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National Cancer Institute 

CARCINOGENESIS DO NOT REMOVE FROM THIS OFFICE 

Technical Report Series 

NO. 69 

1978 

BIOASSAY OF 

AZINPHOSM ETHYL 

FOR POSSIBLE CARCINOGENICITY 

CAS No. 86-50-0 

NCI-CG-TR-69 

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

Public Health Service 

National Institutes of Health 

BIOASSAY OF
 

AZINPHOSMETHYL
 

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) 78-1319
 

BIOASSAY OF
 

AZINPHOSMETHYL
 

FOR POSSIBLE CARCINOGENICITY
 

Carcinogenesis Testing Program
 

Division of Cancer Cause and Prevention
 

National Cancer Institute
 

National Institutes of Health
 

FOREWORD; This report presents the results of the bioassay of
 

azinphosmethyl 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 environmental chemicals have the
 

capacity to produce cancer in animals. Negative results, in
 

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

than control animals, do not necessarily mean that the test
 

chemical is not a carcinogen, inasmuch as the experiments are
 

conducted under a limited set of circumstances. Positive results
 

demonstrate that the test chemical is carcinogenic for animals
 

under the conditions of the test and indicate that exposure to
 

the chemical is a potential risk to man. The actual determination of the risk to man from animal carcinogens requires a wider
 

analysis.
 

CONTRIBUTORS; This bioassay of azinphosmethyl was conducted by
 

Gulf South Research Institute, New Iberia, Louisiana, initially
 

under direct contract to the NCI and currently under a subcontract to Tracer Jitco, Inc., Rockville, Maryland, prime
 

contractor for the NCI Carcinogenesis Testing Program.
 

The experimental design was determined by Drs. J. H.
 

Weisburger*' and R. R. Bates »^; the doses were selected by
 

Drs. T. E. Shellenberger4'5, J. H. Weisburger, and R. R. Bates.
 

Administration of the test chemical and observation of animals
 

were supervised by Drs. T. E. Shellenberger and H. P.
 

Burchfield , with the technical assistance of Ms. D. H.
 

Monceaux1* and Mr. D. Broussard .
 

iii
 
Histopathology of tissues from animals dosed with azinphosmethyl
 

and their matched controls was performed by Dr. D. A. Willigan"
 

at Donald A. Willigan, Inc., and the diagnoses included in this
 

report represent his interpretation.
 

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

Mason Research Institute'. Statistical analyses were performed
 

by Dr. J. R. Joiner^ and Ms. P. L. Yong^, using methods selected
 

for the bioassay program by Dr. J. J. Gart". Chemicals used in
 

this bioassay were analyzed under the direction of Dr. H. P.
 

Burchfield, and the results of the analyses were reviewed by Dr.
 

S. S. Olin°.
 

This report was prepared at Tracer Jitco^ under the direction of
 

NCI. Those responsible for the report at Tracor Jitco were Dr.
 

Marshall Steinberg, Director of the Bioassay Program; Dr. L. A.
 

Campbell, Deputy Director for Science; Drs. J. F. Robens and C.
 

H. Williams, toxicologists; Dr. R. L. Schueler, pathologist; Dr.
 

G. L. Miller, Ms. Y. E. Presley, and Mr. W. D. Reichardt,
 

bioscience writers; and Dr. E. W. Gunberg, technical editor.
 

The following other scientists at NCI were responsible for
 

evaluating the bioassay experiment, interpreting the results, and
 

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

Jr., Dr. J. Fielding Douglas, Dr. Dawn G. Goodman1

^ Dr. Richard
 

A. Griesemer, Dr. Harry A. Milman, Dr. Thomas W. Orme, Dr. Robert
 

A. Squire^-, Dr. Sherman F. Stinson, Dr. Jerrold M. Ward, and Dr.
 

Carrie E. Whitmire.
 

Icarcinogenesis Testing Program, Divison of Cancer Cause and
 

Prevention, National Cancer Institute, National Institutes of
 

Health, Bethesda, Maryland.
 

^Now with the Naylor Dana Institute for Disease Prevention,
 

American Health Foundation, Hammond House Road, Valhalla,
 

New York.
 

iv
 
with the Office of the Commissioner, Food and Drug
 

Administration, Rockville, Maryland.
 

^Gulf South Research Institute, Atchafalaya Basin Laboratories,
 

P. 0. Box 1177, New Iberia, Louisiana.
 

-*Now with the National Center for Toxicological Research,
 

Jefferson, Arkansas.
 

6

Donald A. Willigan, Inc., 309 East Second Street, Bound Brook,
 

New Jersey.
 

Mason Research Institute, 1530 East Jefferson Street,
 

Rockville, Maryland.
 

8

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

Maryland.
 

"Mathematical Statistics and Applied Mathematics Section,
 

Biometry Branch, Field Studies and Statistics, Division of
 

Cancer Cause and Prevention, National Cancer Institute, National
 

Institutes of Health, Bethesda, Maryland.
 

with Clement Associates, Inc., 1010 Wisconsin Avenue, N.W. ,
 

Suite 660, Washington, D.C.
 

•'••'•Now with the Division of Comparative Medicine, Johns Hopkins
 

University, School of Medicine, Traylor Building, Baltimore,
 

Maryland.
 

v
 

SUMMARY
 

A bioassay of technical-grade azinphosmethyl for possible carcinogenicity was conducted by administering the test chemical in feed
 

to Osborne-Mendel rats and B6C3F1 mice.
 

Groups of 50 rats of each sex were administered azinphosmethyl at
 

one of two doses for 80 weeks, then observed for 34 or 35 weeks.
 

Time-weighted average doses of either 78 or 156 ppm were used for
 

the males. Initial doses of 62.5 or 125 ppm used for the females
 

were maintained throughout the bioassay. Matched controls
 

consisted of groups of 10 untreated rats of each sex; pooled
 

controls consisted of the matched controls combined with 95 male
 

and 95 female untreated rats from similar bioassays of 10 other
 

test chemicals. All surviving rats were killed at 114 or 115
 

weeks.
 

Groups of 50 mice of each sex were administered azinphosmethyl at
 

one of two doses for 80 weeks, then observed for 12 or 13 weeks.
 

The doses were either 31.3 or 62.5 ppm for the males and either
 

62.5 or 125 ppm for the females. Matched controls consisted of
 

groups of 10 untreated mice of each sex; pooled controls
 

consisted of the matched controls combined with 130 male and 120
 

female untreated mice from similar bioassays of 11 other test
 

chemicals. All surviving mice were killed at 92 or 93 weeks.
 

High- and low-dose male rats and mice and high-dose female rats
 

and mice had lower mean body weights than corresponding matched
 

controls throughout the bioassay. Typical signs of organophosphate intoxication were observed in a few animals of both
 

species, and included hyperactivity, tremors, and dyspnea.
 

Sufficient numbers of animals were at risk in each species for
 

development of late-appearing tumors.
 

A great many tumors of the endocrine organs were observed in both
 

dosed male and dosed female rats. Those of the adrenal in dosed
 

males and females, the follicular cells of the thyroid in dosed
 

vii
 
females, the anterior pituitary in dosed males, and the
 

parathyroid in dosed males occurred at statistically significant
 

incidences when compared with pooled controls, but not with
 

matched controls, and they were not considered to be related to
 

administration of the test compound. The incidences of tumors of
 

the pancreatic islets and of the follicular cells of the thyroid
 

in the male rats suggest, but do not clearly implicate,
 

azinphosmethyl as a carcinogen in these animals.
 

In mice of each sex there were no increased incidences of tumors
 

that could be related to administration of the test chemical.
 

It is concluded that under the conditions of this bioassay,
 

neoplasms of the thyroid and pancreatic islets suggest but do not
 

provide sufficient evidence for the carcinogenicity of
 

azinphosmethyl in male Osborne-Mendel rats. Azinphosmethyl was
 

not shown to be carcinogenic in female Osborne-Mendel rats or in
 

B6C3F1 mice of either sex.
 

viii
 
TABLE OF CONTENTS
 

Page
 

I. Introduction 1
 

II. Materials and Methods 3
 

A. Chemical 3
 

B. Dietary Preparation 3
 

C. Animals 4
 

D. Animal Maintenance 5
 

E. Subchronic Studies 6
 

F. Designs of Chronic Studies 8
 

G. Clinical and Pathologic Examinations 11
 

H. Data Recording and Statistical Analyses 12
 

III. Results -Rats 19
 

A. Body Weights and Clinical Signs (Rats) 19
 

B. Survival (Rats) 19
 

C. Pathology (Rats) 22
 

D. Statistical Analyses of Results (Rats) 23
 

IV. Results - Mice 31
 

A. Body Weights and Clinical Signs (Mice) 31
 

B. Survival (Mice) 33
 

C. Pathology (Mice) 33
 

D. Statistical Analyses of Results (Mice). 35
 

V. Discussion 39
 

VI. Bibliography 45
 

APPENDIXES
 

Appendix A Summary of the Incidence of Neoplasms in
 

Rats Fed Azinphosmethyl in the Diet 47
 

Table Al Summary of the Incidence of Neoplasms in
 

Male Rats Fed Azinphosmethyl in the Diet 49
 

Table A2 Summary of the Incidence of Neoplasms in
 

Female Rats Fed Azinphosmethyl in the Diet 54
 

ix
 
Page
 

Appendix B Summary of the Incidence of Neoplasms in 

Mice Fed Azinphosmethyl in the Diet 59 

Table Bl Summary of the Incidence of Neoplasms in 

Male Mice Fed Azinphosmethyl in the Diet 61 

Table B2 Summary of the Incidence of Neoplasms in 

Female Mice Fed Azinphosmethyl in the Diet 63 

Appendix C Summary of the Incidence of Nonneoplastic 

Lesions in Rats Fed Azinphosmethyl in the Diet 69 

Table Cl Summary of the Incidence of Nonneoplastic 

Lesions in Male Rats Fed Azinphosmethyl 

in the Diet 71 

Table C2 Summary of the Incidence of Nonneoplastic 

Lesions in Female Rats Fed Azinphosmethyl 

in the Diet 77 

Appendix D Summary of the Incidence of Nonneoplastic 

Lesions in Mice Fed Azinphosmethyl 

in the Diet 81 

Table Dl Summary of the Incidence of Nonneoplastic 

Lesions in Male Mice Fed Azinphosmethyl 

in the Diet 83 

Table D2 Summary of the Incidence of Nonneoplastic 

Lesions in Female Mice Fed Azinphosmethyl 

in the Diet 86 

Appendix E Analyses of the Incidence of Primary Tumors 

in Rats Fed Azinphosmethyl in the Diet 91 

Table El Analyses of the Incidence of Primary Tumors 

in Male Rats Fed Azinphosmethyl in the Diet 93 

Table E2 Analyses of the Incidence of Primary Tumors 

in Female Rats Fed Azinphosmethyl in the Diet 103 

Appendix F Analyses of the Incidence of Primary Tumors 

in Mice Fed Azinphosmethyl in the Diet. Ill 

Table Fl Analyses of the Incidence of Primary Tumors 

in Male Mice Fed Azinphosmethyl in the Diet 113 

X 
Page 

Table F2 Analyses of the Incidence of Primary Tumors 

in Female Mice Fed Azinphosmethyl in the Diet 117 

Appendix G Analysis of Formulated Diets for 

Concentrations of Azinphosmethyl 121 

TABLES 

Table 1 Design of Azinphosmethyl Chronic Feeding 

Studies in Rats 9 

Table 2 Design of Azinphosmethyl Chronic Feeding 

Studies in Mice 10 

FIGURES 

Figure 1 Growth Curves for Rats Fed Azinphosmethyl 

in the Diet 20 

Figure 2 Survival Curves for Rats Fed Azinphosmethyl 

in the Diet 21 

Figure 3 Growth Curves for Mice Fed Azinphosmethyl 

in the Diet 32 

Figure 4 Survival Curves for Mice Fed Azinphosmethyl 

in the Diet 34 

xi
 

I. INTRODUCTION
 

Azinphosmethyl
 

Azinphosmethyl (CAS 86-50-0; NCI C00066) is a broad-spectrum,
 

organophosphorus insecticide that was first produced in 1953 by
 

Farbenfabriken Bayer AG and is used solely for agricultural
 

purposes. In 1974, 3.1 million pounds were estimated to have
 

been used in the United States on the following crops: alfalfa,
 

cotton, deciduous fruits and nuts, tobacco, vegetables and some
 

miscellaneous items (Ayers and Johnson, 1976). Azinphosmethyl is
 

toxic both on contact and by ingestion (Cremlyn, 1974) and it has
 

prolonged residual activity (Metcalf, 1965). The LD50's for
 

azinphosmethyl have been reported to be 16.4 mg/kg in adult
 

female Sprague-Dawley rats (Dubois et al. , 1957), 4.0 mg/kg in
 

adult male CFj mice and 8.7 mg/kg in adult female Holtzman rats
 

1 
(Dubois and Kinoshita, 1968) by the oral route, and 24 mg/kg
 

orally and 90 mg/kg percutaneously in adult female Charles River
 

CD rats (Pasquet et al., 1976).
 

Azinphosmethyl is one of a series of pesticides selected for
 

study in the Carcinogenesis Testing Program because it was
 

produced in large quantities and the potential existed for
 

long-term human exposure to the chemical during agricultural
 

application or to residues of the chemical in food products.
 

2 
II. MATERIALS AND METHODS
 

A. Chemical
 

Azinphosmethyl is the generic name for 0,0-dimethyl-S-t(4-oxol,2,3-benzotriazin-3-(4H)-yl)methyl]phosphorodithioate. It was
 

obtained in a single batch for the chronic studies from Mobay
 

Chemical Corp., Chemagro Agricultural Division, Kansas City,
 

Missouri. The manufacturer's specification for this technical
 

product (Guthion^1) was 90% azinphosmethyl. Throughout the report
 

the term azinphosmethyl is used to refer to the technical-grade
 

material. Analyses at Gulf South Research Institute confirmed
 

the identity of the chemical and were consistent with the manufacturer's specification (elemental analyses of C, H, N, P, S for
 

CiQHl2N3°3PS2; infrared, ultraviolet, and nuclear magnetic
 

resonance spectra; thin-layer and gas-liquid chromatography). No
 

attempt was made to identify or quantitate impurities.
 

The chemical was stored at 4°C in the original container.
 

B. Dietary Preparation
 

All test diets were formulated once per week using Wayne® Lab
 

Blox animal meal (Allied Mills, Inc., Chicago, 111.) to which was
 

added the required amount of azinphosmethyl for each dietary
 

concentration. The test chemical was first dissolved in a small
 

3 
amount of acetone (Mallinckrodt Inc., St. Louis, Mo.), which was
 

then added to the feed. Corn oil (Louana®, Opelousas Refinery
 

Co., Opelousas, La.) was also added to the feed, primarily as a
 

dust suppressant, and the diets were mixed mechanically to assure
 

homogeneity of the mixtures and evaporation of the acetone.
 

Final diets, including those for the control groups of animals,
 

contained corn oil equal to 2% of the final weight of feed. The
 

diets were stored at approximately 17°C until used, but no longer
 

than 1 week.
 

As a quality control test on the accuracy of preparation of the
 

diets, the concentration of azinphosmethyl was determined in
 

different batches of formulated diets during the chronic study.
 

The results are summarized in Appendix G. At each dietary concentration, the mean of the analytical concentrations for the
 

checked samples was within 2% of the theoretical concentration,
 

and the coefficient of variation was never more than 6.4%. Thus,
 

the evidence indicates that the formulated diets were prepared
 

accurately.
 

C. Animals
 

Rats and mice of each sex, obtained through contracts of the
 

Division of Cancer Treatment, National Cancer Institute, were
 

used in these bioassays. The rats were of the Osborne-Mendel
 

4 
strain obtained from Battelle Memorial Institute, Columbus, Ohio,
 

and the mice were B6C3F1 hybrids obtained from Charles River
 

Breeding Laboratories, Inc., Wilmington, Massachusetts. On
 

arrival at the laboratory, all animals were quarantined (rats for
 

8 days, mice for 14 days) and were then assigned to control or
 

dosed groups.
 

D. Animal Maintenance
 

All animals were housed in temperature- and humidity-controlled
 

rooms. The temperature range was 20-24°C and the relative
 

humidity was maintained at 40-70%. The air in each room was
 

changed 10-12 times per hour. Fluorescent lighting provided
 

illumination 10 hours per day. Food and water were available ad.
 

libitum.
 

The rats were housed individually in hanging galvanized steel
 

mesh cages, and the mice were housed in plastic cages with filter
 

bonnets, five per cage for females, and two or three per cage for
 

males. Initially, rats were transferred every week to clean
 

cages; later in the study, cages were changed every 2 weeks.
 

Absorbent sheets under the rat cages were changed three times per
 

week. Mouse cages were provided with Absorb-Dri (Lab Products,
 

Inc., Garfield, N. J.), and the mice were transferred to clean
 

5 
cages every week. Feeder jars and water bottles were changed and
 

sterilized three times per week.
 

Cages for control and dosed mice were placed on separate racks in
 

the same room. Animal racks for both species were rotated
 

laterally every week; at the same time, each cage was changed to
 

a different position within the same column. Rats receiving
 

azinphosmethyl, along with their matched controls, were housed in
 

a room by themselves. Mice fed azinphosmethyl were maintained in
 

the same room as mice fed the following chemicals:
 

(CAS 61-82-5) amitrole
 

(CAS 76-44-8) heptachlor
 

Dosed mice were housed with their respective matched controls.
 

E. Subchronic Studies
 

Subchronic feeding studies were conducted with rats and mice to
 

estimate maximum tolerated doses of azinphosmethyl, on the basis
 

of which two concentrations (hereinafter referred to as "low
 

doses" and "high doses") were determined for administration in
 

the chronic studies. In these Subchronic studies, azinphosmethyl
 

was added to the animal feed in twofold increasing concentrations, ranging from 7.8 to 62.5 ppm for rats and from 7.8 to
 

125 for mice. Dosed and control groups each consisted of five
 

males and of five females. The chemical was provided in feed to
 

6 
dosed groups for 6 weeks, followed by 2 weeks of observation.
 

