1978 

National Cancer Institute 

CARCINOGENESIS 

Technical Report Series 

No. 110 

BIOASSAY OF 

IODOFORM 

FOR POSSIBLE CARCINOGENICITY 

CAS No. 75-47-8 

NCI-CG-TR-110 

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

Public Health Service 

National Institutes of Health 

BIDASSAY OF
 

IODOFORM
 

FOR POSSIBLE CARCINOGENICITY
 

Carcinogenesis Testing Program
 

Division of Cancer Cause and Prevention
 

National Cancer Institute
 

National Institutes of Health
 

Bethesda, Maryland 20014
 

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

Public Health Service
 

National Institutes of Health
 

DHEW Publication No. (NIH) 78-1365 

REPORT ON THE BIOASSAY OF IODOFORM
 

FOR POSSIBLE CARCINOGEN1CITY
 

CARCINOGENESIS TESTING PROGRAM
 

DIVISION OF CANCER CAUSE AND PREVENTION
 

NATIONAL CANCER INSTITUTE, NATIONAL INSTITUTES OF HEALTH
 

FOREWORD: This report presents the results of the bioassay of
 

iodoform conducted for the Carcinogenesis Testing Program, Division
 

of Cancer Cause and Prevention, National Cancer Institute (NCI),
 

National Institutes of Health, Bethesda, Maryland. This is one of a
 

series of experiments designed to determine whether selected chemicals have the capacity to produce cancer in animals. Negative results, in which the test animals do not have a significantly greater
 

incidence of cancer than control animals, do not necessarily mean
 

the test chemical is not a carcinogen because the experiments are
 

conducted under a limited set of circumstances. Positive results
 

demonstrate that the test chemical is carcinogenic for animals under
 

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

The actual determination of the risk to man from animal carcinogens
 

requires a wider analysis.
 

CONTRIBUTORS: This bioassay of iodoform was conducted by Hazleton
 

Laboratories America, Inc., Vienna, Virginia, initially under direct
 

contract to the NCI and currently under a subcontract to Tracer Jitco,
 

Inc., prime contractor for the NCI Carcinogenesis Testing Program.
 

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

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

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

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

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

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

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

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

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

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

L. Schueler (7).
 

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

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

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

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

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

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

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

Walker (6), biochemist Mr. S. C. Drill (6), and technical editor Ms.
 

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

participating organizations.
 

The following other scientists at the National Cancer Institute
 

were responsible for evaluating the bioassay experiment, interpreting
 

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

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

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

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

1.	 Carcinogenesis Testing Program, Division of Cancer Cause and
 

Prevention, National Cancer Institute, National Institutes of
 

Health, Bethesda, Maryland.
 

2.	 Now with the Naylor Dana Institute for Disease Prevention, American Health Foundation, Hamtnon House Road, Valhalla, New York.
 

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

Vienna, Virginia.
 

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

Reston, Virginia.
 

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

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

Boulevard, McLean, Virginia.
 

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

Maryland.
 

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

Rockville, Maryland.
 

9.	 Mathematical Statistics and Applied Mathematics Section, Biometry
 

Branch, Field Studies and Statistics Program, Division of Cancer
 

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

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

University, School of Medicine, Traylor Building, Baltimore,
 Maryland.
 

SUMMARY
 

A bioassay for possible carcinogenicity of technical-grade iodoform was conducted using Osborne-Mendel rats and B6C3F1 mice. lodoform in corn oil was administered by gavage, at either of two dosages,
 

to groups of 50 male and 50 female animals of each species. Administration of the chemical occurred 5 days a week, for a period of 78
 

weeks, followed by an observation period of 34 weeks for rats and 13
 

or 14 weeks for mice. The high and low time-weighted average dosages
 

of iodoform were, respectively, 142 and 71 mg/kg/day for male rats, 55
 

and 27 mg/kg/day for female rats, and 93 and 47 mg/kg/day for male and
 

female mice. For each species, 20 animals of each sex were placed on
 

test as vehicle controls. These animals were gavaged with pure corn
 

oil at the same rate as the high dose group of the same sex. Twenty
 

animals of each sex were placed on test as untreated controls for each
 

species. These animals were not intubated.
 

A significant positive association between dosage and mortality
 

was observed in male rats but not in female rats or in mice of either
 

sex. Adequate numbers of animals in all groups survived sufficiently
 

long to be at risk from late-developing tumors.
 

No statistical significance could be attributed to the incidences
 

of any neoplasms in rats or mice of either sex when compared to their
 

respective controls.
 

Under the conditions of this bioassay, no convincing evidence was
 

provided for the carcinogenicity of iodoform in Osborne-Mendel rats or
 

B6C3F1 mice.
 

VII
 

TABLE OF CONTENTS
 

Page
 

I. INTRODUCTION 1
 

II. MATERIALS AND METHODS 3
 

A. Chemicals 3
 

B. Dosage Preparation 3
 

C. Animals 3
 

D. Animal Maintenance 5
 

E. Gastric Intubation 6
 

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 20
 

D. Statistical Analyses of Results 22
 

IV. CHRONIC TESTING RESULTS: MICE 31
 

A. Body Weights and Clinical Observations 31
 

B. Survival 31
 

C. Pathology 34
 

D. Statistical Analyses of Results 35
 

V. DISCUSSION 42
 

VI. BIBLIOGRAPHY 43
 

APPENDIX A SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

RATS TREATED WITH IODOFORM A-l
 

APPENDIX B SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

MICE TREATED WITH IODOFORM B-l
 

APPENDIX C SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN RATS TREATED WITH IODOFORM C-l
 

APPENDIX D SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN MICE TREATED WITH IODOFORM D-l
 

ix
 
Figure Number
 

1
 

2
 

Table Number
 

Al
 

LIST OF ILLUSTRATIONS 

Page 

CHEMICAL STRUCTURE OF IODOFORM 4 

GROWTH CURVES FOR IODOFORM CHRONIC STUDY 

RATS 19 

SURVIVAL COMPARISONS OF IODOFORM

STUDY RATS 

 CHRONIC 

21 

GROWTH CURVES FOR IODOFORM CHRONIC STUDY 

MICE 32 

SURVIVAL COMPARISONS OF IODOFORM CHRONIC 

STUDY MICE 33 

LIST OF TABLES 

Page 

DESIGN SUMMARY FOR OSBORNE-MENDEL RATS— 

IODOFORM GAVAGE EXPERIMENT 9 

DESIGN SUMMARY FOR B6C3F1 MICE—IODOFORM 

GAVAGE EXPERIMENT 10 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN MALE RATS TREATED WITH 

IODOFORM WHICH SURVIVED AT LEAST 52 WEEKS 23 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN FEMALE RATS TREATED 

WITH IODOFORM 26 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN MALE MICE TREATED WITH 

IODOFORM 36 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS 

AT SPECIFIC SITES IN FEMALE MICE TREATED 

WITH IODOFORM 39 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

MALE RATS TREATED WITH IODOFORM A-3 

X
 
LIST OF TABLES (Concluded) 

Table Number Page 

A2 SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

FEMALE RATS TREATED WITH IODOFORM A-6 

Bl SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

MALE MICE TREATED WITH IODOFORM B-3 

B2 SUMMARY OF THE INCIDENCE OF NEOPLASMS IN 

FEMALE MICE TREATED WITH IODOFORM B-6 

Cl SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN MALE RATS TREATED WITH IODOFORM C-3 

C2 SUMMARY OF THE INCIDENCE OF SONNEOPLASTIC 

LESIONS IN FEMALE RATS TREATED WITH IODOFORM C-7 

Dl SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN MALE MICE TREATED WITH IODOFORM D-3 

D2 SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC 

LESIONS IN FEMALE MICE TREATED WITH IODOFORM D-8 

xi
 

I. INTRODUCTION
 

lodoform (NCI No. C04568), a halogenated alkane with antiseptic
 

and anti-infective properties, was selected for bioassay by the National Cancer Institute because of its use in pharmaceutical preparations and its structural similarity to methyl iodide, which has
 

produced sarcomas in BD rats (Druckrey et al., 1970; Preussmann,
 

1968), and to chloroform, a compound which has been found to induce
 

hepatomas in NLC mice (Eschenbrenner, 1945; Rudali, 1967).
 

The Chemical Abstracts Service (CAS) Ninth Collective Index
 

(1977) name for this compound is triiodo-methane.
 

In the past, iodoform was used by humans chiefly as a topical
 

anti-infective (Windholz, 1976). The mild antibacterial action of
 

the compound results from its gradual release of elemental iodine
 

(Goodman and Gilman, 1970). Use of iodoform for the dressing of
 

wounds was fairly extensive but in recent times it has been replaced
 

almost altogether by more effective antiseptic agents (Goodman and
 

Gilman, 1970).
 

lodoform may still be used in veterinary medicine as an antiseptic and also as a disinfectant on superfical lesions and in the
 

female reproductive tract (Windholz, 1976).
 

Specific production figures for iodoform are not available,
 

lodoform is produced in two grades: technical or nonmedicinal; and
 

*
 

The CAS registry number is 75-48-8.
 
N.F. (National Formulary). Of these, only technical-grade iodoform
 

is produced in commercial quantities (greater than 1000 pounds or
 

$1000 in value annually) in the United States (Stanford Research
 

Institute, 1976).
 

Since iodoform is no longer used to any great extent in the
 

treatment of humans, the potential for exposure is greatest for
 

workers in iodoform production facilities and for those persons using
 

the compound for research purposes.
 

Iodoform is considered moderately toxic (Sax, 1975); the lowest
 

published toxic dose in humans is 114 mg/kg (U.S. Department of
 

Health, Education, and Welfare, 1976). Poisoning, which is often the
 

result of absorption of iodoform through a wound, produces vomiting,
 

rapid pulse, sometimes accompanied by a slight fever, and all degrees
 

of cerebral depression or excitation (Gosselin et al., 1976). Absorption of large amounts of the compound may result in depression of the
 

central nervous system, and damage to the kidneys, liver, and heart
 

(Irish, 1967).
 
II. MATERIALS AND METHODS
 

A. Chemicals
 

One batch of technical-grade iodoform (Figure 1) (triiodomethane)
 

was purchased from Merck and Company, Inc., Rahway, New Jersey.
 

Chemical analysis was performed by Hazleton Laboratories America,
 

Inc., Vienna Virginia. The experimentally determined melting point
 

was 115°C, while the literature value is 120°C (Windholtz, 1976).
 

The results of analysis via reaction with silver nitrate and titration
 

with thiocyanate also suggested a compound of extremely high purity.
 

Throughout this report the term iodoform is used to represent
 

this technical-grade material.
 

B.	 Dosage Preparation
 

Fresh solutions of iodoform in Duke's®corn oil (S. F. Sauer
 

.Company, Richmond, Virginia) were prepared weekly, sealed, and stored
 

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

generally stable for ten days under the indicated storage conditions.
 

The concentrations of iodoform in corn oil ranged from 1.8 to 9.0
 

percent for the rat bioassay and 0.6 to 1.0 percent for the mouse
 

bioassay.
 

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
 
I 

H-— C—I 

I 

FIGURE 1 

CHEMICAL STRUCTURE OF IODOFORM 
tetrachloride of five different strains of rats (Reuber and Glover,
 

1970). The B6C3F1 mouse was selected because it has been used by the
 

NCI for carcinogenesis bioassays and has proved satisfactory in this
 

capacity.
 

Rats and mice of both sexes were obtained through contracts of
 

the Division of Cancer Treatment, National Cancer Institute. The
 

Osborne-Mendel rats 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
 

treated and control groups.
 

D. Animal Maintenance
 

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


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

relative humidity was maintained between 45 and 55 percent. The
 

air conditioning system in the laboratory provided filtered air at a
 

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

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

The rats were individually housed in suspended galvanized-steel
 

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

groups of ten in solid-bottom, polypropylene cages equipped with nonwoven filter tops. Sanitized cages with fresh bedding (Sanichips ,
 

Pinewood Sawdust Company, Moonachie, New Jersey) were provided once
 
each week for mice. Rats received sanitized cages with no bedding
 

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


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

(*F?)
 

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

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

The iodoform-dosed and vehicle control rats were housed in the
 

same room as other rats intubated with 3-sulfolene (77-79-2) and
 

hexachloroethane (67-72-1). The untreated control rats were housed
 

with other rats intubated with 1,1,2-trichloroethane (79-00-5) and
 

tetrachloroethylene (127-18-4).
 

All mice utilized in the iodoform bioassay, including controls,
 

were housed with other mice intubated with allyl chloride (107-05-1);
 

1,1,2,2-tetrachloroethane (79-34-5); chloroform (67-66-3); chloropicrin (76-06-2); carbon disulfide (75-15-0); dibromochloropropane
 

(96-12-8); 1,2-dibromoethane (106-93-4); 1,2-dichloroethane (107-06-2);
 

1,1-dichloroethane (75-34-3); trichloroethylene (79-01-6); 3-sulfolene
 

(77-79-2); methylchloroform (71-55-6); 1,1,2-trichloroethane (79-00-5);
 

tetrachloroethylene (127-18-4); hexachloroethane (67-72-1); trichlorofluoromethane (75-69-4) and carbon tetrachloride (56-23-5).
 

E.	 Gastric Intubation
 

Intubation was performed for five consecutive days per week on
 

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

*
 

CAS registry numbers are given in parentheses.
 
mean body weight as a guide for determining the dose. Mean body
 

weights for each group were recorded at weekly intervals for the
 

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

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

gavaged with the test solution 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 estimate the maximum tolerated dosage of iodoform for
 

administration to treated animals in the chronic studies, subchronic
 

toxicity tests were conducted with both rats and mice. Animals of
 

each species were distributed among six groups, each consisting of
 

five males and five females. Iodoform mixed with corn oil was introduced by gavage to five of the six rat groups at dosages of 56, 100,
 

178, 316 and 562 mg/kg/day and five of the six mouse groups at dosages
 

of 18, 32, 56, 100, and 178 mg/kg/day. The sixth group of each species served as a control group, receiving only the corn oil by gavage.
 

