 

1 (2*) 

(36) 

1 (3*) 

1 (3X> 

1 (3*) 

(19) 

1 (2*) 

2 (IX) 

13 (27*) 

5 (10*) 

(149) 

(12) 

(10) 

(17)

1 (2X) 

3 (6X) 

It (30X) 

2 (»*) 

(17)

1 (2*) 

(15) 
INFLAMMATION, FOCAL
 

CALCIFICATION, 80S
 

LNDOCBISE SYSTEM
 

fPITDITASY
 

CYST, NOS
 

•ADRENAL
 

INFLAMMATION, NOS
 

INFLAMMATION, SDttDRATIVE
 

AHYLCIDOEIS
 

ANG1ECTASIS
 

REPRODUCTIVE SYSTEM
 

*PREPDTIAL GLAKD
 

AbSC?SS, SOS
 

tPROSTATE
 

INFLAMMATION, NOS
 

•TtSlIS
 

INFLAMMATION, NOS
 

INFLAMMATION, SUPPUEATIVE
 

GRANULOMA, SPEl'MATIC
 

CALCIFICATION, DJSTROPHIC
 

ATBOPHY, NOS
 

SERVOUS SYSTEB
 

»NEURO»
 

INPL'.MBATION, KOS
 

tBRAIB/IENISGES
 

INFLABS1ATIOS, NOS
 

• BSAIIJ
 

1KFLAKMATI01I, SOS
 

CALCIFICATION, NOS
 

SPECIAL SENSE ORGANS
 

NOSE
 

* NDKBEK OF ANIHAL S WIT H TISSUE

* NOBBEP OF AHIKAL S NECKOPSIED 

TABLE Dl (CONTINUED) 

CONTROL (UNTR) CONTROL (VEH)


02-B061 02-B051


1	 (6%)
 

(12) (18)


(19) (20)


2 (11%)
 

1 (5S)
 

(19)	 (20)


1 (5*)
 

(18) (20)


(19)	 (20)


1 (5*)
 

|1S) (20)


(18) (20)


(18)	 (20)


1 (6S)
 

 EXABISEU HICSOSCOPICALLY 

D-6 

 LOIF DOSE
 

 02-H062
 

1	 (3%)
 

 (27)
 

1 (»*)
 

 (13)
 

2 (5%)
 

 (50)
 

 (37)
 

2 (5X)
 

 (15)
 

1 (2X>
 

 (50)
 

1 (2%)
 

 (US)
 

1 (2X)
 

 (U5)
 

HIGH DOSE
 

02-1)063
 

1 (2%)
 

1 (2%)
 

<2t)
 

(46)
 

1 (2%)
 

1 (2X)
 

(U9)
 

(35)
 

1 (3X)
 

(K7)
 

1 (2*)
 

K (9*)
 

10 (21*)
 

(«9)
 

(16)
 

(«6)
 

1 (2X)
 
TABLE Dl (CONCLUDED)
 

 LOR DOSE HIGH DOSE
 

 02-B062 02-H063
 

 (50)	 («9)
 

1 (2*)
 

 (50)	 (19)
 

1 <2X)
 

1 (2X)
 

1 (2X)
 

2 (»*)
 

 (50)	 (»9)
 

2 (IX) « (8X)
 

2 5
 

1
 

1
 

[•dSCULOSKELETAL SYSTEK
 

*SKELETAL MUSCLE
 

INFLAHBATI01I, HOS
 

*MUSCIE HIP/THIGH
 

ISPLAMBATION, NOS
 DFGENERATIOIT, BOS
 

CALCIFICATION, BOS
 CALCIFICATION, IHTSTPOPHIC
 

BOOK CAVITIES
 

•PERITONEUM
 

INPLRBBATION, FOS
 

ALL OTHER SYSTEMS
 

NONE
 

SPECIAL "ORPHOLOGJ SUHMARY
 

NO L'SIOH REPORTED
 

ANIKAL BISSING/SO NECHOPSY
 

AUTO/SECROPSY/HIS1O PERP
 

AUTOLJSIE/NO NI,CROPSY
 

CONTROL (ONTR)


02-H061


(19)


(19)


(19)


1
 

 CONTROL (VEH)


 02-H051


 (20)


 (20)


 (20)


