National Cancer Institute 

CARCINOGENESIS 

Technical Report Series 

No. 13 

1977 

BIOASSAY OF
 

TETRACHLOROETHYLENE
 

FOR POSSIBLE CARCINOGENICITY
 

CAS No. 127-18-4 

NCI-CG-TR-13 

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

Public Health Service 

National Institutes of Health 

BIOASSAY OF
 

TETRACHLOROE THYLENE
 

FOR POSSIBLE CARCINOGENICITY
 

Carcinogen Bioassay and Program Resources Branch
 

Carcinogenesis Program
 

Division of Cancer Cause and Prevention
 

National Cancer Institute
 

National Institutes of Health
 

Bethesda, Maryland
 

DHEW Publication No. (NIH) 77-813 

REPORT ON THE BIOASSAY OF TETRACHLOROETHYLENE
 

FOR POSSIBLE CARCINOGENICITY
 

CARCINOGENESIS PROGRAM, DIVISION OF CANCER CAUSE AND PREVENTION
 

NATIONAL CANCER INSTITUTE, NATIONAL INSTITUTES OF HEALTH
 

CONTRIBUTORS: This report presents the results of the bioassay of
 

tetrachloroethylene conducted for the Carcinogen Bioassay and Program
 

Resources Branch, Carcinogenesis Program, Division of Cancer Cause
 

and Prevention, National Cancer Institute (NCI), National Institutes
 

of Health, Bethesda, Maryland. This bioassay 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
 

Bioassay 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); the technical supervisor of animal treatment and observation
 

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

Histopathology was performed by 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. Pathologists from NCI (1)
 

and Tracor Jitco (6) have reviewed selected slides and concur with
 

the overall pathologic evaluation of the study.
 

Compilation of individual animal survival, pathology, and
 

summary tables was performed by EG&G Mason Research Institute (7);
 

the statistical analysis was performed by Dr. J. R. Joiner (6) and
 

Mr. W. W. Belew (8), using methods selected for the Bioassay Program
 

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

This report was prepared at METREK, a Division of The MITRE
 

Corporation (8) under the direction of the NCI. Those responsible
 

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

Thomas (8), the task leader, Dr. M. R. Kornreich (8), and the senior
 

biologist, Ms. P. Walker (8). The final report was reviewed by
 

members of the participating organizations.
 

iii
 
The following scientists at the National Cancer Institute were
 

responsible for evaluating the bioassay experiment, interpreting the
 

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

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

R. A. Griesemer (1), Dr. R. A. Squire (1), and Dr. J. M. Ward (1).
 

1.	 Carcinogenesis Program, Division of Cancer Cause and Prevention, National Cancer Institute, National Institutes of Health,
 

Bethesda, Maryland.
 

2.	 Now with 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.	 Tracor Jitco, Inc., 1776 East Jefferson Street, Rockville,
 

Maryland.
 

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

Rockville, Maryland.
 

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

Boulevard, McLean, Virginia.
 

9.	 Mathematical Statistics and Applied Mathematics Section, Field
 

Studies and Statistics Branch, Division of Cancer Cause and
 

Prevention, National Cancer Institute, National Institutes of
 

Health, Bethesda, Maryland.
 

IV
 
SUMMARY
 

The bioassay of U.S.P. -grade tetrachloroethylene for possible
 

carcinogenicity was conducted using Osborne-Mendel rats and B6C3F1
 

mice. Tetrachloroethylene in corn oil was administered by gavage at
 

either of two dosages to groups of 50 male and 50 female animals of
 

each species, 5 days a week, over a period of 78 weeks followed by an
 

observation period of 32 weeks for rats and 12 weeks for mice.
 

Initial dosage levels for the chronic bioassay were selected on
 

the basis of a preliminary subchronic toxicity test. Subsequent
 

dosage adjustments were made during the course of the chronic bioassay. The high and low time-weighted average dosages of tetrachloroethylene in the chronic study were 941 and 471 mg/kg/day for the male
 

rats, 949 and 474 mg/kg/day for the female rats, 1072 and 536 mg/kg/
 

day for the male mice, and 772 and 386 mg/kg/day for the female mice.
 

For each species, 20 animals of each sex were placed on test as
 

vehicle controls. These animals were gavaged with corn oil at the
 

same time that dosed animals were gavaged with tetrachloroethylene
 

mixtures. Twenty animals of each sex were placed on test as untreated controls for each species. These animals received no gavage
 

treatments.
 

No significant increased incidence of neoplastic lesions was
 

observed in treated rats. In both dosed and control rats, respiratory disease was observed with increasing frequency for the latter
 

part of the first year until termination of the bioassay. Lesions
 

indicative of pneumonia were observed in nearly all rats at necropsy.
 

A high incidence of toxic nephropathy was observed in treated rats.
 

Toxic nephropathy was noted in rats that died early in the study (as
 

early as week 20 for male rats and week 28 for female rats). Mortality of rats was dose-related. Fifty percent of the high dose males
 

had died by week 44 and 50 percent of the high dose females had died
 

by week 66.
 

In both male and female mice, administration of tetrachloroethylene was associated with a significantly increased incidence of
 

heptocellular carcinoma. Hepatocellular carcinomas were observed in
 

2/17 (12 percent) untreated control males, 2/20 (10 percent) vehicle
 

control males, 32/49 (65 percent) low dose males, 27/48 (56 percent)
 

high dose males, 2/20 (10 percent) untreated control females, 0/20
 

vehicle control females, 19/48 (40 percent) low dose females, and
 

19/48 (40 percent) high dose females. Hepatocellular carcinomas
 

metastasized to the kidney in one untreated control male and to the
 

*United States Pharmacopoeia.
 

V 
lung in three low dose males, one low dose female, and one high dose
 

female. Toxic nephropathy, similar to that observed in rats, was
 

also observed in treated but not control mice.
 

Fisher exact tests indicated a highly significant increased incidence of hepatocellular carcinoma for each dosed group compared to
 

each control group. Cochran-Armitage tests showed a highly significant positive association between increased dosage and elevated tumor
 

incidence. Time-adjusted analyses, based on Kaplan and Meier survival
 

curves, indicated that the estimated probability of observing hepatocellular carcinoma by week 91 was 1.00 in a dosed male mouse and 0.938
 

in a dosed female mouse.
 

The results of the bioassay of tetrachloroethylene in Osborne-


Mendel rats do not allow an evaluation of the carcinogenicity of this
 

compound due to the high rate of early death among the treated animals. However, under the condition of this study, tetrachloroethylene
 

is a liver carcinogen in B6C3F1 mice of both sexes.
 

VI
 
TABLE OF CONTENTS
 

Page
 

I. INTRODUCTION 1
 

II. MATERIALS AND METHODS 4
 

A. Chemicals 4
 

B. Dosage Preparation 4
 

C. Animals 4
 

D. Animal Maintenance 5
 

E. Gastric Intubation 7
 

F. Selection of Initial Dose Levels 7
 

G. Experimental Design 8
 

H. Clinical and Histopathologic Examinations 12
 

I, Data Recording and Statistical Analyses 13
 

III. CHRONIC TESTING RESULTS: RATS 18
 

A. Body Weights and Clinical Observations 18
 

B. Survival 20
 

C. Pathology 22
 

D. Statistical Analyses of Results 23
 

IV. CHRONIC TESTING RESULTS: MICE 27
 

A. Body Weights and Clinical Observations . 27
 

B. Survival 29
 

C. Pathology 29
 

D. Statistical Analyses of Results 32
 

V. DISCUSSION 43
 

VI. BIBLIOGRAPHY 46
 

APPENDIX A SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

RATS TREATED WITH TETRACHLOROETHYLENE A-l
 

APPENDIX B SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

MICE TREATED WITH TETRACHLOROETHYLENE B-l
 

APPENDIX C SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN RATS TREATED WITH TETRACHLOROETHYLENE C-l
 

APPENDIX D SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN MICE TREATED WITH TETRACHLOROETHYLENE D-l
 

vii
 
LIST OF ILLUSTRATIONS 

Figure Number Page 

1 GROWTH CURVES FOR TETRACHLOROETHYLENE

CHRONIC STUDY RATS 

 19 

2 SURVIVAL COMPARISONS OF TETRACHLOROETHYLENE

CHRONIC STUDY RATS 

 21 

3 GROWTH CURVES FOR TETRACHLOROETHYLENE

CHRONIC STUDY MICE 

 28 

4 SURVIVAL COMPARISONS OF TETRACHLOROETHYLENE

CHRONIC STUDY MICE 

 3 0 

LIST OF TABLES 

Table Number Page 

1 DESIGN SUMMARY FOR OSBORNE-MENDEL RATS—

TETRACHLOROETHYLENE GAVAGE EXPERIMENT 

9 

2 DESIGN SUMMARY FOR B6C3F1 MICE—TETRACHLOROETHYLENE GAVAGE EXPERIMENT  10 

3 ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS

AT SPECIFIC SITES IN MALE RATS TREATED WITH 

TE TRACHLOROE THYLE NE 

 24 

4 ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS

AT SPECIFIC SITES IN FEMALE RATS TREATED 

WITH TETRACHLOROETHYLENE 

 25 

5 ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS

AT SPECIFIC SITES IN MALE MICE TREATED WITH 

TETRACHLOROETHYLENE 

 33 

6 ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS

AT SPECIFIC SITES IN FEMALE MICE TREATED 

WITH TETRACHLOROETHYLENE 

 35 

7 ANALYSES OF THE INCIDENCE OF HEPATOCELLULAR

CARCINOMA IN MALE MICE TREATED WITH TETRACHLOROETHYLENE 

 40 

viii
 
LIST OF TABLES (Concluded) 

Table Number 

8 ANALYSES OF THE INCIDENCE OF HEPATOCELLULAR

CARCINOMA IN FEMALE MICE TREATED WITH TETRACHLOROETHYLENE 

 41 

Al SUMMARY OF THE INCIDENCE OF NEOPLASMS IN

MALE RATS TREATED WITH TETRACHLOROETHYLENE 

 A-3 

A2 SUMMARY OF THE INCIDENCE OF NEOPLASMS IN

FEMALE RATS TREATED WITH TETRACHLOROETHYLENE 

 A-6 

Bl SUMMARY OF THE INCIDENCE OF NEOPLASMS IN

MALE MICE TREATED WITH TETRACHLOROETHYLENE 

 B-3 

B2 SUMMARY OF THE INCIDENCE OF NEOPLASMS IN

FEMALE MICE TREATED WITH TETRACHLOROETHYLENE 

 B-6 

Cl SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC

LESIONS IN MALE RATS TREATED WITH TETRACHLOROETHYLENE 

 C-3 

C2 SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC

LESIONS IN FEMALE RATS TREATED WITH TETRACHLOROETHYLENE 

 C-7 

Dl SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC

LESIONS IN MALE MICE TREATED WITH TETRACHLOROETHYLENE 

 D-3 

D2 SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC

LESIONS IN FEMALE MICE TREATED WITH TETRACHLOROETHYLENE 

 D-7 

ix
 

I. INTRODUCTION
 

Tetrachloroethylene (NCI No. C04580) is one of a group of halogenated organic solvents selected by the National Cancer Institute
 

(NCI) for inclusion in the Carcinogenesis Bioassay Program. These
 

solvents were selected on the basis of large-scale production,
 

extensive use, and lack of adequate chronic toxicity data.
 

The Chemical Abstracts Service (CAS) Ninth Collective Index
 

(1977) name for this compound is tetrachloroethylene. It is also
 

called perchloroethylene and carbon dichloride.
 

Annual domestic production of tetrachloroethylene in 1974 was
 

approximately 734 million pounds (U.S. International Trade Commission,
 

1976). The 1974 consumption of the chemical was as follows: 69
 

percent in the textile and dry-cleaning industries; 16 percent for
 

metal cleaning and degreasing; 12 percent as a chemical intermediate
 

(e.g., fluorocarbon synthesis); and 3 percent for miscellaneous uses
 

(Fishbein, 1976). The last category includes paint removers and
 

other specialty solvent formulations, as well as a very small
 

quantity for medicinal use as an antihelminthic (e.g., treatment of
 

hookworm infestations) (Senewiratne et al., 1975).
 

Human exposure to tetrachloroethylene is extensive. Approximately 85 percent of the compound consumed is used in a dispersive
 

manner (Stanford Research Institute, 1975). The greatest human
 

The CAS registry number is 127-18-4.
 

1 
exposure takes place in dry-cleaning establishments using tetrachloroethylene, especially when ventilation is inadequate (Fishbein, 1976).
 

Employees of tetrachloroethylene manufacturers and of the industries
 

consuming the chemical may also be directly exposed to the vapors or
 

liquid. Tetrachloroethylene appears to be a widespread environmental
 

contaminant, found in air, water, and food (McConnell et al., 1975).
 

Worldwide air emissions of tetrachloroethylene were estimated at
 

nearly 2.8 x 10 tons in 1974 (Chemical Information Services, 1975),
 

and atmospheric concentrations normally range between 1 and 10
 

ng/liter (McConnell et al., 1975). Concentrations of the chemical in
 

foodstuffs have been reported as high as 13 mg/kg in butter (McConnell
 

et al., 1975). Tetrachloroethylene was found in New Orleans drinking
 

water and in the plasma of persons ingesting that water (no levels
 

were given) (Dowty et al., 1975). Chlorination at sewage treatment
 

plants slightly raises tetrachloroethylene levels in water (Fishbein,
 

1976). Human tissues (body fat) have been found to contain as much
 

as 29 mg/kg wet weight of tetrachloroethylene (McConnell et al•,
 

1975). The mean biological half-life of the compound in man, estimated by measuring the total of tetrachloroethylene and tetrachloroethylene metabolites in urine, is 144 hours (Ikeda and Imamura, 1973).
 

Tetrachloroethylene is degraded fairly rapidly in the environment
 

without significant bioaccumulation (McConnell et al., 1975).
 