Intubation was performed 5 days per week for 6 weeks, followed by a
 

2—week observation period to detect any delayed toxicity.
 

A dosage inducing no mortality and resulting in a depression in
 

mean group body weight of approximately 20 percent was selected as
 

the initial high dose. When weight gain criteria were not applicable,
 

mortality data alone were utilized.
 

Deaths occurred in all groups of treated female rats and in all
 

male groups receiving 316 mg/kg/day or more. All the male and female
 
rats receiving dosages of 562 mg/kg/day died before the end of the
 

experiment. Mean body weight was depressed in male rats receiving
 

dosages of 316 mg/kg/day and in female rats receiving dosages of 56
 

mg/kg/day or higher. The initial high doses selected for the chronic
 

bioassay were 180 and 36 mg/kg/day for males and females, respectively.
 

All male mice receiving 56 mg/kg/day or less survived. One
 

of the five male mice receiving 100 mg/kg/day died and all the male
 

mice receiving 178 mg/kg/day died. All treated female mice survived,
 

except for four of the five female mice treated with 178 mg/kg/day.
 

The only significant mean body weight depression observed was in
 

female mice receiving 178 mg/kg/day. The initial high dose selected
 

for both male and female mice in the chronic bioassay was 56 mg/kg/
 

day.
 

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.
 

All rats were approximately 7 weeks old when they were started
 

on test. Vehicle control and treated rats shared the same median
 

date of birth while untreated control rats were approximately 2 weeks
 

younger than the other groups and were started on test a corresponding 2 weeks after the other groups. Male rats initially received
 

8
 
TABLE 1
 

DESIGN SUMMARY FOR OSBORNE-MENDEL RATS
 

IODOFORM GAVAGE EXPERIMENT
 

INITIAL OBSERVATION PERIOD TIME-WEIGHTED
 

GROUP IODOFORM TREATED UNTREATED AVERAGE
 

SIZE DOSAGE3 (WEEKS) (WEEKS) DOSAGEb
 

MALE
 

UNTREATED CONTROL 20 0 0 112 0
 

VEHICLE CONTROL 20 0 78 34 0
 

LOW DOSE 50 90 28 71
 

60 50
 

0 34
 

HIGH DOSE 50 180 28 142
 

120 50
 

0 34
 

FEMALE
 

UNTREATED CONTROL 20 0 0 112 0
 

VEHICLE CONTROL 20 0 78 34 0
 

LOW DOSE 50 18 18 27
 

30 60
 

0 34
 

HIGH DOSE 50 36 18 55
 

60 60
 

0 34
 

a
 

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

consecutive days per week.
 

2 (dosage X weeks received)
 Ti me»— UPI crhf-pd flvf =>TflPP Hnfiflpfi = ; 2 : : : ,
 2(weeks receiving chemical)
 
TABLE 2
 

DESIGN SUMMARY FOR B6C3F1 MICE
 

IODOFORM GAVAGE EXPERIMENT
 

MALE
 

UNTREATED CONTROL
 

VEHICLE CONTROL
 

LOW DOSE
 

HIGH DOSE
 

FEMALE
 

UNTREATED CONTROL
 

VEHICLE CONTROL
 

LOW DOSE
 

HIGH DOSE
 

a
 

Dosage, given in
 

consecutive days
 

INITIAL OBSERVATION PERIOD TIME -WEIGHTED 

GROUP IODOFORM TREATED UNTREATED AVERAGE 

SIZE DOSAGE3 (WEEKS) (WEEKS) DOSAGEb 

20 0 0 90 0
 

20 0 78 12 0
 

50 28 8 47
 

40 10
 

50 60
 

0 13
 

50 56 8 93
 

80 10
 

100 60
 

0 13
 

20 0 0 90 0
 

20 0 78 12 0
 

50 28 8 47
 

40 10
 

50 60
 

0 13
 

50 56 8 93
 

80 10
 

100 60
 

0 14
 

mg/kg body weight, was administered by gavage five
 

per week.
 

, 2 (dosagB e X weeks
 received)
 Ti TTIP— upi ohfprl a\rtarawp rmsfl&p = : :—: : .
 

10
 
iodoform dosages of 90 and 180 mg/kg/day. Throughout this report
 

those male rats initially receiving the former dosage are referred
 

to as the low dose group, while those initially receiving the latter
 

dosage are referred to as the high dose group. In week 29 the dosages were lowered to 60 and 120 mg/kg/day for low and high dose males,
 

respectively. The dosages were maintained at these levels for the
 

remainder of the period of compound administration. The doses initially utilized for female rats were 18 and 36 mg/kg/day. Throughout
 

this report those female rats initially receiving the former dosage
 

are referred to as the low dose group while those initially receiving
 

the latter dosage are referred to as the high dose group. In week 19
 

the dosages were increased to 30 and 60 mg/kg/day for low and high
 

dose female rats, respectively. These dosages were maintained for
 

the remainder of the period of compound administration.
 

Mice were all approximately 5 weeks old when they were started
 

on test. The vehicle control and treated mice shared the same median
 

date of birth. The untreated control mice were approximately 4 weeks
 

younger than the other groups and were started on test a corresponding 4 weeks later. For the first 8 weeks of the experiment male and
 

female mice received dosages of 28 and 56 mg/kg/day. Throughout this
 

report those mice initially receiving the former dosage are referred
 

to as the low dose groups, while those initially receiving the latter
 

dosage are referred to as the high dose groups. In week 9 dosages
 

were raised to 40 and 80 mg/kg/day for low and high dose mice,
 

11
 
respectively. In week 19 the dosages were again raised, to 50 and
 

100 mg/kg/day for low and high dose mice, respectively. These dosages
 

remained unchanged for both male and female mice for the remainder of
 

the period of compound administration.
 

H. Clinical and Histopathologic Examinations
 

Animals were weighed immediately prior to initiation of the
 

experiment. Body weights, food consumption, and data concerning
 

appearance, behavior, signs of toxic effects, and incidence, size,
 

and location of tissue masses were recorded at weekly intervals for
 

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

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

presence of tissue masses was determined by observation and palpation
 

of each animal.
 

A necropsy was performed on each animal regardless of whether it
 

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

bioassay. The animals were euthanized by exsanguination under sodium
 

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

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

animals and, whenever possible, from animals found dead.
 

Tissues were preserved in 10 percent buffered formalin, embedded
 

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

to microscopic examination. An occasional section was subjected to
 

special staining techniques for more definitive diagnosis.
 

12
 
Slides were prepared from the following tissues: skin, lungs,
 

bronchi, trachea, bone marrow, spleen, lymph nodes, thymus, heart,
 

salivary gland, liver, gallbladder (mice), pancreas, esophagus,
 

stomach, small intestine, large intestine, kidney, urinary bladder,
 

pituitary, adrenal, thyroid, parathyroid, mammary gland, testis,
 

prostate, and brain.
 

A few tissues were not examined for some animals, particularly
 

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

preclude histopathologic interpretation. Thus, the number of animals
 

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

animals that were placed on experiment in each group.
 

I. Data Recording and Statistical Analyses
 

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

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

as recommended by the International Union Against Cancer (Berenblum,
 

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

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

13
 
that bear on the possibility of carcinogenicity are discussed in the
 

statistical narrative sections.
 

Probabilities of survival were estimated by the product-limit
 

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

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

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

missing; animals dying from natural causes were not statistically
 

censored. Statistical analyses for a possible dose-related effect
 

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

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

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

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

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

The incidence of neoplastic or nonneoplastic lesions has been
 

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

specific anatomic site (numerator) to the number of animals in which
 

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

histologically. However, when macroscopic examination was required
 

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

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

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

14
 
The purpose of the statistical analyses of tumor incidence is to
 

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

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

1970, pp. 48-52) was used to compare the tumor incidence of a control
 

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

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

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

significance level of 0.05 may be made. The Bonferroni inequality
 

(Miller, 1966, pp. 6-10) requires that the P-value for any comparison
 

be less than or equal to 0.05/k. In cases where this correction was
 

used, it is discussed in the narrative section. It is not, however,
 

presented in the tables, where the Fisher exact P-values are shown.
 

The Cochran-Armitage test for linear trend in proportions, with
 

continuity correction (Armitage, 1971, pp. 362-365), was also used
 

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

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

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

noted, the direction of the significant trend was a positive dose relationship. This method also provides a two-tailed test of departure
 

from linear trend.
 

A time-adjusted analysis was applied when numerous early deaths
 

resulted from causes that were not associated with the formation of
 

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

15
 
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
 

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

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

t c t
 

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

16
 
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
 

No mean body weight depression was evident during this bioassay
 

for female rats, but a slight compound-related mean body weight
 

depression was observed among male rats during the dosing period
 

(Figure 2). Fluctuations in the growth curve may be due to mortality; as the size of the group diminishes, the mean body weight may be
 

subject to wide variations.
 

During the first 18 weeks of the study the appearance and behavior of the treated rats were generally comparable with those of
 

the untreated controls. From week 20 to the end of the first year,
 

a hunched appearance was observed with greater frequency in the high
 

dose males and females than in the low dose and control groups, but
 

was noted at a comparable rate in all groups during the remainder of
 

the study.
 

Respiratory signs, involving labored respiration, wheezing, and/
 

or nasal discharge, were observed at a low incidence in all groups
 

during the first year, increasing as the animals aged; by week 110
 

most of the surviving rats exhibited respiratory symptoms. Clinical
 

signs associated with aging were noted at a comparable frequency in
 

treated and control rats during the last 10 months of the study.
 

These signs included sores on the body or extremities, alopecia,
 

rough fur, abdominal urine stains, squinted or reddened eyes, swollen
 

areas of the body, tissue masses, and palpable nodules. Isolated
 

18
 
MEAN BODY WEIGHT (GRAMS) MEAN BODY 

1 O O1 C 3 O O c 

m 

> 

f 

m 

> 

3 

m •O CO C/3 

m 

m 

^1 

CO 

I 

O 
observations in one to three rats included tremors, transient salivation, incoordination, ataxia, red vaginal discharge, abnormal gait,
 

and head tilt.
 

B. Survival
 

The estimated probabilities of survival for male and female rats
 

in the control and iodoform-dosed groups are shown in Figure 3. For
 

male rats the Tarone test indicated a significant (P < 0.001) positive
 

association between increased dosage and mortality. For female rats
 

no statistically significant association between dose and mortality
 

was observed.
 

The survival of the dosed males was low, with 50 percent (25/50)
 

of the high dose male rats dead by week 46 and 52 percent (26/50) of
 

the low dose male rats dead by week 76. For each of the control
 

groups, however, 50 percent (10/20) of the rats survived on test at
 

least 100 weeks.
 

There were adequate numbers of females at risk from late-


developing tumors as 54 percent (27/50) of the high dose, 38 percent
 

(19/50) of the low dose, 80 percent (16/20) of the vehicle control
 

and 60 percent (12/20) of the untreated control females survived on
 

test until the end of the study.
 

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).
 

20
 
PROBABILIT

Y OF SURVIVAL PROBABILIT

Y O

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3 0 O 0 0 

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Follicular-cell tumors of the thyroid gland occurred in treated
 

rats and pooled vehicle controls of both sexes but not in matched
 

vehicle controls. Each of the other types of tumors observed in this
 

bioassay has been encountered previously as a naturally occurring
 

lesion in the aged Osborne-Mendel rat.
 

Inflammatory, degenerative, and proliferative lesions as seen
 

in the control and chemically treated rats were similar in number and
 

kind to those lesions occurring spontaneously in untreated aged rats.
 

This histopathologic examination did not provide evidence that
 

iodoform was carcinogenic to Osborne-Mendel rats under the conditions
 

of this experiment.
 

D. Statistical Analyses of Results
 

The results of the statistical analyses of tumor incidence in
 

rats are summarized in Tables 3 and 4. For males (Table 3) because
 

of the high early mortality in the high dose group the statistical
 

analyses were based either on rats which survived at least 52 weeks
 

or, in the case of the combined incidence of follicular-cell carcinomas or follicular-cell adenomas of the thyroid, on rats which
 

survived at least 50 weeks (the time at which the first tumor of
 

interest was detected). For females (Table 4) the standard analyses
 

were performed. The analysis is included for every type of malignant
 

tumor in either sex where at least two such tumors were observed in
 

at least one of the control or iodoform-dosed groups and where such
 

tumors were observed in at least 5 percent of the group.
 

22
 
TABLE 3
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN MALE RATS TREATED WITH IODOFORM
 e
 WHICH SURVIVED AT LEAST 52 WEEKS3

»
 

POOLED MATCHED 

VEHICLE VEHICLE 

TOPOGRAPHY: MORPHOLOGY CONTROL CONTROL 

Pituitary: Chromophobe Adenoma 6/36(0.17) 4/18(0.22) 

P Values0 N.S. N.S. 

Relative Risk (Pooled Vehicle Control) 

Lower Limit 

Upper Limit ___ 

Relative Risk (Matched Vehicle Control) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 105 Ill 

Thyroid: Follicular-Cell Carcinoma 1/34(0.03) 0/16(0.00)
 

P Values0 N.S. N.S.
 

Relative Risk (Pooled Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor Ill
 

LOW
 

DOSE
 

7/36(0.19)
 

N.S.
 

1.167
 

0.363
 

3.697
 

0.875
 

0.258
 

3.560
 

72
 

6/35(0.17)
 

N.S.
 

5.829
 

0.722
 

245.698
 

Infinite
 

0.735
 

Infinite
 

74
 

HIGH
 

DOSE
 

4/20(0.20)
 

N.S.
 

1.200
 

0.276
 

4.348
 

0.900
 

0.198
 

4.141
 

95
 

3/17(0.18)
 

N.S.
 

6.000
 

0.520
 

293.063
 

Infinite
 

0.604
 

Infinite
 

112
 
___ 

___ 

___ 

___ 

___ 

TABLE

TOPOGRAPHY : MORPHOLOGY
 

Thyroid: Follicular-Cell Adenoma or
 

Follicular-Cell Carcinoma** »e
 

P Values0
 

Relative Risk (Pooled Vehicle Control)d
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Vehicle Control)d
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Thyroid: Cr-Cell Adenoma or C-Cell
 

Carcinoma
 

P Values0
 

Relative Risk (Pooled Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

3 (CONTINUED) 

POOLED
 

VEHICLE
 

CONTROL
 

2/34(0.06)
 

N.S.
 