Because there were no deaths and no effects on mean body weights
 

in rats at 7.8 to 62.5 ppm or in female mice at 7.8 to 125 ppm, a
 

second study was performed on rats and female mice using doses
 

ranging from 62.5 to 1,000 ppm.
 

During the first weeks of the second study, depression of mean
 

body weight was evident in the male rats administered 125 or 250
 

ppm and in the female rats administered 62.5 or 125 ppm. Later,
 

these animals appeared to adapt, and mean body weight gains of
 

dosed groups approached those of the controls; in the females,
 

the mean body weight gains of dosed groups often surpassed those
 

of the controls. There were no deaths at these concentrations;
 

however, at concentrations of 500 ppm for males and 250 ppm for
 

females, all animals were dead by week 2. The low and high doses
 

for the chronic studies were set at 125 and 250 ppm for male rats
 

and at 62.5 and 125 ppm for female rats.
 

In mice, males receiving 62.5 ppm initially lost weight, while
 

males receiving 31.3 ppm gained weight. Female mice receiving
 

62.5 ppm or 125 ppm initially lost weight, but in later weeks the
 

gain in mean body weight approached that of the controls. No
 

deaths occurred in males at 31.3 or 62.5 ppm or in females at
 

62.5 or 125 ppm, but deaths occurred in males receiving 125 ppm
 

and in females receiving 250 ppm. The low and high doses for the
 

7 
chronic studies were set at 31.3 and 62.5 for male mice and at
 

62.5 and 125 ppm for female mice.
 

F. Designs of Chronic Studies
 

The designs of the chronic studies are shown in tables 1 and 2.
 

Since the numbers of animals in the matched-control groups were
 

small, other control groups subject to study in this laboratory
 

were used for additional statistical comparisons. For rats,
 

matched controls from the current bioassay of azinphosmethyl were
 

combined with matched controls from the bioassays of toxaphene
 

(CAS 8001-35-2), lindane (CAS 58-89-9), captan (CAS 133-06-2),
 

chloramben (CAS 133-90-4), picloram (CAS 1918-02-1), heptachlor
 

(CAS 76-44-8), chlordane (CAS 57-74-9), dimethoate (CAS 60-51-5),
 

parathion (CAS 56-38-2), and malathion (CAS 121-75-5). The
 

pooled controls for statistical tests using rats consisted of 105
 

males and 105 females.
 

The pooled controls of mice were similarly combined. The
 

controls from the bioassay of azinphosmethyl were combined with
 

those from the bioassays of phosphamidon (CAS 13171-21-6),
 

parathion, heptachlor, lindane, chlordane, dimethoate, tetrachlorvinphos (CAS 961-11-5), malathion, dieldrin (CAS 60-57-1),
 

photodieldrin (CAS 13366-73-9), and captan, constituting a total
 

of 140 males and 130 females.
 

8
 
Table 1. Design of Azinphosmethyl Chronic Feeding Studies in Rats
 

Sex and 

Test 

Group 

Initial 

No. of 

Animals3 

Azinphosmethyl 

in Dietb 

(ppm) 

Time o 

Dosed c 

(weeks) 

n Study 

Observed1* 

(weeks ) 

Time-Weighted 

Average Dose6 

(ppm) 

Male 

Matched-Control 10 0 115 

Low-Dose 50 125 20 

62.5 60 78 

0 34-35 

High-Dose 50 250 20 

125 60 156 

0 34-35 

Female 

Matched-Control 10 0 115 

Low-Dose 50 62.5 80 

0 34-35 

High-Dose 50 125 80 

0 35 

a

All animals were 35 days of age when placed on study.
 

^Doses of male rats were lowered at 20 weeks on study since, based
 

on the pattern of mortality, changes in body weight, and the
 

general condition of the animals used in similar studies of other
 

chemicals at Gulf South Research Institute, it was believed that
 

excessive mortality would occur before termination of the study.
 

C

A11 animals were started on study on the same day.
 

^When diets containing azinphosmethyl were discontinued, dosed rats and
 

their matched controls were fed control diets without corn oil for 7.5
 

weeks, then control diets (2% corn oil added) for an additional 27.5 weeks.
 

e

Time-weighted average dose = £(dose in ppm x no. of weeks at that dose)
 

E(no. of weeks receiving each dose)
 

9 
Table 2. Design of Azinphosmethyl Chronic Feeding Studies in Mice
 

Sex and 

Test 

Group 

Initial 

No. of 

Animals3 

Azinphosmethyl 

in Diet 

(ppm) 

Time o 

Dosed b 

(weeks ) 

n Study 

Observed0 

(weeks ) 

Male 

Matched-Control 10 0 92 

Low-Dose 50 31.3 

0 

80 

12 

High-Dose 50 62.5 

0 

80 

13 

Female 

Matched-Control 10 0 92 

Low-Dose 50 62.5 

0 

80 

12 

High-Dose 50 125 

0 

80 

12 

a

All animals were 35 days of age when placed on study.
 

b

All animals were started on study on the same day.
 

c

When diets containing azinphosmethyl were discontinued, mice received the
 

control diet until termination of the study.
 

10
 
The studies on the chemicals indicated above other than
 

azinphosmethyl were also conducted at Gulf South Research
 

Institute and were started no more that 3 months earlier or later
 

than the controls of azinphosmethyl. The control animals that
 

were used in the pooled-control groups were of the same strains
 

(Osborne-Mendel rats and B6C3F1 mice) and from the same supplier;
 

tissues from the pooled-control animals were diagnosed by several
 

different pathologists.
 

G. Clinical and Pathologic Examinations
 

All animals were observed twice daily for signs of toxicity,
 

weighed at regular intervals, and palpated for masses at each
 

weighing. Animals that were moribund at the time of clinical
 

examination were killed and necropsied.
 

The pathologic evaluation consisted of gross and microscopic
 

examination of major tissues, major organs, and all gross lesions
 

from killed animals and from animals found dead. The following
 

tissues were examined microscopically: skin, lungs and bronchi,
 

trachea, bone and bone marrow, spleen, lymph nodes, heart,
 

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

small intestine, large intestine, kidney, urinary bladder,
 

pituitary, adrenal, thyroid, parathyroid, mammary gland, prostate
 

or uterus, testis or ovary, and brain. Occasionally, additional
 

11
 
tissues were also examined microscopically. The different
 

tissues were preserved in 10% buffered formalin, embedded in
 

paraffin, sectioned, and stained with hematoxylin and eosin.
 

Special staining techniques were utilized when indicated for more
 

definitive diagnosis.
 

A few tissues from some animals were not examined, particularly
 

from those animals that died early. Also, some animals may have
 

been missing, cannibalized, or judged to be in such an advanced
 

state of autolysis as to preclude histopathologic evaluation.
 

Thus, the number of animals from which particular organs or
 

tissues were examined microscopically varies, and does not
 

necessarily represent the number of animals that were placed on
 

study in each group.
 

H. 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.
 

12
 
These data were analyzed using the statistical techniques
 

described in this section. Those analyses of the experimental
 

results that bear on the possibility of carcinogenicity are
 

discussed in the statistical narrative sections.
 

Probabilities of survival were estimated by the product-limit
 

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

report in the form of graphs. Animals were statistically
 

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

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

causes were not statistically censored. Statistical analyses for
 

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

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

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

One-tailed P values have been reported for all tests except the
 

departure from linearity test, which is only reported when its
 

two-tailed P value is less than 0.05.
 

The incidence of neoplastic or nonneoplastic lesions has been
 

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

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

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

the denominators included only those animals for which that site
 

was examined histologically. However, when macroscopic examination was required to detect lesions prior to histologic sampling
 

13
 
(e.g., skin or mammary tumors), or when lesions could have
 

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

consist of the numbers of animals necropsied.
 

The purpose of the statistical analyses of tumor incidence is to
 

determine whether animals receiving the test chemical developed a
 

significantly higher proportion of tumors than did the control
 

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

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

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

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

compared simultaneously with those for a control group, a
 

correction to ensure an overall significance level of 0.05 may be
 

made. The Bonferroni inequality (Miller, 1966) requires that the
 

P value for any comparison be less than or equal to 0.05/k. In
 

cases where this correction was used, it is discussed in the
 

narrative section. It is not, however, presented in the tables,
 

where the Fisher exact P values are shown.
 

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

continuity correction (Armitage, 1971), was also used. Under the
 

assumption of a linear trend, this test determines if the slope
 

of the dose-response curve is different from zero at the one-


tailed 0.05 level of significance. Unless otherwise noted, the
 

direction of the significant trend is a positive dose relation14
 
ship. This method also provides a two-tailed test of departure
 

from linear trend.
 

A time-adjusted analysis was applied when numerous early deaths
 

resulted from causes that were not associated with the formation
 

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

first tumor was observed were excluded by basing the statistical
 

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

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

such an early tumor was found, comparisons were based exclusively
 

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

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

obtained, the standard procedures for analyses of the incidence
 

of tumors (Fisher exact tests, Cochran-Armitage tests, etc.) were
 

followed.
 

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

incidence of tumors. Curves of the proportions surviving without
 

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

The week during which an animal died naturally or was sacrificed
 

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

methods of comparing these curves were used for two groups;
 

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

groups. The statistical tests for the incidence of tumors which
 

15
 
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 with its control was calculated
 

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

relative risk is defined as P£/PC where pt is the true binomial
 

probability of the incidence of a specific type of tumor in a
 

dosed group of animals and pc is the true probability of the
 

spontaneous incidence of the same type of tumor in a control
 

group. The hypothesis of equality between the true proportion of
 

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

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

of unity represent the condition of a larger proportion in the
 

dosed group than in the control.
 

The lower and upper limits of the confidence interval of the
 

relative risk have been included in the tables of statistical
 

analyses. The interpretation of the limits is that in approximately 95% of a large number of identical experiments, the true
 

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

control group would be within the interval calculated from the
 

experiment. When the lower limit of the confidence interval is
 

16
 
greater than one, it can be inferred that a statistically
 

significant result (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. RESULTS - RATS
 

A. Body Weights and Clinical Signs (Rats)
 

Mean body weights of low- and high-dose male and high-dose female
 

rats were lower than those of matched controls throughout the
 

study, while mean body weights of low-dose females were essentially the same as those of the controls (figure 1). Fluctuation in
 

the growth curve may be due to mortality; as the size of a group
 

diminishes, the mean body weight may be subject to wide
 

variation.
 

After 1 week on study, two high-dose males and two high-dose
 

females had generalized body tremors. At week 34, exophthalmos
 

was observed in dosed animals, leading to unilateral blindness in
 

10 high-dose females and bilateral blindness in 5 high-dose
 

females. This was diagnosed by the pathologist at the laboratory
 

as viral conjunctivitis.
 

During the second year of the study, clinical signs including
 

alopecia, rough and discolored hair coats, dyspnea, tachypnea,
 

pale mucous membranes, hematuria, epistaxis, vaginal bleeding,
 

and diarrhea were observed in both dosed and control rats.
 

B. Survival (Rats)
 

The Kaplan and Meier curves estimating the probabilities of
 

19
 
TIME ON STUDY (WEEKS) 

Figure 1. Growth Curves for Rats Fed Azinphosmethyl in the Diet 

20 
Figure 2. Survival Curves for Rats Fed Azinphosmethyl in the Diet 

21 
survival for sale and female rats fed azinphosaethyl in the diet
 

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

controls, are shown in figure 2.
 

In male rats, the result of the Tarone test for positive dose-


related trend in mortality over the bioassay is not significant
 

at the 0.05 level, with 6/10 (60%) of the control, 35/50 (70%) of
 

the low-dose, and 27/50 (54%) of the high-dose rats living to the
 

end of the bioassay. In females, the result of the larone test
 

has a probability level of 0.041, with 7/10 (70Z) of tn« control,
 

34/50 (68%) of the low-dose, and 25/50 (50%) of th« high-dose
 

rats surviving to termination of the study. Sufficient numbers
 

of rats of each sex were at risk for the development of tumors.
 

C. Pathology (Rats)
 

Histopathologic findings on neoplasms in rats are summarized in
 

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

are summarized in Appendix C, tables Cl and C2.
 

A variety of neoplasms are represented aaong the dosed and
 

matched-control groups of animals. Neoplasm occurred in a
 

variety of tissues, and each type has been encountered previously
 

as a spontaneous lesion in the Osborne-Mendel rat. The incidence
 

of neoplasms by type and site, and by group and sex of animal,
 

22
 
does not appear to be related to the administration of
 

azinphosmethyl.
 

A variety of nonneoplastic responses were represented among both
 

matched-control and dosed animals. Such lesions have been
 

encountered previously and are considered to be spontaneous
 

events, not unlike those commonly observed in aging Osborne-


Mendel rats.
 

Based on the histologic examination, there was no evidence for
 

the carcinogenicity of azinphosmethyl in Osborne-Mendel rats
 

under the conditions of this bioassay.
 

D. Statistical Analyses of Results (Rats)
 

Tables El and E2 in Appendix E contain the statistical analyses
 

of the incidences of those primary tumors that occurred in at
 

least two animals in one group and with an incidence of at least
 

5% in one or more than one group.
 

In some instances, the matched-control group had incidences of
 

tumors significantly higher (P < 0.05) than those in the pooled-


control group, exclusive of the matched controls. These
 

instances are indicated in tables El and E2 by the symbol "g"
 

placed beside the incidence shown for the matched controls. This
 

test was conducted assuming a binomial distribution of spontan23
 
eous tumors with the parameter given by the pooled controls
 

excluding the matched controls of the subject chemical (Fears et
 

al. , 1977). In other instances, the matched controls were not
 

statistically different from the pooled controls, but had a
 

higher incidence or an incidence comparable to one or more of the
 

dosed groups. When the incidence in the matched controls either
 

is significantly higher than that in the pooled controls or is
 

comparable to that in the dosed groups, the significance generated by the use of the pooled controls has been discounted in the
 

analysis.
 

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

positive dose-related trend on the combined incidence of islet-


cell adenomas or carcinomas of the pancreas is significant, using
 

either the pooled (P = 0.008) or matched (P = 0.033) controls.
 

The result of the Fisher exact test comparing the incidence in
 

the high-dose group with that in the pooled controls was also
 

significant (P = 0.015). Time-adjusted tests, eliminating
 

animals that died before week 52 on study, were performed on the
 

incidences of tumors of the pancreatic islet. The time-adjusted
 

incidences (pooled controls 2/88 [2%], matched controls 0/9,
 

low-dose 1/47 [2%], high-dose 6/44 [14%]) resulted in essentially
 

the same statistics as described for the non-adjusted tests.
 

24
 
Since, however, the spontaneous incidence of this lesion varies
 

in male Osborne-Mendel rats at this laboratory from 0% to 22%,
 

with a mean of 2%, the incidence found in the high-dose male rats
 

in this study can not be clearly implicated as a chemically
 

induced effect.
 

The Cochran-Armitage analyses of the combined incidence of
 

adenocarcinomas or cortical adenomas of the adrenal in male rats
 

show significant results (P < 0.001) when the pooled-control
 

group is used. The result is not significant using the matched-


control group. The result of the Fisher exact comparison of the
 

incidence in the high-dose group with that in the pooled controls
 

indicates a probability level of 0.001; however, the results of
 

the Fisher exact test are not significant when the incidence in
 

the matched-control group is compared with that in each dosed
 

group. In the incidence of adenocarcinoma of the adrenal alone,
 

the result of the Cochran-Armitage test is significant (P =
 

0.015) using the pooled-control group, but not so when the
 

matched-control group is used. The Fisher exact test comparing
 

the incidence in the high-dose group with that in the pooled-


control group indicates a P value of 0.033, which is above the
 

0.25 level required for significance when the Bonferroni
 

inequality criterion is used for multiple comparison. Therefore,
 

25
 
statistically, the association of the tumors in the adrenal is
 

not well established. No such tumor is observed in female rats.
 

In male rats, the results of statistical tests using the
 

pooled-control animals on the incidences of benign thyroid tumors
 

(follicular-cell adenomas, adenomas, or cystadenomas), malignant
 

thyroid tumors (adenocarcinomas, cystadenocarcinomas, or
 

papillary cystadenocarcinomas), or the combined follicular-cell
 

tumors are all significant. In each analysis, the result of the
 

Cochran-Armitage test is significant (P _< 0.008) using the pooled
 

controls, and the results of the Fisher exact comparisons of the
 

incidences in any of the dosed groups with the pooled-control
 

group show probability levels less than 0.025. The results of
 

the Fisher exact test comparing the incidence in the
 

matched-control group with that in each dosed group are not
 

significant. Time-adjusted analyses, eliminating animals that
 

died before week 52 on study, were performed on the incidences of
 

thyroid tumors. The analysis of time-adjusted data of 7/82 (9%)
 

in the pooled-control group, 1/9 (11%) in the matched-control
 

group, 14/44 (32%) in the low-dose group, and 14/43 (33%) in the
 

high-dose group resulted in essentially the same statistics as
 

those of the non-adjusted analysis. Since, however, the
 

spontaneous incidence of these neoplasms varies in male
 

Osborne-Mendel rats at this laboratory from 0% to 43%, with a
 

26
 
mean of 7%, the incidences found in low-dose or high-dose male
 

rats in this study can not be clearly implicated as a chemically
 

induced effect.
 

In females, the results of the statistical tests on the combined
 

incidence of the malignant thyroid tumors (adenocarcinomas, cystadenocarcinomas, or papillary cystadenocarcinomas) are not
 

significant. The incidence in the matched controls does not
 

differ statistically from that in the pooled controls. When the
 

benign thyroid tumors are combined with the malignant tumors, the
 

result of the Cochran-Armitage test on the combined incidence in
 

female rats, using the pooled controls, is significant (P =
 

0.008), and the results of the Fisher exact test show that the
 

incidences in the dosed groups are significantly higher (low-dose
 

P = 0.002; high-dose P = 0.021) than that in the pooled controls.
 