Depression of the central nervous system, the primary physiologic
 

effect of acute or chronic inhalation, was noted in humans exposed to
 

2 
200 ppm of the chemical (Rowe et al., 1952). Recovery was complete
 

within an hour after exposure to concentrations as high as 1000 ppm
 

for two minutes. Only one of six persons exposed to 100 ppm of
 

tetrachloroethylene for an hour experienced effects attributable to
 

that concentration of vapor (Rowe et al., 1952). Symptoms of acute
 

and fatal intoxication from tetrachloroethylene result from action on
 

the nervous system and include tremor, convulsions, paralysis, mental
 

confusion, and coma (Sax, 1975). Subacute exposures produce irritation of the eyes, nose, and throat, headaches, fatigue, nausea,
 

vomiting, and mental confusion (Sax, 1975).
 

3 
II. MATERIALS AND METHODS
 

A. Chemicals
 

Three batches of U.S.P.-grade tetrachloroethylene were purchased
 

by Hazleton Laboratories America, Inc., Vienna, Virginia, from Aldrich
 

Chemical Company, Milwaukee, Wisconsin. The manufacturer's suggested
 

minimum purity was 99 percent. Gas-liquid chromatography showed the
 

major component comprising over 99 percent of the total peak area and
 

one minor impurity having a greater retention time than the major
 

component. Infrared analysis was consistent with that found in the
 

literature. These results suggested a compound with a purity over 99
 

percent with at least one minor impurity.
 

Throughout this report the term tetrachloroethylene is used to
 

represent this U.S.P.-grade material.
 

B« Dosage Preparation
 

Fresh solutions of tetrachloroethylene and Duke's corn oil
 

(S. F. Sauer Company) were prepared weekly, sealed, and stored at
 

34°F. These tetrachloroethylene solutions were considered generally
 

stable for 10 days under the indicated storage conditions. The
 

concentrations of tetrachloroethylene in corn oil were 6, 8, 9, and
 

11 percent for mice and 50 and 60 percent for rats.
 

C. Animals
 

Two animal 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 at the National Cancer Institute.
 

The Osborne-Mendel rats were procured from the Battelle Memorial
 

Institute, Columbus, Ohio, and the B6C3F1 mice were obtained from the
 

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

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

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

various treatment 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 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 with filter tops. Sanitized cages with
 

(R)
 

fresh bedding (Sanichips , Shurfire) were provided once each week for
 

mice. Rats received sanitized cages with no bedding with the same
 

5 
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 were provided three times a week.
 

Food (Wayne Lab-Blox , Allied Mills, Inc.) and water were available
 

ad libitum.
 

Tetrachloroethylene-treated rats and their untreated controls
 

were housed in the same room with 1,1,2-trichloroethane (79-00-5)­

treated rats. Vehicle control rats for the tetrachloroethylene
 

bioassay were housed in another room with rats treated with dibromochloropropane (96-12-8), 1,2-dichloroethane (107-06-2), trichloroethylene (79-01-6), 1,1-dichloroethane (75-34-3), and carbon disulfide
 

(75-15-0). Tetrachloroethylene-treated and both vehicle and untreated
 

control mice were maintained in the same room as mice receiving
 

1,1,2,2-tetrachloroethane (79-34-5), allyl chloride (107-05-11),
 

chloroform (67-66-3), chloropicrin (76-06-2), 1,2-dichloroethane
 

(107-06-2), 1,1-dichloroethane (75-34-3), 3-sulfolene (77-79-21),
 

iodoform (75-47-8), methylchloroform (71-55-6), 1,1,2-trichloroethane
 

(79-00-5), hexachloroethane (67-72-1), carbon disulfide (75-15-0),
 

trichlorofluoromethane (75-69-4), carbon tetrachloride (56-23-5),
 

trichloroethylene (79-01-6), 1,2-dibromoethane (106-93-4), and
 

dibromochloropropane (96-12-8).
 

*
 CAS registry numbers are given in parentheses.
 

6
 
E. Gastric Intubation
 

Intubation was performed for five consecutive days per week on
 

a mg/kg 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 treatment 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 tetrachloroethylene for administration to treated animals in the chronic
 

studies, subchronic toxicity tests were conducted with both rats and
 

mice. Six groups, each consisting of five males and five females,
 

were utilized for each animal species. Tetrachloroethylene dissolved
 

in corn oil was administered by gavage to five of the six rat groups
 

at dosages of 316, 562, 1000, 1780, and 3160 mg/kg/day and to five of
 

the six mouse groups at dosages of 562, 1000, 1780, 3160, and 5620
 

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

and was gavaged only with corn oil. Intubation occurred 5 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 retardation
 

in body weight gain of approximately 20 percent was to be selected
 

7 
as the initial high dose. When weight gain criteria were not applicable, mortality data alone were utilized.
 

All the rats, both male and female, dosed with 1000 mg/kg/day
 

or less survived the entire 6-week treatment period and the 2-week
 

observation period, while deaths were observed at higher dose levels.
 

As weight gain retardation was not noted in the animals treated with
 

1000 mg/kg/day or less, the high dosage selected for the chronic
 

bioassay for male and female rats was 1000 mg/kg/day.
 

The male mice receiving 562 mg/kg/day experienced no reduction
 

in weight gain relative to controls, while the male mice receiving
 

1000 mg/kg/day experienced a 22 percent reduction in weight gain
 

relative to controls. An initial high dosage of 900 mg/kg/day was
 

selected for the chronic bioassay of male mice. Female mice receiving
 

562 mg/kg/day gained 70 percent of the weight gained by controls,
 

while the female mice receiving 1000 mg/kg/day gained 85 percent of
 

the weight gained by controls. An initial high dosage of 600
 

mg/kg/day was selected for the chronic bioassay of 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 high dose, low dose, and untreated control rats were
 

approximately 7 weeks old at the time they were placed on test. The
 

8
 
TABLE 1
 

DESIGN SUMMARY FOR OSBORNE-MENDEL RATS
 

TETRACHLOROETHYLENE GAVAGE EXPERIMENT
 

MALE
 

UNTREATED CONTROL
 

VEHICLE CONTROL
 

LOW DOSE
 

HIGH DOSE
 

FEMALE
 

UNTREATED CONTROL
 

VEHICLE CONTROL
 

LOW DOSE
 

HIGH DOSE
 

INITIAL
 

GROUP
 

SIZE
 

20
 

20
 

50
 

50
 

20
 

20
 

50
 

50
 

TETRACHLOROETHYLENE
 

DOSAGEa
 

0
 

0
 

500
 

700
 

500
 

500C
 

0
 

1000
 

1400
 

1000
 

1000°
 

0
 

0
 

0
 

500
 

600
 

700
 

500
 

500C
 

0
 

1000
 

1200
 

1400
 

1000
 

1000°
 

0
 

OBSERVATION PERIOD
 

TREATED UNTREATED
 

(WEEKS) (WEEKS)
 

110
 

78 32
 

19
 

6
 

20
 

26 7
 

32
 

19
 

6
 

20
 

26 7
 

32
 

110
 

78 32
 

16
 

3
 

6
 

20
 

26 7
 

32
 

16
 

3
 

6
 

20
 

26 7
 

32
 

TIME-WEIGHTED
 

AVERAGE
 

DOSAGE
 

0
 

0
 

471
 

941
 

0
 

0
 

474
 

949
 

Dosage, given in mg/kg body weight, was administered by gavage five consecutive
 

days per week·
 

b_. . , Σ(dosage X number of weeks received)
 Time-weighted average dosage = -=77 , :—: χ ­ e> & Σ (weeks receiving treatment)
 

These dosages were cyclically administered with a pattern of 1 dose-free week
 

followed by 4 weeks (5 days per week) of dosage at the level indicated.
 
TABLE 2
 

DESIGN SUMMARY FOR B6C3F1 MICE
 

TETRACHLOROETHYLENE GAVAGE EXPERIMENT
 

INITIAL TETRACHLORO­ OBSERVATION PERIOD TIME-WEIGHTED 

GROUP ETHYLENE TREATED UNTREATED AVERAGE 

SIZE DOSAGEa (WEEKS) (WEEKS) DOSAGEb 

MALE 

UNTREATED CONTROL 20 0 90 0 

VEHICLE CONTROL 20 0 78 12 0
 

LOW DOSE 50 450 11 536
 

550 67
 

0 12
 

HIGH DOSE 50 900 11 1072
 

1100 67
 

0 12
 

FEMALE
 

UNTREATED CONTROL 20 0 90 0
 

VEHICLE CONTROL 20 0 78 12 0
 

LOW DOSE 50 300 11 386
 

400 67
 

0 12
 

HIGH DOSE 50 600 11 772
 

800 67
 

0 12
 

Dosage, given in mg/kg body weight, was administered by gavage five consecutive
 

days per week.
 

b Σ(dosage X number of weeks received)
 Time-weighted average dosage =
 (weeks receiving treatment)
 

10
 
vehicle control rats were approximately 4 weeks older than the other
 

rats and, therefore, were started on test 4 weeks earlier. The high
 

and low doses of tetrachloroethylene initially utilized for both
 

males and females were 1000 and 500 mg/kg/day, respectively. After
 

16 weeks on test the female rats appeared to be tolerating the
 

chemical, so their high dose was increased to 1200 mg/kg/day. At
 

the end of week 19, high doses for both sexes were increased to
 

1400 mg/kg/day. Because of toxic effects evidenced during week 25,
 

the dosage administered to the high dose females was decreased in
 

week 26 to the original level of 1000 mg/kg/day. The low doses were
 

adjusted accordingly, so that they consistently remained one-half the
 

high dose. In week 46 intubation ceased for all treated animals for
 

1 week, followed by 4 weeks of dose administration. This pattern
 

continued for the remainder of the treatment period. An untreated
 

period of 32 weeks followed the 78-week treatment period in order to
 

observe any delayed toxicity or tumor development.
 

The high dose, low dose, and untreated control mice were approximately 5 weeks old at the time they were placed on test. The vehicle
 

control mice were approximately 2 weeks older than the other mice and
 

were started on test correspondingly earlier. The high and low doses
 

initially utilized for males and females, respectively, were 900 and
 

450 mg/kg/day and 600 and 300 mg/kg/day. After 11 weeks, the animals
 

appeared to be tolerating the chemical, so the high and low doses
 

were, respectively, increased to 1100 and 550 mg/kg/day for male mice
 

11
 
and 800 and 400 mg/kg/day for female mice. Treatment continued at
 

this level for the remainder of the 78-week treatment period and was
 

followed by approximately 12 weeks of observation.
 

H. Clinical and Histopathologic Examinations
 

Animals were weighed immediately prior to initiation of the
 

experiment. From the first day, all animals were inspected daily
 

for mortality. 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. 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, or gross lesions taken from sacrificed animals and, whenever possible, from animals found dead.
 

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)
 

and bile duct, pancreas, esophagus, stomach, small intestine, large
 

intestine, kidney, urinary bladder, pituitary, adrenal, thyroid,
 

12
 
parathyroid, pancreatic islets, testis, prostate, brain, uterus,
 

mammary gland, and ovary.
 

Tissues for which slides were prepared 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.
 

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.
 

13
 
These data were analyzed using the statistical techniques
 

described in this section. Those analyses of the experimental results
 

that bear on the possibility of carcinogenicity are discussed in the
 

statistical narrative sections.
 

Probabilities of survival were estimated by the product-limit
 

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

in the form of graphs. Animals were statistically censored as of the
 

time that they died of other than natural causes or were found to be
 

missing; animals dying from natural causes were not statistically
 

censored. Statistical analyses for a possible dose-related effect on
 

survival used the method of Cox (1972) for testing two groups for
 

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

testing a dose-related trend. One-tailed P-values have been reported
 

for all tests except the departure from linearity test, which is only
 

reported when its two-tailed P-valueis 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.,
 

14
 
lymphomas), the denominators consist of the numbers of animals necropsied.
 

The purpose of the statistical analyses of tumor incidence is to
 

determine whether animals receiving the test chemical developed a significantly higher proportion of tumors than did the control animals.
 

As a part of these analyses, the one-tailed Fisher exact test (Cox,
 

1970, 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 Ca05 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.
 

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.
 

15
 
A time-adjusted analysis was applied when numerous early deaths
 

resulted from causes that were not associated with the formation of
 

tumors. In this analysis, deaths that occurred before the first tumor was observed were excluded by basing the statistical tests on
 

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

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

tumor was found, comparisons were based exclusively on animals that
 

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

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

Cochran-Armitage tests, etc.) were followed.
 

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

incidence of tumors. Curves of the proportions surviving without an
 

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

during which animals died naturally or were sacrificed was entered as
 

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

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

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

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

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

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


tailed test) were also noted.
 

The approximate 95 percent confidence interval for the relative
 

risk of each dosed group compared to its control was calculated from
 

16
 
the exact interval on the odds ratio (Gart, 1971). The relative risk
 

is defined as pt/pc where p is the true binomial probability of the
 

incidence of a specific type of tumor in a treated group of animals
 

and p is the true probability of the spontaneous incidence of the
 

same type of tumor in a control group. The hypothesis of equality
 

between the true proportion of a specific tumor in a 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.
 

17
 
III. CHRONIC TESTING RESULTS: RATS
 

A. Body Weights and Clinical Observations
 

During the first year of the study, treated rats gained less
 

weight than did their untreated controls. However, the differences
 

in weight gain did not exceed 13 percent. Throughout the second year,
 

treated animals continued to gain less weight than did the untreated
 

controls, but the disparity never exceeded 19 percent (Figure 1).
 

No characteristic signs of the toxic effects of the compound
 

were observed during the first 6 weeks of the study. Clinical signs
 

were observed with slightly greater frequency in the treated rats of
 

both sexes than in the respective control rats from week 7 through
 

week 46. However, during the remainder of the study these signs were
 

noted at comparable rates in treated and control animals.
 

