National Cancer Institute 

CARCINOGENESIS 

Technical Report Series 

No. 4 

January 1977 

BIOASSAY OF 

DIMETHOATE 

FOR POSSIBLE CARCINOGENICITY 

CAS No. 60-51-5 

NCI-CG-TR-4 

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

Public Health Service 

National Institutes of Health 

BIOASSAY OF DIMETHOATE
 

FOR POSSIBLE CARCINOGENICITY
 

Carcinogen Bioassay and Program Resources Branch
 

Carcinogenesis Program
 

Division of Cancer Cause and Prevention
 

National Cancer Institute
 

Bethesda, Maryland
 

November 197 6
 

DHEW Publication No. (NIH) 77-804
 

BIOASSAY OF DIMETHOATE
 

FOR POSSIBLE CARCINOGENICITY
 

Carcinogenesis Program, Division of Cancer Cause and Prevention
 

National Cancer Institute
 

November 1976
 

CONTRIBUTORS: This report presents the results of the
 

carcinogenesis bioassay conducted by the Carcinogen Bioassay and
 

Program Resources Branch, Carcinogenesis Program, Division of
 

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

Bethesda, Maryland. This research was conducted at Gulf South
 

Research Institute, New Iberia, Louisiana, initially under direct
 

contract to the NCI and currently under a subcontract to Tracor
 

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

Bioassay Program.
 

This report was prepared at NCI by Dr. J. F. Douglas* and
 

reviewed by Dr. C. Cueto*. It was subsequently reviewed by the
 

toxicologists, Drs. W. E. MacDonald2

 and J. F. Robens2, and the
 

final report was compiled and edited at Tracor Jitco by Dr. E. W.
 

Gunberg2.
 

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

Weisburger*^ and R. R. Bates*; the dose levels were selected by
 

Drs. T. E. Shellenburger3>5, j# n# Weisburger, and R. R. Bates;
 

animal treatment and observations were supervised by Drs. Τ. Ε.
 

Shellenburger and H. P. Burchfield^ with the technical assistance
 

of Ms. D. H. Monceaux^ and Mr. D. Broussard^; Dr. W. E. Greer^
 

was the veterinarian in charge; and Drs. E. Bernal^ and B.
 

Buratto supervised the necropsies. The histopathologic evaluation was conducted at Experimental Pathology Laboratories,
 

Herndon, Virginia, by Drs. R. A. Renne6

»7, J. F. Ferrell6, and C.
 

E. Gilmore^ and the diagnoses included in this report represent
 

the interpretation of these pathologists. Pathologists at NCI
 

iii
 
and Dr. C. N. Barron2

 have reviewed selected slides and concur
 

with the overall pathologic evaluation of the study.
 

Compilation of individual animal survival, pathology, and summary
 

tables was performed by EG&G Mason Research Institute8

;
 

statistical analyses were performed by Dr. K. C. Chu*, using
 

methods selected for the Bioassay Program by Dr. J. J. Gart^.
 

This report was reviewed by members of the participating organi­ zations*»2

, 3 , 6φ
 

^•Carcinogenesis Program, Division of Cancer Cause and Prevention,
 

National Cancer Institute, National Institutes of Health,
 

Bethesda, Maryland.
 

2

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

Maryland.
 

^Gulf South Research Institute, Atchafalaya Basin Laboratories,
 

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

w with the Naylor Dana Institute for Disease Prevention,
 

American Health Foundation, Hammond House Road, Valhalla,
 

New York.
 

w with the National Center for Toxicological Research,
 

Jefferson, Arkansas.
 

Experimental Pathology Laboratories (EPL), 17 Pine Street,
 

Herndon, Virginia.
 

with Battelle Pacific Northwest Laboratories, Battelle
 

Boulevard, Richland, Washington.
 

8

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

Rockville, Maryland.
 

^Field Studies and Statistics, Division of Cancer Cause and
 

Prevention, National Cancer Institute, National Institutes of
 

Health, Bethesda, Maryland.
 

iv
 
SUMMARY
 

A bioassay of the carcinogenicity of technical-grade dimethoate
 

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

test material was administered in feed to groups of 50 rats of
 

each sex at either of two concentrations for 80 weeks, followed
 

by 35 weeks of observation. Initial doses were not well
 

tolerated; therefore, they were reduced during the study. The
 

"time-weighted average doses" for rats were 155 and 310 ppm for
 

males and 192 and 384 ppm for females. All surviving rats were
 

killed between 113 and 115 weeks.
 