Ill
 

1/34(0.03)
 

N.S.
 __H
 

Ill
 

MATCHED
 

VEHICLE
 

CONTROL
 

0/16(0.00)
 

N.S.
 

1/16(0.06)
 

N.S.
 

«.__
 

Ill
 

LOW
 

DOSE
 

8/35(0.23)
 

P = 0.046*
 

P = 0.037**
 

3.886
 

0.851
 

35.305
 

Infinite
 

1.112
 

Infinite
 

74
 

3/35(0.09)
 

N.S.
 

2.914
 

0.235
 

140.599
 

1.371
 

0.117
 

66.206
 

111
 

HIGH
 

DOSE
 

4/18(0.22)
 

N.S.
 

3.778
 

0.595
 

37.389
 

Infinite
 

0.882
 

Infinite
 

3/20(0.15)
 

N.S.
 

5.100
 

0.520
 

293.063
 

2.400
 

0.259
 

137.988
 

50 

112 
TABLE 3 (CONCLUDED)
 

created groups received time-weighted average doses of 71 or 142 mg/kg by gavage.
 

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

G

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

the corresponding control group when P - 0.05; otherwise, not significant (N.S.) is indicated.
 

The probability level for the Fisher exact test for the comparison of a treated group with the
 

pooled vehicle control group (*) or the matched vehicle control group (**) is given beneath the
 

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

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

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

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

For sites where the first tumor of interest was observed earlier than 52 weeks, the analyses
 

were based upon all animals that survived until or past the date that the first tumor was observed.
 
TABLE 4
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN FEMALE RATS TREATED WITH IODOFORM£
 

POOLED MATCHED
 

VEHICLE , VEHICLE LOW
 

TOPOGRAPHY : MORPHOLOGY CONTROL CONTROL DOSE
 

Pituitary: Chromophobe Adenoma 12/40(0.30) 5/20(0.25) 8/45(0.18)
 

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

Relative Risk (Pooled Vehicle Control) —_ 0.593
 

Lower Limit 0.236
 

Upper Limit 1.411
 

Relative Risk (Matched Vehicle Control) 0.711
 

Lower Limit 0.243
 

Upper Limit 2.485
 ON
 

Weeks to First Observed Tumor 89 112 62
 

Thyroid: Follicular-Cell Carcinoma 1/40(0.02) 0/20(0.00) 4/40(0.10)
 

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

Relative Risk (Pooled Vehicle Control) 4.000
 

Lower Limit 0.420
 

Upper Limit 191.652
 

Relative Risk (Matched Vehicle Control) Infinite
 

Lower Limit 0.483
 

Upper Limit Infinite
 

Weeks to First Observed Tumor Ill
 91
 

HIGH
 

DOSE
 

9/47(0.19)
 

N.S.
 

0.638
 

0.267
 

1.478
 

0.766
 

0.273
 

2.618
 

104
 

2/42(0.05)
 

N.S.
 

1.905
 

0.103
 

109.644
 

Infinite
 

0.146
 

Infinite
 

104
 
___ 

_ __ 

_ __ 

_ _ _ 

___ 

___ 

TABLE 4 (CONTINUED)
 

TOPOGRAPHY: MORPHOLOGY
 

Mammary Gland: Adenocarcinoma NOS
 

P Values0
 

Relative Risk (Pooled Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Vehicle Control)d
 

Lower Limit
 

Upper Limit
 N>
 

--J Weeks to First Observed Tumor
 

Mammary Gland: Fibroadenoma
 

P Values0
 

Relative Rick (Pooled Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Relative Riak (Matched Vehicle Control)d
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

POOLED
 

VEHICLE
 

CONTROL
 

1/40(0.02)
 

N.S.
 

112
 

10/40(0.25)
 

N.S.
 

106
 

MATCHED
 

VEHICLE
 

CONTROL
 

1/20(0.05)
 

N.S.
 

112
 

4/20(0.20)
 

N.S.
 

112
 

LOW
 

DOSE
 

6/50(0.12)
 

N.S.
 

4.800
 

0.620
 

215.902
 

2.400
 

0.325
 

108.021
 

32
 

10/50(0.20)
 

N.S.
 

0.800
 

0.334
 

1.934
 

1.000
 

0.339
 

3.991
 

73
 

HIGH
 

DOSE
 

4/50(0.08)
 

N.S.
 

3.200
 

0.335
 

154.289
 

1.600
 

0.175
 

77.169
 

76
 

8/50(0.16)
 

N.S.
 

0.640
 

0.244
 

1.63.4
 

0.800
 

0.250
 

3.327
 

75
 
___ 

00 

TABLE 4 (CONCLUDED) 

POOLED MATCHED
 

VEHICLE VEHICLE LOW HIGH
 

TOPOGRAPHY: MORPHOLOGY CONTROL CONTROL DOSE DOSE
 

Uterus: Endometrlal Stromal Polyp 2/39(0.05) 1/19(0.05), 2/47(0.04) 3/48(0.06)
 

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

Relative Risk (Pooled Vehicle Control)d 0.830 1.219
 

Lower Limit 0.063 0.147
 

Upper Limit 11.016 14.035
 

Relative Risk (Matched Vehicle Control) _-._ 0.809 1.187
 

Lower Limit 0.046 0.105
 

Upper Limit 46.702 61,031
 

Weeks to First Observed Tumor Ill 112 112 112
 

Treated groups received time-weighted average doses of 27 or 55 mg/kg by gavage.
 

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

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

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

group with the pooled vehicle control group (*) or the matched vehicle control group (**)
 

is given beneath the incidence of tumors in that treated group when P < 0.05; otherwise, not
 

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

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

The 95% confidence interval on the relative risk of the treated group to the control group.
 
Two types of control groups were used for statistical analyses:
 

the vehicle control group (designated in this section as the "matched"
 

vehicle control group) and a pooled vehicle control group, combining
 

the vehicle controls from the studies of iodoform and hexachloroethane. The pooled control rats were of the same strain, were housed
 

in the same room, were started on test within 2 weeks of each other
 

and tested concurrently for more than one year, received the same
 

vehicle, and were diagnosed by the same pathologists.
 

Thyroid tumors were found in both male and female rats. For
 

males for the combined incidence of follicular-cell carcinomas or
 

follicular-cel1 adenomas of the thyroid, the Fisher exact test comparisons of low dose to both the pooled and the matched control had
 

marginal test results which were not significant under the Bonferroni
 

criterion. In historical control data collected by this laboratory
 

for the NCI Carcinogenesis Testing Program, 11/200 (6 percent) of the
 

male vehicle control Osborne-Mendel rats had one of these tumors—
 

compared to the 8/35 (23 percent) and 4/18 (22 percent) observed in
 

the low dose and high dose groups, respectively.
 

No statistical test for any site in either males or females was
 

significant under the Bonferroni criterion. Thus, there was no convincing statistical evidence of the carcinogenicity of iodoform in
 

rats.
 

To provide additional insight into the possible carcinogenicity
 

of this compound, 95 percent confidence intervals on the relative
 

risk have been estimated and entered in the tables based upon the
 

29
 
observed tumor incidence rates. In all 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
 

all of the confidence intervals have an upper limit greater than one,
 

indicating the theoretical possibility of tumor induction in rats by
 

iodoform that could not be established under the conditions of this
 

test.
 

30
 
IV. CHRONIC TESTING RESULTS: MICE
 

A.	 Body Weights and Clinical Observations
 

Distinct patterns of compound-related mean body weight depression
 

were not apparent during this bioassay (Figure 4).
 

Throughout the study, there was no evidence of compound effect
 

with regard to physical appearance and behavior among the iodoformtreated mice. Clinical signs often observed in group-housed laboratory mice were noted at comparable rates in control and treated mice,
 

with the incidences increasing gradually in all groups as the study
 

approached termination. These common signs included sores and/or
 

desquamation on parts of the body, alopecia, stains on the fur,
 

external genital irritation, bloating, palpable nodules, and tissue
 

masses.
 

B.	 Survival
 

The estimated probabilities of survival for male and female mice
 

in the control and iodoform-dosed groups are shown in Figure 5. For
 

both male and female mice no statistically significant positive association between dosage and mortality was observed.
 

There were adequate numbers of male mice at risk from late-


developing tumors as 60 percent (30/50) of the high dose, 68 percent
 

(34/50) of the low dose, and 60 percent (12/20) of the vehicle con-


control mice lived on test until the end of the study. Survival
 

among the untreated control mice was unexpectedly low, as only 10
 

percent (2/20) lived on test until the end of the study.
 

31
 
50- -50 

40- -40 

IX 

<53o­ i-

-30 

(D 

> 20­ D 

O UNTREATED CONTROL 

-20 

m 

VEHICLE CONTROL 

10— LOW DOSE -10 

HIGH DOSE 

MALE MICE 

] I ' 1 ' I 

15 30 45 60 75 90 105 120 

TIME ON TEST (WEEKS) 

50- -50 

40 — — 40 

w 

< 

cc 

ii 30 — -30 

>20H -20 

o 

CD UNTREATED CONTROL 

< 

Ol VEHICLE CONTROL 

10 — -10 

LOW DOSE 

HIGH DOSE 

FEMALE MICE 

15 30 45 60 75 90 105 120 

TIME ON TEST (WEEKS) 

FIGURE 4 

GROWTH CURVES FOR IODOFORM CHRONIC STUDY MICE 

32 
r -1 

PROBABILITY OF SURVIVAL PROBABILIT

Y O

o o P o o b ro -^ CT) bo D 

o —

l 1 l 1 1 1 l 1 i 

|' t 

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01 ~~ 

! ! 

C J 

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g-

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There were adequate numbers of female mice at risk from late-


developing tumors as 86 percent (43/50) of the high dose, 86 percent
 

(43/50) of the low dose, and 90 percent (18/20) of the vehicle control mice lived on test until the end of the study. Fifty-five percent (11/20) of the untreated controls survived on test until the
 

study was terminated, despite the death of seven animals in weeks 64
 

and 65. Six of these mice had congestion of the lungs; the other was
 

autolyzed.
 

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).
 

The incidence of malignant lymphoma, a neoplasm occurring commonly in the B6C3F1 mouse, were increased in high dose male mice
 

(i.e, 2/19 [11 percent] controls, 3/50 [6 percent] low dose, and
 

10/50 [20 percent] high dose). A large variety of other neoplasms
 

were found in various organs of mice in both the control and treated
 

groups; however, they were of the usual number and type observed in
 

hybrid mice of this age and strain.
 

The inflammatory, degenerative, and proliferative lesions were
 

of the usual type observed in mice of this age and strain and were
 

essentially comparable in incidence in the control and treated
 

groups, except for an increase in amyloidosis of the liver, spleen,
 

kidney, and adrenal gland in untreated control males.
 

34
 
This histopathologic examination did not provide convincing evidence for the carcinogenicity of iodoform in B6C3F1 mice, although
 

exposure to the compound may have been associated with an increased
 

incidence of malignant lymphoma in high dose males.
 

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
 

iodoform-dosed groups of either sex is included.
 

Two types of control groups were used for statistical analyses:
 

the vehicle control group (designated in this section as the "matched"
 

vehicle control group) and a pooled vehicle control group, combining
 

the vehicle controls from the studies of iodoform and 1,1,2-trichloroethane. The pooled control mice were of the same strain, were given
 

the same vehicle, were housed in the same room, were started on test
 

in the same month and tested concurrently for at least one year, and
 

were diagnosed by the same pathologists.
 

No statistical tests from any site in male or female mice
 

showed a positive association between administration and tumor incidence. Based upon these results there was no statistical evidence
 

of the carcarcinogenicity of iodoform in mice.
 

To provide additional insight into the possible carcinogenicity
 

of this compound, 95 percent confidence intervals on the relative
 

risk have been estimated and entered in the tables based upon the
 

35
 
_ __ 

_ __ 

___ 

___ 

___ 

TABLE 5
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN MALE MICE TREATED WITH IODOFORMS
 

POOLED MATCHED
 

VEHICLE VEHICLE LOW
 

TOPOGRAPHY -.MORPHOLOGY CONTROL CONTROL DOSE
 

Lung: Alveolar /Bronchlolar Carcinoma 0/39(0.00) 0/19(0.00) 3/50(0.06)
 

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

Relative Risk (Pooled Vehicle Control) Infinite
 

Lower Limit 0.472
 

Upper Limit Infinite
 

u> Relative Risk (Matched Vehicle Control) Infinite
 

Lower Limit 0.238
 

Upper Limit Infinite
 

Weeks to First Observed Tumor 90
 

Lung: Alveolar/Bronchiolar Adenoma or
 

Alveolar /Bronchiolar Carcinoma^ . 1/39(0.03) 1/19(0.05) 4/50(0.08)
 

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

Relative Risk (Pooled Vehicle Control) 3.120
 

Lower Limit 0.327
 

Upper Limit 150.411
 

Relative Risk (Matched Vehicle Control) _— 1.520
 

Lower Limit 0.167
 

Upper Limit 73.309
 

Weeks to First Observed Tumor 90
 90
 90
 

HIGH
 

DOSE
 

1/49(0.02)
 

N.S.
 

Infinite
 

0.043
 

Infinite
 

Infinite
 

0.021
 

Infinite
 

91
 

4/49(0.08)
 

N.S.
 

3.184
 

0.333
 

153.393
 

1.551
 

0.171
 

74.767
 

91
 
___ 

___ 

_ __ 

___ 

TABLE

TOPOGRAPHY: MORPHOLOGY
 

Hematopoietic: Malignant Lymphoma
 

P Values0
 

Relative Risk (Pooled Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Liver: Hepatocellular Carcinoma
 

P Values0
 

Relative Risk (Pooled Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Vehicle Control)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

5 (CONTINUED) 

POOLED
 

VEHICLE
 

CONTROL
 

4/39(0.10)
 

P = 0.009
 

—_
 

66
 

5/39(0.13)
 

N.S.
 