1U


1


t SUBBER OP ANirALS HITB T1SSOE PXAHIHED BICROSCOPICALLI
 » NHBBER OP ANIKALS KECROPSIED
 

D-7 
TABLE D2

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE MICE 

TREATED WITH 1,2-DIBROMOETHANE (EDB) 

COHTROL(OHTR) COBTROL (VEH) 

02-F061 02-F051 

LOW DOSE 

02-F06I4 

ANIMALS HITIALLY IB STUDY 20

AHIHALS KISSIBG 

ABIBALS NECROPSIED 20

AHIMALS EXABIBED KISTOPATHOLOGICALLT ** 20

 20 

 20 

 20 

50 

1 

18 

U8 

IBTEGUBESTARJf SYSTFB
 

•SKIN	 (20) (20) (US)
 

IBFLABBATIOS, CHROMIC 1 (5%)
 

PJRASITISH 1 (2X)
 

•EDBCUT TISSDE (20) (20) (48)
 

ABSCESS, KOS
 

RESPIRATORY SYSTEB
 

«LDNG (20) (20) (43)
 

COBGKSTIOK, BOS 1 UX)
 HEHORRHA6E 2 (5X)
 1SFLAMHAT1OH. FOCAL
 

IHFLAMBATIOX, SBPPOSATI»E 1 (2X)
 PSEUBONIA, CHROH1C HDEUE 11 (55X) 21 («9%)
 HYPEBPLASIA, LYBPHOID 1 (5X) 2 (5X)
 

HEHATOPOIETIC SYS1EB
 

tBONE BARROW (19) (20) (43)
 FIBROOS OSTEODYSTROPHY 7 (16X)
 

»SPLEE« (20) (20) (12)
 COBTRACTURE 2 (5X)
 ISFLABBATIOB, BOS 2 (5X)
 AHYLOIDOS1S 3 (7X)
 ATROPHY, HOS
 

LEUKEBOID REACTION 7 (17X)
 HYPERPLASIA, LYHPHOID 1 (2*)
 

HEBiTOPOIESIS 17 (40X)
 

aCEHVICAI. LYHPH BODE (20) (t9) (43)
 IBFLABBATIOB, BOS
 ...1 [?.*1_. .
 

* NUBBER OF ANIBALS KITH TISSUE EXABINED RICROSCOPICALLY 

* 1IBBBFB OF JIBIBALE NECROPSIED 

**EXCLUDES PARTIALLY A0TOLYZED ANIMALS
 

D-8
 

HIGH DOSE
 02-F065
 

50
 

50
 

50
 

(50)
 

(50)
 

1 (2X)
 

(46)
 

4 (9*)
 

1 (2%)
 

1 (2X)
 

2 (4X)
 

12	 (26X)
 

(46)
 

4 (9S)
 

(12)
 

6 (14%)
 

2 (5X)
 

1 (2*)
 3 (7%)
 

(29)
 
TABLE D2 (CONTINUED) 

COHTBOL (UHTR) COBTROL (rEH)
 

02-P061 02-P051
 

• BRONCHIAL LYHPP NODE (20) (19)
 

INFL&rtHATIOS, HOS
 

HYPERPLASIA, LYBPHOID
 

•1ESENTF8IC L. NODE (20) (19)
 

ISPLABBATIOH, HOS
 

PERIARTERITIS
 AHGI^CTASIS 1 (5X)
 

HYPEFPLASIA, LYBPhOlD
 

• THYSOS (20) (20)
 

CYST, NOS
 

INFLABBATION, BOfc
 

INFL'HBATION, iUPPDSATIVE
 

HYPEBPLASIA, LYBPHOID 1 (551)
 

CIRCULATORY SYSTEH
 

• HEART (20) (20)
 

TflRO"BOE, ORGANIZED
 CALC1FICATIOH, HOS
 

CALCIFICATION, DJSTFOPHIC
 

• HYOCARMOH (20) (20)
 INPLAEBATIOH, NOS 1 (b%)
 