As the study progressed, a hunched appearance, first noted in
 

a few animals during week 7, was observed with gradually increasing
 

frequency in the treated groups, particularly in the high dose
 

females. Urine staining on the lower abdomen was a predominant
 

clinical sign in the treated groups from week 26 to termination of
 

the study. The greatest incidence of this was observed in the high
 

dose females. Other signs observed with comparable frequency in
 

control and treated rats included roughening and/or staining of the
 

fur; eyes squinted or showing a reddish discharge or crust; body
 

sores, particularly on the tail; and localized alopecia of the body
 

or extremities. Isolated observations included circling in one low
 

18
 
TIME ON TEST (WEEKS) 

FIGURE 1 

GROWTH CURVES FOR TETRACHLOROETHYLENE CHRONIC STUDY RATS 

I9 
dose male in week 42, salivation in several high dose males and
 

females during weeks 34 through 42 of the study, and reddish vaginal
 

discharge in one high dose female from week 50 though week 58.
 

Respiratory signs, characterized by dyspnea, wheezing, and/or
 

reddish nasal discharge, were noted in treated and control rats
 

during the latter part of the first year with the incidence increasing for all groups as the animals aged. In week 110, most of
 

the surviving animals had a hunched appearance, sores on the body,
 

and dyspnea.
 

The first palpable nodule was noted during the latter part of
 

the first year in the axilla of a high dose female. Several palpable
 

nodules, tissue masses, or wart-like lesions were noted in all groups
 

during the second year of the study.
 

B.	 Survival
 

The estimated probabilities of survival for male and female rats
 

in the control and tetrachloroethylene-dosed groups are shown in
 

Figure 2.
 

For both male and female rats, the Tarone test indicated a
 

statistically significant association (P < 0.001) between increased
 

dosage and elevated mortality. For both sexes this association was
 

particularly marked after 30 weeks.
 

Fifty percent of the high dose males died by week 44, and 50
 

percent of the high dose females died by week 66. By comparison, the
 

median survival for each of the control groups was over 88 weeks for
 

20
 
TIME ON TEST (WEEKS) 

FIGURE 2 

SURVIVAL COMPARISONS OF TETRACHLOROETHYLENE CHRONIC STUDY RATS 

21 
the males and over 102 weeks for the females.. The early deaths and
 

their significant association with dose levels imply that optimum
 

dosage was exceeded in the rats. These unusually early deaths were
 

not associated with observed tumors.
 

C. Pathology
 

Histopathologic findings on neoplasms in rats are tabulated in
 

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

tabulated in Appendix C (Tables Cl and C2).
 

Toxic nephropathy was noticed early in the study and occurred in
 

43/49 low dose males, 47/50 high dose males, 29/50 low dose females,
 

39/50 high dose females, and in no control animals. Microscopically,
 

toxic nephropathy was characterized by degenerative changes in. the
 

proximal convoluted tubules at the junction of the cortex and medulla,
 

with cloudy swelling, fatty degeneration, and necrosis of the tubular
 

epithelium. Some affected tubules were empty, others were filled with
 

hyalin casts. In occasional tubules, the damaged cells were replaced
 

by enlarged darks taining regenerative tubular epithelial cells. At
 

this stage the kidney often had infiltration of inflammatory cells,
 

fibrosis, and focal mineralization.
 

Renal neoplasms were either malignant mixed tumors or hamartomas. Malignant mixed tumors occurred in 1/19 untreated control
 

males, 2/20 vehicle control males, 1/49 low dose males, and 0/50 high
 

*Nonneoplastic proliferative lesions composed of lipocytes, tubular
 

structures, and fibroblasts in varying proportions.
 

22
 
dose males. One high dose female (1/50) was the only female in which
 

these malignant mixed tumors were observed. Hamartomas occurred in
 

1/20 vehicle control males, 1/50 high dose males, and 1/20 untreated
 

control females. They were not detected in any other animals.
 

Malignant mixed tumors were composed predominantly of spindled cells
 

and immature fat cells with nuclear variability (atypia) and occasional mitotic figures present. The cells comprising the epithelial
 

component (embryonic renal tubules) of the malignant neoplasms were
 

not appreciably different from those present in the hamartomas. The
 

malignant mixed tumors were not well-circumscribed. There was
 

extensive invasion and destruction of the adjacent renal tissue and
 

the neoplasm often extended beyond the renal capsule to involve the
 

surrounding abdominal viscera. The hamartomas were composed of a
 

mixture of mature fat cells, occasional renal tubules that were
 

embryonic in appearance, and spindled cells. These lesions were
 

generally circumscribed from the surrounding renal parenchyma.
 

Other inflammatory, degenerative, and proliferative lesions
 

observed in control and test animals were similar in number and kind
 

to those spontaneous lesions found in aged rats.
 

No pathologic evidence of the carcinogenicity of tetrachloroethylene was noted; however, tetrachloroethylene caused toxic nephropathy in the kidneys of the male and female rats.
 

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 for every type
 

23
 
ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN MALE RATS TREATED WITH TETRACHLOROETHYLENEa
 

TOPOGRAPHY:MORPHOLOGY
 

All Sites: Hemangiosarcomab
 

 Valuesc
 

Relative Risk(Untreated Control)d
 

Lower Limit
 

Upper Limit
 

Relative Risk(Vehicle Control) d
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Pituitary: Chromophobe Adenoma or
 

Carcinomab
 

 Valuesc
 

Departure from Linear Trend
 

Relative Risk(Untreated Control)d
 

Lower Limit
 

Upper Limit
 

Relative Risk(Vehicle Control)d
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Pituitary: Chromophobe Adenoma
 

 Values0
 

Relative Risk(Untreated Control)d
 

Lower Limit
 

Upper Limit
 

Relative Risk(Vehicle Control)d
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

a
 

UNTREATED
 

CONTROL
 

2/20(0.10)
 

N.S.
 

—
 

—
 

93
 

4/19(0.21)
 

 = 0.002(N)
 

 = 0.036
 

1
 

—
 

93
 

3/19(0.16)
 

 = 0.008(N)
 

—
 

93
 

VEHICLE LOW 

CONTROL DOSE 

1/20(0.05) 2/50(0.04) 

N.S. N.S. 

0.400 

0.032 

— 5.277 

0.800 

0.045 

— 46.273 

70 67 

0/20(0.00) 1/49(0.02) 

N.S. = 0.019*(N) 

— 

0.097 

0.002 

— 0.913 

Infinite 

0.023 

— - Infinite 

112 

0/20(0.00) 1/49(0.02) 

N.S. N.S. 

0.129 

0.003 

1.517 

Infinite 

0.023 

Infinite 

112 

HIGH
 

DOSE
 

1/50(0.02)
 

N.S.
 

0.200
 

0.007
 

3.681
 

0.400
 

0.005
 

30.802
 

103
 

0/44(0.00)
 

 = 0.007*(N)
 

0.000
 

0.000
 

0.459
 

—
 

0/44(0.00)
 

 = 0.024*(Ν)
 

0.000
 

0.000
 

0.709
 

—
 

24 

Dosed gro.ups received time-weighted average doses of 471 and 949 mg/kg by gavage.
 

b

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

c
Beneath the incidence of each of the controls is the probability level for the Cochran-Armitage test for
 

dose-related trend in proportions when it is below 0.05, otherwise N.S. - not significant. Departure from
 

linear trend is noted when it is below 0.05 for any comparison. Beneath the dose group incidence is the
 

probability level for the Fisher exact (conditional) test for the comparison of that dose group with the
 

tetrachloroethylene untreated control group (*) and the vehicle control group (**) when either is below
 

0.05, otherwise N.S. - not significant.
 

(N) Less incidence in the dose group(s) than in a control group results in a negative indication.
 

Relative Risk of the treated group versus the control group is shown along with the lower and upper limit
 

of the 95% confidence interval for that Relative Risk.
 
25 

TABLE 4
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN FEMALE RATS TREATED WITH TETRACHLOROETHYLENEa
 

Relative Risk(Untreated Control) 0.933
 

UNTREATED VEHICLE LOW 

TOPOGRAPHY: MORPHOLOGY CONTROL CONTROL DOSE 

Mammary Gland: Fibroadenoma" 3/20(0.15) 3/20(0.15) 7/50(0.14) 

 Values0 N.S. N.S. N.S. 

d 

Lower Limit 0.245
 

Upper Limit 5.215
 

Relative Risk(Vehicle Control)d 0.933
 

Lower Limit 0.245
 

Upper Limit 5.215
 

Weeks to First Observed Tumor 106 112
 

All Sites: Hemangiosarcomab 0/20(0.00) 0/20(0.00) 1/50(0.02)
 

 Values0 N.S. N.S. N.S.
 

Relative Risk(Untreated Control)b Infinite
 

Lower Limit 0.022
 

Upper Limit Infinite
 

Relative Risk(Vehicle Control)d Infinite
 

Lower Limit 0.022
 

Upper Limit Infinite
 

Weeks to First Observed Tumor 60
 

Pituitary: Chromophobe Adenomab 8/20(0.40) 4/20(0.20) 9/50(0.18)
 

 Values0 = 0.009(N) N.S. N.S.
 

Relative Risk(Untreated Control)d 0.450
 

Lower Limit 0.191
 

Upper Limit 1.177
 

Relative Risk(Vehicle Control)d 0.900
 

Lower Limit 0.294
 

Upper Limit 3.660
 

Weeks to First Observed Tumor 85 85 73
 

HIGH
 

DOSE
 

7/50(0.14)
 

N.S.
 

0.933
 

0.245
 

5.215
 

0.933
 

0.245
 

5.215
 

97
 

0/50(0.00)
 

N.S.
 

6/50(0.12)
 

 = 0.012*(N)
 

0.300
 

0.104
 

0.871
 

0.600
 

0.165
 

2.659
 

97
 

Dosed groups received time-weiglited average doses of 474 and 949 mg/kg by gavage.
 

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

C

Beneath the incidence of each of the controls is the probability level for the Cochran-Armitage test for
 

dose-related trend in proportions when it is below 0.05, otherwise N.S. - not significant. Departure from
 

linear trend is noted when it is below 0.05 for any comparison. Beneath the dose group incidence is the
 

probability level for the Fisher exact (conditional) test for the comparison of that dose group with the
 

tetrachloroethylene untreated control group (*) and the vehicle control group (**) when either is below
 

0.05, otherwise N.S. - not significant.
 

(N) Less incidence in the dose group(s) than in a control group results in a negative indication.
 

d

Relative Risk of the treated group versus the control group is shown along with the lower and upper limit
 

of the 95% confidence interval for that Relative Risk.
 
of tumor that was observed in more than 5 percent of any of the
 

tetrachloroethylene-dosed groups of either sex is included.
 

Neither the Cochran-Armitage tests nor the Fisher exact tests
 

indicated any statistically significant increase in the proportion
 

of tumors found in dosed groups over that found in either control
 

group for any tumor type for either sex. This experiment, therefore,
 

provides no evidence of the carcinogenicity of tetrachloroethylene in
 

rats.
 

To provide additional insight, 95 percent confidence intervals
 

on the relative risk have been estimated and entered in the tables
 

based upon the observed tumor incidence rates. The implication of
 

such intervals is that in 95 percent of a large number of identical
 

experiments, the true ratio of the tumor rate of the dosed group to
 

that of the control group would be inside the interval as calculated
 

from this experiment. In many of the intervals shown in Tables 3 and
 

4, the value one is included; this indicates the absence of statistically significant results. It should also be noted that: many of the
 

confidence intervals have an upper limit greater than one, indicating
 

the theoretical possibility of a significantly increased rate of tumor
 

incidence induced in rats by tetrachloroethylene that could not be
 

established under the conditions of this test.
 

26
 
IV. CHRONIC TESTING RESULTS: MICE
 

A. Body Weights and Clinical Observations
 

There were no appreciable differences in mean body weight gain
 

between dosed mice and untreated mice of either sex during this
 

bioassay (Figure 3). Dosed male mice did, however, gain less weight
 

than vehicle control males after the first three months, and dosed
 

female mice did gain less than vehicle control females during the
 

second year of the bioassay.
 

Appearance and behavior were generally similar for control and
 

treated mice during the first 26 weeks of the study. Signs often
 

observed in group-housed laboratory mice were noted with a slightly
 

greater frequency in the treated mice of both sexes than in the
 

respective control animals during the remainder of the first year.
 

These signs included body sores (particularly in the males), anal or
 

penile irritation, rough or stained fur, and generali2ied or localized
 

alopecia.
 

A greater number of treated mice of both sexes showed a hunched
 

appearance from week 42 through week 62. Thereafter, surviving test
 

animals exhibited a hunched appearance at a comparable frequency to
 

the controls. A low incidence of bloating or abdominal distension
 

was noted in the treated groups during the second year of the study.
 

Nodules were palpated on the ventral region of a few animals as early
 

as week 6; however, most of these palpable nodules were not persistent
 

27
 
TIME ON TEST (WEEKS)

 

FIGURE 3 

GROWTH CURVES FOR TETRACHLOROETHYLEIME CHRONIC STUDY MICE 

28 
and were probably abscesses that drained and healed during the course
 

of the study.
 

B. Survival
 

The estimated probabilities of survival for male and female mice
 

in the control and tetrachloroethylene-dosed groups are shown in
 

Figure 4.
 

For mice of both sexes the Tarone test indicated a significant
 

(P < 0.001) association between increased dosage of tetrachloroethylene and elevated mortality. Fifty percent of each control group
 

of male mice survived to termination of the experiment (over 90 weeks),
 

compared to a median survival of 78 weeks in the low dose males and
 

43 weeks in the high dose males. In female mice, the median survival
 

for both vehicle and untreated controls was over 90 weeks (termination
 

of the experiment) compared to 62 weeks in the low dose group and 50
 

weeks in the high dose group. As may be seen in Figure 4, the survival curves for the high dose groups of both sexes were substantially
 

lower than the control group curves after 40 to 45 weeks. While the
 

early mortality in mice may indicate that the optimum dose was
 

exceeded, it must also be noted that liver tumors were found in
 

substantial numbers of the mice of both sexes that died early in the
 

experiment.
 

C. Pathology
 

Histopathologic findings on neoplasms in mice are tabulated in
 

Appendix B (Tables Bl and B2); findings on nonneoplastic lesions are
 

tabulated in Appendix D (Tables Dl and D2).
 