88
 

MATCHED
 

VEHICLE
 

CONTROL
 

2/19(0.11)
 

N.S.
 

74
 

3/19(0.16)
 

N.S.
 

88
 

LOW
 

DOSE
 

3/50(0.06)
 

N.S.
 

0.585
 

0.091
 

3.266
 

0.570
 

0.073
 

6.511
 

70
 

5/49(0.10)
 

N.S.
 

0.796
 

0.198
 

3.228
 

0.646
 

0.144
 

3.881
 

90
 

HIGH
 

DOSE
 

10/50(0.20)
 

N.S.
 

1.950
 

0.616
 

7.953
 

1.900
 

0.468
 

16.901
 

40
 

7/50(0.14)
 

N.S.
 

1.092
 

0.325
 

4.061
 

0.887
 

0.234
 

4.945
 

91
 
TABLE 5 (CONCLUDED)
 

rt
 

Treated groups received time-weighted average doses of 47 or 93 mg/kg by gavage.
 

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

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

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

group with the pooled vehicle control group (*) or the matched vehicle control group (**)
 

is given beneath the incidence of tumors in that treated group when P< 0.05; otherwise, not
 

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

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

The 95% confidence interval on the relative risk of the treated group to the control group.
 
TABLE 6
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS AT
 

SPECIFIC SITES IN FEMALE MICE TREATED WITH IODOFORM3
 

POOLED MATCHED
 

VEHICLE VEHICLE LOW
 

TOPOGRAPHY: MORPHOLOGY CONTROL CONTROL DOSE
 

Hematopoietic: Malignant Lymphoma 9/40(0.22) 5/20(0.25) 5/49(0.10)
 

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

Relative Risk (Pooled Vehicle Control) 0.454
 

Lower Limit 0.130
 

Upper Limit 1.383
 

Relative Risk (Matched Vehicle Control) 0.408
 

Lower Limit 0.109
 

Upper Limit 1.614
 

VO Weeks to First Observed Tumor 69
 81 70
 

Liver: Hepatocellular Carcinoma 1/40(0.02) 1/20(0.05) 1/49(0.02)
 

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

Relative Risk (Pooled Vehicle Control)d 0.816
 

Lower Limit 0.011
 

Upper Limit 62.794
 

Relative Risk (Matched Vehicle Control) 0.408
 

Lower Limit 0.005
 

Upper Limit 31.413
 

Weeks to First Observed Tumor 90
 90 91
 

HIGH
 

DOSE
 

4/45(0.09)
 

N.S.
 

0.395
 

0.096
 

1.298
 

0.356
 

0.081
 

1.502
 

0/45(0.00)
 

N.S.
 

0.000
 

0.000
 

16.555
 

0.000
 

0.000
 

8.288
 

91 
TABLE 6 (CONCLUDED)
 

A
 

Treated groups received time-weighted average doses of 47 or 93 mg/kg by gavage.
 

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

The probability level for the Cochran-Armitage test is g'iven beneath the incidence of tumors
 

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

group with the pooled vehicle control group (*) or the matched vehicle control group (**)
 

is given beneath the incidence of tumors in that treated group when P< 0.05; otherwise, not
 

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

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

The 95% confidence interval on the relative risk of the treated group to the control group.
 
observed tumor incidence rates. In all of the intervals shown in
 

Tables 5 and 6, the value one is included; this indicates the absence
 

of statistically significant results. It should also be noted that
 

all of the confidence intervals have an upper limit greater than one,
 

indicating the theoretical possibility of tumor induction in mice by
 

iodoform that could not be established under the conditions of this
 

test.
 

41
 
V. DISCUSSION
 

There was a significant positive association between the dosage
 

of iodoform administered and mortality in male rats; this was not
 

the case for female rats or mice of either sex. Adequate numbers of
 

animals in all groups survived sufficiently long to be at risk from
 

late-developing tumors.
 

The possibility that female rats and mice of both sexes did not
 

receive dosages of iodoform approximating the maximum tolerated dosages must be considered, as intubation with the compound had no significant effect upon the mean body weights for these treated animals
 

when compared to their respective controls.
 

Of the neoplasms of histopathologic interest observed in treated
 

animals (i.e., follicular-cell thyroid tumors in rats and malignant
 

lymphomas in high dose male mice), neither showed a significant positive association between administration of the compound and tumor incidence and neither of these neoplasms was unusua'l in these species.
 

Because of poor survival in male rats, however, the possibility that
 

compound administration resulted in thyroid tumors cannot be excluded.
 

No neoplasms occurred in statistically significant increased
 

incidences when treated rats and mice were compared to their respective controls.
 

Under the conditions of this bioassay, no convincing evidence
 

was provided for the carcinogenicity of iodoform in Osborne-Mendel
 

rats or in B6C3F1 mice.
 

42
 
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, B.C., 1977.
 

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.
 

Druckrey, H., H. Kruse, R. Preussmann, S. Ivankovic, and C. Landschutz,
 

"Cancerogene alkylierende Substanzen. III. Alkyl-halogenide,
 

-sulfate, -sulfonate und ringgespannte Heterocyclen." Z. Krebsforsch 74:241-270, 1970.
 

Eschenbrenner, A.B., "Induction of Hepatomas in Mice by Repeated Administration of Chloroform, With Observations on Sex Differences."
 

Journal of the National Cancer Institute 5:251:255, 1945.
 

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

Tests, Confidence Limits, and Adjustments for Stratification."
 

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

Goodman, L.S., and A. Gilman, The Pharmacological Basis of Therapeutics , 4th edition. The MacMillan Company, New York, 1970.
 

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

Toxicology of Commercial Products, 4th edition. The Williams
 

and Wilkins Company, Baltimore, Maryland, 1976.
 

Irish, D.D., "Aliphatic Saturated Hydrocarbons." Industrial Hygiene
 

and Toxicology, 2nd revised edition. F.A. Patty, editor.
 

Interscience, New York, 1967.
 

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

Observations." Journal of the American Statistical Association
 

53:457-481, 1958.
 

43
 
Linhart, M.S., J.A. Cooper, R.L. Martin, N.P. Page, and J.A. Peters,
 

"Carcinogenesis Bioassay Data System." Computers and Biomedical
 

Research 7:230-248, 1974.
 

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

Co., New York, 1966.
 

Preussmann, R., "Direct Alkylating Agents as Carcinogens." Food and
 

Cosmetics Toxicology 6:576-577, 1968.
 

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.
 

Rudali, G., "A Propos de 1'Activite oncogene de quelques hydrocarbures
 

halogenes utilises en therapeutique." UICC Monograph Series 7:
 

138-143, 1967 (French). ~
 

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., "General Chemicals." Dangerous Properties of Industrial
 

Materials. N.I. Sax, editor. Van Nostrand Reinhold Company,
 

New York, 1975.
 

Stanford Research Institute, 1976 Directory of Chemical Producers.
 

Menlo Park, California, 1976.
 

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

62_:679-682, 1975.
 

U.S.	 Departmen ot f Health, Education, and Welfare, Registry of Toxic
 

Effects of Chemical Substances, 1976. HEW Publication No.
 

(NIOSH)76-191, Washington, D.C., 1976.
 

Windholz, M., editor, The Merck Index: An Encyclopedia of Chemicals
 

and Drugs, Ninth edition. Merck and Co., Rahway, New Jersey,
 

1976.
 

44
 
APPENDIX A
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS
 

IN RATS TREATED WITH IODOFORM
 

TABLE A1

 

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

CONTROL (ONTR)

01-141(1

 CONTROL (VEH)

 01-111M

 1011 DOSE 

 01-112W HIGH DOSE 01-113M 

ASIRA1S INITIALLY IN STUDY 20

ANIMALS NECRCPSIFD 20

ANIMALS EXAMINED HISTOFATHOLOGICALLY ** 20

 20

 20

 20

 50 

 1*9 

 49 

50 

50 

50 

INTEGUMENTARY SYSTEM 

*SUBCUT TISSUE

FIBROMA FIEROSARCOBA

HEMANGIOMA NEUROFIBROSA8CORA

NEOROFIBROSAHCOMA, METASTATIC

 (20)

 1 (5X)

 (20)

 1 (5X) 

1 (5X) 

1 (5%) 

 (1(9) 

1 (2%) 

1 (2X) 

(50) 

RESPIBATORY SYSTEM 

ILUNG

ALVEOLAR/BEONCHIOLAR ADENOMA

NEUROFIBEOSARCOMA, METASTATIC

 (20) (19)

 1 (5%) 

 (49) 

1 (2X) 

(50) 

HEBATOPOIETIC SYSTEM 

•MULTIPLE ORGAN S

MALIG.LYMPHOMA, HISTIOCYTIC TYPE

 (20) (20)

 1 (5X)

 («9) 

1 (2X) 

(50) 

»SPLEEN

HEMANGIOSAfiCOMA HALIG.LYBPHOMA, HISTIOCYTIC TYPF 

 (19)

 2 (11X) 

 (19) (47) (50) 

1 (2X) 

1 <2X) 

iLYKPH NODE

NEURCFIBBOSARCOMA. METASTATIC

 (19) (17)

 1 (6JS) 

 (41) (37) 

CIRCULATORY SYSTEM 

NCNE 

DIGESTIVE SYSTE M 

ISALIVAR Y GLAN D

NEyEgFIBBOSARCOMAi_MST ASTATIC

 (14) (16)

 i_J 

 (31) (13) 

* NUMBE R OF ANIMAL S HITH TISSUE EXAMINE D

* NUMBER OF ANIMALS NECFOPSIED 

**EXCLUDES PARTIALLY AUTOLY2ED ANIMALS 

 MICROSCOPICALLY 

A-3 
TABLE A1 (CONTINUED) 

CONTROL (ONTR)

01-141(1

 COHTROL (VEH)

 01-111B

 LOB DOSE 

 01-112H 

HIGH DOSE 01-113H 

URINAR Y SYSTEM 

IKICNEY KIXED TUMOR, MALIGNANT (19)

1 (5X) 

 (20) (49) (50) 

ENDOCBINI SYSTEM 

tPITUITARY 

CKROKOEHOBE ADENOMA 

CHROMOPHOBE CARCINOMA 

tADRENAL PKEOCHROMOCYTOMA 

ITHYROIC 

FOLLICULAR-CELL ADENOMA FGLLICULAR-CELL CARCINOMA C-CELL ADENOM A 

C-CELL CARCINOMA NEUBOFIBBOSARCOfIA, METASTATIC 

tPANCHEATIC ISLETS ISLET-CELL ADENOMA 

(19)

3 (16X)

1 (5X) 

(19)

(19)

1 (5X)

(19)

2 (11X)

 (19)

 4 (21S)

 (19)

1 (5X) 

 (17)

1 (6X)

1 (6X) 

 (19)

 1 (5X) 

 (43) 

7 (16*) 

 (48) 

 (43) 

2 (5X) 

6 (14X) 

1 (2X) 

2 (5X) 

 (48) 

(33) 

4 (12X) 

(19) 

(37) 

1 (3X) 

3 (8X) 

3 (8%) 

(45) 

REPRODUCTIVE SYSTEM 

*BABMARY GLAND 

ADENCCARCINOMA, NOS 

FIB8CADENOMA 

(20)

1 (5X) 

 (20)

1 (5X)

 (49) 

1 (2X> (50) 

NEBVOOS SYSTEM 

tERAIN CHROMOPHOBE CARCINOMA, METASTATI 

(19)

1 (5X) 

 (20) (48) (50) 

SPECIAL SENSE ORGANS 

NCNE 

MDSCULOSKELETAL SYSTEM 

I NUC.BES OF ANIMALS 8ITH TISSUE EXAMINED

* NUKBE R OF ANIMAL S NECROPSIED 

 MICROSCOPICALLY 

A-4 
TABLE A1 (CONCLUDED) 

CONTROL (UNTR)

01-141M

 CONTROL(VEH)

 01-111M

 LOW DOSE

 01-112(1

 HIGH DOSE 

 01-113R 

BODY CAVITIES 

NONE 

ALI OTHER SYSTEMS 

*BULTIPLE ORGANS

FIBROUS HISTIOCYTOMA, MALIGNANT

 (20) (20)

 1 (5*)

 (19) (50) 

1(2%) 

ANIflAL DISECSITICN SUMMARY 

ANIHALS INITIALLY IN STUDY

NATURAL DEATHS!