However, the incidence of 2/9 (22%) in the matched controls,
 

higher than that of either dosed group, makes the significance
 

seen in the use of the pooled controls questionable. Although
 

the results of the statistical tests of the combined incidence of
 

cystadenomas and adenomas in the thyroid are significant, the
 

incidence seen in the matched controls is comparable to those in
 

the dosed groups.
 

When the the number of female rats with some type of pituitary
 

tufflor (chromophobe adenomas, adenocarcinomas, adenomas, or
 

27
 
cystadenomas) are analyzed, the results of the Cochran-Armitage
 

test are not significant, and the Fisher exact comparison of
 

incidences in the low-dose and pooled-control groups indicates a
 

probability level of 0.040, which is above the 0.025 level
 

required by the Bonferroni inequality criterion when multiple
 

comparison is considered. The incidence in the high-dose group
 

is not significant.
 

In female rats, when hemangiomas and hemangiosarcomas are grouped
 

for analysis, the results of the Cochran-Armitage test are not
 

significant, but an indicated departure from linear trend is
 

observed (P = 0.018), using the pooled controls, since the incidence in the low-dose group is greater than that in the high-dose
 

group. The Fisher exact comparison of the incidences in the
 

low-dose and pooled-control groups indicates a probability level
 

of 0.036, which is above the 0.025 level required by the
 

Bonferroni inequality criterion when multiple comparison is
 

considered. The incidence in the high-dose group is not
 

significant. The incidence of these tumors in the male rats is
 

not significant.
 

Some incidences at specific tumor sites indicate a higher
 

incidence in the matched controls than in the pooled controls
 

(marked "g" in the tables) or a comparable or higher incidence in
 

the matched controls than in the dosed groups. Under these
 

28
 
circumstances, the significance generated by the use of the
 

pooled controls is questionable. The tumors which are not said
 

to be dose associated, because of these reasons, are the
 

pituitary tumors, the parathyroid tumors, and hemangiomas or
 

hemangiosarcomas in male rats; along with the liver tumors,
 

cortical adenomas in the adrenal, fibroadenomas of the mammary
 

gland, tumors of the uterus, and tumors of the pancreatic islet
 

in female rats.
 

In summary, the statistical tests suggest that the incidences of
 

thyroid and pancreatic islet-cell tumors in male rats are
 

associated with administration of azinphosmethyl. None of the
 

tumors in females could be associated with the test chemical.
 

29
 

IV. RESULTS - MICE
 

A. Body Weights and Clinical Signs (Mice)
 

Mean body weights of the high-dose female mice were lower than
 

those of the matched controls throughout most of the study, while
 

mean body weights of the low-dose females and both the high- and
 

low-dose males were essentially the same as those of the controls
 

(figure 3). Fluctuation in the growth curve may be due to mortality; as the size of a group diminishes, the mean body weight may
 

be subject to wide variation.
 

During the first year on study, the dosed animals were generally
 

comparable to the controls in appearance and behavior. At week
 

49, all dosed females appeared to be hyperactive.
 

During the second year of the study, clinical signs, including
 

rough hair coats, alopecia, abdominal distention, and hyperactivity (in a few incidences hyperactivity alternated with
 

hypoactivity), were noted in both dosed and control animals.
 

Rough hair coats were observed in high-dose males beginning at
 

week 60 and in low-dose males beginning at week 74. Convulsions
 

in one high-dose female, in one high-dose male, and in one
 

control male were periodically observed during the second year of
 

the study.
 

31
 
Figure 3. Growth Curves for Mice Fed Azinphosmethyl in the Diet 

32 
B. Survival (Mice)
 

The Kaplan and Meier curves estimating the probabilities of
 

survival for male and female mice fed azinphosmethyl in the diet
 

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

controls, are shown in figure 4.
 

The results of the Tarone test for positive dose-related trend in
 

mortality over the bioassay are not significant at the 0.05 level
 

in either sex. At least 74% of the male mice (controls 8/10
 

[80%], low-dose 45/50 [90%], high-dose 42/50 [84%]) and at least
 

70% of the female mice (controls 7/10 [70%], low-dose 44/50
 

[88%], high-dose 42/50 [84%]) lived to the end of the study.
 

Sufficient numbers of dosed mice of each sex were at risk for the
 

development of tumors.
 

C. Pathology (Mice)
 

Histopathologic findings on neoplasms in mice are summarized in
 

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

are summarized in Appendix D, tables Dl and D2.
 

A variety of neoplasms are represented among the dosed and
 

matched-control animals. Benign and malignant neoplasms occurred
 

in a variety of tissues, and each type has been encountered
 

previously as a spontaneous lesion in the B6C3F1 mouse. It is
 

33
 
Figure 4. Survival Curves for Mice Fed Azinphosmethyl in the Diet 

34 
apparent that the incidence of neoplasms by type and site, and
 

also by group and sex of animals, is without relationship; hence,
 

it is unattributable to chemical exposure. The significance of
 

hepatocellular carcinomas or adenomas in Bale mice is equivocal
 

(controls 2/8 [25%], low-dose 11/49 [22%], high-dose 19/50
 

[38%]).
 

A variety of nonneoplastic responses are represented aaong both
 

control and dosed aniaals. Such lesions have been encountered
 

previously and are considered spontaneous events, not unlike
 

those commonly observed in aging B6C3F1 mice. There was an
 

apparent increase in the incidence of cystic endoave trial hyperplasia in females (controls 2/7 [29%], low-dose 32/48 [67%],
 

high-dose 32/48 [67%]). Endo»etrial stroval polyps occurred only
 

in dosed females of the low-dose group (4%).
 

Based on the histologic examination, there we« *o evidence for
 

the careinog«nicity of arinpho»*«thyl i» K4C1V1 mice under the
 

conditions of this bioassay.
 

D« Statistical Analyses of Results (Mice)
 

Tables Fl and F2 in Appendix F contain the statistical analyses
 

of the incidences of those primary tumors that occurred in at
 

least two animals in one group and with an incidence of at least
 

5% in one or nore than one group.
 

35
 
In male mice, the incidence of hepatocellular carcinomas
 

indicates a significant linear trend (P = 0.006) when the
 

matched-control group is used in the Cochran-Armitage test, but
 

none of the results of the Fisher exact test using either matched
 

or pooled control groups have significance in the positive
 

direction. When the numbers of male mice with hepatocellular
 

adenomas or carcinomas or neoplastic nodules are tested, the
 

results of the Cochran-Armitage test using the pooled-control
 

group are significant (P = 0.048), but the Fisher exact
 

comparison of incidences of the high-dose and pooled-control
 

groups indicates a probability level of 0.040, which is above the
 

0.025 level required by the Bonferroni inequality criterion when
 

multiple comparison is considered. The overall analysis is that
 

the association of these tumors with the administration of the
 

chemical is not established.
 

The incidence of hemangiosarcomas of all sites in male mice is
 

significant when the incidence in the low-dose group (P = 0.020)
 

is compared with that in the pooled controls; however, dose
 

association is not apparent, because the results of the Cochran-


Armitage test and the incidence in the high-dose group are not
 

significant. The incidence of hemangiomas in the matched
 

controls (1/10 [10%]) exceeds the incidence of hemangiomas or
 

36
 
hemangiosarcomas in either dosed group. Thus, the dose
 

association of these tumors is questionable.
 

In female mice, there is no incidence of tumors with significant
 

statistical results.
 

In summary, there is no conclusive statistical evidence of the
 

association of tumors with the administration of azinphosmethyl
 

in B6C3F1 mice of either sex.
 

37
 

V. DISCUSSION
 

In this bioassay, azinphosmethyl had a toxic effect on both rats
 

and mice, as demonstrated by depressed mean body weights, clinical signs, and/or lower survival. High- and low-dose male rats,
 

high-dose female rats, and high-dose female mice had lower mean
 

body weights than their corresponding controls throughout the
 

study. Typical signs of organophosphorus intoxication were
 

present in a few animals of both species and included hyperactivity, tremors, and dyspnea. Convulsions in the mice may have
 

been related to organophosphorus intoxication, although they were
 

also seen in one control male mouse. In male rats and in both
 

male and female mice, tests for dose-related trends in mortality
 

over the bioassay were not significant at the 0.05 level. In
 

female rats, 50% of the high-dose animals survived until the end
 

of the bioassay, compared with 68% of the low-dose animals and
 

70% of the controls. Sufficient numbers of animals were at risk
 

in each species for development of late-appearing tumors.
 

A great many tumors of the endocrine organs were observed in both
 

dosed male and female rats but the small size of the matched
 

control groups made interpretation difficult. Those of the
 

adrenal in dosed males and females, the follicular cells of the
 

thyroid in dosed males and females, the anterior pituitary in
 

dosed males, and the parathyroid in dosed males occurred at
 

39
 
statistically significant incidences when compared with pooled
 

controls, but not with matched controls. Since the pathologist
 

examining the dosed and matched-control animals did not examine
 

the pooled controls, and since the incidences of the pituitary
 

and parathyroid in males, and of the thyroid in females were
 

significantly higher in the matched controls than in the pooled
 

controls, these neoplasms cannot be clearly related to
 

administration of azinphosmethyl. The incidence of
 

adenocarcinoma of the pituitary in female rats cannot be clearly
 

associated with administration of the test chemical, since the
 

dose-related trend and the incidence of tumors in the high-dose
 

group were not significant; also, the combined benign and
 

malignant tumors of the pituitary occurred at a lower level of
 

significance than the adenocarcinoma alone. Although the
 

incidence of tumors of the liver showed a dose-related trend in
 

the male rats, the incidences in the dosed groups were not
 

significantly higher than those in the controls, and these tumors
 

cannot, therefore, be clearly related to administration of the
 

test chemical.
 

In male rats, islet-cell adenomas or carcinomas of the pancreas
 

occurred at a significant incidence (P = 0.015) in the high-dose
 

male rats when compared with pooled controls (pooled controls
 

2/92, matched controls 0/9, low-dose 1/47, high-dose 6/45), and
 

40
 
the incidences showed a dose-related trend (P = 0.008), using the
 

pooled controls. Two of the high-dose males had carcinomas,
 

while the remaining four had adenomas. Since, however, the
 

spontaneous incidence of this lesion varies in male
 

Osborne-Mendel rats at this laboratory from 0% to 22%, with a
 

mean of 2%, the incidence found in the high-dose male rats in
 

this study can not be clearly implicated as a chemically induced
 

effect.
 

Follicular-cell tumors of the thyroid, either benign (adenomas,
 

follicular-cell adenomas, or cystadenomas), malignant (adenocarcinomas, cystadenocarcinomas, or papillary cystadenocarcinomas),
 

or combined benign and malignant occurred at significant incidences in dosed male rats when compared with pooled controls; the
 

combined tumors occurred at significant incidences (P = 0.001) in
 

both low- and high-dose groups when compared with pooled controls
 

(pooled controls 7/86, matched controls 1/9, low-dose 14/44,
 

high-dose 14/43), and the incidences showed a dose-related trend
 

(P < 0.001), using the pooled controls. Since, however, the
 

spontaneous incidence of these neoplasms varies in male
 

Osborne-Mendel rats at this laboratory from 0% to 43%, with a
 

mean of 7%, the incidences found in low-dose or high-dose male
 

rats in this study can not be clearly implicated as a chemically
 

induced effect.
 

41
 
In mice, hepatocellular adenomas or carcinomas occurred at a
 

significant incidence (P = 0.040) in the high-dose male mice when
 

compared with pooled controls (pooled controls 30/128, matched
 

controls 2/8, low-dose 11/49, high-dose 19/50), and the
 

incidences showed a dose-related trend (P = 0.048).
 

Hepatocellular adenomas and carcinomas were diagnosed among the
 

dosed and matched-control groups, and neoplastic nodules of the
 

liver were diagnosed in addition in animals of the pooled-control
 

group. The probability level of the liver tumors in the
 

high-dose group is above that required for significance using the
 

Bonferroni inequality criterion for multiple comparisons, and
 

similar high incidences have been noted in other groups of
 

controls at the same laboratory; thus, these liver tumors in male
 

mice are not considered to be related to administration of the
 

test chemical.
 

Azinphosmethyl is an organophosphorus chemical with a primary
 

biological action of inhibiting acetylcholinesterase. This
 

activity was very low when serum, homogenized brain, or submaxillary gland were tested in vitro; however, the chemical is rapidly
 

oxidized in vivo to the active chemical (DuBois et al., 1957).
 

In a 2-year feeding study using Wistar rats, there was no
 

indication that administration of the chemical at concentrations
 

up to 50-100 ppm induced tumors (Worden et al., 1973). This
 

42
 
concentration was comparable to that fed to the low-dose rats in
 

the present study.
 

It is concluded that under the conditions of this bioassay,
 

neoplasms of the thyroid and pancreatic islets suggest but do not
 

provide sufficient evidence for carcinogenicity of azinphosraethyl
 

in male Osborne-Mendel rats. Azinphosmethyl was not shown to be
 

carcinogenic in female Osborne-Mendel rats or in B6C3F1 mice of
 

either sex.
 

43
 

VI. BIBLIOGRAPHY
 

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

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

Ayers, J. and Johnson, 0., Chemical Economics Handbook, Stanford
 

Research Institute, Menlo Park, Calif., 1976, sec. 573.3007G
 

and 573.3007H.
 

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

Panel on Carcinogenicity of the Cancer Research Commission
 

of the UICC? Vol. _2, International Union Against Cancer,
 

Geneva, 1969.
 

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

Soc. B 34(2);187-220, 1972.
 

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

1970, PP. 48-52.
 

Cremlyn, R. J. W., Organophosphorus insecticides. Internatl. Pest
 

Control 16(6):7. 1974.
 

DuBois, K. P. and Kinoshita, F. K. , Influence of induction of
 

hepatic microsomal enzymes by phenobarbital on toxicity of
 

organic phosphate insecticides. Proc. S pc. Exptl. Bio. Med.
 

_L29:699-702, 1968.
 

DuBois, K. P., Thursh, D. R., and Murphy, S. D., Studies on the
 

toxicity and pharmacologic actions of the dimethoxy ester of
 

benzotriazine dithiophosphoric acid (DBD, Guthion).
 

J. Pharmacol. Exptl. Therap. 119; 208-218, 1957.
 

Fears, T. R., Tarone R. E., and Chu, K. C., False-positive and
 

false-negative rates for Carcinogenicity screens. Cancer
 

Res. 37;1941-1945, 1977.
 

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

significance tests, confidence limits and adjustments for
 

stratification. Rev. Int. Statist. Inst. _39 (2): 148-169,
 

1971.
 

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

incomplete observations. J. Amer. Statist. Assoc. 53;
 

457-481, 1958.
 

45
 
Linhart, M. S. , Cooper, J. A., Martin, R. L., Page, N. P., and
 

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

and Biomed. Res. 7:230-248. 1974.
 

Metcalf, R. L., Insecticides. In: Kirk - Othmer Encyclopedia of
 

Chemical Technologyf Vol. II, Interscience Publishers, New 

York, 1965, p. 702. 

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

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

Pasquet, J. , Mazuret, A., Fournel, J., and Koenig, F. H., Acute
 

oral and percutaneous toxicity of phosalone in the rat, in
 

comparison with azinphosmethyl and parathion. Toxicol Appl.
 

Pharmacol. 37:85-92. 1976.
 

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

Kaufman, D. G., Respiratory tract carcinogenesis in hamsters
 

induced by different numbers of administrations of benzo (a)
 

pyrene and ferric oxide. Cancer Res. 32:1073-1081, 1972.
 

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

Biometrika 62(3);679-682. 1975.
 

Uorden, A. N. , Wheldon, G. H., Noel, P. R. B., and
 

Mawdesley-Thomas, L. E., Toxicity of gusathion for the rat
 

and dog. Toxicol. Appl. Pharmacol. 14:405-412, 1973.
 

46
 
APPENDIX A
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

RATS FED AZINPHOSMETHYL IN THE DIET
 

47
 

TABLE A1.

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE RATS 

FED AZINPHOSMETHYL IN THE DIET 

CONTROL LOW DOSE HIGH DOSE
 

ANIMAL S INITIALLY IN STUDY 10 50 50
 

ANIMALS NECFOPSIED 10 50 49
 

ANIMAL S EXAMINE D HISTOP ATHOLOGICA LLY 10 49 49
 

INTEGUMENTAR Y SYSTEM
 

*SKI H (10) (50) (49)
 

SwUAMOU S CELL CARCINOMA 1 (2%)
 

FIBRCM A 1 (2X)
 

FIB fCSARCCMA 1 (2%) 1 (2%)
 

*SUBCUT TISSUE (10) (50) (49)
 

LIPCSARCOMA 1 (10X)
 

RESPISATCHY SYSTEM
 

SLUNG (10) (49) (48)
 

ALVECLAR/BRONCHIOLAB ADENOMA 1 (2%)
 

HEMATOtCISTIC SYSTEM
 

*SKIN (10) (50) (49)
 

MAST-CELL SARCOM A 1 (2%)
 

#BONE MArBO K (10) (49) (46)
 

LYMFHOM A METASTATIC 1 (231)
 

tfSPLEEN (9) (49) (47)
 

LEIOMYCMA 1 (2%)
 

HEHANGIOM A 1 (2%)
 

HEMANGIOSAPCOMA 2 (22%) 4 (9%)
 

MALIGNAN T LYMPHOMA, NOS 2 (4%) 1 (2%)
 

SLYMPH NODE (8) (49) (44)
 

LEIOMYOSABCOMA, METASTATIC 1 (2%)
 

MALIGNAN T LYMPHOMA , NOS 1 (2«)
 

* SKELETAL MUSCLE (10) (50) (49)
 

MALIG.LYKPHOMA^. HISTIOCYTIC TYPE i H2SL_.
 