29
 
TIME ON TEST (WEEKS) 

FIGURE4 

SURVIVAL COMPARISONS OF TETRACHLOROETHYLENE CHRONIC STUDY MICE 

30 
Hepatocellular carcinomas occurred in 2/17 (12 percent) untreated
 

control males, 2/20 (10 percent) vehicle control males, 32/49 (65
 

percent) low dose males, 27/48 (56 percent) high dose males, 2/20 (10
 

percent) untreated control females, 0/20 vehicle control females,
 

19/48 (40 percent) low dose females, and 19/48 (40 percent) high dose
 

females. Hepatocellular carcinomas metastasized to the kidney in
 

1/18 untreated control males and to the lung in 3/49 low dose males,
 

1/49 low dose females, and 1/48 high dose females.
 

The hepatocellular carcinomas varied greatly in appearance.
 

Some lesions consisted of well-differentiated hepatocytes that were
 

arranged in relatively uniform hepatic cords. Other hepatocellular
 

carcinomas had very anaplastic cells with large hyperchromatic
 

nuclei, often with inclusion bodies and with vacuolated, pale cytoplasm. Arrangement of the neoplastic cells varied from short stubby
 

cords to nests of hepatic cells and occasionally acinar formation.
 

Mitotic figures were often present. Some of the tumors were characterized by discrete areas of highly anaplastic cells. The hepatic
 

neoplasms occurring in the control mice were not different in appearance from those noted in the mice receiving tetrachloroethylene.
 

Nonneoplastic hepatic cell proliferation (foci of altered hepatic cells) was found only in 3/48 high dose male mice.
 

Tetrachloroethylene also caused toxic nephropathy in 40/49
 

low dose males, 45/48 high dose males, 46/48 low dose females, and
 

48/48 high dose females. This condition was not observed in control
 

31
 
animals. The toxic effect of this chemical on the morphology of the
 

epithelium of the proximal convoluted tubules was similar to that
 

seen in the treated rats.
 

Chronic murine pneumonia occurred frequently. Other nonneoplastic lesions, such as degeneration and inflammation of various tissues,
 

occurred in the treated and control animals in a relatively low
 

incidence.
 

Results of this pathologic examination indicate that tetrachloroethylene is hepatocarcinogenic and also causes toxic nephropathy
 

in the kidneys of both male and female mice.
 

D. Statistical Analyses of Results
 

The results of the statistical analyses of tumor incidence in
 

mice are summarized in Tables 5 and 6. The analysis for every type
 

of tumor that was observed in more than 5 percent of any of the
 

tetrachloroethylene-dosed groups of either sex is included.
 

Two control groups were used in the standard statistical analyses: the untreated control group and the vehicle control group.
 

The specific tumor incidences of these control groups were compared
 

to the corresponding spontaneous tumor rates for the historical
 

controls compiled to date on B6C3F1 mice by this bioassay program.
 

No significant differences were observed.
 

In male mice, hepatocellular carcinomas were found in large
 

numbers in the dosed groups. The Cochran-Armitage tests for positive
 

dose-related trend were highly significant using either the untreated
 

32
 
33 

TABLE 5
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN MALE MICE TREATED WITH TETRACHLOROETHYLENEa
 

TOPOGRAPHY: MORPHOLOGY
 

Liver: Hepatocellular Carcinoma
 

 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
 

 Values0
 

Departure from Linear Trend
 

Relative Risk(Untreated Control)d
 

Lower Limit
 

Upper Limit
 

Relative Risk(Vehicle Control)d
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Hematopoietic System: Malignant
 

Lymphoma b
 

 Valuesc
 

Relative Risk(Untreated Control)d
 

Lower Limit
 

Upper Limit
 

Relative Risk(Vehicle Control)d
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

UNTREATED VEHICLE LOW HIGH
 

CONTROL CONTROL DOSE DOSE
 

2/17(0.12) 2/20(0.10)	 32/49(0.65) 27/48(0.56)
 

 = 0.018 = 0.006	 < 0.001* = 0.001
 

 < 0.001** < 0.001**
 

 = 0.002 = 0.001
 

5.551 4.781
 

1.709 1.440
 

42.979 37.964
 

6.531 5.625
 

1.972 1.660
 

50.795 44.815
 

91	 90 27 40
 

2/18(0.11) 0/20(0.00)	 3/49(0.06) 0/48(0.00)
 

 = 0.036(N) N.S.	 N.S. N.S.
 

 = 0.047
 

0.551 0.000
 

0.071 0.000
 

6.284 1.259
 

Infinite
 

0.255
 

Infinite
 

84	 91
 

1/18(0.06) 2/20(0.10) 0/49(0.00) 0/48(0.00)
 

N.S. = 0.026(N) N.S. N.S.
 

0.000 0.000
 

0.000 0.000
 

6.864 7.004
 

0.000 0.000
 

0.000 0.000
 

1.372 1.400
 

91	 66
 
TABLE 5
 

(CONCLUDED)
 

a

Dosed groups received time-weighted average doses of 536 and 1072 mg/kg by gavage.
 

b
 

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

c
 

Beneath the incidence of each of the controls is the probability level for the Cochran-Armitage test for
 

dose-related trend in proportions when it is below 0.05, otherwise N.S. - not significant. Departure from
 

linear trend is noted when it is below 0.05 for any comparison. Beneath the dose group incidence is the
 

probability level for the Fisher exact (conditional) test for the comparison of that dose group with the
 

untreated control group (*) and the vehicle control group (**) when either is below 0.05, otherwise N.S. ­

not significant.
 

(N) Less incidence in the dose group(s) than in a control group results in a negative indication.
 

Relative Risk of the treated group versus the control group is shown along with the lower and upper
 

limit of the 95% confidence interval for that Relative Risk.
 

34 
TABLE 6
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN FEMALE MICE TREATED WITH TETRACHL0R0ETHYLENEa
 

TOCOGRAPHY:MORPHOLOGY
 

Liver: Hepatocellular Carcinoma
 

 Values
 

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
 

 Valuesc
 

Relative Risk(Untreated Control)d
 

Lower Limit
 

Upper Limit
 

Relative Risk(Vehicle Control)d
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

UNTREATED VEHICLE LOW 

CONTROL CONTROL DOSE 

2/20(0.10) 0/20(0.00) 19/43(0.40) 

 = 0.033 = 0.006 = 0.014* 

 < 0.001** 

 = 0.030 

3.953 

1.109 

32.790 

Infinite 

2.656 

Infinite 

91 41 

1/20(0.05) 0/20(0.00) 0/48(0.00) 

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

0.000 

0.000 

7.780 

91 

HIGH
 

DOSE
 

19/43(0.40)
 

 = 0.014*
 

 < 0.001**
 

3.958
 

1.109
 

32.790
 

Infinite
 

2.656
 

Infinite
 

1/47(0.02)
 

N.S.
 

0.426
 

0.006
 

32.720
 

Infinite
 

0.023
 

Infinite
 

91
 

35 

50 
c 

36 

TABLE 6 

(CONCLUDED) 

UNTREATED VEHICLE LOW 

TOPOGRAPHY:MORPHOLOGY CONTROL CONTROL DOSE 

Hematopoietic System: Malignant 

Lymphoma 0/20(0.00) 4/20(0.20) 0/48(0.00) 

 Valuesc N.S. = 0.010(N) = 0.006**(N) 

Relative Risk(Untreated Control)d 

Lower Limit 

Upper Limit 

Relative Risk(Vehicle Control)d 0.000 

Lower Limit 0.000 

Upper Limit 0.444 

Weeks to First Observed Tumor 69 __ 

HIGH
 

DOSE
 

1/48(0.02)
 

 = 0.024**(N)
 

Infinite
 

0.024
 

Infinite
 

0.104
 

0.002
 

0.982
 

91
 

a

Dosed groups received time-weighted average doses of 386 and 772 mg/kg by gavage.
 

b

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

Beneath the incidence of each of the controls is the probability level for the Cochran-Armitage test for
 

dose-related trend in proportions when it is below 0.05, otherwise N.S. - not significant. Departure froir
 

linear trend is noted when it is below 0.05 for any comparison. Beneath the dose group incidence is the
 

probability level for the Fisher exact (conditional) test for the comparison of that dose group with the
 

untreated control group (*) and the vehicle control group (**) when either is below 0.05, otherwise N.S. ­

not significant.
 

(N) Less incidence in the dose group(s) than in a control group results in a negative indication.
 

d
 

Relative Risk of the treated group versus the control group is shown along with the lower and upper limit
 

of the 95% confidence interval for that Relative Risk.
 
controls (P = 0.018) or the vehicle controls (P = 0.006). The departures from linear trend were also significant (P = 0.002 and P =
 

0.001, using the untreated control and the vehicle control, respectively) because of the large proportions of dosed animals with this
 

tumor. Additionally, the Fisher exact tests comparing incidences
 

among the control and dosed groups all confirmed this positive
 

finding: untreated control to low dose (P < 0.001), vehicle control
 

to low dose (P < 0.001), untreated control to high dose (P = 0.001),
 

and vehicle control to high dose (P < 0.001). Finally, the entire
 

region of the 95 percent confidence interval on the relative risk of
 

the dosed group(s) to the control group(s) was greater than the value
 

one.
 

The first of the hepatocellular carcinomas to be detected in
 

male mice at necropsy was found in week 27 in the low dose group,
 

compared to week 40 in the high dose group and weeks 90 and 91 in the
 

vehicle and untreated control groups. An additional time-adjusted
 

analysis was performed to estimate the probability of observing a
 

hepatocellular carcinoma in a necropsied male mouse. Based on Kaplan
 

and Meier techniques, the probability of observing a hepatocellular
 

carcinoma by week 91 was estimated to be 1.00 for a high dose male
 

mouse.
 

These statistical results indicate that the occurrence of
 

hepatocellular carcinomas in male mice was associated with the
 

administration of tetrachloroethylene at the dose levels of this
 

37
 
experiment. There were no other tumors of male mice for which
 

statistical tests indicated a positive association between tetrachloroethylene administration and tumor incidence.
 

The incidence of hepatocellular carcinoma was also highly significant in female mice. The Cochran-Armitage tests for positive dose-


related trend in proportions were found to be significant compared
 

both to the untreated control (P = 0.033) and to the vehicle control
 

(P = 0.006). A departure from linear trend (P = 0.030) was noted
 

with the vehicle controls due to the sharp increase of the incidence
 

of hepatocellular carcinomas in the dosed groups. The results of the
 

Fisher exact tests confirmed this positive finding: both the low and
 

high dose animals demonstrated significant tumor increases as compared
 

to either the untreated controls (P = 0.014) or the vehicle controls
 

(P < 0.001). Finally, the lower limits of the 95 percent confidence
 

interval of the relative risk of the dosed group(s) versus the control
 

group(s) were greater than one.
 

The first of the hepatocellular carcinomas to be detected in
 

female mice at necropsy was found in week 41 in the low dose group,
 

compared to week 50 in the high dose group and week 91 in the untreated control group. An additional time-adjusted analysis was
 

performed to estimate the probability of observing a hepatocellular
 

carcinoma in a necropsied female mouse. Based on adjusted Kaplan
 

and Meier techniques, the probability of observing hepatocellular
 

38
 
carcinoma by week 91 was estimated to be 0.938 for a high dose female
 

mouse.
 

These statistical results indicate that the occurrence of
 

hepatocellular carcinomas in female mice was associated with the
 

administration of tetrachloroethylene at the dose levels used in this
 

experiment. There were no other tumors of female mice for which
 

statistical tests indicated a positive association between tetrachloroethylene administration and tumor incidences.
 

In addition to the previous analyses, the incidence of hepatocellular carcinomas in dosed mice was compared to the incidence in
 

pooled controls. A pooled group of untreated controls was formed by
 

combining the untreated controls from the tetrachloroethylene study
 

with the untreated controls from the studies of methylchloroform,
 

1,1-dichloroethane, and chloroform. Vehicle controls from the same
 

four studies were also combined to form a pooled vehicle control.
 

These pooled controls were of the same strain and were placed on test
 

in the same room during a time span exceeding a year. The results of
 

these analyses are presented in Tables 7 and 8.
 

The Cochran-Armitage tests indicated a significant: positive
 

dose-related trend (P < 0.001) in both sexes using either of the
 

pooled control groups. The significant departures from linear trend
 

(P < 0.001 in the male mice for both pooled untreated and pooled
 

vehicle controls, P = 0.011 in female mice using the pooled untreated
 

controls, and P = 0.006 in female mice using the pooled vehicle
 

39
 
TABLE 7
 

ANALYSES OF THE INCIDENCE OF HEPATOCELLULAR CARCINOMA
 

IN MALE MICE TREATED WITH TETRACHLOROETHYLENEa
 

POOLED POOLED 

UNTREATED VEHICLE LOW HIGH 

TOPOGRAPHY: MORPHOLOGY CONTROL CONTROL DOSE DOSE 

Liver: Hepatocellular Carcinoma 7/84(0.08) 7/97(0.07)	 32/49(0.65) 27/48(0.56)
 

 Va lues < 0.001 < 0.001	 < 0.001* < 0.001*
 

 < 0.001** < 0.001**
 

Departure from Linear Trend < 0.001 < 0.001
 

Relative Risk(Pooled Untreated Control) 7.837 6.750
 

Lower Limit . 3.811 3.177
 

Upper Limit 18.041 16.153
 

Relative Risk(Pooled Vehicle Control) 9.050 7.795
 

Lower Limit 4.384 3.654
 

Upper Limit 20.868 18.687
 

Weeks to First Observed Tumor	 27 40
 

a

Dosed groups received time-weighted average doses of 536 and 1072 mg/kg by gavage.
 

b

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

c

Beneath the incidence of each of the controls is the probability level for the Cochran-Armitage test for dose-related
 

trend in proportions when it is below 0.05, otherwise N.S. - not significant. Departure from linear trend is noted when
 

it is below 0.05 for any comparison. Beneath the dose group incidence is the probability level for the Fisher exact
 

(conditional) test for the comparison of that dose group with the pooled untreated control group (*) and the pooled
 

vehicle control group (**) when either is below 0.05.
 

d.
d

Relative Risk of the treated group versus the control group is shown along with the lower and upper limit of 95%
 

confidence interval for that Relative Risk.
 