HORIBUND SACRIFICE

SCHEDULEi: SACRIFICE 

ACCIDENTALLY KILLED 

TERMINAL SACRIFICE

ANIflAL KISSING 

i INCLUDES AUTCLYZED ANIMALS 

 20

 11*

 1 

5

 20

 11

 9

 50

 36

 11

 50 

 U2 

8 

TUMOR SUBBARI 

TOTAL ANIMALS KITH PRIMARY TUMORS* 9 7 17 

TOTAL PRIMARY TUMORS 12 12 23 

TOTAL ANIMALS KITH BENIGN TUMORS 6 4 11 

TOTAL BESIGN TDBORS 7 7 13 

TOTAL ANIMALS KITH MALIGNANT TUMORS 5 U 10 

TOTAL MALIGNANT TUMORS 5 5 10 

TOTAL ANIMALS »ITH SECONDARY TUMORS! 1 1 

TOTAL SECONDARY TUHORS 1 5 

TOTAL ANIMALS KITH TUMOBS UNCERTAINBENIGN OR MALIGNANT 

TOTAL UNCERTAIN TUBORS 

TOTAL ANIMALS WITH TUMORS UNCERTAINFEIBARY OR METASTATIC 

TOTAL UNCERTAIN TUMORS 

* PRIBARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS 

* SECONDARY TUMORS: METASTATIC TUMORS OR TUBORS INVASIVE INTO AN ADJACENT ORGAN 

10 

1U 

A-5 
TABLE A2 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS TREATED WITH 1ODOFORM 

CONTROL(UNTR)

01-1U1F

ANIBAI S INITIALLY IN STUDY 20

ANIMALS NECECPSIED 20

ANIMAL S EXAMINED HISTOPATHOLOGICALLY** 20

 CONTROL(VEH)

 01-111F

 20

 20

 20

 LOU DOSE

 01-114F

 50

 50

 50

 HIGH DOSE 

 01-115F 

 50 

 50 

 50 

INTEGUMENTARY SYSTEM 

*SUBCUT TISSUE

FIERCSARCOMA

 (20)

 1 (5X) 

 (20) (50) (50) 

RESPIRATORY SYSTEM 

•TRACHEA

FGLLICULAE-CELL CARCINOMA, METAS

ttLUNG

ADENCCARC1NOMA, NOS, METASTATIC

HEB1NGIOSA6COMA. METASTATIC

 (20)

 (20)

 (20)

 (20)

 (50)

 1 (2X) 

 (50)

 (19) 

 (50) 

1 (2%) 

1 (2X) 

HEhATOEOIETIC SYSTEM 

• SPLEEN

HEMANGIOSARCOMA

 (20) (20) (U9)

 1 (2X)

 (50) 

2 (IK) 

CIRCULATORY SYSTEM 

NCNE 

DIGESTIVE SYSTEM 

• LIVER

NEOPLASTIC NODULE

HEEATOCELLOLAR CARCINOMA

HEKANGIOSARCOBA

 (20)

 1 (5X)

 (20)

 1 (5X) 

1 (5S) 

 (U9)

 1 (2X) 

 (49) 

URINAR Y SYSTEM 

#KIENE Y (20) (20) 

____ MI XEE_TUBOS X _ MALIGNAN T _______________________________ I_ 

t NUMBE R O F ANIMAL S WITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBE R OF ANIMAL S NECROPSIED 

**EXCLUDtS PARTIALLY AU10LYZED ANIMALS 

(19) (50) 

A-6 
TABLE A2 (CONTINUED) 

CONTROL (UNTB) CONTROL (VEH) LOU DOSE HIGH DOSE
 

01-141F 01-111F 01-114F 01-1 15F
 

HABAETOMA +	 1 (5%)
 

ENCCCRINE SYSTEM 

*PITOITARY 

CHROMOPHOBE ADENOMA 

(20) 

8 (40%) 

(20)

5 (25%)

 (45) 

8 (18%) 

(47) 

9 (19%) 

I ADRENAL 

PHEOCHROMOCY10MA 

HEMANGIOSARCOMA. METASTATIC 

(20) (20) (49) (50) 

1 

1 

(2%) 

(2%) 

ITHYROID 

FOLIICULAH-CELL CARCINOMA 

C-CELL ADENOMA 

C-CELL CARCINOMA 

(19) 

2 (11%) 

(20)

1

1

 (5%) 

 (5%)

 (40) 

4 (10%) 

1 (3%) 

(42) 

2 (5%) 

tPANCREATIC ISLETS 

ISLET-CELL ADENOMA 

(20) 

1 (5%) 

(20) (47) 

2 (4%) 

(50) 

REPRODUCTIVE SYSIEH
 

*MAMMAR Y GLAND (20) (20) (50) (50)
 ADENCCARCINOMA, DOS 1 (5*) 6 (12%) 4 (8%)
 FIBBOADENOMA 3 (15%) 4 (20%) 10 (20%) 8 (16%)
 

*CLITORAL GLAND (20) (20) (50) (50)
 ADENCCARCINOMA, NOS 1 (2%)
 

tOTERUS (20) (19) (47) (48)
 

ADENOCARCINOMA, NOS 1 (5%)
 

INDOBETRIAL STROMAL POLYP 1 (5%) 1 (5%) 2 (4%) 3 (6%)
 

tCEFVIX UTERI (20) (19) (47) (48)
 

SCUAMOUS CELL CARCINOMA 1 (2%)
 

IOVARJ (20) (19) (47) (50)
 

GRANULCSA-CELL TUMOR 1 (2%)
 

NEBVCUS SYSTEM
 

NONE
 

SPECIAL SENSE ORGAN S 

* NUMBE R OF ANIMAL S KITH TISSUE EXAMINE D MICROSCOPICALLY 

* liUMBE R OF ANIMAL S NECROPSIE D 

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

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

A-7 
TABLE A2 (CONTINUED)
 

CONTROL(nNTR) COBTROL(VEH) LOU DOSE HIGH DOSE 

01-1IMF 01-111F 01-11UF 01-115F 

MUSCULOSKELETAL SYSTEM
 

NCNE
 

BODY CAVITIES
 

NONE
 

ALL CTHER SYSTEMS
 

•MULTIPLE ORGANS (20) (20) (50) (50)
 

FIBROUS HISTIOCYTOMA, MALIGNANT 1(21)
 

ANIKA1 DISEOSIIICN SUMMARY
 

ANIMALS INITIALLY IN STUDY 20 20 50 50
 

NA1UEAL EFATHS 8 I* 30 23
 

MORIBUND SACRIFICE 1
 

SCHEDULED SACRIFICE
 

ACCIDENTALLY KILLED
 

TERMINAL SACRIFICE 12 16 19 27
 

ASIMAL MISSING
 

# NUHBEB OF ANIMALS KITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

A-8
 
TABLE A2 (CONCLUDED)
 

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

01-141F 01-111F 01-114F 01-115F
 

TUtOR SUMMAR Y
 

TOTAL ANIMAL S KITH PRIMARY TUMORS* 13 10 27 23
 

TOTAL PRIMAR Y TUMORS 18 17 37 31
 

TOTAL ANIMALS WITH BENIGN TOMORS 13 9 20 18
 

TOTAL BENIGN TUMORS 16 11 22 21
 

TOTAL ANIMALS KITH MALIGNANT TUMOBS 12 9
 TOTAL MALIGNANT TDMOBS 1* 10
 

TOTAL ANIMALS WITH SECONDARY TUMORS* 1
 

TOTAL SECONDARY TUMORS 1
 

TOTAL ANIMALS WITH TUMORS UNCERTAINBENIGN OR MALIGNANT 1 1 1
 

TOTAL UNCERTAIN TUMORS 1 1 1
 

TOTAL ANIMALS WITH TUMORS UNCERTAINPEIMAEY OR METASTATIC
 

TOTAL UNCERTAIN TUMORS
 

PRIMARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 

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

A-9
 

APPENDIX B
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS
 

IN MICE TREATED WITH IODOFORM
 

TABLE Bl

 

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

CONTROL (ONTR) CONTROL (VEH) LOR DOSE HIGH DOSE
 

02-M121 02-M111 02-B112 02-H113
 

ANIMALS INITIALLY IN STUDY 20 20 50 50
 

ANIMALS KISSING 1
 

ANIMALS NECRCPSIED 15 19 50 50
 

ANIMALS EXAMINE D HISTOPATHOLOGICALLY ** 15 19 49 50
 

INTEGUMENTARY SYSTEM
 

*SKIN (15) (19) (50) (50)
 

SQUAKOUS CELL CARCINOMA 1 (2)1)
 

RESPIRATORY SYSTEM
 

»LUNG (15) (19) (50) («9)
 

SQUAKOUS CELL CARCINOMA, METASTA 1 (2*)
 

ALVECLAR/BRONCHIOLAR ADENOMA 1 (7X) 1 (5X) 1 (2*) 3 <6X)
 

ALVECLAR/BBONCHIOLA8 CARCINOMA 3 (6%) 1 <2X)
 

HEMATOEOIETIC SYSTEM
 

*MULTIPLE ORGANS (15) (19) (50) (50)
 

MALIG.LYMPHOMA, LYHPHOCYTIC TYPE 1 <5X> 1 (2%) 6 (12X)
 

MALIG.LYrPHOMA, HISTIOCYTIC TYPE 2 (»X) 2 (HX)
 

ISFLEEN (15) (19) (50) (50)
 

MALIGNANT LYMPHOMA. SOS 1 (7X)
 

MALIG.LYMPHOMA, HISTIOCYTIC TYPE 1 (7X)
 

ILYMEH NODE (15) (19) (18) (K5)
 

MALIG.LYMPHOMA, HISTIOCYTIC TYPE 1 (7X)
 

tCERVICAL LYtiEH NODE (15) (19) (18) (15)
 

SQUAMOUS CELL CARCINOMA, METASTA 1 (2X)
 

MAIIG. LYMPHOMA, HISTIOCYTIC TYPE 1 (2X)
 

*MESENTERIC L. NODE (15) (19) (48) (H5)
 

MALIG.LYMPHOMA, HISTIOCYTIC TYPE 1 (5*) 1 (2%)
 

•LIVER	 (15) (19) (19) (50)
 

LYMPHOMA METASTATIC 1 (7X)
 

CIRCULATORY SYSTEM
 

NONE
 

I NUMBE R OF ANIMAL S HITH TISSUE EXAMINE D MICROSCOPICALLY 

» NUMBE R OF ANIMAL S NECFOPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

B-3 
TABLE Bl (CONTINUED) 

CONTROL (ONTR) 

02-M121 

CONTROL(VFH) 

02-M111 

LOU DOSE 

02-H112 

HIGH DOSE 

02-H113 

DIGESTIVE SYSTEM 

•SALIVARY GLAND 

SQUAMOUS CELL CARCINOMA, METASTA 

ttlVEfi 

HEPATOCELLULAR CARCINOMH 

HEHAKGIOMA 

HEHANGIOSARCOMA 

*STOBACH

CARCINOMA,NOS

SQOAHOUS CELL CARCINOMA

(15) 

(15) 

 (15)

(18) 

(19) 

3 (16*) 

 (19)

(18) 

(49) 

5 (10*) 

 (50)

(KO) 

1 (3%) 

(50) 

7 (1UX) 

1 (2X> 

1 (2%) 

 (19) 

1 (2«) 

1 (2X) 

URINABY SYSTEM 

NONE 

ENDOCRINE SYSTEH 

tlHYROID

FOLLICULAR-CEL1 ADENOMA

 (15) (17) (41)

 1 (2X) 

 (38) 

REPRODUCTIVE SYSTEM 

NONE 

NERVOUS SYSTEM 

HONE 

SPECIAL SENSE ORGANS 

*EYE/LACRIMAL GLAND

ADENOMA, NOS

 (15) (19) (50)

 1 (21)

 (50) 

1 (2%) 

MDSCBLOSKELETAL SYSTEM 

NCNE 

BODY CAVITIES 

BONE 

* KUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OE ANIMALS NECROPSIED 

B-4 
TABLE Bl (CONCLUDED)
 

CONTROL (UNTH) CONTROL (VEH) LOU DOSE HIGH DOSE
 

02-M121 02-M111 02-B112 02-H113
 

ALL CTHER SYSTEMS
 

NCNE
 

ANIMAt DISPOSITION SUMMAR Y
 

ANIMALS INITIALLY IN STUDY 20 20 50 50
 NATURA L DEATHS 17 8 15 15
 MORIBUND SACRIFICE 1 I)
 

SCHEDULED SACRIFICE
 

ACCIDENTALLY KILLED 1
 

TERMINAL SACRIFICE 2 12 31 30
 

ANIMAL MISSING 1
 

9 INCLUDES AUTCLYZED AKIMALS
 

TUHOR SUMMAR Y
 

TOTAL ANIMALS KITH PEIMARY TUMORS* 2 5 11 23
 TOTAL PRIMAR Y TUMORS 4 6 1I» 27
 

TOTAL ANIMAL S WITH BENIGN TUMORS 1 1 3 5
 TOTAL BENIGN TUMORS 1 1 3 5
 

TOTAL ANIMALS KITH MALIGNANT TUMORS 2 1 1 1 20
 

TOTAI MALIGNAN T TUMOHS 3 5 1 1 22
 

TOTAL ANIKAL S »ITH SECONDARY TUMORS* 1
 

TOTAL SECONDARY TUMORS 1
 

TOTAL ANIKAL S KITH TUKORS UNCERTAINBENIGN OR MALIGNAN T
 TOTAL UNCERTAIN TUMORS
 

TOTAL ANIMALS KITH TUMORS UNCERTAIN-
 EflMAR Y OR METASTATIC
 TOTAL UNCERTAIN TUMORS
 

* PRIMARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 * SECONDARY TUMORS: METASTATIC TUMORS OR TUMORS INVASIV E INTO AN ADJACENT ORGA N
 

B-5
 
TABLE B2

 

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

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

02-F121 02-F111 02-F114 02-F115
 

ANIMALS INITIALLY IN STUDY 20 20 50 50
 

ANIMALS HISSING 2
 

ANIMALS SECROPSIED 18 20 49 45
 

ANIMALS EXAMINED HISTOPATHOLOGICALLY ** 18 20 49 45
 

INTEGUMENTARY SYSTEM
 

*SKIN (18) (20) (49) (45)
 

SQUAMOUS CELL CARCINOMA 1 (2X)
 

BESPIBATORY SYSTEM
 

tlUNG (18) (20) (49) (45)
 ALVEOLAH/BBONCHIOLAR ADENOMA 1 (5*) 1 (2X)
 

HEMATOEOIETIC SYSTEM
 

*NERVE TRACT (18) (20) (49) C*5)
 MALIG.LYMPHOMA, LYMPHOCYTIC TYPE 1 (5X)
 

IERAIN (16) (20) (49) (45)
 MALIGNANT LYfiPHOMA, NOS 1 (6X)
 

*HULTIPLE ORGANS (18) (20) (49) (<*5)
 MALIG.LYMPHOMA, LYMPHOCYTIC TYPE 3 (6X) 2 (4X)
 MALIG.LYMPHOMA, HISTIOCYTIC TYPE 1 <5X) 2 (IX)
 

ISPLEEN (18) (20) (49) (45)
 MALIGNANT LYMPHOMA, NOS 1 <6X)
 LYMPHOMA METASTATIC 1 (6X)
 MALIG.LYMPHOMA. HISTIOCYTIC TYPE 3 (15X)
 

ILYMPH NODE (18) (20) (47) («5)
 FIBROUS HISTIOCYTOMA, MALIGNANT 1 <2X)
 MALIGNANT LYMPHOMA. SOS 2 (11X)
 

•MESENTERIC	 L. NODE (18) (20) (47) (45)
 MALIG.LYMPHOMA. HISTIOCYTIC TYPE 1 <5X)
 

*LIVER	 (18) (20) (U9) (<*5)
 

I NUMBE R OF ANIMAL S KIT H TISSUE EXAMINE D MICROSCOPICALLY 

* KUMBE R OF ANIMAL S NECROPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

B-6 
TABLE B2 (CONTINUED) 

MALIG.LYMPHOMA , HISTIOCYTIC TYPE 

tPANCREAS

LYMPHOBA METASTATIC

*SMALL INTESTINE

MALIG.LYMPHOBA, HISTIOCYTIC TYPE 

IKIDNEY

LYMPHOMA METASTATIC

BALIG.LYBPHOBA, LYBPHOCYTIC TYPE 

IOVARY 

LYMPHOMA METASTATIC 

tADRENA L

MALIG.LYMPHOMA, LYMPHOCYTIC TYPE

CONTROL (UNTR) 

02-F121 

 (18) 

1 (6X) 

 (18) 

 (18) 

2 (11J6) 

(18) 

2 (11X) 

 (18)

CONTROL (VEH) 

02-F111 

1 (5%) 

(20) 

(20) 

(20) 

(20) 

 (20)

 1 (5X) 

LOB DOSE 

02-F11I* 

(U9) 

(U9) 

1 (2%) 

(49) 

<2X) 

(49)

 (49)

HIGH DOSE 

02-F115 

(U5) 

 (44) 

 (45) 

CIECULATCBY SYSTEM 

NONE 

DIGESTIVE SYSTEM 

*LIVEF

HEPATOCELLULAR CARCINOMA

ENDOMETBIAL STROMAL SARCOMA, MET

HEMANGIOBA

HEBANGIOSARCOBA

 (18) (20)

 1 (5X)

 .