# NUMBE R O F ANIMAL S WIT H TISSU E EXAMINE D MICROSCOPICALL Y 

* NUMBE R O F ANIMAL S NECHOFSIE D 

49 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE
 

#LUNG (10) (49)
 

LYMPHOMA METASTATIC
 

#HEART (10) ("8)
 

LYMPHOMA METASTATIC
 

#LIVER (9) (49)
 

LYMPHOMA METASTATIC 1 (2%)
 

#PANCREAS {9) (47)
 

LYMPHOMA METASTATIC 1 (2%)
 

#ADRENAL (9) (45)
 

LYMPHOMA KE1ASTATIC
 

CIRCUUTCRY SYSTEM
 

#HEART (10) (48)
 

FIDHOSARCCMA, METASTATIC 1 (2%)
 

HEMANGIOSABCOMA, METASTATIC
 

DIGESTIVE SYSTEM
 

#LIVER (9) (49)
 

ADENOMA, NOS 1 (2%)
 

HEPATOCEi.LUI.AR ADtNOM A 1 (1V/.) 3 (6*)
 

*PANCREAS (9) (47)
 

ACINAfe-CtLL ADENOM A 1 (2%)
 

LIFCSARCOMA, METASTATIC 1 (27.)
 

#STOMACH (9) (47)
 

LEIOMYOSARCGKA
 

#5i1ALL INTESTINE (9) (47)
 

LEICMYOSAHCOKA, METASTATIC
 

URINAH Y SYSTEM
 

#KIDNEY (10) (49)
 

TRANSITIONAL-CELL CARCINOMA 1 (2%)
 

LIPOSARCOHA 2 Jl%)


* NUMBE R OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBE R OF ANIMAL S NECHOESIED
 

HIGH DOSE
 

(48)
 

1 (2*)
 

(47)
 

1 (2%)
 

(46)
 

1 (2%)
 

(45)
 

(46)
 

1 (2%)
 

(47)
 

1 (2%)
 

(46)
 

5 (11X)
 

(45)
 

(47)
 

1 (2%)
 

(48)
 

1 (2%)
 

(47)
 

__,
 

50
 
TABU A1. MALE RATS: NEOPLASM! (CONTMUJEB) 

CONTROL LOH DOSE HIGH DOSE
 

ENDOCRINE SYSTEM
 

#FITUITABY	 (»)
 (46) (43)
 

ADENOMA, NOS 3 (7%)
 

CHROBOPHOBZ ADENOMA u (<*ux) 21 (46%) 13 (30%)
 

CHROMOPHOBE CARCINOMA 2 (5%)
 

CYSTADENOMA, HOS 2 (5%)
 

•ADRENAL	 (9) (45) (46)
 

ADENOCARCINOMA, NOS 1 (2*) 3 (7X)
 

CORTICAL ABENOKA 1 (11X) 3 (7«) 7 (15%)
 

PHECCHROBOCYTOMA 1 (2«)
 

*THlfiOID (9) (44) (43)
 

ADENOHA. NOS 2 (5X) 2 (5»)
 

ABI8CCA8CINOMA, NOS 3 (7%) 3 (7X)
 

FQLUCULAR-CEIL AEtNOBA 1 (11») 1 (2«)
 

CYStADf BOBA. NOS 7 (16S) 10 (23S)
 

CYSTADENOCARCINQMA, NOS 1 (2X)
 

PAPILLARY CYSTADENOCARCINOMA. NOS 1 (2%)
 

#PARATHYROID (5) (26) (24)
 

ADENCBA, NOS 1 (20%) 4 (17X)
 

#PAHCREATle ISLETS ,t9) (47) (45)
 

ISLET-CELL ADENOMA 1 (2X) 4 (9X)
 

ISLET-CELL CARCINOMA 2 (4%)
 

REPRODUCTIVE SYSTEM
 

*MAMMARY GLAND (10) (50) (49)
 

CYSTADENOCARCINOMA, NOS 1 (2X)
 

FIBBftBA 2 (4X)
 

CYSIflBEOADENOMA	 1 (10%)
 

#PROSTATE ( 10) (47) (45)
 

PAPI1LARY ADENOMA 1 (2%)
 

fTESTIS (10) (49) (48)
 

INTERSTITIAL-CELL TUHOR 1 (2X)
 

. • - " ­ NERVOUS SYSTEM
 

IBRAIN (10) (49) (48)
 

_ GLIQBL4STOMA_M£tIII2£fiE . .i_UiJ
 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROFSIED
 

51
 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE
 

SPECIAL SENSE ORGANS
 

NONE
 

HUSCULCSKELETAL SYSTEM
 

*RIB (10) (50) (49)
 

HEHANGIOSAECOHA 1 (2%)
 

*SKELETAL MUSCLE (10) (50) (49)
 

RHABDOMYOSABCOHA 1 (2%)
 

BODY CAVITIES
 

*ABDOMINAL CAVITY (10) (50) (49)
 

HEMANGIOKA 1 (2%)
 

*PARIETAL PERITONEUM (10) (50) (49)
 

LEIOMYOSARCOMA, METASTATIC 1 (2%)
 

*TUNICA VAGINALIS (10) (50) (49)
 

MESOTHELICMA, NOS 1 (2X)
 

ALL OTHEE SYSTEMS
 

*MULTIPLE ORGANS (10) (50) (49)
 

LIECSARCOMA, BETASTATIC 1 (10%)
 

ANIMAL EISFOSITION SUMMARY
 

ANIMALS INITIALLY IN STUDY 10 50 50
 

NATURAL DEATHS 2 it 9
 

MORIBUND SACRIFICE 2 1 1 14
 

SCHEDULED SACRIFICE
 

ACCIDENTALLY KILLED
 

TERMINAL SACRIFICE 6 35 27
 

ANIfiAL MISSING
 

a INCLUDES AUTOLYZED ANIMALS
 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBEE OF ANIMALS NECROPSIED
 

52
 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

CONTROL LOB DOSE HIGH DOSE
 

TUMOR SUMMAR Y
 

TOTAL ANIMALS WITH ERIMARY TUMORS* 7 40 41
 

TOTAL PRIMARY TUMORS 13 61 76
 

TOTAL ANIMALS WITH BENIGN TUHORS 6 32 33
 

TOTAL BENIGN TUMORS 8 45 55
 

TOTAL ANIMALS WITH MALIGNANT TUMORS 4 15 15
 

TOTAL MALIGNANT TUMORS 4 15 21
 

TOTAL ANIMALS WITH SECONDARY TUMORS* 1 3 3
 

TOTAL SECONDARY TUMORS 1 5 8
 

TOTAL ANIMALS WITH TUMORS UNCERTAIN­ BENIGN OR MALIGNAN T 1 1
 

TOTAL UNCERTAIN TUMORS 1 1
 

TOTAL A N I M A LA N I M A LS WITH TUMORS UNCEHTAIN UNCEHTAIN-­ PRIMAEY OR METASTATI METASTATIC
 

TOTAL UNCERTAI UNCERTAIN TUMORS
 

* PRIMARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 

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

53
 
TABLE A2.

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS 

FED AZINPHOSMETHYL IN THE DIET 

ANIMALS INITIALLY IN STUDY
 

AHIMALS &ECROESIED
 

ANIMALS EXAMINED HISTOP ATHOLOGICA LLY
 

INTEGUMENTARY SYSTEM
 

*SKIN
 

KERATOACANTHOMA
 

LIPCSARCOMA
 

RESPIBATCBY SYSTEM
 

#LUNG
 

ALVECLAR/BRONCHIOLAB ADENOMA
 

HEMATOFCIETIC SYSTEM
 

*SPLEEN
 

HEMANGIOMA
 

HEMANGIOSARCOMA
 

CIRCUIATCRY SYSTEM
 

NONE
 

DIGESTIVE SYSTEM
 

#LIVEB
 

ADENCCARCINOMA, NOS
 

HEPATOCELLULAR ADENOM A
 

HEPATOCELLULAR CARCINOMA
 

HEMANGIOSAECOMA, ME1ASTATIC
 

tSTOMACH
 

H2MANGIOS.A.RC.OMA.
 

CONTROL
 

10
 

10
 

9
 

(10)
 

1 (10*)
 

(9)
 

(9)
 

(*)
 

2	 (22%)
 

(9)
 

L0« DCSE HIGH DOSE
 

au9 50
 

49 49
 

48 46
 

(49)	 (49)
 

1 (2%)
 

(48)	 (46)
 

1 (2%)
 

(43)	 (41)
 

1 (2*) 1 (2%)
 

1 (2%)
 

(47)	 (45)
 

1 (2%)
 

2 (4«) 4 (9%)
 

1 (2%)
 

1 (2%)
 

(46) (44)
 

JLJ1S1
 

#	 NUM3ER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

*	 NUMBE R OF ANIMALS NECBOfSIED
 

a l 5 0 ANIMAL S WER E INITIALL Y IN THE STUDY , BUT 1 ANIMA L HAS FOUN D TO EE A MAL E 

ANIMA L IN A FEMAL E GROUP . 

54 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED) 

CONTRO L L OW DOSE 

URINAR Y SYSTE M 

#KIDNE Y (9) (48)

 

MULTIPL E POLYEOSI S 1 (11% )

 

ENDOCRIN E SYSTE M 

#PITUITARY (3) (U4) 

ADENOMA , SOS 

ADENCCAHCINOMA , NO S 8 (18») 

CHROMOPHOB E ADENOM A 2 (25%) U (32%) 

CYSTADENCMA , NO S 

#ADRENA L ( 9) (<*5) 

CORTICA L ADENOM A 1 (11%) 4 (9%) 

PHECCHROMOCYTOK A 

#THYROI D (9) (45) 

ADENCMA , NO S 1 (11%) 2 (4%) 

ADENCCARCINOMA , NO S 1 (2%) 

PAPILLAR Y ALENOCARCINOM A 

CYSTADENOMA , NO S 4 (9%) 

PAPILLAR Y CYSTADENOCARCINOMA.NO S 1 (11%) 1 (2%) 

#PARATHYROI D (7) (31)

 

ADENCMA , NOS 

tPANCREATI C ISLETS (7) (41) 

ISLET-CELL ADENOM A 2 (29% ) 1 (2%) 

REPRODUCTIV E SYSTE h 

*MAMMAR Y 3LAN D (10) (49) 

ADENCMA , NO S 1 (2%) 

ADENCCARCINOMA , NO S 2 (4%) 

CYSTADENOCARCINOMA , NO S 1 (2%) 

PAPILLAR Y CYSIADENOCAECINOMA,NO S 

LIPOMA 1 (2%) 

LEICBYOSARCOfl A 1 (2%) 

FIBRCADENOM A 2 (20%) 9 (18%) 

#UTERU S (9) (43) 

ENDOMETRIA L STROM AL_POLYP 1 (1UL 311%) 

# NUMBER OF ANIMALS WITH 1ISSUI EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECHOPSIED
 

HIGH DOSE 

(45) 

(41) 

1 (2%) 

1 (2%) 

12 (29%) 

1 (2%) 

(41 ) 

8 (2 C%) 

2 (5%) 

(38) 

1 (3%) 

1 (3%) 

3 (8%) 

1 (3%) 

(19) 

1 (5%) 

(39) 

1 (3%) 

(49) 

1 (2%) 

9 (18%) 

(41) 

55 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED) 

HEMANGIOMA
 

#OVAR Y
 

AEENCCARCINOMA, NOS
 

PAPI1LARY ADENOCARCINOMA
 

NERVOUS SYSTEM
 

NONE
 

SPECIAL SENSE CIiGANS
 

NONE
 

MUSCULOSKELETAL SYSTEM
 

NONE
 

BODY CAVITIES
 

NONE
 

ALL OTHER SYSTEMS
 

NONE
 

ANIMAL DISPOSITION SUMMARY
 

ANIMALS INITIALLY IN STUDY
 

NATURAL DEATHS
 

MORIBUND SACRIFICE
 

SCHEDULED SACRIFICE
 

ACCIDENTALLY KILLED
 

TERMINAL SACRIFICE
 

ANIMAL MISSING
 

31 INCLUDES AUTOLYZED ANIHALS
 

CONTROL LOW DOSE HIGH BOSE
 

1 (2%)
 

(9)	 (47) (42)
 

1 (2%)
 

1 (2X)
 

10 50 50
 

1 5 9
 

2 10 16
 

7 34	 25
 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECBOPSIED
 

56
 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE
 

TUMOR SUMMARY 

TOTAL ANIMALS WITH PRIMARY 1UMORS* 

TOTAL PRIMARY TUMORS 

7 

14 

37 

62 

26 

51 

TOTAL ANIMALS WITH BENIGN TUKOBS 

TOTAL BENIGN TUMORS 

7 

12 

32 

44 

24 

45 

TOTAL ANIMALS WITH MALIGNANT TUMORS 

TOTAL MALIGNANT TUMORS 

2 

2 

13 

18 

6 

6 

TOTAL ANIMALS WITH SECONDARY TUMORS* 

TOTAL SECONDARY TUMORS 

1 

1 

TOTAL ANIMALS WITH TUMORS UNCERTAIN­ BENIGN OR MALIGNANT 

TOTAL UNCERTAIN TUMORS 

TOTAL ANIMALS WITH TUMORS UNCERTAINPRIMARY OR METASTATIC 

TOTAL UNCERTAIN TUMORS 

* PRIMARY TUMORS: ALL TUM06S EXCEPT SECONDARY TUMORS 

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

57
 

APPENDIX B
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

MICE FED AZINPHOSMETHYL IN THE DIET
 

59
 

TABLE B1 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE MICE 

FED AZINPHOSMETHYL IN THE DIET 

CONTROL LOW DOSE HIGH DOSE
 

ANIKALS INITIALLY IN STUDY 10 50 50
 

ANIMALS NECROPSIED 10 50 50
 

ANIMALS EXAMINED HI STCPATHOLOGICALLY 10 i»9 50
 

INTEGUMENTARY SYSTEM
 

*SKIN (10) (50) (50)
 

FIBSCSARCOMA 1 (2%)
 

LEIOMYOSARCOMA 1 (2%)
 

*SUBCUT TISSUE (10) (50) (50)
 

FIBRC5ARCCMA 1 (2%)
 

LEIOMYOSARCOMA 1 (2%)
 

RESPIRATORY SYSTEM
 

»LUNG (10) (49) (50)
 

ALVECLAE/BRONCHIOLAR ADENOMA 1 (10K) 6 (12*) 4 (8%)
 

ALVEOLAR/BRONCHIOLAR CARCINOMA 1 (in») 2 (H%)
 

HEMATOECIEIIC SYSIEM
 

#BONS MARRO W (1C) (49) (50)
 

HEMANGICMA 1 (2X)
 

HEMANGIOSARCOHA, METASTATIC 1 (2%)
 

»SPLEEN (8) (46) (46)
 

HEMANGIOMA 1 (2«)
 

HEMANGIOSABCOMA 1 (2%)
 

MALIG.LYMPHOMA, LYMPHOCYTIC TYPE 1 (2%)
 

#LYMPH NODE (9) (46) (46)
 

HEMANGIOMA 1 (1H)
 

MALIGNANT LYMPHOMA, NOS 1 (2%)
 

tMESENTERIC L. NODE (9) (46) (46)
 

MALIG. LYMPHOMA, HISTIOCYTIC TYPE 1 (2X)
 

CIHCULA1CRY SYSTEM
 

NONE .
 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECHOFSIED
 

61
 
TABLE B1. MALE MICE: NEOPLASMS (CONTINUED) 

CONTRO L LOW DOSE HIGH DOSE 

DIGESTIV E SYSTE M 

#LIVE R (8) (<*9) (50) 

HEPATOCELLULAf i ADENOM A 2 (25%) 8 (16%) 7 (1U% ) 

HEPATOCELLULA R CARCINOM A 3 (6X) 12 (2U%) 

HIMANGIOSAECOM A 2 (US) 

URINAR Y SYSTE M 

NON E 

ENDOCRIN E SYSTE M 

NON E 

REPRODUCTIV E SYSTE M 

NON E 

NERVOU S SYSTEM 

NON E 

SPECIAL SENSE ORGAN S 

*EYE/LACRIMA L GLAN D (10) (50) (50) 

PAPILLAR Y CYSTADENOMA , NO S 1 (10%) 

MUSCULOSKELETA L SYSTEfl 

NON E 

BODY CAVITIES 

NON E 

A LL OTHE R SYSTEMS 

NON E 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECEOPSIED
 

62
 
TABLE B1. MALE MICE: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE
 

ANIMA L DISPOSITION SUMMAR Y
 

ANIMALS INITIALLY IN STUDY 10 50 50
 

NATUFA L DEATHS 1 1 1
 

MORIBUND SACRIFICE 1 it 7
 

SCHEDULED SACRIFICE
 

ACCIDENTALLY KILLED
 

TERMINAL SACRIFICE 8 45 42
 

ANIKA L MISSING
 

a INCLUDES AUTOLY2ED ANIMALS
 

TUMOR SUMMAR Y
 

TOTAL ANIMALS WITH PRIMARY TUMORS* a 23 23
 

TOTAL PRIMARY TUMORS 6 26 28
 

TOTAL ANIMALS WITH BENIGN TUMORS a 16 1C
 

TOTAL BENIGN TUMORS 5 16 11
 

TOTAL ANIMALS WITH MALIGNANT TUMORS 1 8 15
 

TOTAL MALIGNANT TUMORS 1 10 17
 

TOTAL ANIMALS WITH SECONDARY TUMORS# 1
 

TOTAL SECONDARY TUMORS 1
 

TOTAL ANIMALS WITH TUMORS UNCERTAIN­ BENIGN OR MALIGNANT
 

TOTAL UNCERTAIN TUMORS
 

TOTAL ANIMALS WITH TUMORS UNCERTAIN­ FRIMABY OR METASTATIC
 

TOTAL UNCERTAIN TUMORS
 

* PRIMARY TUMORS: ALL TOMORS EXCEPT SECONDARY TUMORS
 

# SECCNDARY TUMORS: METASTATIC TUHORS OR TUMORS INVASIVE INTO AN ADJACENT OEGAN
 

63
 
TABLE B2.