41
 

TABLE 8
 

ANALYSES OF THE INCIDENCE OF HEPATOCELLULAR CARCINOMA
 

IN FEMALE MICE TREATED WITH TETRACHLOROETHYLENEa
 

POOLED POOLED 

UNTREATED VEHICLE LOW HIGH 

TOPOGRAPHY: MORPHOLOGY CONTROL CONTROL DOSE DOSE 

Liver: Hepatocellular Carcinoma 4/97(0.04) 2/99(0.02)	 19/48(0.40) 19/48(0.40)
 

 Valuesc 

 < 0.001 < 0.001	 < 0.001* < 0.001*
 

 < 0.001** < 0.001**
 

Departure from Linear Trend = 0.011 = 0.006
 

Relative Risk(Pooled Untreated Control)d 9.599 9.599
 

Lower Limit 3.425 3.425
 

Upper Limit 35.988 35.988
 

Relative Risk(Pooled Vehicle Control)d 19.594 19.594
 

Lower Limit 5.024 5.024
 

Upper Limit 164.707 164.707
 

Weeks to First Observed Tumor	 41 50
 

Dosed groups received time-weighted average doses of 386 and 772 mg/kg by gavage.
 

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

Beneath the incidence of each of the controls is the probability level for the Cochran-Armitage test for dose-related
 

trend in proportions when it is below 0.05, otherwise N.S. - not significant. Departure from linear trend is noted when
 

it is below 0.05 for any comparison. Beneath the dose group incidence is the probability level for the Fisher exact
 

(conditional) test for the comparison of that dose group with the pooled untreated control group (*) and the pooled
 

vehicle control group (**) when either is below 0.05.
 

Relative Risk of the treated group versus the control group is shown along with the lower and upper limit of the 95%
 

confidence interval for that Relative Risk.
 
controls) were due to the sharp increase in the incidence of hepatocellular carcinomas in the dosed groups. Finally, the Fisher exact
 

tests also provided evidence of the existence of a positive dose-


response relationship, since every comparison of a dosed group to a
 

pooled control was highly significant (P < 0.001).
 

42
 
V. DISCUSSION
 

Under the conditions of this study, administration of tetrachloroethylene was associated with a significantly increased incidence
 

of hepatocellular carcinomas in both low and high dose groups of male
 

and female mice. Because of inadequate survival, the bioassay on
 

rats must be considered inconclusive.
 

Statistical tests indicated a strong association between administration of tetrachloroethylene and the occurrence of hepatocellular
 

carcinomas in both male and female mice. Incidence of hepatocellular
 

carcinomas exhibited a significant positive dose-related trend in
 

mice of both sexes. Hepatocellular carcinomas appeared early in
 

dosed mice. The first hepatocellular carcinoma observed at necropsy
 

occurred in a male low dose mouse that died during week 27. No
 

hepatocellular carcinomas were observed in control mice dying before
 

week 90. A time-adjusted analysis, based on Kaplan and Meier
 

techniques, estimated that the probability of observing hepatocellular
 

carcinoma by week 91 was 1.00 for a high dose male mouse and 0.938 for
 

a high dose female mouse. A small number of hepatocellular carcinomas
 

in tetrachloroethylene-treated mice of both sexes metastasized to the
 

lung, while a single hepatocellular carcinoma in an untreated control
 

male metastasized to the kidney.
 

No other tumors were observed in male or female mice for which
 

statistical tests indicated a positive association between tetrachloroethylene treatment and tumor incidence.
 

43
 
Mice were housed in a room where other bioassays for carcinogenicity were being performed; however, stringent measures were taken to
 

prevent cross-contamination of animals. The low incidence of neoplasms in control mice suggests that no significant extraneous exposure to carcinogens occurred.
 

No significant increase in tumor incidence was observed among,
 

rats treated with tetrachloroethylene, but because of a high rate of
 

early deaths in treated rats the results of this bioassay do not
 

allow an evaluation of the carcinogenicity of this compound. Mortality rates for rats were dose-related. Fifty percent of the high dose
 

male rats had died by week 44 and 50 percent of the high dose females
 

had died by week 66, Toxic nephropathy was observed in rats that
 

died early in the study (as early as week 20 for male rats and week
 

28 for female rats). Lesions indicative of pneumonia were observed
 

at necropsy in nearly all rats in this bioassay.
 

In bioassays using the same strain of rats following a similar
 

protocol and conducted by the same laboratory, only a low incidence
 

(about 5 percent) of hepatocellular carcinoma was observed in rats
 

receiving carbon tetrachloride (considered a positive control)
 

(National Cancer Institute, 1976). It appears, therefore, that the
 

Osborne-Mendel rat has a low degree of sensitivity to induction of
 

hepatocellular carcinoma by chlorinated organic compounds.
 

The results of this study indicate that tetrachloroethylene is
 

a liver carcinogen in B6C3F1 mice of both sexes. The lack of an
 

44
 
observable carcinogenic effect in rats may be due to poor survival of
 

high dose rats and to a low degree of susceptibility to hepatocellular
 

carcinoma in the Osborne-Mendel rat. The toxic effect of tetrachloroethylene on the kidney was evident in both species. Toxic nephropathy
 

was observed in 79 percent of the dosed rats and 93 percent of the
 

dosed mice.
 

45
 
VI. BIBLIOGRAPHY
 

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

J. Wiley & Sons, New York, 1971.
 

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

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

Union Against Cancer, Geneva, 1969.
 

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

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

Society, Washington, D.C., 1977.
 

Chemical Information Services, Stanford Research Institute. Menlo
 

Park, California, 1975.
 

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.
 

Dowty, B., D. Carlisle, and J.L. Laseter, "Halogenated Hydrocarbons
 

in New Orleans Drinking Water and Blood Plasma." Science
 

l87 (4171):75-77, 1975.
 

Fishbein, L., "Industrial Mutagens and Potential Mutagens. I. Halogenated Aliphatic Derivatives." Mutation Research 32:267-308, 1976.
 

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

Tests, Confidence Limits, and Adjustments for Stratification."
 

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

Ikeda, M. and T. Imamura, "Biological Half-Life of Trichloroethylene
 

and Tetrachloroethylene in Human Subjects." International
 

Archives of Occupational Health 31(3):209, 1973.
 

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.
 

46
 
McConnell, G., D.M. Ferguson, and C.R. Pearson, "Chlorinated Hydrocarbons and the Environment." Endeavor 34:13-27, 1975.
 

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

Co., New York, 1976.
 

National Cancer Institute, "Carcinogenesis Bioassay of Trichloroethylene." Carcinogenesis Technical Report Series No. 2,
 

NCI-CG-TR-2, DHEW Publication No. (NIH)76-802, 1976.
 

Reuber, M.D., 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.
 

Rowe, V.K., D.D. McCollister, H.C. Spencer, E.M. Adams, and D.D.
 

Irish, "Vapor Toxicity of Tetrachloroethylene for Laboratory
 

Animals and Human Subjects." American Medical Association
 

Archives of Industrial Hygiene and Occupational Medicine
 

5:566-579, 1952.
 

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.
 

Sax, N.I,, Dangerous Properties of Industrial Materials. Van Nostrand
 

Reinhold Company, New York, 1975.
 

Senewiratne, B., J. Hettiarachchi, and K. Senewiratne, "A Comparative
 

Study of the Relative Efficacy of Pyrantel Pamoate, Bephenium
 

Hydroxynaphthoate and Tetrachloroethylene in the Treatment of
 

Necator americanus Infection in Ceylon." Annals of Tropical
 

Medicine and Parasitology 69(2):233-239, 1975.
 

Stanford Research Institute, Research Program on Hazard Priority
 

Ranking of Manufactured Chemicals: Phase II, Final Report.
 

Menlo Park, California, 1975.
 

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

62:679-682, 1975.
 

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

United States Production and Sales, 1974. USITC Publication 776,
 

Washington, D.C., 1976.
 

47
 

APPENDIX A
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS
 

IN RATS TREATED WITH TETRACHLOROETHYLENE
 

TABLE A1

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE RATS TREATED WITH TETRACHLOROETHYLENE 

CONTEOL (UNTR) CONT?OL(VEH) LOW DOS 3 HIGH DOSE 

01-1U1M 01-091 M 01-1U2M 01-1U3 * 

ANIMALS INITIALLY IN STUDY 20 20 50 SO 

ANIMALS NFCROPSIED 20 20 5 n SO 

ANIMALS EXAMINED HI5TOPATHOLOGICALLY ** 2^ 2 0 U9 SO 

INTEGUMENTARY SYSTEM 

*SUBCUT TISSUE	 (20) (20) (SO) (SO)
 

FIBRCMA 1 (5%) 1 (2%) 

HEMANGIOSAPCOK A 1 (2*) 1 (2%) 

°ESPTRATORY SYSTEM 

• LUNG (20) (20) (48) (50) 

AEENOSQUAMCUS CARCINOMA 1 (5%) 

HEMATOPOIF.TIC SYSTEM 

*SU3CUT TISSUE (20) (20) (50) (SO) 

MALIG.LYMPHCNA, HISTIOCYTIC TYPE 1 (2%) 

tSPLEEN (19) (20) (49) (SO) 

HEMANGIOSARCOMA 2 (11%) 1 (5%) 1 {2%) 

•CERVICAL LYMPH NODE (19) (20) (49) (49) 

AEENOSgUAMOUS CARCINOMA, MSTASTA 1 (5%) 

CIFCULATOCY SYSTEM 

NONE 

DIGESTIVE SYSTEM 

NONE 

URINARY SYSTEM 

#KIDNEY (19) (20) (49) (50) 

ACENOSQUAMOUS CARCINOMA, METASTA 1 (5*) 

MIXED TUMOR, MALIGNANT 1 (5%) 2 (10%) 1 (2%) 

HAMAR1QJ1A 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMALS NECPOPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

A-3 
TABLE Al (CONTINUED) 

CONTROL (UNTR)

0 1- 1U in

 CONTROL (VSH)

 01-091 1

 LOW DOSS

 01-142 1 .

 HIGH DOSE 

 01-143 M 

ENDCCPINE SYSTEM 

#PITUITAPY

CH&OMCFHOBE

CHROMOPHOSE

 ADENOMA

 CAPCINGKA

 (19)

 3 (16%)

 1 (5%) 

 (20 ) (49)

 1 (2%) 

 (44) 

• THYROID

PGLIIC0LA5-CELL

FOLLICULAR-CELL

C-CELL ADENOMA

 ADENOMA

 CARCINOMA

 (19)

 1 (5%) 

 (20)

 1 (5%) 

 (48) (49) 

1 (2%) 

#PANCPEATIC ISLETS

ISL£T-C2LL ADENOMA

 (19)

 2 (11*)

 (19) (48)

 1 (2%)

 (50) 

1 (2%) 

REPRODUCTIVE SYSTEM 

•MAMMARY GLAND

FIBF.CACENOKA

 (20)

 1 (5%) 

 (20) (SO) (50) 

NE3VCUS SYSTEM 

#BRAIN

CHP0MCFH03E CARCINOMA, ^ETASTATI

 (19)

 1 (5%) 

 (2^) (49) (53) 

SPECIAL SENSE ORGANS 

NONE 

MUSCULOSKFLETAL SYSTEM 

NONE 

BODY CAVITIES 

• ABDOMINAL CAVITY

SPINCLE/GIANT-CSLL CARCINOMA

 (20) (20)

 1 (5%) 

 (5C) (50) 

ALL OTHER SYSTEMS 

..NONE 

# NUMBER

• NUMBER

 OF ANIMALS

 OF ANIMALS

 WITH TISSUE

 NECROPSIED 

 EXAMINED MICROSCOPICALLY 

A-4 
TABLE Al (CONCLUDED) 

CONTPPL (ITNTR) 

0 1- 14 IN 

CONTROL (VEH) 

0 1-091M 

LOW DOSE 

01-142M 

HIGH DOSE 

01-143M 

ANIMAL DISPOSITION SUMMARY 

ANIMALS INITIALLY IN STUDY 

NATURAL DEATHS* 

MORIBUND SACRIFICE 

SCHEDULED SACRIFICE 

ACCIDENTALLY KILLED 

TERMINAL SACRIFICE 

ANIMAL MISSING 

20 

14 

1 

20 

1P 

50 

43 

1 

50 

US 

3> INCLUDES AUTOLYZED ANIMALS 

TUMCR 

TOTAL ANIMALS WITH PRIMARY 

TOTAL PRIMARY TUMORS 

TUMORS* 9 

12 

TOTAL ANIMALS WITH BENIGN

TOTAL BENIGN TUMORS

 TUMORS 6

 7

 2

 2

 2 

2 

TOTAL ANIMALS WITH MALIGNANT

TCTAL MALIGNANT TUMORS

 TUMORS 5

 5

 5

 5

 3 

3 

TOTAL ANIMALS WITH SECONDARY

TOTAL SECONDARY TUMORS

 TUMORS* 1

 1

 1 

2 

TOTAL ANIMALS WITH TUMORS

BENIGN OP MALIGNANT 

TOTAL UNCERTAIN TUMORS 

 UNCERTAINTOTAL ANIMALS WITH TUMORS

PRIMAFY CR METASTATIC 

TOTAL UNCERTAIN TUMORS 

 UNCEPTAIN­

* PFTMAFY TUMORS: ALL TUMORS EXCFPT SECONDARY TUMORS 

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

A-5 
TABLE A2

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS TREATED WITH TETRACHLOROETHYLENE 

CONTROL (UNTR) 

0 1- 141F 

CONTROL (VEH) 

0 1-091F 

ANIMALS INITIALLY IN STUDY 20 20 

ANIMALS NSCROPSISD 20 20 

ANIMALS EXAMINED HI5T0PATHOLOGICALLY ** 2^ 20 

INTEGUMENTARY SYSTEM 

*5KIN (20) (20) 

?IBRO SARCOMA 

•SUBCHT TISSUE (20) (20) 

FIBROMA 

FIBPOSAPCOMA 1 (5%) 

LIPOMA 

HEMANGIOSAPCOMA 

^.ES PIP ATOPY SYSTEM 

#LUNG (20) 

ADENCCAPCINOMA, NOS, METASTATIC 

HFMATOPOIETIC 

*KULTIPLE ORGANS (20) [2 0) 

SALIG.LY51PH0HA, HISTIOCYTIC TYPE 

LYMPHOCYTIC LEUKEMIA 

•SUBCHT TISSUE (20) (2<M 

"1ALIG.LY1PHOMA, HISTIOCYTIC TYPE 

# SPLEEN (2 0) 

ADENCCARCINOMA, NOS, METASTATIC 

MALIG.LYMPHOMA, HISTIOCYTIC TYPE 1 ( 5%) 

#THYMUS (16) (15) 

IIPO MA 

CIRCULATORY SYSTEM 

» JNE 

# NUM3EF OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMALS NEC RO? SI ED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

LOW DOSE 

0 1 - 1 

50 

50 

50 

(50) 

(50) 

1 (2%) 

1 (2%) 

(50) 

1 (2%) 

(50) 

1 (2%) 

(50) 

1 (2%) 

(50) 

1 (2%) 

(31) 

HIGH DOSE 

01-145 F 

(50) 

1 (2%) 

(50) 

1 (2%) 

2 (4%) 

1 (2%) 

(SO) 

1 (2%) 

(50) 

1 (2%) 

(50) 

(50) 

(2 3) 

1 <U%\ 

A- *U.S. GOVERNMENT PRINTING OFFICE: 1977 241-161/3124 1-3 6 
TABLE A2 (CONTINUED) 

CONTROL(UNTR) 

0 1- 141F 

CONTROL (VEH) 

C1-091 F 

LOW DOSS 

01-144 ? 