 (49)

 1 (2X) 

1 (2X) 

1 (2X) 

1 (2X) 

 (45) 

URINARY SYSTEM 

iKIDNEY

INDOMETRIAL STROMAL SARCOMA, MET

 (18) (20) (49)

 1 (2X) 

 (45) 

ENDOCRINE SYSTEM 

IPITDITARY (16) (19) CHROMOPHOBE ADENOMA

tADRENAL (18) (20)

CORTICAL_ADENOMA J_ifiXJ 

* NUMBER OF ANIMALS KITH TISSUE EXAMINED MICROSCOPICALLY 

* SOMBER OF ANIMALS NECROPSIED 

 (39) 1 (3X) 

 (49)

 (43) 

 (45) 

B-7 
TABLE B2 (CONTINUED) 

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

02-F121 02-F111 02-F114 02-F115 

REPRODUCTIV E SYSTE M 

*MAMflAR Y GLAN D (18) (20) (1*9) (K5) 

ADENOCARCINOMA , NO S 1 (2%) 1 (2X) 

IUTERD S (18) (20)
 

LEIOflYCSARCOBA 1 (2X)
 ENDOPIETRIA L STROMA L POLY P 1 (2X>
 ENBOMET8IA L STBOMAL SARCOM A 1 (2X)
 

tCVAR Y (18) (20) (49) (41)
 

CYSTADENCMA, NOS 1 (2X)
 

NERVOUS SYSTEM
 

"CRANIAL NERVE (18) (20) (U9) (H5)
 

NEURCFIBROSARCOHA 1 (2X)
 

SPECIAL SENSE ORGANS
 

NCNE
 

HUSCULOSKELETAL SYSTEM
 

NCNE
 

BODY CAVITIES
 

NCNE
 

ALL CTHEE SYSTEMS
 

NCNE
 

* NUBBER OF ANIMALS KITH TISSUE TXAMINE D MICROSCOPICALLY 

* KDMBF R O F ANIMAL S NECROPSIE D 

B O

p
TABLE B2 (CONCLUDED)
 

CONTROL (DHTR) CONTROL (VEH ) LOH DOSE HIGH DOSE 02-F121 02-F111 02-F11U 02-F115 

ANIf.AL DISFCSITICN SUMMAR Y
 

ANIMALS INITIAILY IN STUDY 20 20 50 50
 

NATURA L DEATHS
 

MORIBUND SACRIFICE
 SCHEDULED SACRIFICE
 

ACCIDENTALLY KILLED
 

TERMINAL SACRIFICE 11 18 U3 U3
 ANIMAL MISSING 2
 

a INCLUDES AUTOLYZED ANIMALS
 

TUBCR SUMMAR Y
 

TOTAL ANIMALS WITH PRIMARY TUMOilS* It 7 14 5
 TCTA1 PRIMARY TUMORS 5 10 18 5
 

TOTAL ANIMALS WITH BENIGN TUMO6S 1 1 5
 TOTAL BENIGN TUMORS 1 1 5
 

TOTAL ANIMALS WITH MALIGNANT TUMORS 3 6 10 5
 TOTAL HALISNANT TUHOHS 1 9 13 5
 

TOTAL ANIMAL S WITH SECONDARY TUMOHS* 3 1
 

TOTAL SECONDARY TUMORS 7 2
 

TOTAL ANIMALS WITH TUMORS UNCERTAIN­ BENIGN OR MALIGNANT
 

TOTAL UNCERTAIN TUflOHS
 

TOTAL ANIMALS WITH TUMORS UNCERTAIN­ ERIHARY OB MITASTATIC
 

TOTAL UNCEHTAIN TUMORS
 

* PRIMARY TUBORS: ALL TDMORS EXCEPT SECONDARY TUMORS
 * SECONDARY TUMORS: MFTASTATIC TUMORS OR TUMORS INVASIVE INTO AN ADJACENT ORGAN
 

B-9
 

APPENDIX C
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN RATS TREATED WITH IODOFORM
 

TABLE Cl

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE RATS TREATED WITH IODOFORM 

CONTEOL(UNTR) CONTROL (VEH) LOS DOSE HIGH DOSE 

01-111M 01-111M 01-112M 01-113 M 

ANIMALS INITIALLY 111 STUDY 20 20 50 50
 

ANIMALS NECECPSIED 20 20 19 50
 ANIMALS EXAMINED HISTOPATHOLOGICALLY ** 20 20 19 50
 

INTEGUMENTABY SYSTEM
 

*SKIN (20) (20) (1*9) (50)
 

EPIDERMAL INCLUSION CYST 1 (5X)
 

INFLAMMATION, HOS 1 (5X)
 

*SOBCUT TISSUE (20) (20) (49) (50)
 

EPIDERMAL INCLUSION CYST 1 (5X)
 

THROMBUS, ORGANIZED 1 (2X)
 

ABSCESS, NOS 2 (IX)
 

RESPIRATORY SYSTEM
 

ILUNG (20) (19) (19) (50)
 

PNEUMONIA, CHRONIC MURINE 16 (BOX) 11 (58X) 30 (61X) 32
 

CALCIUM DEPOSIT 1 (2X)
 

HBHATOPOIETIC SYSTEM
 

ISPLEEN (19) (19) (17) (50)
 

HEMATOPOIESIS 1 (5X) 1 (5%)
 

CIRCULATORY SYSTEM
 

tBEART (20) (19) (19) (50)
 

CALCIUM DEPOSIT 2 (10X) 1 (S%) 1 (2*)
 

tMYOCARDIUK (20) (19) (19) (50)
 

FIBROSIS 1 (5X) 2 (11X) 1 (8X) 1 (2X)
 

DEGENEEATION, NOS 2 ( 1 1 % ) 5 (10*) 1 (2*)
 

tENDOCAFDIUM (20) (19) (19) (50)
 

* NUMBE R OF ANIMAL S KITH TISSUE EXAMINE D MICROSCOPICALLY 

* NDMBER OF ANIMAL S NECROPSIED 

**EXCLUDES PARTIALLY AU10LYZED ANIMALS 

C-3 
TABLECl (CONTINUED) 

CONTROL (UNTB) 

01-111H 

CONTROL (VEH) 

01-1111! 

LOH DOSE 

01-112W 

HIGH DOSE 

01-113B 

*AORTA 

MEDIAL CALCIFICATION 

(20) 

3 (15*) 

(20) 

4 (20*) 

(K9) 

9 (18X) 

(50) 

2 (IX) 

*CORONARY ARTERY 

MEDIAL CALCIFICATION 

(20) 

2 (10X) 

<20) 

2 (10*) 

(U9) (50) 

*MESENTERIC ARTERY 

MEDIAL CALCIFICATION 

(20) 

1 (5%) 

(20) 

2 (10*) 

(K9) 

3 (6X) 

(50) 

2 (IX) 

DIGESTIVE SYSTEM 

ILIVEB 

THBOKBUS, ORGANIZED 

INFLAMMATION, DOS 

PELIOSIS HEPATIS 

METAKORPHOSIS FATTY 

*BILE DUCT 

HYPEEPLASIA, NOS 

*f ANCREAS 

PEBIARTERITIS 

•ESOPHAGUS 

EUFTURE 

INFLAMMATION, NOS 

(20) 

1

1

(20) 

(19) 

(19) 

 (5X) 

 (5X) 

(20) 

1 (5%) 2 (10*) 

(20) 

1 (5«) 

(19) 

(20) 

(«9) 

1 (2X) 

2 (IX) 

(149) 

3 (6X) 

(tB) 

2 (tX) 

(19) 

(50) 

1 (2X) 

2 («X) 

(50) 

(15) 

(50) 

2 (IX) 

2 (IX) 

•STOMACH 

INFLAMMATION, FOCAL 

CALCIUM DEPOSIT 

(20) 

3 (15X) 

(20) 

1 (5%) 

3 (15X) 

(K9) 

5 (10X) 

(50) 

1 (2X) 

URINAR Y SYSTEM 

IKIDNEY PYELONEPHRITIS. NOS 

INFLAMMATION, CHRONIC 

CALCIUM DEPOSIT 

tURINARY BLADDER 

INFLAMMATION, NOS 

(19) 

2

13

1

(19) 

1

 (11X) 

 (68%) 

 (5X) 

 (5X) 

(20) 

1 (5*) 

11 (55X) 

(18) 

(19) 

23 (17X) 

5 (10X) 

(18) 

1 (2X) 

(50) 

8 (16%) 

2 (IX) 

(37) 

ENDOCRINE SYSTEM 

•ADRENAL 

CYSTX NOS_ . 

(19) (19) 

._ _1 -1551

# NUMBER OF ANIMALS KITH TISSUE EXAMINED MICROSCOPICALLY 

* KUBBER OF ANIMALS NECROPSIED 

_ . (18) 

-

(19) 

— . 

C-4 
TABLE Cl (CONTINUED) 

CONTROL (UNTB) 

01-141H 

CONTROL (VEH) 

01-111M 

THROMBUS, ORGANIZED 

IADRENAL COHTEX 

DEGENERATION, NOS 

(19) (19) 

1 (5%) 

tADRENAL MEDULLA 

CYST, NOS 

(19) (19) 

1 (5X) 

ITHYROID 

FOLLICULAR CYST, NOS 

HYPERPLASIA, FOLLICULAR-CELL 

(19) 

1 (5%) 

(17) 

•PARATHYROID 

HYPEBPLAEIA, NOS 

(19) 

1 (5%) 

(10) 

3 (30%) 

REPRODUCTIVE SYSTEM
 

tFBOSTATE (19) (19)
 

INFLAMMATION, NOS 2 (11%) 2 (11%)
 

tlESTIS (19) (19)
 

CALCIUM DEPOSIT
 

CALCIFICATION, NOS
 

ATROPHY, NOS 8 (12%) K (21%)
 

*EPIDIDY«IS (20) <20)
 EPIDERMAL INCLUSION CYST
 

NECROSIS, FAT 2 (10%)
 

NEBVCUS SYSTEM
 

NONE
 

SPECIAL SENSE ORGANS
 

*EYE/COeNEA (20) (20)
 

INFLAMMATION, NOS
 

HOSCULCSKELETA L SYSTEM 

*SKELETA L MUSCL E (20) (20) 

* NUMBER OF ANIMALS KITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

C-5
 

10H DOSE
 

01-112M
 

1 (2%)
 

(18)
 

2 (<tX)
 

(«8)
 

(«3)
 

4 (9%)
 

1 (2%)
 

(U1)
 

4 (10%)
 

(39)
 

3 (8X)
 

(18)
 

U (8%)
 

1 (2%)
 

11 (23%)
 

(H9)
 

1 (2%)
 

» (8%)
 

(U9)
 

1 (2%)
 

HIGH DOSE
 

01-1138
 

(19)
 

1 (2%)
 

(119)
 

(37)
 

1 (3%)
 

(23)
 

1 (1%)
 

(25)
 

(50)
 

1 (2%)
 

6 (12%)
 

(50)
 

(50)
 

(50)
 
TABLECl (CONCLUDED)
 

CONTROL(UNTR) CONTROL (YEH) LOi DOSE HIGH DOSE
 

01-1U1M 01-111M 01-112H 01-113H
 

BODY CAVITIES
 

*PEBICARDIUM (20) (20) (U9) (50)
 

INFLABBATION, NOS 2 (10*) 1 (2X)
 

»BESENTERY (20) (20) (U9) (50)
 

PEKIARTEEITIS 2 (10X) 1 (2K)
 

ALL OTHEF SYSTEHS
 

HCNE
 

SPECIAL MORPHOLOGY SUMMARY
 

NO LESION REPORTED 1 7 10
 

AUTOLYSIS/NO NECROPSY 1
 

* NUBEER OF ANIMALS BI1H TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

C-6
 
TABLE C2 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE RATS TREATED WITH IODOFORM 

CONTROL (ONTR) 

01-141F 

CONTROL (VEH)