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE MICE 

FED AZINPHOSMETHYL IN THE DIET 

HIGH DOSE 

50 

50 

49 

(50) 

3 (6*) 

(50) 

1 (2*) 

1 (2X) 

(50) 

1 (2%) 

(50) 

1 (2%) 

(50) 

(50) 

1 (2X) 

3 (6%) 

(45) 

2_Ji«I_ 

ANIMALS INITIALLY IN STUDY 

ANIMAL S NECEOFSIE D 

ANIMAL S EXAMINE D HISTOPAT HOLOGICA LL Y 

INTEGUMENTAR Y SYSTE M 

NON E 

RESPIBA1CF Y SYSTE M 

#LUN G 

ALVEOLAR/BRONCHIOLA R ADENOM A 

PAPILLAR Y CYSTADENOCARCINOMA.ME T 

HEMATOECIETI C SYSTE M 

'MULTIPL E ORGAN S 

MALIGNAN T LYMPHOMA , NO S 

MALIG.LYMPHOMA , LYMPHOCYTI C TYP E 

LYMFHCM A LYMPHOCYTI C MEIASTATIC 

MALIG.LYMPHOK A HISTIO-TYPE

GRANULOCYTI C LEUKEMI A 

*SUBCU T TISSUE 

MALIG.LYMPHOKA , LYMEHOCYTI C

*MAMMAR Y GLAN D 

LYKPHCM A METASTATI C 

#BON E MARRO W 

LYMPHOM A MEIASTATIC 

*SPLEEN 

HEMANGIOSAfiCOM A 

MALIGNAN T LYMPHOMA , NO S 

 META S 

 TYP E 

MALIG.LYMPHOMA , LYMPHOCYTIC TYPE 

MALIG.LYMPHOMA , HISTIOCYTIC TYP E 

#LYMP H NODE 

MALIG N A NT_LYMPHOMAt._]iOS 

CONTROL 

10. 

10 

10 

(10) 

1 (10*) 

(10) 

1 (10*) 

(10) 

(10) 

(10) 

1 (10%) 

(9) 

1 (11%) 

(9) 

„.-,„„ -g-rf- -n — — -. , rm ­

LCW DOSE 

50 

50 

49 

(50)

1 (2X) 

(50) 

1 (2%) 

1 (2X) 

(50) 

(50) 

(K7 ) 

(49) 

1 (2%) 

2 (US) 

(40)

i_JML__ 

* NUMBER OF ANIMALS WITH 1ISSUE EXAMINED MICROSCOPICALLY
 

* NUMBE R OF ANIMALS NECKOPSIED
 

64 
TABLE B2. FEMALE MICE: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE
 

LYMPHOMA METASTATIC 1 (11%)
 

LYMPHOMA LYMPHOCYTIC METASTATIC
 

MALIG. LYMPHOMA. HISTIOCYTIC TYPE 1 (3%)
 

#LUNG (10) (50)
 

LYMFHOMA METASTATIC 1 (10%)
 

GRANULOCYTIC LEUKEMIA 1 (2%)
 

tLIVER (10) (49)
 

LYKPHCMA METASTATIC 1 (10%)
 

LYMPHOMA LYMPHOCYTIC METASTATIC
 

#SMALL INTESTINE (10) C*8)
 

MALIG.LYMPHOMA, LYMFHOCYTIC TYPE 1 (10%)
 

LYMPHOMA LYMPHOCYTIC METASTATIC
 

SKIDNEY (10) (49)
 

MALIC. LYMPHOMA, LYMEHOCYTIC TYPE
 

MALIG.LYKPHOM A HISTIO-TYPE BETAS 1 (2%)
 

fKIDNEY/CORTEX (10) (49)
 

LYKFHCMA METASTATIC 1 (10%)
 

#ADRENAL (10) (47)
 

LYKPHCMA METASTATIC 1 (10%)
 

CIRCULATCRY SYSTEM
 

NCNE
 

DIGESTIVE SYSTEM
 

#SALIVABY GLAND CAPSU (10) (49)
 

HEtlANGICMA 1 (2%)
 

#LIVER (10) (49)
 

HEPATOCELLULAR ADENOM A
 

HEPATOCELLULAR CARCINOMA 1 (10%)
 

URINAR Y SYSTEM
 

NONE
 

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

HIGH DOSE
 

1 (2%)
 

(50)
 

1 (2%)
 

(50)
 

1 (2%)
 

1 (2%)
 

(50)
 

1 (2%)
 

(50)
 

1 (2%)
 

(5C)
 

(49)
 

(49)
 

(5C)
 

1 (2%)
 

65
 
TABLE B2. FEMALE MICE: NEOPLASMS (CONTINUED) 

CONTRO L LOW DOSE 

ENDOCRIN E SYSTE M 

((PITUITAR Y 

CHEOMOPHOB E ADENOM A 

(7) (39) 

1 (3«) 

#THYROI D 

CYSTADENCMA , NO S 

PAPILLAR Y CYSTADENOMA , NO S 

PAPILLAR Y CYSTADENOCARCINOMA,NO S 

(9) 

1

1

 (11% ) 

 (11X ) 

(42 ) 

REPRODUCTIV E SYSTE M 

*MAMMAR Y GLAN D (10) (50) 

PAPILLAR Y CYSTADENOCARCINOMA.NO S 

FIBRCADENOM A 

#UTERU S (7) (48) 

LEICBYOSAECOM A 

ENDOMETRIA L STROBA L POLY P 2 (4«) 

• CERVI X UTERI (7) (48) 

LEICMYOSARCOM A 1 (2%) 

tOVAR Y (9) (47) 

GRANULOSA-CEL L TUMO R 

NERVOU S SYSTEM 

NCN E 

SPECIAL SENS E ORGAN S 

NON E 

HUSCOLOSKELETA L SYSTE M 

NON E 

BODY CAVITIE S 

*PELVIS (10) (50) 

LIECSARCOM A 

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

* NUMBE R OF ANIMAL S NECfiOESIE D 

HIG H DOSE 

(40 ) 

(46 ) 

1 (2%) 

(50) 

1 (2%) 

1 (2%) 

(48) 

1 (2%) 

(48) 

(41) 

1 (2X) 

(50) 

_J_12SI. 

66 
TABLE B2. FEMALE MICE: NEOPLASMS (CONTINUED) 

ALL OTHER SYSTEMS
 

*MUL1IELE ORGANS
 

LIPOSARCOMA, METASTATIC
 

ANIMAL DISPOSITION SUMMARY
 

ANIMALS INITIALLY IN STUDY
 

NATURAL DEATHS
 

MORIBUND SACRIFICE
 

SCHEDULED SACRIFICE
 

ACCIEENTALLY KILLED
 

TERMINAL SACRIFICE
 

ANIMA L MISSING
 

a INCLUDES AUTOLYZED ANIMALS
 

TUMOR SUMMARY
 

TOTAL ANIMALS WITH ERIMARY


TOTAL PRIMARY TUMORS
 

CONTROL
 

(10)
 

10
 

3
 

7
 

 1UHORS* 5
 

6
 

TOTAL ANIMALS WITH BENIGN TUMORS 

TOTAL BENIGN TUMORS 

1 

1 

TOTAL ANIMALS WITH MALIGNANT TUMORS 

TOTAL MALIGNANT TUMORS 

5 

5 

TOTAL ANIMALS WITH SECONDARY TUMOHS* 

TOTAL SECONDARY TUMORS 

3 

7 

TOTAL ANIMALS WITH TUMOBS

BENIGS OR MALIGNANT 

TOTAL UNCERTAIN TUMOBS 

 UNCEBTAINTOTAL ANIMALS WITH TOHOHS UNCERTAIN ­

PEIBABY OH BETASTATIC 

TOTAL UNCERTAIN TUHORS
 

* PRIMARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 

LOW DOSE HIGH DOSE 

(50) (50) 

1 (2%) 

50 

3 

3 

50 

2 

6 

44 42 

10 

13 

5 

5 

7 

a 

2 

2 

17 

19 

6 

6 

11 

12 

i) 

8 

1 

1 

* SECONDARY TUMORS: METASTATIC TUMORS OR TUMORS INVASIVE ISTO AN ADJACENT ORGAN
 

67 

APPENDIX C
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS
 

IN RATS FED AZINPHOSMETHYL IN THE DIET
 

69
 

TABLE C1 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE RATS 

FED AZINPHOSMETHYL IN THE DIET 

CONTROL LOW DOSE
 

ANIMALS INITIALLY IN STUDY 10 50
 

ANIMALS NECEOPSIED 10 50
 

ANIMALS EXAMINED HISTOPATHO LOGICALLY 10 49
 

INTEGUMENTAR Y SYSTEM
 

*SKIN (10) (50)
 

ULCER, CHRONIC 2 (20%)
 

*SUBCUT TISSUE (10) (50)
 

FIBRCSIS 1 (2%)
 

RESPIRATCEY SYSTEM
 

#LUNG (10) (49)
 

CONGESTION, NOS 1 (10%) 3 (6%)
 

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

HEMOEKHAGE 2 (>4%)
 

INFLAMMATION, NOS 3 (30%) 12 (24«)
 

INFLAMMATION, FOCAL 1 (10%)
 

#LUNG/ALVEOLI (10) (49)
 

MINERALIZATION
 

HEMORRHAGE 1 (2%)
 

INFLAMMATION, NOS 1 (28)
 

HEMATOFCIETIC SYSTEM
 

#BONE MARRO W (10) (49)
 

CONGESTION, NOS
 

EDEMA, NOS
 

HEMOERHAGE
 

HYEEBELASIA, HEM A TO POIETIC 1 (10%)
 

HYEOFLASIA, H EMATOPOIETIC
 

APLASIA, HEMATOPOIETIC
 

#SPLEEN (9) (49)
 

CONGESTION,. NOS . _ _ _3 J6%L _ _
 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

HIGH DOSE
 

50
 

49
 

49
 

(49)
 

(49)
 

(48)
 

7 (15%)
 

1 (2%)
 

1 (2%)
 

9 (19%)
 

2 (4%)
 

(48)
 

1 (2%)
 

(46)
 

2 (4%)
 

1 (2%)
 

1 (2%)
 

6 (13*)
 

2 (4%)
 

1 (2%)
 

(47)
 

1 _[2%1
 

71
 
TABLE C1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE
 

HEM06EHAGE 1 (2%)
 

MYELCID METAPLASIA 1 (2%) 6 (13*)
 

SLYHPH NODE (8) (49) (44)
 

INFLAMMATION, ACUTE 1 (2%)
 

INFLAMMATION, CHRONIC 1 (2X)
 

PLASMA-CELL INFILTRATE 1 (2%)
 

PLASMACYTOSIS 2 (25%)
 

HYPEBPLASIA, RETICULUM CELL 1 (13%) 2 (4%) 1 (2%)
 

HYPEBPLASIA, LYMPHOID 8 (16%)
 

CIRCU1ATCEY SYSTEM
 

#HEART (10) (48) (47)
 

FIBROSIS, DIFFUSE 2 (20%) 2 (4%) 9 (19%)
 

#APEX OF HEART (10) (48) (47)
 

FIBRCSIS, DIFFUSE 1 (2X)
 

ttHEART/VENTRICLE (10) (48) (47)
 

FIBROSIS, DIFFUSE 1 (10%) 1 (2%) 5 (11X)
 

ttMYOCARDIUM (10) (48) (47)
 

FIBROSIS 5 (10%)
 

FIBRCSIS, DIFFUSE 2 (4%)
 

#ENDOCARDIUM (10) (48) (47)
 

FIBROSIS 1 (10%)
 

*AORTA (10) (50) (49)
 

MEDIAL CALCIFICATION 1 (10%) 1 (2X)
 

*PULMONARY ARTERY (10) (50) (49)
 

MINERALIZATION 1 (2X)
 

HYPERPLASIA, NOS 1 (2X)
 

*MESENTERIC ARTERY (10) (50) (49)
 

THRCKBOSIS, NOS 3 (6X)
 

INFLAMMATION, CHRONIC 1 (2X)
 

PERIAHTERITIS 1 (2%) 3 (6X)
 

MEDIAL CALCIFICATION 1 (2X)
 

*TESTICULAR ARTERY (10) (50) (49)
 

PERIARTERITIS 1 (2X)
 

tHEPATIC SINUSOID (9) (49) (46)
 

CONGESTION^ NOS 1 J2X1_.
 

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

72
 
TABLE C1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE
 

DIGESTIVE SYSTEM
 

#SALIVAEY GLAND (10) (48)
 

INFLAMMATION, CHBONIC
 

ATROEHY, NOS
 

SLIVER (9) (49)
 

CONGESTION, NOS 1 (11*) 3 (6%)
 

NECBCSIS, FOCAL
 

METAMORPHOSIS FATTY 1 (118) 1 (2%)
 

CYTOPLASMIC CHANGE, NOS
 

CYTOELASMIC VACUOLI ZATION
 

HYPEETROPHY, NOS 1 (11%) 5 (10%)
 

HYFEETBOPHY, FOCAL 8 (16%)
 

HYPEEPLASIA, NOS 3 (6%)
 

HYFEEPLASIA, FOCAL 5 (10%J
 

ANGIECTASIS 1 (11%) 6 (12%)
 

HEMATOPOIESIS
 

#HEPATIC CAPSULE (9) (49)
 

CONGESTION, NOS 2 (22%) 7 (14%)
 

ANGIECTASIS 5 (10%)
 

#LIVER/PERIPORTAL (9) (49)
 

METAMORPHOSIS FATTY 1 (11*)
 

CYTOPLASMIC CHANGE, NOS 1 (2%)
 

CYTOPLASMIC VACUOLI ZATION 2 (4%)
 

*BILE DUCT (10) (50)
 

INFLAMMATION, FOCAL
 

HYPERPLASIA, NOS 4 (40%) 9 (18%)
 

#PANCREAS (9) (47)
 

INFLAMMATION, ACUTE
 

INFLAMMATION, CHRONIC 1 (2%)
 

INFLAMMATION, CHRONIC NECROTIZIN
 

FI3RCSIS, DIFFUSE 1 (11*) 1 (2%)
 

PERIARTERITIS 2 (4%)
 

tPANCREATIC DUCT (9) (47)
 

HYPERPLASIA, NOS 1 (11%) 2 (4%)
 

#PANCREATIC ACINUS (9) (47)
 

ATROPHY, NOS 1 (11%) 2 (4%)
 

tSTOMACH (9) (47)
 

INFLAMMATION^. ACUTE
 

# NUMBER OF ANIMAL S WITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBE R O F ANIMAL S NECfiOPSIED 

HIGH
 

(47)
 

1
 

1
 

(46)
 

5
 

2
 

2
 

3
 

1
 

5
 

2
 

2
 

9
 

1
 

(46)
 

6
 

1
 

(46)
 

(49)
 

1
 

3
 

(45)
 

1
 

1
 

1
 

4
 

1
 

(45)
 

5
 

(45)
 

3
 

(47)
 

1
 

DOSE
 

(2%)
 

(2%)
 

(11%)
 

(4%)
 

(4%)
 

(7%)
 

(2%)
 

(11%)
 

(4%)
 

(4%)
 

(2C%)
 

(2%)
 

(13%)
 

(2%)
 

(2%)
 

(6%)
 

(2%)
 

(2%)
 

(2%)
 

(9%)
 

(2%)
 

(11%)
 

(7%)
 

J2%)_.
 

73 
TABLE C1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE
 

ULCER, ACUTE 2 (4%) 

#GASTRIC MUCOSA 

MINERALIZATION 

CYSI, NOS 

(9) 

1 (11%) 

(47) 

#DUODENUM 

ULCER, ACUTE 

(9) (47) 

#COLONIC SUBMUCOSA 

HYPEBPLASIA, LYMPHOID 

(5) (24) 

1 (4%) 

URINARY SYSTEM
 

#KIDNEY (10) (49)
 

MINERALIZATION 2 (20%)
 

HYDRONEPHROSIS 1 (2%)
 

CONGESTION, NOS
 

INFLAMMATION, CHRONIC 4 (40%) 38 (78J4)
 

INFLAMMATION, CHRONIC SUPPURATIV
 

INFLAMMATION CHRONIC CYSTIC
 

#KIDNEY/CORTEX (10) (49)
 

CYSI, NOS
 

fcKIDNEY/MEDULLA (10) (49)
 

HYPERPLASIA, EPITHELIAL 1 (10%)
 

*URINARY BLADDER (9) (49)
 

INFLAMMATION, ACUTE 1 (2%)
 

INFLAMMATION, ACU1E HEMORRHAGIC 1 (2%)
 

INFLAMMATION, ACUTE/CHRONIC 1 (2%)
 

INFLAMMATION, CHRCNIC 1 (2%)
 

ENDOCRINE SYSTEM
 

#PITUITARY (9) (46)
 

CYST, NOS 1 (11%) 7 (15%)
 

MULTILOCULAR CYST 1 (2%)
 

MULTIPLE CYSTS 3 (33%) 1 (2%)
 

HEMCRRHAGIC CYST 1 (2%)
 

rtADRENAL [9) (45)
 

HEMOEEHAGIC CYST 1 J2%1 _ _
 

* NUMBE R OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBE R OF ANIMALS NECROFSIED
 

HIGH DOSE
 

1 (2%)
 

(47)
 

1 (2%)
 

(48)
 

1 (2%)
 

(39)
 

(47)
 

2 (4%)
 

2 (4%)
 

1 (2%)
 

32	 (68%)
 

1 (2%)
 

1 (2%)
 

(47)
 

1 (2%)
 

(47)
 

(44)
 

1 (2%)
 

(43)
 

10 (23%)
 

4 (9%)
 

1 (2%)
 

(46)
 

74
 
TABLE C1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE
 

ANGIECTASIS 1 (2%)
 

ffADRENAL CORTEX (9) (45)
 

LIECIDOSIS 2 (22%) 31 (69%)
 

HYPE6TROPHY, NOS 1 (2%)
 

ANGIECTASIS
 

#THYROID (9) (1*4)
 

CYST, NOS 1 (1H)
 

FCLLICULAR CYST, NOS 3 (7*)
 

HYPEBPLASIA, NOS 1 (11%) 1 (2%)
 

^PARATHYROID (5) (26)
 

HYPERPLASIA, NOS 2 (40S) 6 (23%)
 

REPROEUCTIVE SYSTEM
 

#PSOSTATE (10) (47)
 

INFLAMMATION, ACUTE 5 (11%)
 

INFLAMMATION, ACUTE SUPPURATIVE
 

INFLAMMATION, ACUTE HEMOSRHAGIC 1 (2%)
 

INFLAMMATION, ACUTE/CHRONIC 2 (20%)
 

INFLAMMATION, CHRONIC 1 (10») 9 (19X)
 

INFLAMMATION, CHRONIC SUPPURATIV 1 (2%)
 

FIBROSIS, DIFFUSE
 

PERIARTERITIS
 

HYPEEPLASIA, NOS 1 (10X)
 

HYPEBPLASIA, FOCAL
 

#TESTIS (10) (49)
 

EDEMA, NOS 2 (20%)
 

PERIAHTERITIS 1 (10X) 3 (6X)
 

AT8CEHY, NOS 2 (20%) 11 (22%)
 

ATROPHY, FOCAL 3 (30») 9 (18*)
 

ASPEEMATOGENESIS 1 (2%)
 

tTESTIS/TUBULE (10) (49)
 

DEGENERATION, NOS 1 (2%)
 

NERVOUS SYSTEM 

#3RAIN/MENINGES (10) (49) 

INFLAMMATION, NOS 1 (2%) 

tBRAIN 

HEMORRHAGE _ _ __ (10) (49) 

1 J2XI 

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

1 (2%)
 

(46)
 

23 (50%)
 

1 (2%)
 

(43)
 

4 (9%)
 

(24)
 

3 (13*)
 

(45)
 

2 (4X)
 

1 (2%)
 

2 (4K)
 

3 (7%)
 

1 (2%)
 

2 (4X)
 

1 (2%)
 

1 (2%)
 

1 (2%)
 

(48)
 

4 (8*)
 

2 (4%)
 

16 (33%)
 

14 (29?)
 