INFL1HHATIOP, FOCAL
 DEGENERATION, NOS
 

• ENDOCAPDIUB (20) (20)
 IRFLABBATION, NOS
 

*PEMORAL ARTERY (20) (20)
 ISPLABBATIOS, HOS
 

DIGESTIV SYETEB
 

• LIVER (20) (20)
 CONGESTION, NOS
 INFLABBATIOK, NOS
 INFLAHHAT1OH, FOCAL
 INFLABRATION, SUPPURATI»E
 

ABSC"SS, DOS
 

NECBOEIS,, HOS
 

» HUBBBB OF ANIMAL S KITH TISSOE BXAHISBD HICBOSCOPICALLY * NUBBER OF ANI»ALS SECROPSIED 

LOW DOSE
 02-P061
 

(13)
 

1 (2X)
 

(13)
 

3 (7X)
 

1 (2X)
 

3 (7%)
 

(3«)


1 (3*)
 

1 (3%)
 

1 (11*)
 

(13)
 

2 (5X)
 

(13)
 

1 <2X)
 

2 (5*)
 

2 (5*)
 

(13)
 

(18)
 

(11)
 

1 (2X)
 

5 (11X)
 

1 (2X)
 

1 (2%)
 

HIGH DOSE
 

02-F065
 

(29)
 

1 (3*)
 

(29)
 

1 (3X)
 

3 (10%)
 

(19)
 

1 (5%)
 

1 (5%)
 

(16)
 

1 (2X)
 

1 (2X)
 

(16)
 

3 (7X)
 

(16)
 

1 (2%)
 

(50)
 

1 (2X)
 

(17)
 

2 (1%)
 

1 (2%)
 

1 f2X)
 

D-9 
TABLE D2 (CONTINUED)
 

COSTROL (OSTH) 

02-F061 

COHTROL(VEH)

02-P051 

ABYLOIDOSIS 

BETABORPBOSIS FATTY 

CYtOPLASBIC VACUOLIZATIOH 

»LIVER/CEHTBILOBULAB 

DBGEHERATI01, SOS 

NECROSIS, HOS 

(20) 

2 (10%) 

1 (5%) 

(20) 

*HUCOSA OF GALLBLADDE 

EDBHA, HOS 

(20) (20) 

»B1LE DUCT 

DILATAT10H, WOS 

IHFLABBATIO8, BOS 

HFLABBATIOH, FOCAL 

(20) 

1 (5*) 

1 (5%) 

(20) 

»PA1fCHEAS 

IHPLABHAT101T, SOS 

IHFLABBATIOH, FOCAL 

PERIABTER1T1S 

(19) (20) 

tSTOBACH 

IHPLABBATIOH, SOS 

1HFLABBATIOB, SOVPURATI VE 

ABSCESS, HOS 

CALCIFICAT1OH, HOS 

RYPERKERATOS1S 

ACAHTHOSIS 

(20) (20) 

*LABGE IHTESTHE 

PARiSITISH 

(19) (20) 

»COLOH 

PARASITISR 

(19) (20) 

ORIBARI STSTEB
 

•XIDHE* (20) (20)
 

HJDROHEPHROSIS
 PTELOHEPHRITIS, NOS
 

IRFLABBATIOH, SUPPURATIVE
 

ISFLABBATIOS, CHBOHIC 13 (65X)
 

CALCIFICATIOH, DYSTSOPHIC
 

tKIDHEY/TUBULE (20) (20)
 

_ _ BIHERALIZATIOH
 

* NUBBER OF AH1BALS KITH TISSUE EXABIHED BICROSCOPICALLY
 

» ROBBER OF AHIHALS BECSOPSIED
 

D-10 

 LOS DOSE
 02-P061
 

5 (11%)
 

3 (7%)
 

(tit)
 

5 (11%)
 2 (5%)
 

(US)
 

1 (2%)
 

(US)
 

3 (6%)
 

(43)
 

1 (2%)
 

1 (2%)
 

(«9)
 

1 (2%)
 

1 (2%)
 

1 (2%)
 

(HO)
 

4 (10%)
 

(40)
 

1 (3%)
 

(43)
 

2 (5%)
 

1 (2%)
 

1 (2%)
 

22 (51%)
 

(43)
 

1 (2%)
 

HIGH DOSE
 

02-F065
 

2 (4%)
 

1 (2%)
 

4 (9%)
 

(47)
 

7 (15%)
 

1 (2%)
 

(50)
 

(50)
 

1 (2%)
 

1 (2%)
 

(39)
 

1 (3%)
 

(50)
 

1 (2%)
 

2 (4%)
 