01-111F

 LOW DOSE

 01-111F

 HIGH DOSE 

 01-115F 

ANIMALS INITIALLY IK STUDY 20 

ANIMALS NECBCPSIED 20 

ANIMALS EXAMINED HISTOPATHOLOGICALLY** 20 

20

20

20

 50 50

 50

 50 50 

 50 

INTEGUMENTARY SYSTEM 

»SKIN

INFLAMMATION, NOS

HYPERKERATOSIS 

 (20) 

1 (5*) 

(20) (50)

1 <2X) 1 <2X) 

 (50) 

*SUBCDT TISSUE

ABSCESS, NOS 

NECROSIS, FAT 

 (20) (20) (50)

2 (4X) 

 (50) 

1 (2%) 

HESPIRATORY SYSTEM 

tLUNG

INEUHONIA, CHRONIC MURINE

 (20) 

 19 (95X) 

(20)

18 (90*)

 (50)

 37 (lt%)

 (50) 

 37 (71*) 

HEMATCEOIETIC SYSTEM 

tSPLEEN

LEDKOCYTCSIS, NOS 

HEMATOPOIESIS

 (20) 

3 (15X) 

(20) (49) (50) 

1 (2%) 

3 (6%) 

tCERVICAL LYMPH NODE

INFLAMMATION, NOS 

 (20) <18) (UK)

1 (2X)

 («U) 

1 (2%) 

tTHYMUS

CYST, NOS 

INFLAMMATION, NOS 

 (16) (13) (3«)

2 (6%) 

1 (3X) 

 (26) 

CIECULA1CRY SYSTEM 

*MYOCABDIDM

INFLAMMATION, NOS 

 (20) (20) (50)

3 (6X) 

 (U9) 

• ENDOCARDIUM

jJXEIREliSIA,. JJO.S

 (20) 

1 i5Sl 

(20) (50) (U9) 

* NUMBE R OF ANIMAL S BITH TISSUE EXAMINE D

« NUMBE R OF ANIMAL S NECROPSIED 

"EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

 MICROSCOPICALLY 

C-7 
TABLE C2 (CONTINUED) 

CONTROL (DNTR) 

01-141F 

CONTROL (VEH) 

01-111P 

LOB DOSE 

01-114F 

HIGH DOSE 

01-115F 

*AORTA 

MEDIA L CALCIFICATION 

(20) 

1 (5*) 

(20) (50) (50) 

DIGESTIVE SYSTEM 

•SALIVARY GLAND 

CYST, NOS 

(16) (17) 

1 (6X) 

(27) (34) 

•LIVER 

INFLAMMATION , NOS 

PELICSIS HEPATIS 

METAMORPHOSIS FATTY 

(20) 

1

2

 (5X) 

 (10X) 

(20) 

1 (551) 

(49) 

1 

4 

(2X) 

(8X) 

(49) 

1 (2X) 

tLIVEfi/EERIEORTAL 

METAMORPHOSIS FATTY 

(20) (20) (49) 

1 (2X) 

(49) 

*BILE DUCT 

HYPERPLASIA, NOS 

(20) 

2 (10X) 

(20) 

1 (5*) 

(50) (50) 

1 (2X) 

*ESOPHAGUS 

INFLAMMATION, NOS 

(20) (20) (50) 

3 (6X) 

(45) 

*STCMACH 

ULCER, FOCAL 

(20) 

3 (15X) 

(20) (48) 

2 <4X) 

(50) 

*COLON 

NEMATODIASIS 

(20) (18) (34) (33) 

1 (3X) 

URINAR Y SYSTEM 

IKIDNEY 

HYDEONEPHEOSIS 

PYELONEPHEITIS, NOS 

INFLAMMATION, CHRONIC 

CALCIUM DEPOSIT 

(20) 

6 (30*) 

1 (5X) 

(20) 

1 (5X) 

1 <5X) 

1 <5X) 

(49) 

10 

4 

(20X) 

(8X) 

(50) 

1

5

 (2X) 

 (10X) 

#URINAR Y BLADDER 

INFLAMMATION, NOS 

(20) (20) (40) (41) 

1 (2X) 

ENtCCHINE SYSTEM 

tADRENA L 

CALCIUM DEPOSIT 

(20) 

1 X5&1. (20) (49) (50) 

t NUMBE R

* NUMBE R

 O F

 O F

 ANIMAL S

 ANIMAL S

 KIT H TISSUE EXAMINE D

 NECROPSIE D 

 MICROSCOPICALLY 
TABLE C2 (CONTINUED) 

.. _ CONTROL (UNTR) 

01-141F 

CONTROL (VEH) 

01-111F 

ANGIECTASIS 2 (10X) 

•ADRENAL CORTEX DEGENERATION, NOS 

ANGIECTASIS 

(20) 

5 (25X) 

(20) 

3

1

 (15X) 

 (5X) 

tlHYROID 

FOLLICULAR CYST. NOS 

HYPEEPLASIA, C-CELL 

HYPERPLASIA. FOLLICULAR-CELL 

(19) 

2 (11X) 

(20) 

2 (1051) 

IPARATHYROIC 

HYPESPLASIA, NOS 

(20) (13) 

REPRODUCTIVE SYSTEB
 

*HAMBARY GLAND (20) (20)
 NECROSIS, FAT 1 (5X)
 

*VAGINA (20) (20)
 INFLAMMATION, NOS 1 (5%)
 E01YP, INFLAMMATORY 1 (5X)
 

IBTERliS (20) (19)
 HYEBOMETBA
 

INFLAMMATION, NOS
 

PYOMZTRA
 

IUTERUS/ENDOMET8IOM (20) (19)
 INFLAMMATION, NOS 2 (10X)
 HYPEFPLASIA, CYSTIC
 

ICVARY/OVIDUCT (20) (19)
 

INFLAMMATION, NOS
 

IOVARY (20) (19)
 CYST, NOS 1 (5X) 1 (5*)
 

NERVOUS SYSTEM
 

»BRAIN/«ENINGES (20) (20)
 

INFLAMMATION, NOS
 

SPECIAL SENSE ORGANS
 

*EYE (20) (20)
 §YjiicHiAt EOSTERIOR
 

• NUMBER OF ANIMALS KITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS SECROPSIED
 

C-9
 

LOU DOSE
 

01-114F
 

(49)
 

1 <2X)
 

3 (6X)
 

(«0)
 

2 (5X)
 

(50)
 

1 (2X)
 

(50)
 

(50)
 

(«7)
 

2 {<•*)
 

1 (2X)
 

(47)
 

1 (2X)
 

(it 7)
 

(17)
 

2 (tX)
 

(50)
 

1 (2X)
 

(50)
 

HIGH DOSE
 

01-115F
 

1 12%)
 

(50)
 

6 (12X)
 

1 <2X)
 

(12)
 

2 (5X)
 

1 (2X)
 

1 (2X)
 

(33)
 

(50)
 

(50)
 

(18)
 

1 <2X)
 

1 (2X)
 

1 (2X)
 

(US)
 

1 (2X)
 

(48)
 

1 (2X)
 

(50)
 

1 (2X)
 

(50)
 

(50)
 

1 J2SI _
 
TABLE C2 (CONCLUDED)
 

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

01-141F 01-111F 01-11UF 01-115F
 

HUSCULOSKELETAL SYSTEM
 

NONE
 

BODY CAVITIES
 

*EERICAPDIUM (20) (20) (50) (50)
 

INFLAMMATION, NOS 2 (10X) 1 (8%) 1 (2X)
 

ALL CTHEB SYSTEMS
 

NONE
 

SPECIAL MORPHOLOGY SUMMARY
 

BO LESION REPORTED 3 5
 

t NUfEE R OF ANIMALS HITH TISSUE FXAMINFD MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

c-io
 
APPENDIX D
 

SUMMARY OF THE INCIDENCE OF NQNNEOPLASTIC
 

LESIONS IN MICE TREATED WITH IODOFORM
 

TABLED!

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE MICE TREATED WITH IODOFORM 

CONTHOL(UNTR) CONTROL (VEH)

02-M121 02-M111

 LOU DOSE

 02-B112

 HIGH

 02-M

 DOSE 

113 

ANIMALS INITIALLY IN STUDY 

ANIMALS MISSING 

ANIMALS NECROPSIED 

ANIMALS EXAMINED HISTOPATHOLOGICALLY** 

20

1 

15

15

 20

 19

 19

 50

 50 «9

 50 

 50 

 50 

INTEGUMENTARY SYSTEM
 

*SKIN (15) (19) (50) (50)
 INFLAMMATION, CHRONIC 1 (2%)
 ABSCISS, CHRONIC 1 (7%)
 

*SUBCUT TISSUE (15) (19) (50) (50)
 EDEMA, NOS 1 (7%)­ ABSCESS, NOS 1 <5X)
 

GRANULOMA, NOS 1 (2%)
 

RESPIRATORY SYSTEM
 

tTFACHEA (15) (19) (UU) (UO)
 

INFLAMMATION, NOS 1 (3%)
 

• LUNG (15) (19) (50) (U9)
 

CONGESTION, NOS 9 (60%) 2 (U%)
 INFLAMMATION, NOS 1 (7X)
 PNEUMONIA, CHRONIC SURINE 2 (11%) 13 (26%) 12 (2U%)
 

HEBATOPOIETIC SYSTEM
 

*EONE MARROS (15) (19) (U8) («8)
 

NECROSIS, NOS 1 (2%)
 

HYPEEPLASIA, HEMATOPOIETIC 1 (7%)
 

tSPIEEN (15) (19) (50) (50)
 AMYLOIDOSIS 7 (U7%) 2 (11%) 9 (18%) 5 (10%)
 HYPERPLAEIA, LYMPHOID 1 (7%) 1 (2%)
 

((LYMPH NODE (15) (19) (18) (45)
 

CONGESTION, NOS 2 (13%)
 

i*S£i!2!P_DEPI.E.TIO.J! 1 QJJ
 

* NUMBE R OF ANIMAL S WITH TISSUE EXAMINE D MICROSCOPICALLT 

* NUMBE R OF ANIHAL S NECROPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

D-3 
TABLE Dl (CONTINUED)
 

CONTROL (DNIR) CONTROL (VEH)

02-M121 02-M111 

HYEEEPLASIA, LYMEHOID 1 <7X) 

ICERVICAL LYMP H NODE (15) (19) 

CYST, NOS 

ANGIECTASIS 1 (5%) 

•SUPERIOR DEEP CERVIC (15) (19) 

ANGIECTASIS 1 (5X) 

tERCNCHIAL LYMPH NODE (15) (19) 

ABSCESS, NOS 

tMESENTFRIC L. NODE­ (15) (19) 

CONGESTION, NOS 

HYPEEPLASIA, LYMPHOID 

CIBCULATOEY SYSTEM
 

tHEART (15) (19)
 

MINEFALIZAIION
 

*AORTA (15) (19)
 

INFLAMMATION, ACUTE 1 (7X)
 

DIGESTIVE SYSTEM
 

tSALIVAR Y GLAND (15) (18)
 

CYST, NOS
 

*IIVER (15) (19)
 

INFABCT, NOS
 

AMYLCIDCSIS 7 (47X) 2 (11*)
 

ANGIECTASIS 1 <7X)
 

*LIVER/CENTRILOBULAR (15) (19)
 

NECROSIS, NOS
 

NECROSIS, FOCAL
 

IFANCEEAS (15) (19)
 

AKYLOIDOSIS
 

((ESOPHAGUS (15) (19)
 

RUPTURE
 

INFLAMMATION^ SUPPUKATIVF
 

* NUMBE R OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBE R OF ANIMALS NF.CROPSIED
 

D-4
 

 LOB DOSE
 

02-H112
 

1 <2X)
 

(48)
 

1 <2X)
 

(48)
 

(48)
 

(48)
 

1 (2X)
 

(50)
 

3 (6X)
 

(50)
 

(48)
 

(49)
 

1 (2X)
 6 (12X)
 

(49)
 

1 (2X)
 

(50)
 

6 (12X)
 

(50)
 

_
 

HIGH DOSE
 

02-H113
 

(45)
 

(45)
 

(45)
 

1 <2X)
 

(45)
 

2 (4X)
 

(50)
 

(50)
 

(40)
 

1 <3X)
 

(50)
 

1 (2X)
 

2 (4X)
 

(50)
 

1 (2X)
 

(49)
 

(48)
 

1 (2X)
 . l_12il
 
TABLE Dl (CONTINUED) 

CONTROL (UNTB)

02-B121 CONTROL (VEH)  02-M111 LOW DOSE 02-H112 

HIGH DOSE 

02-M113 

tSTCMACH 

HYPEFKERATOSIS 

tLARGE INTESTINE 

NEMATODIASIS 

*COLON 

NEMATODIASIS 

(15)

(15)

(15)

 (19) 

 (19) 

 (19) 

3 (16%) 

(50) 

(48) 

2 («%) 

(48) 

(19) 

1 (2%) 

(47) 

(47) 

OBINABY SYSTEH 

IKIDNEY 

MINERALIZATION 

HYERONEPHBOSIS 

LTMPHOCYTIC INFILTRATE 

PYELONEPHRITIS SUPPUBATIVE 

INFLAHBATION. ACUTE SUPPURATIVE 

INFLAMMATION, CHRONIC 

FIBBOSIS, DIFFUSE 

AHYLOIDOSIS 

CALCIFICATION, FOCAL 

IKIDNEY/TUBULE 

CYTOPLASHIC VACDOLIZATION 

•URINARY BLADDER 

INFLAMMATION, NOS 

HYPEFPLASIA. EPITHELIAL 

(15)

2 (13X) 

2 (13%) t (27X)

2 (13%) 

3 (20%) 

(15)

2 (13%) 

(15)

 (19) 

1 (5*) 

1 (5%) 

 (19) 

 (19) 

1 (5*) 

(50) 

1 (2%) 

2 (1%) 

9 (18%) 

(50) 

(50) 

(50) 

6 (12%) 

1 (2%) 

(50) 

(49) 

3 (6%) 

EHEOCHINE SYSTEM 

* ADRENAL 

AMYLOIDOSIS 

•THYROID 

HYPERPLASIA, FOLLICULAR-CELL 

(15)

3

(15)

 (20%) 