2 (4%)
 

(48)
 

(48)
 

(48)
 

•• 1. •TIT- ~ •
 

75
 
TABLE C1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

ATROPHY, NOS
 

SPECIAL SENSE ORGANS
 

NONE
 

MUSCULOSKELETAL SYSTEM
 

*BONE
 

OSTEOPOROSIS
 

*SKULL
 

EXOS10SIS
 

BODY CAVIIIES
 

*MESENTERY
 

PERIAETERITIS
 

ALL OTHEB SYSTEMS
 

NCNE
 

SPECIAL KCREHOLOGY SUMMAR Y
 

NECBOESY PEEF/NO HISTO PERFORMED
 

AU10LYSIS/NO NECROPSY
 

CONTROL LOW DOSE HIGH DOSE 

1 (2») 1 (2%) 

(10) (50) (49) 

1 (10£) 1 (2%) 

(10) (50) (49) 

1 (10%) 

(10) (50) (49) 

1 (2%) 

1 

1 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUHBEH OF ANIMALS NECHOPSIED
 

76
 
TABLE C2.

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE RATS 

FED AZINPHOSMETHYL IN THE DIET 

CONTROL LOW DOSE
 

ANIMALS INITIALLY IN STUDY 10 d49
 

ANIMALS NECEOESIED 10 49
 

ANIMALS EXAMINED HISTOPATHO LOGICALLY 9 48
 

INTEGUMENTARY SYSTEM
 

*SUBCUT TISSUE (10) (49)
 

HEMATOMA, NOS
 

RESPIBATCRY SYSTEM 

#LUNG 

CONGESTION, NOS 

(9) (48) 

4 (&%) 

EDEMA, NOS 

INFLAMMATION, NOS 7 (78%) 16 (33%) 

HYFEBPLASIA, AtVEOLAfi EPITHELIUM 1 (2%) 

HEMATOECIETIC SYSTEM
 

#BONE MARROW (9) (46)
 

CONGESTION, NOS 1 (2%)
 

HEMORRHAGE 1 (2«)
 

HYPOELASIA, NOS 1 (2%)
 

*SPLEEN (9) (43)
 

ATROPHY, NOS
 

MYELCID METAPLASIA 1 (11%) 1 (2%)
 

#LYMPH NODE (9) (44)
 

HYPEBPLASIA, RETICULUM CELL 2 (5»)
 

HYPERPLASIA, LYMPHOID 1 (11X) 3 (7»)
 

CIRCUIA1CRY SYSTEM
 

#HEART (9) (48)
 

FIBfiOSIS. DIFFUSE 2 (22%)
 

*MYOCARDIUM (9) (48)
 

FIBROSJSi DIFFUSE
 

*	 NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

*	 NUMBER OF ANIMALS NEC80PSIED
 

^	 5 ANIMAL 0 S HERE INITIALLY IN THE STUDY, BUT 1 ANIMAL HAS FOUND


ANIMAL IN A FEMALE GBOUP.
 

HIGH DOSE
 

50
 

49
 

46
 

(49)
 

1 (2%)
 

(1*6)
 

7 (15%)
 

2 (4«)
 

21 (46%)
 

(40)
 

2 (5%)
 

1 (3%)
 

1 (3%)
 

(41)
 

1 (2«)
 

1 (2%)
 

(«0)
 

1 (3«)
 

1 (3%)
 

(46)
 

1 12%)
 

(46)
 

1_i2«).
 

 TO BE A MALE
 

77
 
TABLE C2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

HIGH DOSE
 

(45)
 

(45)
 

4 (9%)
 

2 (4%)
 

3 (1%)
 

1 (2%)
 

1 (2%)
 

(45)
 

7 (16%)
 

(45)
 

4 (9%)
 

(49)
 

2 (4%)
 

2 (4%)
 

(39)
 

1 (3%)
 

(39)
 

1 (3%)
 

(39)
 

1 (3%)
 

(44)
 

1 (2%)
 

1 (2%)
 

(42)
 

(3D
 

(45)
 

9 120 %).
 

DIGESTIVE SYSTEM
 

#SALIVARY GLAND
 

CYST, NOS
 

#LIVER
 

CONGESTION, NOS
 

NECROSIS, NOS
 

METAMORPHOSIS FATTY
 

HYPERTROPHY, NOS
 

HYPERTROPHY, FOCAL
 

ANGIECTASIS
 

#HEPATIC CAPSULE
 

CONGESTION, NOS
 

KLIVER/PERIPORTAL
 

METAMORPHOSIS FATTY
 

*BILE DUCT
 

CYST, NOS
 

HYPERPLASIA, NOS
 

#PANCSEAS
 

FI3HOSIS
 

FIBHOSIS, DIFFUSE
 

ATRCPHY, NOS
 

#PANCREATIC DUCT
 

HYPERPLASIA, NOS
 

#PANCREATIC ACINUS
 

ATROPHY, NOS
 

4STOMACH
 

INFLAMMATION, ACUTE
 

ULCER, ACUTE
 

#DUODENUM
 

ULCER, ACUTE
 

rtCOLONIC SUBMUCOSA
 

HYPERPLASIA, LYMPHOID
 

URINAR Y SYSTEM
 

*KIDNEY
 

MINERALIZATION
 

CONTROL
 

(9)
 

(9)
 

1 (11%)
 

1 (11%)
 

2 (22%)
 

(9)
 

2 (22%)
 

(9)
 

1 (11%)
 

(10)
 

4 (40%)
 

(7)
 

(7)
 

(7)
 

(9)
 

(9)
 

(<*)
 

(9)
 

3_J33J1
 

LOW DOSE
 

(46)
 

1 (2%)
 

(47)
 

7 (15%)
 

1 (2%)
 

1 (2%)
 

6 (13%)
 

2 (4%)
 

(47)
 

6 (13%)
 

(47)
 

4 (<)%)
 

(49)
 

10 (20%)
 

(41)
 

1 (2%)
 

1 (2%)
 

1 (2%)
 

(41)
 

3 (7%)
 

(41)
 

3 (7%)
 

(46)
 

(41)
 

1 (2%)
 

(28)
 

1 (4%)
 

(48)
 

JO J2!%1_ _
 

* NUMBE R OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROFSIED
 

78
 
TABLE C2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE
 

HYDBCNEPHBOSIS 1 (11%) 1 (2%)
 

INFLAMMATION, CHBONIC 14 (29%)
 

CALCIFICATION, DYSTROPHIC
 

#KIDNEY/CORTEX (9) (48)
 

FIBBOSIS 1 (2%)
 

*KIDNEY/TUBULE {9) (48)
 

DILATATION, NOS 2 (4%)
 

CAST, NOS 2 (4%)
 

*U. BLADDER/SUBMUCOSA (9) (44)
 

HEMORRHAGE
 

EHDOCEINI SYSTEM 

#PITUITABY (8) (44) 

CYST, NOS 

HEflCEBHAGIC CYST 

1 (13%) 2 

1 

(5%) 

(2%) 

HYFEEPLASIA, CHEOMOPHOBE-CELL 1 (13%) 

#ADRENAL 

CONGESTION, NOS 

0) (45) 

1 (2%) 

ANGIECTASIS 5 (56%) 17 (38%) 

#ADRENAL CORTEX (9) (45) 

CYST, NOS 

HEMOEBHAGE 

HEMOEBHAGIC CYST 

LIPCIDOSIS 5 (56%) 

1 

1 

1 

11 

(2%) 

(2%) 

(2%) 

(24%) 

ATfiOFHY, NOS 2 (4%) 

ANGIECTASIS 

#THYROID 

CYST, NOS 

HYPEEPLASIA, NOS 

(9) (45) 

2 

1 

(<**)

(2%) 

tPARATHYROID 

CYST, NOS 

HYPEEPLASIA, NOS 

(7) 

2 (29%) 

(31) 

1 

2 

(3%) 

(6%) 

#PANCREATIC ISLETS (7) (41) 

HYPERPLASIA, NOS 1 (2%) 

REPRODUCTIVE SYSTEM
 

#UTERUS (9) (43)
 

HYDRCMETRA 1 J11%1 J J7

*l
 

# NUMBER 0? ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

HIGH DOSE
 

1


9


1


(45)
 

(45)
 

2


2


(38)
 

1


(41)
 

3


(41)
 

16


(41)
 

9


1


(38)
 

2


2


(19)
 

(39)
 

(41)
 

 (2%)
 

 (20%)
 

 (2%)
 

 (4%)
 

 (4%)
 

 (3%)
 

 (7%)
 

 (39%)
 

 (22%)
 

 (2%)
 

 (5%)
 

 (5%)
 

3 i7%]_
 

79
 
TABLE C2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE
 

# UTERUS/ EN DOM ETKI0M (9) (43) (41)
 

CYST, SOS 3 (338) 8 (19%) 8 (20%)
 

#OVARY (9) (47) (42)
 

CYST, NOS 1 (11S)
 

FOLLICULAR CYST, NOS 2 (22%) 5 (11%) 2 (5%)
 

NERVOUS SYSTEM
 

#ERAIN (9) (48) (45)
 

ATROEHY. NOS 2 (4%) 1 (2%)
 

SPECIAL SENSE ORGANS
 

*EYE/CORN5A (10) (49) (49)
 

ULCER, CHRONIC 1 (2%)
 

*£YE/RETINA (10) (49) (49)
 

INFLAMMATION, CHBONIC 1 (2%)
 

MIJSCUIOSKELETAL SYSTEM
 

*BONE (10) (49) (49)
 

CYST, NOS 1 (2%)
 

OSTEOPOROSIS 1 (2%)
 

BODY CAVITIES
 

NCN E
 

ALL OTHIF SYSTEMS
 

NONE
 

SPECIAL KOftFHOLOGY SUMMAR Y
 

NO LESION REPORTED 1 1
 

AUTO/NECROPSY/NO HI STO 1 1 3
 

AUIOLYSIS/NO NECROPSY 1
 

# NUMBE R OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBE R OF ANIMALS NECBOFSIED
 

80
 
APPENDIX D
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS
 

IN MICE FED AZINPHOSMETHYL IN THE DIET
 

81
 

TABLE 01.

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE MICE 

FED AZHKPHOSMETHYL IN THE DIET 

CONTROL LOW DOSE HIGH DOSE
 

ANIMALS INITIALLY IN STUDY 10 50 50
 

ANIMALS NECROPSIED 10 50 50
 

ANIMALS EXAMINED HISTOPATHOLOGICALLY 10 49 50
 

INTEGUNJKTABY SYSTEM
 

NONE
 

RESPIRATORY SYSTEM
 

#LUNG/BFCSCHIOLE (10) (49) (50)
 

INFLAMMATION, NOS 1 (10%)
 

fLUNG (10) (a 9) (50)
 

EMPHYSEMA, NOS 2 (4S)
 

CONGESTION, NOS 1 (10%) 2 (4») 5 (10%)
 

HEMOSRHAGE 1 (2%)
 

INFLAMMATION, NOS 1 (10*) 1 (2%)
 

INFLAMMATION, GEANOLOMATOUS 1 (2%)
 

HYPEFPLASIA, ALVEOLAR EPITHELIUM 1 (10%) 1 (2%)
 

HEMATOECIETIC SYSTEM
 

tBONE MARROW (10) (49) (50)
 

HYPEEPLASIA, HEMATOfOIETIC 1 (10«)
 

tSPLEEN (8) C*6)
 (46)
 

HYPEBPLASIA, LYHPHOID 1 (2%)
 

MYELOID METAPLASIA 1 (2%)
 

#LYMPH NODE (9) (46) (46)
 

LYMPHANGIECTASIS 1 (2X) 1 <2X)
 

CONGESTION, NOS 1 (2%) 2 (4%)
 

EBYTHEOPHAGOCYTOSIS 1 (2%)
 

HYPEBPLASIA, BETICULUM CELL 1 (11%) 2 (4%) 4 (9%)
 

HYEE6PLASIA, LYMPHOID 2 (4%)
 

MYELOID METAPLASIA 1 (2%)
 

tBESENTERIC L. NODE (9) (46) (46)
 

LYMPHANGIECTA.SIS _ 1_J2%1_.
 

* NUMBER OF ANIMALS HITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECBOPSIED
 

83
 
TABLE 01. MALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

HIGH DOSE
 

1 (2%)
 

(50)
 

1 (2%)
 

(50)
 

1 (2%)
 

(50)
 

1 (2%)
 

(50)
 

1 (2%)
 

(47)
 

1 (2X)
 

(50)
 

1 (2X)
 

(50)
 

1 (2%)
 

(50)
 

1 <2X)
 

7 (14»)
 

(49)
 

HEMORRHAGE
 

CIRCUIATCRY SYSTEM
 

•HEART/VENTRICLE
 

FIBFOSIS, FOCAL
 

DIGESTIVE SYSTEM
 

#tIVER
 

HEMORRHAGE
 

NECRCSIS, NOS
 

NECROSIS, FOCAL
 

#LIVER/CENTRILOBULAR
 

CYTOFLASMIC V ACUOLI2 ATION
 

*BILE DUCT
 

LYMPHOCYTIC INFILTRATE
 

#PANCREAS
 

INFLAMflATION, CHRONIC
 

tSMALL INTESTINE
 

INFLAMMATION, GRANUtOMATOOS
 

URINAR Y SYSTEM
 

#KIDNEY
 

LYMPHOCYTIC INFILTRATE
 

#KIDNEY/CORTEX
 

LYMPHOCYTIC INFILTRATE
 

CYTOPLASBIC V ACUOLIZATION
 

#URINARY BLADDER
 

CALCULUS, NOS
 

INFLAMMATION, CHRONIC
 

ENDOCRINE SYSTEM
 

NONE
 

CONTROL LOW DOSE
 

(10) (48)
 

(8)	 (49)
 

1 (2%)
 

1 (2%}
 

1 (13X)
 

(8) (49)
 

(10) (50)
 

(8)	 (49)
 

1 (13%)
 

(7)	 (48)
 

(9)	 (49)
 

(9) (49)
 

(7)	 (48)
 

1 (14»)
 

1 (14X)
 

t	 NUMBER OF ANIHALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

*	 NUMBER OF ANIMALS NEC80PSIED
 

84 
TABLE D1. MALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE
 

REPRODUCTIVE SYSTEM
 

*PREPU'IIAL GLAND (10) (50)
 

CYST, NOS
 

tTESTIS (9)- (49)
 

CYTOLOGIC DEGENERATICN
 

ASPEEflATOGENESIS
 

IT2STIS/TUBULE (9) (49)
 

CYTOLOGIC DEGENERATION
 

NERVOUS SYSTEM
 

#BRAIN (10) (48)
 

CCRECHA AMYLACEA 1 (10%) 16 (33%)
 

SPECIAL SENSE ORGAN S
 

NONE
 

BUSCULOSKELETAL SYSTEM
 

NONE
 

BODY CAVITIES
 

*PLEURA (10) (50)
 

HEMGBBHAG E 1 (2%)
 

ALL OTHER SYSTEMS
 

NCNE
 

SPECIAL fCEEHOLCGY SUMMAR Y
 

NO LESION filPORTED 4 16
 

NECROPSY PERF/NO HISTO PERFORMED 1
 

# NUMBE R O F ANIMAL S WIT H TISSU E EXAMINE D MICROSCOPICALL Y 

* NUMBE R OF ANIMAL S NECBOESIED 

HIGH DOSE
 

(50)
 

1 (2%)
 

(50)
 

1 (2»)
 

4 (3%)
 

(50)
 

3 (6X)
 

(50)
 

6 (12X)
 

(50)
 

14
 

85
 
TABLE D2

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE MICE 

FED AZINPHOSMETHYL IN THE DIET 

CONTROL LOW DOSE
 

ANIMALS INITIALLY IN STUDY 10 50
 

ANIMALS NECROPSIED 10 50
 

ANIMALS EXAMINED HISTOP ATHOLOGICALLY 10 49
 

INTEGUMENTARY SYSTEM
 

NONE
 

RESPIRATORY SYSTEM
 

#LUNG (10) (50)
 

CONGESTION, NOS 1 (10%) 6 (12%)
 

HEMCBBHAGE
 

INFLAMMATION, NOS 3 (30%) 6 (12%)
 

LYKPHOCYTIC INFIL1RATE
 

INFLAMMATION, INTERSTITIAL 1 (2%)
 

#LUNG/ALVEOLI (10) (50)
 

HEMORRHAGE 2 (20%) 1 (2%)
 

HEMATOECIETIC SYSTEM
 

*BONE MARRO W (10) (47)
 

HYPERPLASIA, HEMAIOEOIETIC 1 (2%)
 

#SPLEEN (9) (49)
 

INFLAMMATION, ACUTE 3 (6X)
 

HYPERPLASIA, LYMPHOID 1 (11%)
 

KYELCID METAPLASIA 2 (22%) 1 (2%)
 

#LYMPH NODE (9) (40)
 

ERYTHRO PHAGOCYTOSIS 1 (11%)
 

HYPERPLASIA, RETICULUM CEL'L 1 (11%) 1 (3%)
 

HYPEEPLASIA, LYMPHOID 2 (5%)
 

MYELCID METAPLASIA 1 (11%)
 

#PANCREATIC L.NODE (9) (40)
 

INFLAMMATION^ GRANULOMATOUS
 

t NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBE R OF ANIMALS NECROPSIED
 

HIGH
 

50
 

50
 

49
 

(50)
 

2
 

1
 

3
 

1
 

(50)
 

(50)
 

(50)
 

1
 

2
 

(45)
 

(45)
 

1
 

DOSE
 

(4%)
 

(2%)
 

(6%)
 

(2%)
 

(2%)
 

(4%)
 

(2%1 .
 