1 (2%)
 

12 (24%)
 

9 (18%)
 

(42)
 

2 (5%)
 

(42)
 

(46)
 

1 (2%)
 

1 (2%)
 

6 (13%)
 

1 (2%)
 

(46)
 
TABLE D2 (CONTINUED)
 

CONTROL (DNTB) CONTROL (VEH)
 

02-F061 02-F051
 

IORUARY BLADDER (18) (19)
 

INFLAMMATION, HOS
 

INFLAMMATION, FOCAL 4 (22*)
 

ENDOCRIHE SYSTES
 

•PITUITARY	 (18) (19)
 CYST, HOS
 

•ADRENAL	 (19) (19)
 INFLAMMATION, NOS
 

INFLAMMATION, SDFPUSATI»E
 

ANGIECTASIS
 

•ADRENAL CORTEX (19) (19)
 

HYPERPLASIA, DOS
 

REPRODDCTIVE SYSTEM
 

*BAM««R» GLAND (20) (20)
 

METAPLASIA, SgUA.IOOS
 

*DTEPOS (20) (20)
 

HYDROBETRA 4 (20*)
 

CONGESTION, NOS
 

• OTESDS/ENDOMETRItJH (20) (20)
 INFLAMMATION, KOS
 

HYPBPPLASIA, CYSTIC 17 (85*) 3 (15*)
 

*OVAEY (20) (20)
 CYST, HOS 3 (15*)
 FOLLICOLAR CYST, HOS
 

PAROVARIAW CYST 4 (20*)
 1»FL*HC«TIOS, SOS 1 (5X)
 ANGIKCTASIS 1 (5*)
 

KtRVOnS SYSTEM
 

*BRAI»/W?RINGEE (20) (20)
 

IHFLSMMATIOS, HOS
 

INFLAHHATIOS. FOCAL 1 (5XJ
 

* SOMBER OF ANIMALS 1ITH TISSUE EltAHINED H1CROSCOPICALLT
 

* NUMBER OP ANIHALS KECROPSIED
 

D-ll
 

tO« DOSE
 

02-P061
 

(37)
 

3 (8*)
 

13 (35X)
 

(28)
 

1 (4X)
 

(41)
 

3 (7*)
 

1 (2X)
 

1 <2X)
 

(41)
 

1 <2X)
 

(48)
 

1 (2X)
 

(38)
 

1 (3*)
 

1 (3*)
 

(38)
 

2 (5X)
 

19 (50*)
 

(37)
 

3 (8*)
 

1 (3X)
 

(40)
 

1 (3X)
 

HIGH DOSE
 

02-F065
 

(41)
 

2 (5*)
 

(27)
 

(45)
 

(45)
 

(50)
 

1 <2X)
 

(44)
 

3 (7X)
 

(44)
 

7	 (T6X)
 

(41)
 

2 (5X)
 

1 (2*>
 

(45)
 

2 (4X)
 
•SPINAL COSC
 

CYST, NOS
 

*ACCESSORY SERVE
 

INPLABBATIO*, NOS
 

SPECIAL IrENSF OSGASS
 

NONE
 

MOSCULOSHELETAL SYSTEM
 

»bONE
 

PlrlROUS OSTEODYSTROmX
 

*SKELETJL BUSCLE
 

INFLABBAIIO*, FOCAL
 

*BUSCLE HIP/THIGH
 

DEGENERATION, SOE
 

CALCIFICATION, ROS
 

BODY CAVITIES
 

*PERITONEUH
 

1SFLAMMATIOS, SDPkUBAllVE
 

'PLEURA
 

INFLAn(!ATIO», VOS
 

»PER1CASD1U1
 

IHFLABBATIOR, NOS
 

ALL 01HFR SYSTEBS
 

KOBE
 

SPECIAL SOSPROLOGY SUBHAEY
 

NO L1SION REPORTED
 

» NUBBER Of ANIBALS WITH 1ISSUE

OF ASIrtALS M.CFOPSIED 

TABLE D2 (CONTINUED) 

CONTROL (UNTR) CODTSOL (VEH)


02-P061 02-F051


(20)	 (20)


1 (5%)
 

(20) (20)


(20) (20)


(20)	 (20)


1 (5%)
 

(20) (20)


(20) (20)


(20) (20)


(20) (20)