 (19) 

 (17) 

(50) 

(41) 

2 (5%) 

(50) 

2 <<•%) 

(38) 

REPRODUCTIVE SYSTEH 

tPROSTATE 

INFLAMMATION, ACUTE 

SfiAl!ULQMA1._SPEJIIATIC 

(15)

1 (7%) 

 (18) (50) (50) 

_l_i2SI_-

* NUMBER OF ANIMALS KITH TISSUE EXAMINED MICROSCOPICALLY 

» NUMBER OF ANIMALS NECROPSIED 

D-5 
TABLE DI (CONTINUED) 

CONTROL (UNTR) CONTROL (VEH)
 

02-M121 02-M111
 

tTESTIS (15) (18)
 

ATBOFHY, NOS
 

*EPIDIDYMIS (15) (19)
 GRANDLCMA, SPERMATIC 1 (5%)
 

NECBCSIS, FAT
 

NEEVOUS SYSTEM
 

tERAIN/KENINGES (15) (19)
 

INFLAMMATION, NOS
 

INFLAMMATION, ACUTF 1 (71)
 

tERAIN/FPENCYHA (15) (19)
 

INFLAMMATION, NOS
 

*EfiAIK (15) (19)
 

COMPKESSION
 

SPECIAL SENSE ORGANS
 

*EYE (15) (19)
 

INFLAMMATICS, CHRONIC
 

*EYE/CORNEA (15) (19)
 

INFLAMMATION. NOS
 

MUSCULOSKEIETAL SYSTEM
 

NCNE
 

BODY CAVITIES
 

*ELEURA (15) (19)
 

INFLAMMATION, SUPPUEATIVE
 

ALL CTHEB SYSTEMS
 

—NONE
 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBE R OF ANIMALS NECROPSIED
 

D-6
 

LOU DOSE
 

02-H112
 

(09)
 

1 (2X)
 

(50)
 

2 (HX)
 

(50)
 

(50)
 

(50)
 

(50)
 

(50)
 

(50)
 

HIGH DOSE
 

02-H113
 

(50)
 

(50)
 

(148)
 

1 (2X)
 

(U8)
 

1 (2X)
 

(US)
 

1 (2X)
 

(50)
 

1 (2X)
 

(50)
 

1 (2%)
 

(50)
 

1 (2X)
 
TABLE DI (CONCLUDED)
 

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

02-M121 02-M111 02-M112 02-M113
 

SPECIAL MORPHOLOGY SUMMAR Y
 

NO LESION REPORTED 1 8 12 13
 

ANIMAL HISSING/NO NECROPSY 1
 AUTO/NECROPSY/NO HISTO 1
 AUTOLYSIS/NO NECBOPSY 4 1
 

* KUMEE R OF ANIMAL S KITH TISSUE EXAMINED MICROSCOPICALLY
 * NUMBE R OF ANIMALS NECROPSIED
 

D-7
 
TABLE D2 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE MICE TREATED WITH IODOFORM 

c:ONTROI(UNTR) CONTROL (VEH) LOW DOSE HIGH DOSE
 

02-F121 02-F111 02-F114 02-F115
 

A8IKALS INITIALLY IN STUDY 20 20 50 50
 ANIMALS KISSING 2
 ANIMAL S NECBCPSIED 18 20 49 45
 ANIMALS EXAMINED HISTOFATHOLOGICALLY** 18 20 49 145
 

INTEGUMENTAR Y SYSTEM
 

*SKIN (18) (20) (49) (45)
 ACANTHOSIS 8 (44X)
 

RESPIBATORY SYSTEM
 

ITRACHEA (18) (20) (47) (44)
 

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

tLBNG (18) (20) (49) (45)
 CONGESTION, NOS 9 (5C%)
 EDEMA, NOS 1 (6X)
 HEMORRHAGE 1 (2X) 3 (7X)
 INFLAMMATION, NOS 4 (22X)
 PNEUMONIA, CHRONIC MURINE 1 (6X) 2 (10X) 5 (10X) 4 (9X)
 

HEMATOPOIEIIC SYSTEM 

tEONE MARRO H (18) (20) (49) (45) 

HEHORHHAGE 1 (6X) HYPEPPLASIA, HEMATOPOIETIC 2 (11X) 

ISPLEFN (18) (20) (49) (45) INFLAMMATION, ACUTE 1 (6X) AMYLOIDOSIS 1 (2X) HYPERPLASIA, RETICULUB CELL 1 <2X) HYPERPLASIA, LYKPHOID 5 (28X) 1 (2X) 2 (4%) 

tLYMFH NODE (18) (20) (47) (45) INFLAMMATION, CHRONIC 1 (6%) HYPEFPLASIA, LYMPHOID 2 (11X) 

tCERVICAL LYMPH NODE (18) (20) (47) (45) 

INFLAMMATION^ NOS -,._..._,., _ _ . ,­ , _ 1 ,J2X) , 

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

* NUMBE R OF ANIMAL S NECROPSIED 

**EXCLUDES PARTIALLY AUTOLYZED ANIMALS 

D-8 
HYPEFPLASIA, LYHFHOID
 

IMESENTEHIC L. NODE
 

INFLAMMATION. NOS
 

AHGIECTASIS
 

HYPERPLASIA, LYMPHOID
 

CIRCULATORY SYSTEM
 

tHEAET
 

PEEIABTEBITIS
 

DIGESTIVE SYSTEM
 

ILIVEE
 

THBOHBUS, ORGANIZED
 

LYBPHOCYTIC INFILTRATE
 

INFLAMMATION, ACUTE/CHRONIC
 

NECROSIS, NOS
 

INFABCT, NOS
 

HYPFRPLA2IA, FOCAL
 

tLIVEB/CENTBILOBULAB
 

NECROSIS, NOS
 

•PANCREAS
 

CYSTIC DUCTS
 

ATROPHY, NOS
 

•PANCREATIC	 DUCT
 

EILATATICN, NOS
 

•PANCREATIC	 ACINUS
 

ATFOFHY, NOS
 

*STOMACH
 

INFLAMMATION, FOCAL
 

ULCEB, ACUTE
 

•SMALL	 INTESTINE
 

HYPEBPLASIA, LYMPHOID
 

ICOLON
 

NEMATODIASIS
 

#	 NUMBER OF ANIMALS KITH TISSUE


*	 NUMBER OF ANIMALS NECROPSIED
 

TABLE D2 (CONTINUED)
 

CONTROL (DNTR) CONTROL (VEH)
 

02-F121 02-F111
 

(18) (20)
 

(18) (20)
 

(18) (20)
 

2 (11X)
 

1 (6%)
 

(18) (20)
 

(18) 120)
 

(18)	 (20)
 

1 (5X)
 

(18) (20)
 

(18)	 (20)
 

1 (6%)
 

(18)	 (20)
 

1 (6X)
 

(18)	 (20)
 

3 J15J1
 

 EXAMINE D MICROSCOPICALLY
 

D-9
 

LOB DOSE
 

02-F11U
 

2 («%)
 

(47)
 

2 (IX)
 

2 (KX)
 

(19)
 

(19)
 

1 (2X)
 

1 (2X)
 

(19)
 

1 (2*)
 

(1*9)
 

6 (12*)
 

1 (2X)
 

(19)
 

(19)
 

1 (2X)
 

(19)
 

(19)
 

(18)
 

HIGH DOSE
 

02-F115
 

(15)
 

1 (2X)
 

2 (IX)
 

(15)
 

1 <2X)
 

(15)
 

1 (2X)
 

2	 (IX)
 

(15)
 

(15)
 

2 (IX)
 

(15)
 

(15)
 

(15)


1 <2X)
 

(15)
 

(13)
 
TABLE D2 (CONTINUED) 

CONTROL (UNTR) 

02-F121 

CONTROL (VEH) 

02-F111 

LOU DOSE

02-F114

 HIGH DOSE 

 02-F115 

URINAR Y SYSTEM 

IKIENEY 

HYCRCNEPHROSIS 

CYST, NOS 

PYELONEPHRITIS, NOS 

LYflPHOCYTIC INFILTRATE 

INFLAMMATION, CHRONIC 

ATROPHY, NOS 

(18) 

1 (6X) 

4 (22X) 1 (6X) 

(20) 

1 (5X) 

1 (5X) 

(49)

1 (2X) 

 (45) 

1 (2X> 

tUPINARY BLADDER 

LYMPHOCYIIC INFILTRATE 

(18) 

1 (6X) 

(19) (48) (44) 

ENDOCRINE SYSTEM 

IADRENAI CORTEX 

DEGENERATION, NOS 

HYPEtPLASIA, NOS 

(18) 

1 (6X) 

(20) (49) (45) 

1 (2X) 

RF.PECDUCTIVE SYSTEM 

*MAMMAR Y GLAND 

GALACTOCELE 

(18) (20) (49)

1 (2X) 

 (45) 

•UTERUS 

HYDROMETRA 

INFLAMMATION, NOS 

PYOMETFA 

INFLAMMATION, ACUTE

ANGIECTASIS 

 SUPPURATIVE 

(18) 

1 (6X) 

(20) 

2 (10X) 

2 (10X) 

(48)

2 <4X)

1 <2X) 

 (44) 

1 (2X) 

1 (2X) 

IUTERUS/ENDCMETRIDM 

HYPEEiPLASIA, CYSTIC 

(18) 

15 (83X) 

(20) 

9 (1*5X) 

(48)

39 (81X)

 (44) 

 41 (93X) 

JtOVAHY 

CYST, NOS 

FOLLICULAR CYST, NOS 

ABSCESS, NOS 

ATROPHY, NOS 

(18) 

2 (11X) 

1 <6X) 

2 (11X) 

(20) 

2 (10X) 

(49)

4 (8X)

1 (2X)

 (44) 

7 (16X) 

6 (14X) 

1 (2X) 

8EEVCUS SYSTEM 

tERAIN 

MALACJA _ _ 

(16) (20) (49) (45) 

J (2%) 

# NUMBE R OF ANIHALS HITH TISSUE EXAMINED MICROSCOPICALLY 

* NUNEFR OF ANIMALS NECROPSIED 

D-IO 
TABLE D2 (CONCLUDED)
 

CONTROL (UNTB) CONTROL (VEH) LOU DOSE HIGH DOSE
 

02-F121 02-F111 02-F11U 02-F115
 

SPECIAL SENSE ORGAN S
 

*EYE (18) (20) (49) (45)
 

PHTHISIS SULEI 1 (2X)
 

HUSCULOSKELEIAL SYSTEM
 

NCNE
 

BOCY CAVITIES
 

*PEEITCNEUK (18) (20) (49) (45)
 

INFLAMMATION , NOS 1 (2*)
 

ALL C1HEB SYSTEMS
 

*BULTIPIE ORGAN S (18) (20) (49) (45)
 

AMYLOIDOSIS 1 (2*)
 

SPECIAI hOKFHOLOGY SUMMAR Y
 

NO LESION EEFORTED 2 1 2
 

ANIMA L MISSING/NC NECROPSY 2
 

AUTOLYSIS/NC NECECPSY 2 1 3
 

f NUBEI R OF ANIMAL S UI7H TISSUE EXAMINE D MICROSCOPICALLY
 

» NUMBE R OF ANIKAL S NECROPSIED
 

D-l
 

Review of the Bioassay of lodoform* for Carcinogenicity
 

by the Data Evaluation/Risk Assessment Subgroup of the
 

Clearinghouse on Environmental Carcinogens
 

April 26, 1978
 

The Clearinghouse on Environmental Carcinogens was
 

established in May, 1976, in compliance with DHEW Committee
 

Regulations and the Provisions of the Federal Advisory
 

Committee Act. The purpose of the Clearinghouse is to
 

advise the Director of the National Cancer Institute (NCI)
 

on its bioassay program to identify and to evaluate chemical
 

carcinogens in the environment to which humans may be
 

exposed. The members of the Clearinghouse have been drawn
 

from academia, industry, organized labor, public interest
 

groups, State health officials, and quasi-public health and
 

research organizations. Members have been selected on the
 

basis of their experience in carcinogenesis or related
 

fields and, collectively, provide expertise in chemistry,
 biochemistry, biostatistics, toxicology, pathology, and
 

epidemiology. Representatives of various Governmental
 

agencies participate as ad hoc members. The Data Evaluation/
 

Risk Assessment Subgroup of the Clearinghouse is charged
 

with the responsibility of providing a peer review of
 

reports prepared on NCI-sponsored bioassays of chemicals
 

studied for carcinogenicity. It is in this context that the
 

below critique is given on the bioassay of lodoform for
 

carcinogenicity.
 

The primary reviewer said that the study did not
 

provide evidence that lodoform was carcinogenic in rats
 

or mice, under the conditions of test. After a brief
 

description of the experimental design, Me commented
 

that the subchronic study was deficient in that it provided
 

little help in establishing chronic dose levels. He noted
 

the numerous dose changes which occurred during the chronic
 

phase and the fact that a maximum tolerated dose may not
 

have been achieved. The only statistically significant
 

neoplasm observed was a follicular-cell tumor of the thyroid
 

in low dose male rats.
 

The secondary reviewer opined that the dose levels
 

administered were sufficiently high, based on an inspection
 

of survival curves. He concurred with the conclusion in
 

the report that lodoform was not carcinogenic under the
 

conditions of test.
 

It was moved that the report on the bioassay of
 

lodoform be accepted as written. The motion was seconded
 

and approved unanimously.
 

Members present were:
 

Michael Shimkin (Acting Chairman), University of California
 

at San Diego
 

Joseph Highland, Environmental Defense Fund
 

George Roush, Jr., Monsanto Company
 

Louise Strong, University of Texas Health Sciences Center
 

John Weisburger, American Health Foundation
 

Subsequent to this review, changes may have been made
 

in the bioassay report either as a result of the review
 

or other reasons. Thus, certain comments and criticisms
 

reflected in the review may no longer be appropriate.
 

•ft U. S. GOVERNMEN T PRINTIN G OFFICE : 1978-260-899/316 3 

DHEW Publication No. (NIH1 78-1365