HIGH DD SE 

01-1U5 F 

DIGESTIVE SYSTEM 

#LIVE? 

ADENCCARCINCflA, ?IOSr

VSOPLASTIC NODULE 

 METASTATIC (20) 

1 (5%) 

(19) (50) 

1 (2*) 

(33) 

•PANCREAS 

AFENCXJARCINOIA, NOS, MEIA3TATIC 

(2n) (18) (50) 

1 (2%) 

(50) 

tSTCMACH 

ADENCCARCINOMA, FOS, META STATIC 

(20) (20) (50) 

1 {2%) 

(50) 

URINARY SYSTEM 

•KIDNEY 

HA MA?TCIA 

(20) 

1 (5%) 

(2 0) (50) 

#?IGHT KIDNEY 

HIXED TUMOR, MALIGNANT 

(20) (20) (5C) (50) 

1 (21) 

ENDOCRINE SYSTEM 

•PITUITARY 

CHHCM0FH03E ADENOMA 

(20) 

8 (40%) 

(20) 

4 (20%) 

(50) 

9 (19*) 

(50) 

(121 

#ADRENAL 

CORTICAL CARCINOMA 

^IXED TUMOR, KETASTATIC 

#THYROID 

FCIIICULAR-CFLL ADENOMA 

C-CSLL ADENOMA 

C-CELL CARCINOMA 

(20) 

(10) 

2 (11*) 

(20) 

(20) 

(50) 

(49) 

(SO) 

1 

1 

(50) 

1 

1 

(2*) 

(2*) 

(2*) 

(2*) 

• PANCREATIC ISLETS 

ISLET-CELL ADENOMA 

(20) 

1 

(18) (50) 

1 (2%) 

(50) 

H3PF0DUCT IVE SYSTEM 

•MAMMARY GLAND

ACENCMA, NOS 

AD2N0CA9CIN0MA,

FIBPOKA 

FISEOADENOMA

 NOS 

 (20) 

 J-.1JJ51 i_l! 5*L. 

(20) 

1 (5%) 

(50) 

1 

1 

(2%) 

(2%) 

(50)

1 

2 

(2*) 

(4*) 

# NUMBER

* NUMBER

 CF

 OF

 ANIMALS

 ANIMALS

 WITH TISS'JE

 NEC POP SI SO 

 EXAMINED MICROSCOPICALLY 

A-7 
TABLE A2 (CONTINUED) 

CONTROL (UNTR)

01-1U1 F

 CONTROL (VS H)

 C1-091 F

 LOW DOSE

 01-14U F

 HIGH DOSE 

 01-145 F 

ADENCCAPCINCMA, NOS 

ENDOMDTPIAL 5TF.CMAL POLYP 

#~)VARY 

ADENOCARCINGMA, NOS, MSTASTATIC 

CYSTADENOCAF.CINOMA, NOS 

GRANUL0SA-C2LL CARCINOMA 

(20) 

1 (5%) 

(20) 

(1Q) 

(20) 

. 1 (5%) 

(48)

1 (2%) 

(50)

1 (2%) 

1 (2%) 

 (50) 

 (50) 

NERVOUS SYSTEM 

NONF 

SPECIAL SENS E ORGANS 

NCN? 

MUSCrJLOSKELE?AL SYSTEM 

BODY CAVITI2S 

*ABDCMINAL CAVITY 

AD5NCCAHCINO1A, NOS, HETASTATIC 

{2u) (2 0) (50) 

1 (2%) 

(50) 

ALL OTHER SYSTEMS 

NONE 

ANIMAL DISPOSITION SUMMARY 

ANIMALS INITIALLY I !J STUDY 

NATURAL DEATH5) 

MORIBUND SACPIFIC2 

SCHsDHLED SACRIFICE 

ACCIDENTALLY KILLED 

TERMINAL SACDI?ICE 

ANIMAL MISSING 

20 

12 

20 

12 32 

1 

17 

50 

36 

S_IiiC I UD£ S_ A UTOLYZED_ ANIMALS 

# MTjfiBEF

* NUMBE?

 OF ANIMALS

 OF ANIMALS

 WITH TISS'IZ

 N EC ^0 ? 31 ED 

 FXAMIMSD MICROSCOPICALLY 

A-8 
TABLE A2 (CONCLUDED) 

CONTP.OL (UNTR) CONTROL (VEH) LOW DOSE HIGH DOSE 

0 1 - 141 F ft 1-091 F 01-144 F 01-145 F 

TUMOR SUMMARY 

TOTAL ANIMALS WITH PRIMARY THMOPS* 13 1 17 15 

TCTAL PRIMARY TUMORS 18 10 25 27 

TOTAL ANIMALS WITH 3ENIGN TUMORS 13 6 14 12 

TOTAL BENIGN TUMORS 16 7 19 18 

T^TAL ANIMALS WITH MALIGNANT TUMORS 1 2 6 

TOTAL MALIGNANT TUMORS 1 3 6 

TOTAL ANIMALS WITH SECONDARY TUMORS# 1 

TCTAL SECONDARY TUMORS 7 

TOTAL ANIMALS WITH TUMORS UNCERTAINBENIGN OR MALIGNANT 1 

TOTAL UNCERTAIN TUMORS 1 

TOTAL ANIMALS WITH TUMORS UNCERTAINPRIMARY CR METASTATIC 

TOTAL UNCERTAIN TUMORS 

* PRTMARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS 

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

A-9 

APPENDIX B
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS
 

IN MICE TREATED WITH TETRACHLOROETHYLENE
 

TABLE Bl

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE MICE TREATED WITH TETRACHLOROETHYLENE 

CONTROL (UNTR) 

0 2-M141 

CONTROL (VSH) 

0 2-M131 

LOW DOSE 

02-M142 

ANIMALS

ANIMALS

ANIMALS

ANIMALS

 INITIALLY IN STUDY 

 MISSING 

 NECROPSIED 

 EXAMINED HISTOPATHOLOGICALLY** 

20 

18 

18 

20 

20 

20 

50 

49 

49 

INTEGUMENTARY SYSTEM 

NONE 

RESPIRATORY SYSTEM 

#LUNG 

HEPATOCSLLnLAR CARCINOMA, MSTAST 

AI.VEOLAR/BPCNCHIOLAR ADENOMA 

(18) 

2 (11%) 

(20) (49) 

3

3

 (6%) 

 (6%) 

3EMATOPCIETIC SYSTEM 

• MULTIPLE ORGANS 

MALIG.LYMPHOMA,

#LIVER 

MALIG,LYMPHOMA,

 HISTIOCYTIC

 HISTIOCYTIC

 TYPE 

 TYPE 

(18) 

1 (6%) 

(2 0) 

1

(20) 

1

 (5*) 

 (5%) 

(49) 

(49) 

:iPCriLATO?Y SYSTEM 

NONE 

DIGESTIVE SYSTEM 

#LIVER 

HEPATOCSLLULAR CARCINOMA 

(17) 

2 (12%) 

(2 0) 

2 (10%) 

(49) 

32 (6 5%) 

JEINAPY SYSTEM 

#MDNSY 

HEPATOCELLULA? CARCINOMA, METAST 

(18) 

1 (6%) 

(2 0) (49) 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED

* NUMBER OF ANIMALS NECROPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

 MICROSCOPICALLY 

HIGH D3SE 

02-M143 

50 

2 

47 

(48) 

< ^ , 

(48) 

(4«) 

27 (56%) 

B-3 
TABLE B-l (CONTINUED) 

CONTROL (UNTR) CONTROL (VE H) LOW DCSS HIGH DOSE 

0 2-SU 1 02-M131 02-K14 2 02-M143 

ENCCCRINE SYSTEM 

tTHYROID (18 ) (20 ) (U^) (UB) 

FCLLICULAR-CELL ADENOMA 1 (5%) 1 {2%) 

REPRODUCTIVE SYSTEM 

NONE 

NEPVOUS SYSTEM 

fCESBBF.UM (18 ) (1 Q ) (U9) (UR) 

HFI-NCYMOfiA 1 (5%) 

SPECIAL SENSE ORGANS 

NONE 

HUSCULOSK^LSTAL SYSTEM 

NGN'. 

BODY CAVITIES 

NONE 

ALL OTHER SYSTEMS 

—N.ONE 

# NU?!BEF OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMALS NEC HOP SI ED 

B-4 
TABLE Bl (CONCLUDED) 

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

0 2-M141 02-H13 1 P2-M142 02-M1U3 

ANIMAL DISPOSITION SUMMARY 

ANIMALS INITIALLY IN STUDY 20 50 50 

NATURAL DEATHS) 10 28 38

 

MORIBUND SAC?IF ICE 3

 

SCHEDULED SACRIFICE 

ACCIDENTALLY KILLED 

TERMINAL SACRIFICE 11 10 19 1 0

 

ANIMAL MISSING 2

 

INCLUDES AUTCLYZED ANIMALS 

TUMOR SUPMARY 

TOTAL ANIMALS WITH PRIMARY TUMORS* 33 27

 

TOTAL PRIMARY TUMORS 36 28

 

TOTAL- ANIMALS WITH BENIGN TUMORS 

TOTAL BENIGN TUMORS 

TOTAL ANIMALS WITH MALIGNANT TUMOFS 32

 

TCTAL MALIGNANT TUMORS 33 27

 

TOTAL ANIMALS WITH SECONDARY TUMORS* 1 3 

TCTAL SECONDARY TUMORS 1 3 

TO^AL ANIMALS WITH TUMORS UNCERTAINBENIGN OR MALIGFANT

 

TOTAL UNCERTAIN TUMORS 

TCTAL ANIMALS WITH TUMORS UNCERTAINP3IKAEY OP. "IETA STATIC

 

TOTAL UNCERTAIN TUMORS 

* PRIMARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMOPS 

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

B-5 
TABLE B2

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE MICE TREATED WITH TETRACHLOROETHYLENE 

CONTROL (UNTF) CONTEOL(VEH) LCW DOSE HIGH DOSE 

02-F14 1 02-F13 1 02-P144 02-F145 

\NIMALS INITIALLY IN STUDY 20 20 50 

U1IMAL3 KISSING 1 

ANIMALS NECROPSIED 20 20 48 43 

ANIMALS EXAMINED H ISTOPATHOLOGICA LL Y ** 19 20 43 aa 

INTEGUMENTARY SY 

(20 ) (20 ) (48 ) 

SgUAKCUS CELL CA3CI17 3MA 1 (5%) 

RE3PI5ATCRY SYSTEM 

#LUMG (20) (20) (48) (U7) 

HEPATCCELLUT.AE CARCINOMA, METAST 1 (2%) 1 (2%) 

ALVEOL AP./EROS CHIO LAP. ADENOMA 1 ( 5%) 1 (2%) 

HEMATCPCIZTIC SYSTE1 

*MuLTIPLii OPGANS (20) (20) (48) (48) 

"lALlG. LY HPHOMA, LYMPHOCYIIC TYPE 1 («5%) 

MALIG.LYMPHOMA , HISTIOCYTIC TYPE 2 (10%) 1 (2%) 

#LU 1BAK LY^^H NODE (20) (20) (48) (48) 

MALIG.LYMPHOMA, LYMPHOCYTIC TYPE 1 (5%) 

CIRCULATOR Y SYSTE M 

NONE 

DIGESTIVE SYSTEM 

#LIVES (20) (2 0) (48) (48) 

2 (10%) 19 (40%) (40%) 

URINARY SYSTEM 

NONE 

# NTHBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

B-6 
TABLE B2 (CONTINUED) 

CONTROL (UHTR) CONTPOL (V3 H) LOW DOS S HIGH D^SE 

O2*-F131 < y C2-F14 5 

ENDOCRINE SYSTEM 

NONE 

R-^PH^CUCTIVE SYSTEM 

*MAMMASY GLAND (48) (U8) 

ADENCCAF.CINOMA, MO S 1 

(20) (2G) (Ufi) (47) 

GRANULCSA-CELL 1 

KEFVOUS SYSTEM 

NONE 

SPECIAL SENSE OHGANS 

NONE 

MUSCULOSK2LETAL SYSTE-i 

3ODY CAVITIES 

NONE 

ALL SYSTEMS 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED WICBOSCOP JCALLY 

* NU13IP OF ANIMALS N3CROPSIB!) 