86
 
TABLE D2. FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

HIGH DOSE
 

(45)
 

1 (2%)
 

(49)
 

1 (2%)
 

(50)
 

1 (2%)
 

2 (4»)
 

1 (2%)
 

1 (2%)
 

1 (2%)
 

(50)
 

(48)
 

1 (255)
 

1 (2%)
 

1 (2%)
 

(48)
 

(50)
 

1 (2%)
 

1 (2%)
 

(40)
 

i_Jl *!__
 

*«£SENTERIC I. NODE
 

INFLAMMATION, CHRONIC
 

CIRCULATORY SYSTEM
 

NONE
 

DIGESTIVE SYSTEM
 

#SALIVARY GLAND
 

LYMPHOCYTIC INFILTRATE
 

#LIVER
 

LYBPHOCYTIC INFILTRATE
 

INFLAMMATION, FOCAL GRANULOMATOU
 

NECBCSIS, FOCAL
 

NECROSIS, COAGULATIVE
 

HYPEEPLASIA, MODULAR
 

HEMATOPOIESIS
 

MYELOID METAPLASIA
 

#LIVER/CENTHILOBULAR
 

CYTOPLASMIC CHANGE, NOS
 

tfPANCREAS
 

DILATATION/DUCTS
 

CYST, NOS
 

MULTILOCULAE CYST
 

LYMPHOCYTIC INFILTRATE
 

INFLAMMATION, ACUTE/CHRONIC
 

#PANCREATIC ACINDS
 

CYTOPLASMIC VACUOLIZATION
 

URINARY SYSTEM
 

IKIDNEY
 

HYDRCNEPHROSIS
 

LYMPHOCYTIC INFILTRATE
 

ENDOCRINE SYSTEM
 

#PITUITARY
 

HEMOREHAGIC CjfST
 

CONTROL
 

(9)
 

(10)
 

(10)
 

2 (20%)
 

(10)
 

1 (10S)
 

(9)
 

1 (11*)
 

(9)
 

1 (11X)
 

(10)
 

1 (10X)
 

(7)
 

LOW DOSE
 

(HO)
 

(49)
 

1 (2%)
 

(49)
 

1 (2X)
 

2 (4X)
 

2 («X)
 

(49J
 

(40)
 

1 (31)
 

C*0)
 

(49)
 

1 (2XJ
 

(39)
 

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

87
 
TABLE 02. FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE
 

#THYROID (9) (42)
 

CYST, NOS
 

REPRODUCTIVE SYSTEM 

KUTERUS (7) (48) 

HYDRCMETRA 

#UTERU£/ENDOMETRIUM 

CYST, NOS 

(7) 

1 (14*) 

(48) 

1 (2%) 

INFLAMMATION, ACU1E 

INFLAMMATION. ACUTE VESICULAR 

1 

2 

(2*) 

(4%) 

HYPEEPLASIA, NOS 

HYPERPLASIA, CYSTIC 2 (29%) 32 (67%) 

HETAELASIA, SQUAMOUS 

tUTERUS/MYOMETRIUH 

INFLAMMATION, ACUTE 

(7) (48) 

1 (2%) 

#OVARY (9) (47) 

CYST, NOS 5 (11%) 

FCLLICULAR CYST, NOS 1 (11%) 2 (4%) 

INFLAMBATION, CHBONIC 1 (2%) 

INFLAMMATION, CHRONIC SUPPUEATIV 3 (6%) 

DEGENERATION, NOS 1 (2%) 

NERVOUS SYSTEM
 

fBRAIN (10) (49)
 

CORPORA AMYLACEA 2 (20X) 3 (6%)
 

SPECIAL SENSE ORGANS
 

NONE
 

MUSCULOSKELETAL SYSTEM
 

NONE
 

BODY CAVITIES
 

*PERITONEUB (10) (50)
 

INFLABBATION.. NOS _
 

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

. _


HIGH DOSE
 

(46)
 

1 (2%)
 

(48)
 

3 (6%)
 

(48)
 

3 (6%)
 

2 (U%)
 

2 (4%)
 

1 (2%)
 

32	 (67%)
 

1 (2%)
 

(48)
 

(41)
 

3 (7%)
 

4 (10%)
 

(50)
 

(50)
 _i im .
 

88
 
TABLE D2. FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOU DOSE HIGH DOSE
 

ALL OTHER SYSTEMS
 

NONE
 

SPECIAL BOEPHOLOGY SUHHARY
 

NO LESION BEPORTED 2 6 1
 

NECROPSY PERF/NO HISTO PERFORMED 1
 

AUTC/NECROPSY/NO HISTO 1
 

* NUMBER OF ANIMALS HITH TISSUE EXAMINED MICROSCOPICALLY
 * NUMBEE OF ANIMALS NECBOPSIED
 

R9
 

APPENDIX E
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS
 

IN RATS FED AZINPHOSMETHYL IN THE DIET
 

91
 

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

Fed Azinphosmethyl in the Dieta
 

Topography: Morphology
 

Hematopoietic System:
 

Lymphotnab
 

P ValuesC,d
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Liver: Hepatocellular Adenomab
 

P Values0>d
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control) f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Pooled
 

Control
 

5/101 (5)
 

N.S.
 

3/99 (3)
 

P = 0.044
 

Matched
 

Control
 

1/10 (10)
 

N.S.
 

115
 

1/9 (11)
 

N.S.
 

115
 

Low
 

Dose
 

3/50 (6)
 

N.S.
 

1.212
 

0.194
 

5.931
 

0.600
 

0.058
 

30.890
 

68
 

3/49 (6)
 

N.S.
 

2.020
 

0.278
 

14.484
 

0.551
 

0.055
 

28.360
 

115
 

High
 

Dose
 

1/49 (2)
 

N.S.
 

0.412
 

0.009
 

3.527
 

0.204
 

0.003
 

15.723
 

113
 

5/46 (11)
 

N.S.
 

3.587
 

0.726
 

22.059
 

0.978
 

0.139
 

45.235
 

97
 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats 

Fed Azinphosmethyl in the Diet3 

(continued) 

Pooled Matched Low High 

Tomography: Morphology Control Control Dose Dose 

Pituitary: Chromophobe 

Adenomab 13/85 (15) 4/9 (44)8 21/46 (46) 13/43 (30) 

P Valuesc » d P = 0.012 N.S. P < 0.001** P = 0.042** 

Departure from Linear Trend6 P = 0.004 

Relative Risk (Pooled Control)f 2.985 1.977 

Lower Limit 1.581 0.920 

Upper Limit 5.696 4.147 

Relative Risk (Matched Control)f 1.027 0.680 

Lower Limit 0.513 0.312 

Upper Limit 3.432 2.420 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats
 

(continued)
 

Topography: Morphology
 

Pituitary: Chromophobe
 

Adenoma or Carcinoma"
 

P Valuesc»d
 

Departure from Linear Trend6
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Li-nit
 

Relative Risk (Matched Control )f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Fed Azinphosmethyl in the Dieta
 

Pooled Matched
 

Control Control
 

13/85 (15) 4/9 (44)8
 

P = 0.003 N.S.
 

P = 0.009
 

103
 

Low
 

Dose
 

21/46 (46)
 

P < 0.001**
 

2.985
 

1.581
 

5.696
 

1.027
 

0.513
 

3.432
 

102
 

High
 

Dose
 

15/43 (35)
 

P = 0.012**
 

2.281
 

1.110
 

4.634
 

0.785
 

0.371
 

2.733
 

111
 
Adenoma, Chromophobe Carcinoma,
 

Cystadenoma, NOSb
 

P Values0 «d
 

Relaive Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Adrenal: Adenocarcinoma, NOSb
 

P Values0 >d
 

Relative Risk (Pooled Control)*
 

Lower Litiit
 

Upper Limit
 

Relative Risk (Hatched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 —
 

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

Fed Azinphosmethyl in the Diet3
 

(continued)
 

Pooled Matched 

Topography: Morphology Control Control 

Pituitary: Adenoma, NOS, Chromophobe 

Low
 

Dqs_e
 

21/46 (46)
 

P < 0.001**
 

2.985
 

1.581
 

5.596
 

1.027
 

0.513
 

3.432
 

102
 

1/45 (2)
 

N.S.
 

Infinite
 

0.112
 

Infinite
 

Infinite
 

0.012
 

Infinite
 

104
 

or 

13/85 (15) 4/9 (44)8 

P < 0.001 N.S. 

103 

0/95 (0) 0/9 (0) 

P = 0.015 N.S. 

High
 

Dose
 

20/43 (47)
 

P < 0.001**
 

3.041
 

1.601
 

5.796
 

1.047
 

0.519
 

3.493
 

77
 

3/46 (7)
 

P = 0.033**
 

Infinite
 

1.228
 

Infinite
 

Infinite
 

0.133
 

Infinite
 

92
 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats
 

Fed Azinphosmethyl in the Diet3
 

(continued)
 

Topography: Morphology
 

Adrenal: Adenocarcinoma, NOS,
 

or Cortical AdenomaV

0
 

P Values0 »d
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)^
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Thyroid: Follicular-cell
 

Adenoma, Adenoma, NOS,
 

or Cystadenomab
 

P Values0>d
 

Relative Risk (Pooled Control)

f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)^
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Pooled
 

Control
 

3/95 (3)
 

P < 0.001
 

7/86 (8)
 

P = 0.002
 

Matched
 

Control
 

1/9 (11)
 

N.S.
 

115
 

1/9 (11)
 

N.S.
 

115
 

Low
 

Dose
 

4/45 (9)
 

N.S.
 

2.815
 

0.494
 

18.356
 

0.800
 

0.099
 

38.517
 

104
 

10/44 (23)
 

P = 0.022**
 

2.792
 

1.026
 

7.965
 

2.045
 

0.375
 

86.341
 

68
 

High
 

Dose
 

10/46 (22)
 

P = 0.001**
 

6.884
 

1.871
 

36.913
 

1.957
 

0.358
 

82.720
 

92
 

12/43 (28)
 

P = 0.004**
 

3.429
 

1.340
 

9.403
 

2.512
 

0.480
 

104.131
 

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

Fed Azinphosmethyl in the Diet3
 

(continued)
 

Pooled Matched
 

Topography: Morphology Control Control
 

Thyroid: Adenocarcinoma,
 

Cystadenocarcinoma, or
 

Papillary Cystadenocarcinoma^ 0/86 (0) 0/9 (0)
 

P Values0>d P = 0.008 N.S.
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 —
 

Thyroid:
 

All Follicular-cell Tumorsb»h 7/86 (8) 1/9 (11)
 

P Values0 »d P < 0.001 N.S.
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control )f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor 115
 

Low
 

Dose
 

4/44 (9)
 

P = 0.012**
 

Infinite
 

1.794
 

Infinite
 

Infinite
 

0.215
 

Infinite
 

104
 

14/44 (32)
 

P = 0.001**
 

3.909
 

1.596
 

10.434
 

2.864
 

0.564
 

117.305
 

68
 

High
 

Dose
 

4/43 (9)
 

P = 0.011**
 

Infinite
 

1.836
 

Infinite
 

Infinite
 

0.220
 

Infinite
 

115
 

14/43 (33)
 

P = 0.001**
 

4.000
 

1.635
 

10.649
 

2.930
 

0.577
 

119.913
 

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

Fed Azinphosmethyl in the Dieta
 

(continued)
 

Topography: Morphology
 

Parathyroid: Adenoma, NOSb
 

P Valuesc«d
 

Departure from Linear Trend6
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

All Sites: Hemangio sarcoma"
 

P Values0 »d
 

Departure fromLinear Trend6
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Pooled
 

Control
 

1/81 (1)
 

P = 0.004
 

P = 0.039
 

5/101 (5)
 

N.S.
 

P = 0.036
 

Matched
 

Control
 

1/5 (20)8
 

N.S.
 

P = 0.042
 

107
 

2/10 (20)8
 

N.S.
 

P = 0.006
 

89
 

Low
 

Dose
 

0/26 (0)
 

N.S.
 

0.000
 

0.000
 

57.066
 

0.000
 

0.000
 

3.557
 

—
 

0/50 (0)
 

P = 0.025*(N)
 

0.000
 

0.000
 

1.608
 

0.000
 

0.000
 

0.667
 

—
 

High
 

Dose
 

4/24 (17)
 

P = 0.009**
 

13.500
 

1.403
 

632.360
 

0.833
 

0.130
 

39.161
 

113
 

5/49 (10)
 

N.S.
 

2.061
 

0.494
 

8.485
 

0.510
 

0.107
 

5.008
 

71
 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats
 

Fed Azinphosmethyl in the Diet3
 

(continued)
 

Topography: Morphology
 

All Sites: Hemangiosarcoma or
 

Hemangioma"
 

P Values0 >d
 

Departure from Linear Trend6
 

Relative Risk (Pooled Control)^
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Pancreatic Islets: Islet-cell
 

Adenoma"3
 

P Values0»d
 

Relative Risk (Pooled Control) ^
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Pooled
 

Control
 

5/101 (5)
 

N.S.
 

2/92 (2)
 

N.S.
 

— •
 

Low
 

Dose
 

1/50 (2)
 

N.S.
 

0.404
 

0.009
 

3.459
 

0.100
 

0.002
 

1.810
 

52
 

1/47 (2)
 

N.S.
 

0.979
 

0.017
 

18.203
 

Infinite
 

0.011
 

Infinite
 

115
 

High
 

Dose
 

6/49 (12)
 

N.S.
 

2.473
 

0.657
 

9.689
 

0.612
 

0.141
 

5.791
 

71
 

4/45 (9)
 

N.S.
 

4.089
 

0.607
 

43.556
 

Infinite
 

0.210
 

Infinite
 

115
 

Matched
 

Control
 

2/10 (20)8
 

N.S.
 

P = 0.022
 

89
 

0/9 (0)
 

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

Fed Azinphosmethyl in the Diet3
 

(continued)
 

Pooled Matched Low High
 

Topography: Morphology Control Control Dose Dose
 

Pancreatic Islets: Islet-cell
 

Adenoma or Carcinoma" 2/92 (2) 0/9 (0) 1/47 (2) 6/45 (13)
 

P Values0>d P = 0.008 P = 0.033 N.S. P = 0.015**
 

Relative Risk (Pooled Control)f 0.979 6.133
 

Lower Limit 0.017 1.144
 

Upper Limit 18.203 59.753
 

Relative Risk (Matched Control)^ Infinite Infinite
 

Lower Limit 0.011 0.363
 

Upper Limit Infinite Infinite
 

Weeks to First Observed Tumor 115 97
 —
 

a

Dosed groups received 78 or 156 ppm in feed.
 

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

c

Beneath the incidence of tumors in a control group is the probability level for the Cochran—
 

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

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

the comparison of that dosed group with the matched—control group (*) or with the pooled-


control group (**) when P < 0.05 for either control group; otherwise, not significant (N.S.)
 

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

Fed Azinphosmethyl in the Dieta 

(continued) 

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

e

The probability level for departure from linear trend is given when P < 0.05 for any comparison
 

^The 95% confidence interval of the relative risk between each dosed group and the specified
 

control group.
 

Sine incidence in the matched-control group is significantly higher (P < 0.05) than that in the
 

pooled controls (excluding the controls of the subject study).
 

"These tumors consist of adenoma, NOS, adenocarcinoma, NOS, follicular-cell adenoma,
 

cystadenoma, NOS, cystadenocarcinoma, NOS, and papillary cystadenocarcinoma, NOS.
 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Fed Azinphosmethyl in the Dieta
 

Topography: Morphology
 

Liver: Hepatocellular Adenoma or
 

Hepatocellular Carcinoma^
 

P Valuesc»d
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Pituitary: Chromophobe
 

Adenoma'3
 

P Valuesc.d
 

Relaitve Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Pooled
 

Control
 

6/104 (6)
 

N.S.
 

25/89 (28)
 

N.S.
 

Matched
 

Control
 

2/9 (22)
 

N.S.
 

115
 

2/8 (25)
 

N.S.
 

84
 

Low
 

Dose
 

2/47 (4)
 

N.S.
 

0.738
 

0.074
 

3.918
 

0.191
 

0.017
 

2.467
 

110
 

14/44 (32)
 

N.S.
 

1.133
 

0.600
 

2.001
 

1.273
 

0.411
 

10.504
 

110
 

High
 

Dose
 

5/45 (11)
 

N.S.
 

1.926
 

0.485
 

7.118
 

0.500
 

0.108
 

4.871
 

95
 

12/41 (29)
 

N.S.
 

1.042
 

0.525
 

1.901
 

1.171
 

0.366
 

9.792
 

95
 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Fed Azinphosmethyl in the Diet3
 

(continued)
 

Pooled
 

Topography: Morphology Control
 

Pituitary:
 

Adenocarcinoma, NOS^ 0/89 (0)
 

P Value sc»d N.S.
 