12
 

 EXABINED BICROSCOPICALLY 

D-12 

 LOW DOSE
 

 02-FOb*
 

 (US)
 

 («8)
 

 (U8)
 

1 (2*)
 

 (18)
 

 (18)
 

1 (2*)
 

1 (2*)
 

 (U8)
 

1 (2%)
 

 (U8)
 

1 (2*)
 

 («8)
 

1 (2*)
 

HIGH DOSE
 

02-F065
 

(50)
 

(50)
 

1 (2%)
 

(50)
 

(50)
 

(50)
 

(50)
 

(50)
 

(50)
 

8 
TABLE D2 (CONCLUDED)
 

CONTROL(IINTR) CONTROL(VEB) LOW DOSE HIGH DOSE
 

02-F061 02-P051 02-F06U 02-F065
 

ANIMAL HISSING/NO HECROPSS 1
 AUTOLISIS/FO HiCROPSJ 1
 

* NUHBES OF AHIBALE HITH TISSUE EXAHIHED BICROSCOPICALllf
 

» KUMBEE OP ANIMALS NECROPSIED
 

D-13 

Review of the Bioassay of 1,2-Dibromoethane* for Carcinogenicity
 

by the Data Evaluation/Risk Assessment Subgroup
 

of the Clearinghouse on Environmental Carcinogens
 

April 26, 1978
 

The Clearinghouse on Environmental Carcinogens was
 

established in May, 1976, in compliance with DHEW Committee
 

Regulations and the Provisions of the Federal Advisory
 

Committee Act. The purpose of the Clearinghouse is to
 

advise the Director of the National Cancer Institute (NCI)
 

on its bioassay program to identify and to evaluate chemical
 

carcinogens in the environment to which humans may be exposed.
 

The members of the Clearinghouse have been drawn from
 

academia, industry, organized labor, public interest groups,
 State health officials, and quasi-public health and research
 

organizations. Members have been selected on the basis of
 

their experience in carcinogenesis or related fields and,
 collectively,' provide expertise in chemistry, biochemistry,
 biostatistics, toxicology, pathology, and epidemiology.
 Representatives of various Governmental agencies participate
 

as ad hoc members. The Data Evaluation/ Risk Assessment
 

Subgroup of the Clearinghouse is charged with the responsibility
 

of providing a peer review of reports prepared on NCI-
 sponsored bioassays of chemicals studied for carcinogenicity.
 It is in this context that the below critique is given on
 

the bioassay of 1,2-Dibromoethane for carcinogenicity.
 

The primary reviewer said that the compound induced
 

squamous-cell carcinomas of the forestomach in both sexes
 

of rats and mice, hepatocellular carcinomas in female
 

rats, and hemangiosarcomas in male rats. After a brief
 

description of the experimental design, he noted the poor
 

survival among control male rats and mice and that the data
 

from the subchronic study was not very useful in establishing
 

the chronic dose levels. Despite the experimental short­ comings, the primary reviewer said that the evidence for
 

the carcinogenicity of 1,2-Dibromoethane was convincing
 

enough that the results of the bioassay could be considered
 

valid. He concluded that 1,2-Dibromoethane may pose a
 

carcinogenic risk to man.
 

The secondary reviewer also agreed with the conclusion
 

that 1,2-Dibromoethane was carcinogenic in both the treated
 

rats and mice. She questioned, however, the appropriateness
 

of the route of exposure since humans are exposed mainly by
 

63
 
inhalation. Another Subgroup member said that the oral
 

exposure allowed the administration of a sufficiently high
 

dose to produce cancer within the animals' lifespan. He
 

added that particular routes of exposure should be considered
 

in the risk assessment process.
 

It was moved that the report on the bioassay of
 

1,2-Dibromoethane be accepted as written. The motion was
 

seconded and approved unanimously.
 

Members present were:
 

Michael Shimkin (Acting Chairman), University of California
 

at San Diego
 

Joseph Highland, Environmental Defense Fund
 

George Roush, Jr., Monsanto Company
 

Louise Strong, University of Texas Health Sciences Center
 

John Weisburger, American Health Foundation
 

*	 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.
 

<IU S GOVERNMEN T PRINTIN G OFFIC E 1978-260 899/3164
 

64
 

DHEW Publication No. (NIH) 78-1336