B-7 
TABLE B2 (CONCLUDED) 

CONTROL (ONTR) 

0 2-F 1 U 1 

CONTROL (VEH) 

"2-F13 1 

LOW DCSS 

02-F14U 

HIGH DDSfi 

02-F1U5 

ANIMAL DISPOSITION SUMMARY 

ANIMALS INITIALLY IN STUDY 

NATURAL DEATHS 

MORIBUND SACRIFICE 

SCHEDULED SACRIFICE 

ACCIDENTALLY KILLED 

TERMINAL SACRIFICE 

ANIMAL MISSING 

20 

11 

20 50 

37 

1 

1 

11 

50 

$ INCLUDES AU7OLYZSD ANIMALS 

TOTAL ANIMALS WITH PRIMARY

TOTAL PRIMARY TUMORS 

 TUTORS* 19 

20 

19 

21 

TOTAL ANIMALS WITH BENIGN

TOTAL BENIGN TUMORS

 TUMQ3S 1 

1 

TOTAL ANIMALS WITH MALIGNANT

TCTAL MALIGNANT TUMORS

 TTJ«OPS 3

 3

 4

 4

 19 

 20 20 

TOTAL ANIMALS WITH SECONDARY

TOTAL SECONDARY TUMORS

 TUMORS* 1 

1 

1 

TOTAL ANIMALS WITH TUMORS

BENIGN O? MALIGNANT

TOTAL UNCERTAIN TUMORS

 UNCERTAIN1 

1 

TOTAL ANIMALS WITH TUMORS

?3I*A9 Y CR META STATIC 

TOTAL UNCERTAIN TUMORS 

 UNCSP.TAIN­

* PRIMARY TUMORS: ALL THMORS EXCEPT SECONDARY TUMORS 

# SECONDARY TUMORS: METASTATIC TUMORS 0 ? TUMORS INVASIVE INTO AN' ADJACENT O?G 

B-8 
APPENDIX C
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN RATS TREATED WITH TETRACHLOROETHYLENE
 

TABLE Cl

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE RATS 

TREATED WITH TETRACHLOROETHYLENE 

CONTROL (UNTR) 

G1-1 4 1M 

CONTROL (VEH) 

01-Q91P! 

LCW DOSE 

01-142M 

HIGH DOSE 

01-143M 

ANIMALS INITIALLY IN STUDY

ANIMALS NECRCFSIED

ANIMALS EXAMINED HISTOPA THOLOGIC ALLY **

 20 

 20 

 20 

20 

20 

20 

50 

50 

U9 

50 

50 

50 

INTEGUMENTARY SYSIEM 

*SKIN 

EPIDERMAL INCLUSION

INFLAMMATION, NGS 

HY^EFKEPATOSIS 

ACANTHOSIS 

 CYST 

(2H) 

1 (5%) 

1 (5%) 

(2 0) 

1

1

1

 (5%) 

 (5%) 

 (5%) 

(50) 

1 (2%) 

(SO) 

*SUBCUT TISSUE 

EPIDERMAL INCLUSION

HEMORRHAGE 

INFLAMMATION, NCS 

ABSCESS, NOS 

 CYST 

(2 0) 

1 (5%) 

(20) 

1 (5%) 

(50) (50) 

1

2

1

 (2%) 

 (4%) 

 (2%) 

RESPIRATORY SYSTEM 

#L UNG/BFONCHUS 

ABSCESS, NOS 

(20) (20) (48) (50) 

1 (2%) 

#LUNG 

PNEn^CNIA, CHRONIC MURINc 

(20) 

16 (80%) 

(20) 

(95%) 

(48) 

3 8 (19%) 

(SO) 

31 (62%) 

HEMATOPOIETIC SYSTEM 

#SPT.EEN 

INFLAMMATION,

HEMATOPOIESIS 

 NOS 

1 (5%) 

(20) 

2 (10%) 

(49) 

1 

2 

(2%) (50) 

1 (2%) 

#CERVICAL LYMPH NODE 

INFLAMMATION, NOS 

(19) (2C) (49) (49) 

1 (2%) 

#ME3ENTEPIC L. NODE 

PERIA3TSRITIS 

(19) (20) 

1 (5%) 

(49) 

1 (2%) 

(49) 

(16) (17) (18) (10) 

# NUMBER OF ANIMALS MITH TISSUE EXAMINED

* NUMBER OF ANIMALS NSCROPSI^T) 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

 MICROSCOPICALLY 

C-3 
TABLE Cl (CONTINUED) 

CONTPOL (UNTR) CONTROL (VfiH) LOW DOSS HIGH DOSE 

0 1- 141M 0 1-091H 0 1-1421 01-1U3M 

CIECHLATCFY SYSTEM 

#HEA?T (20) (20) (49) (50) 

CALCIUM DEPOSIT 2 (10%) 

#KYOCARDIW (20) (20) (49) (50) 

INFLAFFATICN, NO5 1 (2%) 

"IBROSIS 1 (5%) 

*ENDCCA?DIUM 

HYPEBPLASIA, VO5 

(20) 

1 

(20) (49) 

1 (2%) 

(5") 

•AO3TA (20) (20) (BO) (50) 

MEDIAL CALCIFICATION 3 (15%) 3 (f>%) 1 (2%) 

•CO RON A?.Y Ar.TEPY (20) (50) (50) 

MEDIAL CALCIFICATION 2 (10*) 

•MESENTERIC ArTSPY 

MS DIAL CALCIFICATION 

(20) 

1 

(20) (5C) 

2 {*%) 

(50) 

2 (4%) 

DIGESTIVE SYSTEM 

#SALIVA?Y GLAND (14) ) (24) (11) 

INFLAMMATION, VQS 11 (655) 

#LIVSR (49) (49) 

INFLAMMATION, KOS 

ABSCESS, N'OS 

MFTAMO^PHOSIS ^ATTY 1 (5%) 1 1 

4 

(2%) 

(8%) 

1 

•y 

(2%) 

(14%) 

?^CAL CELLULAR CHAKGE 1 (2%) 2 (4%) 

ANGIECTA3IS 2 1 (2%) 

# LIVEF/CS NT ?ILOBULAR 

DEGENFPATICN, NOS 

(20) nQ

) (40) (49) 

1 (2%) 

#LIV2R/FE?IPOSTAL (20) (19) (49) (49) 

FI3PCSIS 1 (2%) 

•BILE C'TCT (2~) (20) (50) (50) 

HYPHP^tASIA , N'OS 1 (2%) 6 (12%) 

#PANCREAS 

£SRIARIE?III S

(1°) 

1_. 

(48) (50) 

# NHMBER CF ANIMALS WITH TISS'IE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMALS N5CROPSIED 

C-4 
TABLE Cl (CONTINUED) 

CONTROL (UNTE) CONTROL (VSH) LCW DOSE HIGH D3SE 

01-141 M 01-091 M 0 1-142 1 01-143 M 

•STCMACH (20) (1 Q ) (U9) (48) r

JLCER, FOCAL 1 (5%) 

CALCIUM DEPOSIT 3 (15%) 1 (5%) 4 2 (4%) 

URINARY SYSTEM 

•KIDNEY (19) (49) (50) 

CYST, NOS 2 (4%) 

PYELONEPHRITIS, NOS 

INFIAMMATIGN, NOS 

2 (11%) 3 (6%) 9 

1 

(18%) 

(2%) 

ABSCESS, UCS 1 (5*)-

INFLAMMATION, CHRONIC 13 (68%) 7 (35%) 2 (U%) 4 (3%) 

NEPHROPATHY, TOXIC 43 (88%) 47 (9 4%) 

CALCIUM DEPOSIT 1 (5%) 2 (4%) 1 (2%) 

• URINARY BLADDER 

CALCULUS, NOS 

INFLAMMATION, NOS 

HYPERPLASIA, EPITHELIAL 

(19) 

1 (5%) 

(1° ) (49) 

1 

1 

( 2%) 

(2%) 

(49) 

2 

1 

(4%) 

(10%) 

(2%) 

POLYP 2 (4%) 

F.NDOCRINE SYSTEM 

#PITUITABY 

INFLAMMATION, NOS 

(19) (2^) 

1 

(49) (44) 

• THYROID (19) (20) (48) (49) 

CYST, NOS 1 (5%) 

POI-LICOLAP. CYST, NOS 1 (5%) 3 (6%) 1 (2%) 

•PA^ATHYPCID (19) (19) (49) (SO) 

HYPERTROPHY, NOS 1 ( 2%) 

HYPERPLASIA, NOS 1 (5%) 1 (2*) 2 (4%) 

?. S??"DUCTIVF. SYSTEM 

•PROSTATE (19 ) (2 ) (33) (25) 

IN^LAfrATICN, NOS 2 (11% ) 1 4 (12%) 3 (12%) 

•SEMINAL VESICLE 

INFLAMMATION, NOS 

(20) (20) 

1 (5%) (50) (50) 

(1° ) (20) (41) (49) 

5-1125L­

• NUMBER OF ANIMALS WITH TISSU E EXAMINED MICROSCOPICALLY 

* NTJM3E? OF ANIMALS NECROPSISD 

C-5 
TABLE Cl (CONCLUDED) 

CONTROL (UNTR)

01-141M

 CONTROL (VE H)

 01-091M

 LOW DOSE

 01-U2 M

 HIGH DOSE 

 01-143M 

•EPIDIDYMIS 

NECROSIS, FAT 

(20) (20) 

1 (5%) 

(50) 

2 (tt*) 

(50) 

3 (6%) 

NERVOUS SYSTEM 

tBRAIN 

HYDRCCEPHALUS, NOS 

INFLAMMATION, NOS 

(19) (20) (U9) 

1 (2%) 

1 (2%) 

(50) 

SPECIAL SENSE ORGANS 

NONE 

MUSCULOSKELETAL SYSTEM 

•SKELETAL MUSCLE 

INFLAMMATION, NOS 

(20)

1 (5%) 

(2 0) (50) (50) 

BODY CAVITIES " 

• PLEURA 

INFLAMMATION, NOS 

•PERICARDIUM 

INFLAMMATICN, NOS 

•MESENTERY 

PERIARIERITIS 

(20) 

(20) 

(20)

2 00%) 

(2 0) 

(20) 

(2 0) 

1 (5%) 

(50) 

(50) 

(50) 

3 (6%) 

.

(50) 

1 (2%) 

 (50) 

2 (4%) 

(50) 

3 (6%) 

ALL OTHER

NONE 

 SYSTEMS 

SPECIAL MORPHOLOGY SUMMARY 

NO LESION REPORTED 

NECROPSY PERF/NO HISTO PERFORMED 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED

• NUMBER OF ANIMALS NECROPSIED 

 MICROSCOPICALLY 

C-6 
TABLE C2

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE RATS 

TREATED WITH TETRACHLOROETHYLENE 

CONTROL (UNTR) CONTROL (VEH) LOW DOSE 

M-141F 01-091F 01-144F 

ANIMALS INITIALLY IN STUDY 20 20 50 

ANIMALS NECROPSIED 20 20 50 

ANIMAL ** 20 S EXAMINED HISTOPATHOLOGIC ALLY 20 50 

i 

INTEGUMENTARY SYSTEM 

*SKIN (20) (20) (50)

 

INFLAMMATION, NOS 1 (5%)

 

RESPIPATCRY SYSTEM 

tTEACHEA (20) (16) (U9) 

INFLAMMATION, NOS 1 (2%) 

#LUNG (20) (20) (50) 

PNEUMONIA, CHRONIC MURINE 19 {95%) 20 (100%) 31 (62%) 

HEMATOPOIETIC SYSTEM 

#BONE MARROW (20) (20) (50)

 

KETAMCFPHOSIS FATTY 6 (30%)

 

#SPLSEN (20) (20) (50) 

ABSCESS, NOS 

HEMATOPOIESIS 3 (15%) 1 (5%) 1 (2%) 

CIRCULATORY SYSTEM 

#ENDOCAPDIUM (20) (20) (50) 

HYPERPLASIA, NOS 1 (5%) 1 (2%) 

*ACRTA (20) (20) (50)

 _.. ^JDIAL^CALCIFICATION __ _

 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

HIGH DOSE 

01-145 F 

50 

50 

50 

(50) 

(50) 

(50)

37 (74%) 

(50) 

1 (2%) 

(50) 

1 (2%) 

3 (6%) 

(U9) 

(50) 

C-7 
TABLE C2 (CONTINUED) 

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

01-141F 0 1-091F 0 1-144F 01-145F 

DIGESTIVE SYSTEM 

#LIVER 

INFLAMMATION, NOS 

(20) 

1 (5%) 

(19) 

1 (5%) 

(50) (33) 

1 (3%) 

INFLAMMATION, FOCAL 1 (2%) 

ABSCESS, NOS 1 (3%) 

DEGENERATION, NOS 1 (3%) 

METAMORPHOSIS FATTY 2 (10%) 1 (5%) 2 (4%) 4 (12%) 

FOCAL CELLULAR CHANGE 1 (2%) 

ANGIECTASIS 1 (2%) 1 (3%) 

•LIVER/CENTRILOBULAR (20) (19) (50) (33) 

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

• LIVES/PERI PORTAL (20) (19) (50) (33) 

FIBRCSIS 1 (3%) 

•BILE DUCT (20) (20) (50) (50) 

HYPERPLASIA, NOS 2 (10%) 1 (2%) 

•PANCREAS (20) (18) (50) (50) 

CYST, NOS 

ABSCESS, NOS 

1 (6%) 

1 (2%) 

PEPIARTERITIS 1 (2%) 

ATROPHY, NOS 1 (6%) 

#STCMACH (20) (20) (50) (50) 

ULCER, FOCAL 3 (15%) 1 (5%) 

URINARY SYSTEM 

#KIDNEY 

CYST, NOS (20) (20) 

1 (5%) (50) (50) 

PYELONEPHRITIS, NOS 1 (2%) 6 (12%) 

INFLAMMATION, CHRONIC 6 (30%) 5 (2 5%) 1 (2%) 

NEPHROPATHY, TOXIC 29 (5 3%) 38 (76%) 

CALCIUM DEPOSIT 1 (5%) 2 (4%) (8%) 

HYPERPLASIA, EPITHELIAL 1 (2%) 2 (4%) 

#LEFT KIDNEY (20) (20) (50) (50) 

NEPHRCPATHY, TOXIC 1 (2%) 

tURINARY BLADDER (20) (18) (50) (49) 