Departure from Linear Trend6 P < 0.001
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limt
 

Weeks to First Observed Tumor
 

Pituitary: Chromophobe Adenoma,
 

Adenocarcinoma, NOS, Adenoma, or
 

Cystadenoma, NOSb 29/89 (33)
 

P Values0 »d N.S.
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched
 

Control
 

0/8 (0)
 

N.S.
 

P = 0.019
 

—
 

2/8 (25)
 

N.S.
 

84
 

Low
 

Dose
 

8/44 (18)
 

P < 0.001**
 

Infinite
 

4.572
 

Infinite
 

Infinite
 

0.481
 

Infinite
 

98
 

22/44 (50)
 

P = 0.040**
 

1.534
 

0.952
 

2.360
 

2.000
 

0.693
 

15.699
 

98
 

High
 

Dose
 

1/41 (2)
 

N.S.
 

Infinite
 

0.115
 

Infinite
 

Infinite
 

0.012
 

Infinite
 

99
 

15/41 (37)
 

N.S.
 

1.123
 

0.624
 

1.882
 

1.463
 

0.479
 

11.921
 

95
 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

(continued)
 

Topography: Morphology
 

Adrenal: Cortical Adenoma*5
 

P Value sc»d
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Thyroid: Cystadenoma or
 

Adenoma, NOSb
 

P Valuesc.d
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Fed Azinphosmethyl in the Dieta
 

Pooled Matched
 

Control Control
 

2/95 (2) 1/9 (11)
 

P = 0.001 N.S.
 

75
 

1/94 (1) 1/9 (ll)g
 

P = 0.010 N.S.
 

115
 

Low
 

Dose
 

4/45 (9)
 

N.S.
 

4.222
 

0.626
 

44.978
 

0.800
 

0.099
 

38.517
 

115
 

6/45 (13)
 

P = 0.005**
 

12.533
 

1.580
 

562.024
 

1.200
 

0.185
 

53.895
 

98
 

High
 

Dose
 

8/41 (20)
 

P = 0.001**
 

9.268
 

1.944
 

85.579
 

1.756
 

0.302
 

75.723
 

115
 

4/38 (11)
 

P - 0.024**
 

9.895
 

1.014
 

473.300
 

0.947
 

0.118
 

45.380
 

75
 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Fed Azinphosmethyl in the Diet3
 

(continued)
 

Topography: Morphology
 

Thyroid: Adenocarcinoma,
 

Cystadenocarcinoma, or
 

Papillary Cystadenocar cinema"
 

P Value sc»d
 

Relative Risk (Pooled Control)^
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)

f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Thyroid:
 

All Follicular-cell Tumorsb>h
 

P Valuesc»d
 

Departure from Linear Trend6
 

Relative Risk (Pooled Control)

f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Pooled
 

Control
 

1/94 (1)
 

N.S.
 

2/94 (2)
 

P = 0.008
 

P = 0.039
 

Matched
 

Control
 

1/9 (11)8
 

N.S.
 

115
 

2/9 (22)8
 

N.S.
 

115
 

Low
 

Dose
 

2/45 (4)
 

N.S.
 

4.178
 

0.222
 

240.910
 

0.400
 

0.025
 

23.103
 

115
 

8/45 (18)
 

P = 0.002**
 

8.356
 

1.748
 

77.514
 

0.800
 

0.214
 

7.147
 

98
 

High
 

Dose
 

1/38 (3)
 

N.S.
 

2.474
 

0.032
 

189.044
 

0.237
 

0.003
 

18.138
 

115
 

5/38 (13)
 

P = 0.021**
 

6.184
 

1.056
 

62.055
 

0.592
 

0.129
 

5.728
 

75
 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

^continued)
 

Topography: Morphology
 

All Sites: Heraangioma or
 

Heraangiosarcoraaa
 

P Value s°'d
 

Departure from Linear Trend6
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)^
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Mammary Gland: Adenocarcinoma,
 

Cystadenocarcinoma, or
 

Papillary Cystadenocarcinoma"
 

P Values0 >d
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)^
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Fed Azinphosmethyl in the Diet3
 

Pooled Matched
 

Control Control
 

1/105 (1) 0/10 (0)
 

N.S. N.S.
 

P = 0.018
 

——
 

3/105 (3) 0/10 (0)
 

N.S. N.S.
 

•
 

Low
 

Dose
 

4/49 (8)
 

P = 0.036**
 

8.571
 

0.873
 

412.952
 

Infinite
 

0.211
 

Infinite
 

51
 

3/49 (6)
 

N.S.
 

2.143
 

0.295
 

15.366
 

Infinite
 

0.136
 

Infinite
 

98
 

*igh
 

Dsoe
 

1/49 (2)
 

N.S.
 

2.143
 

0.028
 

164.796
 

Infinite
 

0.012
 

Infinite
 

115
 

1/49 (2)
 

N.S.
 

0.714
 

0.014
 

8.575
 

Infinite
 

0.012
 

Infinite
 

40
 
Table Ii2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Fed Azinphosmethyl in the Diet3
 

(continued)
 

Pooled Matched Low
 

Topography: Morphology Control Control Dose
 

Mammary Gland: Fibroadenoma'3 13/105 (12) 2/10 (20) 9/49 (18)
 

>d
 P Valuesc N.S. N.S. N.S.
 

Relative Risk. (Pooled Control)f 1.484
 

Lower Limit 0.595
 

Upper Limit 3.456
 

Relative Risk (Matched Control)f 0.918
 

Lower Limit 0.247
 

Upper Limit 8.129
 

Weeks to First Observed Tumor 84 66
 

Uterus: Endometrial Stromal
 

Polypb 15/105 (14) 1/9 (11) 3/43 (7)
 

P Valuesc»d P = 0.005(N) N.S. N.S.
 

Relative Risk (Pooled Control)f 0.488
 

Lower Limit 0.094
 

Upper Limit 1.607
 

Pvelative Risk (Matched Control)f 0.628
 

Lower Limit 0.062
 

Upper Limit 32.213
 

Weeks to First Observed Tumor 84 80
 

High
 

Dose
 

9/49 (18)
 

N.S.
 

1.484
 

0.595
 

3.456
 

0.918
 

0.247
 

8.129
 

95
 

0/41 (0)
 

P = 0.005**(N)
 

0.000
 

0.000
 

0.544
 

0.000
 

0.000
 

4.097
 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Fed Azinphosmethyl in the Dieta
 

(continued)
 

Topography: Morphology 

Pooled 

Control 

Matched 

Control 

Low 

Dose 

High 

Dose 

Pancreatic Islets:

Adenoma'5 

 Islet-cell 

5/97 (5) 2/7 (29)8 1/41 (2) 1/39 (3) 

P Values0 » d N.S. N.S. N.S. N.S. 

Departure from Linear Trend6 P = 0.015 

Relative Risk (Pooled Control)f 

Lower Limit 

Upper Limit 

0.473 

0.010 

4.017 

0.497 

0.011 

4.214 

Relative Risk (Matched Control)f 

Lower Limit 

Upper Limit 

0.085 

0.002 

1.513 

0.090 

0.002 

1.588 

Weeks to First Observed Tumor 115 115 115 

a

Dosed groups received 62.5 or 125 ppm in feed.
 

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

c

Beneath the incidence of tumors in a control group is the probability level for the Cochran-


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

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

the comparison of that dosed group with the matched-control group (*) or with the pooled-


control group (**) when P < 0.05 for either control group; otherwise, not significant (N.S.)
 

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

Fed Azinphosmethyl in the Diet3
 

(continued)
 

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

e

The probability level for departure from linear trend is given when P < 0.05 for any comparison.
 

fine 95% confidence interval of the relative risk between each dosed group and the specified
 

control group.
 

SThe incidence in the matched-control group is significantly higher (P < 0.05) than that in the
 

pooled controls (excluding the controls of the subject study).
 

n

These tumors consist of adenoma, NOS, adenocarcinoma, NOS, papillary adenocarcinoma,
 

cystadenoma, NOS, and papillary cystadenocarcinoma, NOS.
 
APPENDIX F
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS
 

IN MICE FED AZINPHOSMETHYL IN THE DIET
 

111
 

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

Fed Azinphosmethyl in the Diet3
 

Topography: Morphology
 

Lung: Alveolar/Bronchiolar
 

Adenoma"
 

P Values0 »d
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Lung: Alveolar/Bronchiolar
 

Adenoma or Carcinoma'3
 

P Value sc»d
 

Relaitve Risk (Pooled Control)*
 

Lower Linit
 

Upper Limit
 

Relative Risk (Matched Control)^
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Pooled
 

Control
 

13/129 (10)
 

N.S.
 

14/129 (11)
 

N.S.
 

Matched
 

Control
 

1/10 (10)
 

N.S.
 

92
 

2/10 (20)8
 

N.S.
 

90
 

Low
 

Dose
 

6/49 (12)
 

N.S.
 

1.215
 

0.396
 

3.192
 

1.224
 

0.184
 

55.127
 

92
 

8/49 (16)
 

N.S.
 

1.504
 

0.577
 

3.555
 

0.816
 

0.211
 

7.351
 

92
 

High
 

Dose
 

4/50 (8)
 

N.S.
 

0.794
 

0.195
 

2.412
 

0.800
 

0.097
 

38.616
 

93
 

4/50 (8)
 

N.S.
 

0.737
 

0.183
 

2.201
 

0.400
 

0.073
 

4.141
 

93
 
__ 

__ 

__ 

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

Fed Azinphosmethyl in the Diet3
 

(continued)
 

Topography: Morphology
 

All Sites: Hemangiosarcoma'3
 

P Values0 »d
 

Departure from Linear Trend6
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

All Sites: Hemangioma or
 

Hemangiosarcoma'3
 

P Values0 »d
 

Departure from Linear Trend6
 

Relative Risk (Pooled Control) f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)^
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Pooled
 

Control
 

0/131 (0)
 

N.S.
 

P = 0.002
 

1/131 (1)
 

N.S.
 

P = 0.002
 

90
 

Low
 

Dose
 

3/50 (6)
 

P = 0.020**
 

Infinite
 

1.551
 

Infinite
 

Infinite
 

0.134
 

Infinite
 

88
 

4/50 (8)
 

P = 0.021**
 

10.480
 

1.064
 

505.052
 

0.800
 

0.097
 

38.616
 

88
 

High
 

Dose
 

0/50 (0)
 

N.S.
 

—
 

—
 

—
 

—
 

—
 

0/50 (0)
 

N.S.
 

0.000
 

0.000
 

48.855
 

0.000
 

0.000
 

3.747
 

—
 

Matched
 

Control
 

0/10 (0)
 

N.S.
 

1/10 (10)8
 

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

(continued)
 

Topography: Morphology
 

Liver: Hepatocellular
 

Carcinoma"
 

P Valuesc.d
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Liver: Hepatocellular Adenoma or
 

Hepatocellular Carcinoma'3
 

P Values0>d
 

Relative Risk (Pooled Control)^
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)f
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Fed Azinphosmethyl in the Dieta
 

Pooled Matched
 

Control Control
 

27/128 (21) 0/8 (0)
 

N.S. P = 0.006
 

—
 

30/128 (23) 2/8 (25)
 

P = 0.048 N.S.
 

92
 

Low
 

Dose
 

3/49 (6)
 

P = 0.012**(N)
 

0.290
 

0.058
 

0.882
 

Infinite
 

0.113
 

Infinite
 

74
 

11/49 (22)
 

N.S.
 

0.958
 

0.465
 

1.782
 

0.898
 

0.274
 

7.665
 

74
 

High
 

Dose
 

12/50 (24)
 

N.S.
 

1.138
 

0.564
 

2.106
 

Infinite
 

0.679
 

Infinite
 

75
 

19/50 (38)
 

P = 0.040**
 

1.621
 

0.946
 

2.638
 

1.520
 

0.515
 

12.264
 

57
 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice
 

Fed Azinphosmethyl in the Dieta
 

(continued)
 

a

Dosed groups received 31.3 or 62.5 ppm in feed.
 

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

G

Beneath the incidence of tumors in a control group is the probability level for the Cochran-


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

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

the comparison of that dosed group with the matched-control group (*) or with the pooled-


control group (**) when P < 0.05 for either control group; otherwise, not significant (N.S.)
 

is indicated.
 

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

e

The probability level for departure from linear trend is given when P < 0.05 for any comparison.
 

^The 95% confidence interval of the relative risk between each dosed group and the specified
 

control group.
 

§The incidence in the matched-control group is significantly higher (P < 0.05) than that in the
 

pooled controls (excluding the controls of the subject study).
 
Table F2. Analyses of the Incidence of Primary Tumors in Female Mice
 

Topography: Morphology
 

Lung: Alveolar/Bronchiolar
 

Adenoma'3
 

P Value sc»d
 

Relative Risk (Pooled Control)f
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)f
 

Lower LiTiit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Hematopoiet ic System:
 

Lymphoma^
 

P Value sc'd
 

Relative Risk (Pooled Control)^
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control)^
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Fed Azinphosmethyl in the Diet3 

Pooled 

Control 

Matched 

Control 

Low 

Dps_e 

3/127 (2) 0/10 (0) 1/50 (2) 

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

0.847 

0.016 

10.179 

Infinite 

0.012 

Infinite 

— 92 

15/128 (12) 3/10 (30)3 5/50 (10) 

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

0.353 

0.253 

2.306 

0.333 

0.086 

1.939 

64 84 

High
 

Dose
 

3/50 (6)
 

N.S.
 

2.540
 

0.349
 

18.245
 

Infinite
 

0.134
 

Infinite
 

92
 

6/50 (12)
 

N.S.
 

1.024
 

0.341
 

2.600
 

0.400
 

0.114
 

2.229
 

86
 
Table F2. Analyses of the Incidence of Primary Tumors in Female Mice
 

Fed Azinphosmethyl in the Dieta
 

(continued) 

Pooled Matched Low High 

Topography: Morphology Control Control Dose Dose 

Heraatopoietic System:
 

Lymphoma or Leukemia"3 16/128 (13) 3/10 (30) 5/50 (10) 7/50 (14)
 

P Values0 »d N.S. N.S. N.S. N.S.
 

Relative Risk (Pooled Control)f 0.800 1.120
 

Lower Limit 0.239 0.410
 

Upper Limit 2.132 2.668
 

Relative Risk (Matched Control)^ 0.333 0.467
 

Lower Limit 0.086 0.143
 

Upper Limit 1.939 2.518
 

Weeks to First Observed Tumor 64 84 86
 

a

Dosed groups received 62.5 or 125 ppm in feed.
 

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

c

Beneath the incidence of tumors in a control group is the probability level for the Cochran-


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

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

the comparison of that dosed group with the matched-control group (*) or with the pooled-


control group (**) when P < 0.05 for either control group; otherwise, not significant (N.S.)
 

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

Fed Azinphosmethyl in the Diet3
 

(continued)
 

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

e

The probability level for departure from linear trend is given when P < 0.05 for any comparison.
 

^The 95% confidence interval of the relative risk between each dosed group and the specified
 

control group.
 

§The incidence in the matched-control group is significantly higher (P < 0.05) than that in the
 

pooled controls (excluding the controls of the subject study).
 

APPENDIX G
 

ANALYSIS OF FORMULATED DIETS FOR
 

CONCENTRATIONS OF AZINPHOSMETHYL
 

121
 

APPENDIX G
 

Analysis of Formulated Diets for
 

Concentrations of Azinphosmethyl
 

A 10-g sample of the diet mixture was shaken with 125 ml hexane
 

at room temperature for 16 hours, then filtered through Celite
 

with hexane washes, and reduced to 10 ml in volume. The solution
 

was extracted with three successive 10-ml aliquots of acetonitrile. The combined acetonitrile extracts were evaporated
 

nearly to dryness, diluted to 10 ml with hexane, and quantitatively analyzed for azinphosmethyl by gas-liquid chromatography
 

(electron capture detector, 10% DC-200 on Gas Chrom Q column).
 

Recoveries were checked with spiked samples, and external
 

standards were used for calibration.
 

Theoretical No. of Sample Coefficient of Range (ppm) 

Concentrations Samples Analytical Variation (%) 

in Diet (ppm) Mean (ppm) 

31.2(5) 17 31.2 4.3% 28.3-34.6 

62.5 22 61.2 5.9% 50.0-68.0 

125.0 21 126.0 6.4% 114.0-148.0 

250.0 5 256.0 2.0% 250.0-262.0 

123
 

Review of the Bioassay of Azinphosmethyl* for Carcinogenicity
 

by the Data Evaluation/Risk Assessment Subgroup
 

of the Clearinghouse on Environmental Carcinogens
 

June 29, 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 Azinphosmethyl for carcinogenicity.
 

The reviewer noted that the compound is an organophosphorus cholinesterase inhibitor. Although the neoplasms of
 

the thyroid and pancreatic islets in treated male rats were
 

only suggestive evidence of carcinogenicity, she said that
 

the experimental design was sufficiently flawed as to
 

preclude any definite conclusions being drawn from the
 

bioassay. The study was particularly deficient due to the
 

small number of matched controls and limited number of
 

organs examined. The reviewer questioned the practice used
 

for concluding that a tumor incidence, observed in treated
 

animals, was within the spontaneous range. Because of the
 

inadequacies of the bioassay, she said that no conclusion
 

could be drawn regarding the carcinogenicity of Azinphosmethyl,
 

She suggested that the compound be tested in short-term in
 

vitro assays and, if found to be positive, that it be
 

125
 
considered for retest in a long-term animal bioassay. A
 

motion was made by the reviewer that the report on the
 

bioassay of Azinphosmethyl be accepted as written. The
 

motion was approved without objection.
 

Clearinghouse Members present:
 

Arnold L. Brown (Chairman), Mayo Clinic
 

Paul Nettesheim, National Institute of Environmental
 

Health Sciences
 

Verne Ray, Pfizer Medical Research Laboratory
 

Verald K. Rowe, Dow Chemical U.S.A.
 

Michael B. Shimkin, University of California at San Diego
 

Louise Strong, University of Texas Health Sciences Center
 

*	 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.
 

•ttU.S. GOVERNMENT PRINTIN G OFFICE ] 1978-260-899/3178
 

126
 

DHEW Publication No. (NIH) 78-1319