Dimethoate was administered in feed to groups of 50 male and 50
 

female mice at two concentrations. Female mice received diets
 

containing 250 and 500 ppm of dimethoate for 80 weeks; male mice
 

received the same dosage. However, high-dose males were returned
 

to the control diet at 60 weeks, and low-dose males at 69 weeks.
 

All surviving mice were killed between 93 and 94 weeks.
 

Tremors and hyperexcitability, both indications of dimethoate
 

toxicity, were observed in the treated animals. However, it is
 

considered that the low-dose group of rats and both dose groups
 

of mice survived long enough to permit an evaluation of carcinogenicity. Pathologic evaluation revealed no statistically
 

significant increase in tumors associated with dimethoate
 

treatment in either species of animal, and it is concluded that
 

there was no carcinogenic effect under the conditions of the
 

experiment.
 

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 4
 

E. Subchronic Toxicity Test 5
 

F· Design of Chronic Studies 6
 

G. Clinical and Pathologic Examinations 8
 

H. Data Recording and Statistical Analyses 9
 

III. Results - Rats 11
 

A. Body Weights and Clinical Signs (Rats) 11
 

B. Survival (Rats) 13
 

C. Pathology (Rats) 15
 

D. Statistical Analyses of Results (Rats) 20
 

IV. Results - Mice 23
 

A. Body Weights and Clinical Signs (Mice) 23
 

. Survival (Mice) 25
 

C. Pathology (Mice) 27
 

D. Statistical Analyses of Results (Mice) 31
 

V. Discussion 33
 

VI. Bibliography 35
 

APPENDICES
 

Appendix A Summary of the Incidence of Tumors and
 

Proliferative Lesions in Rats Fed
 

Dimethoate in the Diet 37
 

Appendix Β Summary of the Incidence of Tumors and
 

Proliferative Lesions in Mice Fed
 

Dimethoate in the Diet 47
 

Appendix C Summary of the Incidence of Nontumor
 

Pathology in Rats Fed Dimethoate in
 

the Diet 55
 

vii
 
PAGE 

Table CI Summary of the Incidence of Nontumor 

Pathology in Male Rats Fed Dimethoate 

in the Diet 5 7 

Table C2 Summary of the Incidence of Nontumor 

Pathology in Female Rats Fed Dimethoate 

in the Diet 63 

Appendix D Summary of the Incidence of Nontumor 

Pathology in Mice Fed Dimethoate 

in the Diet 69 

Table Dl Summary of the Incidence of Nontumor 

Pathology in Male Mice Fed Dimethoate 

in the Diet 71 

Table D2 Summary of the Incidence of Nontumor 

Pathology in Female Mice Fed Dimethoate 

in the Diet 74 

TABLES 

Table 1

Table 2

Table 3

 Design of Dimethoate Chronic Feeding 

Study in Rats and Mice

 Dimethoate Chronic Feeding Study: Number 

and Survival of Tumor-Bearing Rats

 Dimethoate Chronic Feeding Study: Number 

and Survial of Tumor-Bearing Mice

 7 

 15 

 27 

FIGURES 

Figure 1

Figure 2

Figure 3

Figure 4

 Growth Curves of Rats Fed Dimethoate 

in Diet

 Survival Curves of Rats Fed Dimethoate 

in Diet

 Growth Curves of Mice Fed Dimethoate 

in Diet

 Survival Curves of Mice Fed Dimethoate 

in Diet

 12 

 14 

 24 

 26 

viii
 
I. INTRODUCTION
 

Dimethoate is the common name for the organophosphorous
 

insecticide, 0,0-dimethyl-S-(N-methylcarbamoylmethyl)phosphorodithioate. This compound, which has been in use since 1956 as an
 

insecticide and acaricide, is registered for insect and mite
 

control on agricultural crops and ornamental plants (Federal
 

Register, 1975). It is also registered as a residual fly spray
 

in animal quarters (Chemical Economics Handbook, 1969).
 

Dimethoate was tested as part of the carcinogenesis bioassay
 

because it is a widely used organophosphorous pesticide. Recent
 

research on Wistar rats and AB strain mice by Gibel et al.,
 

(1973) suggests that dimethoate may have carcinogenic properties.
 