CALCULUS, NOS 1 (2%) 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

C_ QO 
TABLE C2 (CONTINUED) 

CONTRO L (UNTR) CONTR OL (VE H) LOW DOSE HIGH DDSE 

01-141F 01-091F 01-144 F 01-145 F 

ENDOCRINE SYSTEM 

•PITUITARY 

ANGIECTASIS (20) (2 0) (50) 

4 (8%) 

(50) 

2 (4%) 

•ADRENAL 

CALCIUM DEPOSIT 

(20) 

1 (5%) 

(20) (50) (50) 

#ADRENAL CORTEX (20) (20) (50) (50) 

DEGENERATION, NOS 

ANGIECTASIS 5 (25%) 2 (10%) 3 (6%) 7 (14%) 

•THYROID 

FOLLICULAR CYST, NOS 

(19) 

2 (11%) 

(20) (49) 

2 (4%) 

(50) 

3 (6%) 

REPRODUCTIVE SYSTEM 

•MAHKARY GLAND 

NECROSIS, FAT 

(20) 

1 (5%) (2 0) (50) (50) 

*VAGINA 

INFLAMMATION, NOS 

(2C)

1 (5%) 

(2C) (50) (50) 

1 (2%) 

•UTERUS (20) (19) (48) (50) 

HYDROMETRA 2 (4%) 4 (8%) 

•UTERUS/ENDOMETRIUM 

INFLAMMATION, NOS 

HYPERPLASIA, CYSTIC 

(20) 

2 (10%) 

(19) (48) 

2 

1 <«»*) 

(2%) 

(50) 

1 (2%) 

• OVARY (20) (20) (50) (50) 

CYST, NOS 

INFLAMMATION, NOS 

1 (5%) 1 (2%) 

NERVOUS SYSTEM 

NONE 

SPECIAL SENSE ORGANS 

NONE 

MUSCULOSKELETAL SYSTEM 

NONE 

• NUMBER CF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

C-9 
TABLE C2 (CONCLUDED) 

CONTROL (ONTR) CONTROL (VEH) LOW DOSE HIGH DOSE 

01-1U1 F 01-091F 01-1UUF 01-145F 

BODY CAVITIES 

• MESENTERY (20) (20) (50) (50) 

PERIARTERITIS 1 (2%) 

ALL OTHER SYSTEMS 

THORACIC CAVITY 

ABSCESS, NOS 1 

SPECIAL MORPHOLOGY SUMMARY 

NO LESION REPORTED 8 5 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMALS NBCROPSIED 

C-IO 
APPENDIX D
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN MICE TREATED WITH TETRACHLOROETHYLENE
 

CONTROL (UNTR) CONTROL (VEH) 

0 2-M141 02-M13 1 

ANIMALS INITIALLY IN STUDY 20 20 ANIMALS MISSING 

ANIMALS NECROPSIED 18 20 ANIMALS EXAMINED HISTOPATHOLOGICALLY** 18 20 

INTEGUMENTARY SYSTEM 

*SKIN (18) (20)

 INFLAMMATION, NOS 1 (6%)

 

•SUBCUT TISSUE (18) (20)

 EPIDERMAL INCLUSION CYST 2 (10%)

 ABSCESS, NOS 2 (10%)

 

RESPI3ATORY SYSTEM 

iTRACHEA (18) (20)

 INFLAMMATION, NOS

 

#LUNG (18) (20) PNEUMONIA, CHRONIC MURINE 5 (28%)

 

LEUKEMOID REACTION 1 (5%)

 

HEMATOPOIETIC SYSTEM 

#BONE MARROW (18) (19)

 LEUKEMCID REACTION 1 (5%)

 

iSPLEEN (18) (20) AMYLOIDOSIS 3 (15%) HEMATOPOIESIS 

•CERVICAL LYMPH NODE (18) (20)

 INFLAMMATION, NOS 1 (6%)

 

#MESENTERIC L. NODE (18) (20) INFLAMMATION, NOS 9 (50%) 1 (5%) ANGIECTASIS 2 (11%) 2 (10%) 

• THYMUS (18) (20)

 

_ANGIECTASIS___ _ _ _ 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

TABLE Dl 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE MICE 

TREATED WITH TETRACHLOROETHYLENE 

. LOW DOSE 

02-M142 

50 

49 

49 

(49) 

(49)

1 (2%) 

(49)

14 (29%) 

(49) 

(49) 

4 (8%) 

(49) 

(49) 

8 (16%) 

4 (8%) 

(49) 

_L12£L 

HIGH DOSE 

02-M143 

50 

2 

47 

47 

C*7) 

(47) 

(48) 

(48)

29 (60%) 

(48) 

(48) 

1 (2%) 

(30) 

(30)

1 (3%) 

1 (3%) 

(30) 

D-3 
TABLE Dl (CONTINUED) 

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

02-M14 1 0 2-M131 02-M14 2 02-M143 

CIRCULATORY SYSTEM 

•HEART (18) (20) (30) 

CALCIUM DEPOSIT 2 (10%) 1 (3%) 

• MYOCARDIUM (18) (20) (49) (30) 

DEGENERATION, NOS 1 (5%) 

DIGESTIVE SYSTEM 

•LIVEP (17) (2 0) (49) (48) 

THROMBUS, ORGANIZED 1 (2%) 2 (4%) 

INFLAMMATION, NOS 2 (10%) 

AMYLOIDOSIS 1 (5%) 

FOCAL CELLULAR CHANGE 3 (6%) 

ANGIECTASIS 1 (2%) 

•LIVER/CSNTRILOBULAR (17) (20) (49) (48) 

NECROSIS, NOS 2 (4%) 

•BIL E DUCT (18) (20) (49) (47) 

DILATATION, NOS 1 (2%) 

•STOMACH (18) (2 0) (49) (48) 

HYPERKERATOSIS 1 (2%) 

ACANTHOSIS 1 (2%) 

#COLCN (18) (20) (49) (48) 

NEMATOEIASIS 1 (6%) 11 (22%) 5 (10%) 

•RECTUM (18) (20) (49) (47) 

INFLAMMATION, NOS 1 (2%) 

URINARY SYSTEM 

•KIDNEY 

HYEP.CNEPHROSIS 

(18) 

3 (17%) 

(20) (49) 

1 (2%) 

(48) 

2 (4%) 

PYELONEPHRITIS, NOS 

INFLAMMATION, CHRONIC 

1 (6%) 1 

6 

(5%) 

(3 0%) 

1 (2%) 

NEPHROPATHY, TOXIC 40 (82%) 45 (9 4%) 

AMYLOIDOSIS 4 (20%) 

CALCIUM DEPOSIT 

1 

1 (5%) 

• NUM3ER CF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

D-4 
• URINARY BLADDER

 

CALCULUS, NOS

 

INFLAMMATION, NOS 

ENDOCRINE SYSTEM 

#THYROID 

FOLLICULAR CYST, NOS

 

REPRODUCTIVE SYSTEM 

#PRCSTATE 

INFLAMMATION, NOS 

•SEMINAL VESICLE 

INFLAMMATION, NOS

 

• TESTIS 

GRANULCMA, SPERMATIC
 

CALCIUM DEPOSIT
 

ATROPHY, NOS
 

•EPIDIDYMIS
 

GRANULCMA, SPERMATIC
 

NERVOUS SYSTEM 

NONE 

SPECIAL SENSE ORGANS 

•EYE 

PHTHISIS BULBI 

• EYI/LACRIMAL GLAND 

INFLAMMATION, NOS

 

NECROSIS, NOS 

MUSCULOSKELETAL SYSTEM 

* NUMBER OF ANIMALS WITH TISSUE

* NUMBER OF ANIMALS NECROPSIED 

TABLE Dl (CONTINUED) 

CONTROL (UMTR) CONTROL(VEH) 

02-M141 02-M131 

(18) (19) 

(18) (20) 

(18) (19) 

(18) (20) 

(17) (19) 

1 (5%) 

1 (5%) 

1 (6X) 3

 (16X) 

(18) (20) 

1 <5X) 

(18) (20) 

(18) (20) 

 EXAMINED MICROSCOPICALLY 

LOW DOSE 

02-M142 

(49) 

1 (2%) 

(49) 

1 (2%) 

(49) 

(49) 

(**9) 

3 (6%) 

(49) 

(49) 

1 (2%) 

(49) 

1 (2%) 

1 (2%) 

HIGH DOSE 

02-M143 

(48) 

1 (2%) 

(48) 

(48) 

2 (4%) 

(47) 

1 {2%) 

0*8) 

(47) 

(47) 

(47) 

D-5 
TABLE Dl (CONCLUDED) 

CONTROL (UNTR) CONTROL (VEH) LOi DOSE HIGH DOSE 

Q2-M141 02-H131 02-M1U2 02-M143 

BODY CAVITIES 

NONE 

ALL OTHIR SYSTEMS 

NONE 

SPECIAL MORPHOLOGY SUMMARY 

NO LESION REFORTED 1 6 1 

ANIMAL MISSING/NO NECROPSY 2 

ADTO/NECROPSY/HISTO PERF 1 

AOTOLYSIS/NO NECROPSY 2 1 1 

t NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

0-6 
TABLE D2

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE MICE 

TREATED WITH TETRACHLOROETHYLENE 

CONTROL (UNTR) 

02-F141 

CONTROL (VEH) 

02-F131 

LOW DOSE 

02-F144 

HIGH DOSE 

02-F145 

ANIMALS INITIALLY IN STUDY 20 

ANIMALS MISSING 

ANIMALS NECROPSIED 20 

ANIMALS EXAMINED HISTOPATHOLOGICALLY** 19 

20 

20 

20 

50 

48 

48 

50 

1 

48 

48 

INTEGUMENTARY SYSTEM 

•SUBCUT TISSUE 

ABSCESS, NOS 

(20) (20) 

1 (5%) 

(48) 

RESPIRATORY SYSTEM 

•TRACHEA 

INFLAMMATION, NOS 

(20) (19) (48) 

1 (2%) 

0*7) 

• LUNG 

PNEUMONIA, CHRONIC MURINE 

(20) 

7 (35%) 

(20) (48) 

27 (56%) 

(47) 

31 (66%) 

HEMATOPOIFTIC SYSTEM 

•SPLEEN 

INFLAMMATION, NOS 

HEMATOPOIESIS 

(20) 

1 (5%) 

(2 0) 

1 (5%) 

(48) 

5 (10%) 

(48) 

1 (2%) 

•CERVICAL LYMPH

ANGIECTASIS 

 NODE (20) (20) (48) 

3 (6%) 

(48) 

•MESENTERIC L . NODE 

INFLAMMATION, NOS 

ANGIECTASIS 

(20) 

6 

2 

(30%) 

(10%) 

(20) 

3 (15%) 

(48) 

3 

4 

(6%) 

(8%) 

(48) 

2 

3 

(4%) 

(6%) 

CIRCULATORY SYSTEM 

•MYOCARDIUM 

I1BRC.SIS 

(20) (20) (48) (47) 

• NUMBER OF ANIMALS WITH TISSUE EXAMINED

* NUMBER OF ANIMALS NECROPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

 MICROSCOPICALLY 

D-7 
TABLE D2 (CONTINUED) 

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

02-F141 02-F131 02-F144 02-F145 

DIGESTIVE SYSTEM 

#LIVER (20) (20) (48) (48) 

THROMBUS, ORGANIZED 1 (5%) 1 (2%) 2 (4%) 

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

PELIOSIS HEPATIS 1 (5%) 

METAMORPHOSIS FATTY 2 (4*) 

# PANCREAS (20) (20) (48) (48) 

INFLAMMATION, NOS 1 (5%) 

#STOMACH (20) (20) (48) (47) 

ULCER, FOCAL 1 (2%) 

HYPERKERATOSIS 1 (5%) 

ACANTHOSIS 1 (5%) 1 (5%) 

#COLCN (20) (20) (48) (47) 

NEMATODIASIS U (20%) 2 2 (<*%) 

URINARY SYSTEM 

•KIDNEY (20) (2 0) (48) (48) HYERONEPHROSIS 

PYELONEPHRITIS, NOS 

NEPHROPATHY, TOXIC 

1 (5%) 

46 (96%) 1 (2%) 48 (100%) 

ENDOCRINE SYSTEM 

•ADPENAL CORTEX (20) (2 0) (48) (48) 

ANGIECTASIS 1 (2%) 

•THYROID (20) (20) (48) (47) 

FCLLICULAR CYST, NOS 1 (5%) 2 (10%) 

REPRODUCTIVE SYSTEM 

•UTERUS (20) (2 0) (48) (47) 

HYDRCMETRA 4 (20%) 4 (2 0%) 1 (2%) 

•UTERUS/ENDCMETRIUM (20) (20) (48) (47) 

INFLAMMATION, NOS 1 (5%) 2 (4%) 

HYPERPLASIA, CYSTIC 3 (15%) 11 (55%) 1 (2%) 

•OVARY (20) (20) (48) (47) 

CYST, NOS 11 (55%) 6 (30%) 11 (2 3%) 6 (13%) 

INFLAMMATIONX_NOS J-J5%1 

• NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

D-8 
TABLE D2 (CONCLUDED) 

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

02-F141 0 2-F131 02-F144 02-F145 

NERVOUS SYSTEM 

NONE 

SPECIAL SENSE ORGANS 

*EYEAACRIMAL GLAND (2 0) (2 0) (48) (48) 

INFLAMMATION, NOS 1 (5%) 

MUSCOLOSKELETAL SYSTEM 

NONE 

BODY CAVITIES 

•PERITONEUM (20) (2 0) (48) (48) 

INFLAMMATION, NOS 1 (5%) 

ALL OTHIR SYSTEMS 

NONE 

SPECIAL MORPHOLOGY SUMMARY 

NO LESION REPORTED 

ANIMAL MISSING/NO NECROPSY 

AUTO/NECROPSY/NO HISTO 

AUTOLYSIS/NC NECROPSY 

# NUMEER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

D-9 

 1977 TETRACHLOROETHYLENE NCI-CG-TR-13 

DHEW Publication No. (NIH) 77-813