II. MATERIALS AND METHODS
 

A. Chemical
 

Technical-grade dimethoate (CYGO1#), generally 94-96% pure
 

(Martin, 1971), was purchased from American Cyanamid, Princeton,
 

New Jersey, in one batch for use in the chronic study. The batch
 

was analyzed at Gulf South Research Institute by melting point,
 

infrared, ultraviolet and mass spectroscopy, nuclear magnetic
 

resonance spectrometry, thin-layer chromatography, and gas-liquid
 

chromatography which showed the purity of the batch to be
 

90-100%. This technical-grade batch was spectroscopically and
 

chromatographically similar to analytical-grade dimethoate (99.3%
 

pure). No attempt was made to identify impurities.
 

B. Dietary Preparation
 

All diets were formulated using Wayne® Lab Blox Meal (Allied
 

Mills, Inc., Chicago, 111.) to which was added the required
 

amount of dimethoate for each dietary concentration. The test
 

compound was first dissolved in a small amount of acetone
 

(Mallinckrodt Chemical Works, St. Louis, Mo.), which was then
 

added to the feed. Corn oil equal to 2% of the final feed weight
 

was then added, primarily as a dust suppressant. The diets were
 

mechanically mixed to assure homogeneity and to allow for
 
evaporation of the acetone. The corn oil (Louana^J) was produced
 

by Opelousas Refinery Co., Opelousas, Louisiana. The prepared
 

diets were analyzed regularly throughout the test to assure
 

uniformity. Water and the formulated diets were made available
 

ad libitum to the experimental animals and were replaced three
 

times per week.
 

C. Animals
 

Osborne-Mendel rats, procured from Battelle Memorial Institute,
 

Columbus, Ohio, and B6C3F1 hybrid mice (C57B1/6 female χ C3H/He
 

male), procured from Charles River Breeding Laboratories, Inc.,
 

Wilmington, Massachusetts, were used in this study. Upon
 

receipt both species were quarantined for 7-10 days, determined
 

to be free from observable disease or parasites, and then
 

assigned to test and control groups.
 

D. Animal Maintenance
 

All animals were housed in temperature and humidity-controlled
 

rooms. No other chemicals were tested, and no other rats were
 

housed in the room in which dimethoate-treated rats and their
 

matched controls were housed. The mice were housed in a room
 

where dimethoate, parathion, and phosphamidon were concurrently
 

under test. The rats were maintained individually in suspended
 

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

4
 
caps, five per cage for females, and two to three per cage for
 

males. Initially, rats were transferred to clean cages once per
 

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

Cages for mice were changed weekly. Absorbent sheets under the
 

rat racks were changed three times per week. Animal racks were
 

rotated laterally for both species at weekly intervals; at the
 

same time, each cage was changed to a different position in the
 

row within the same column.
 

E. Subchronic Toxicity Test
 

Feeding studies were conducted to evaluate subchronically the
 

toxicity of dimethoate in order to establish the maximum
 

tolerated doses (MTD) for administration in the chronic study.
 

The low dose was one-half of the MTD. Dimethoate was added to
 

the animal feed at twofold increasing concentrations, starting
 

with 62.5 ppm and ending with 4,000 ppm. The compound was
 

provided in feed to experimental groups of five male and five
 

female rats and mice for 6 weeks followed by a 2-week observation
 

period·
 

In both male and female rats, at 250 and 500 ppm, weight
 

depression was apparent during the first weeks. Later these
 

animals apparently adapted, and weight gains approached those of
 

the controls. There was no mortality at these dosages; however,
 

5
 
all rats receiving 1,000 ppm died. The high and low doses for
 

rats were therefore set at 500 and 250 ppm.
 

In mice, the males initially lost weight at 500 ppm; however,
 

male mice at 250 ppm and female mice at both 250 and 500 ppm
 

gained weight normally. No deaths occurred in either sex at
 

doses of 250 or 500 ppm. There were also no deaths at 1,000 ppm.
 

The high and low doses were set at 1,000 and 500 ppm for mice.
 

F. Design of Chronic Studies
 

The design of the chronic study, including both test and matched-


control groups, is illustrated in table 1.
 

The pooled-control group, not shown in table 1, initially
 

consisted of the matched controls for dimethoate plus the matched
 

controls for the studies of aldrin, chlordane, dichlorvos,
 

dieldrin, and heptachlor; these studies overlapped the dimethoate
 

feeding study for at least a year. Because additional matched
 

controls were started simultaneously with restarted treatment
 

groups for some of these compounds, the total number of pooled-


control animals varied. All treated and pooled-control animals
 

were placed on study as weanlings at 35 days of age except for
 

the matched-control rats for dichlorvos. Because dichlorvos was
 

the last bioassay of this series to be started, there were
 

slight differences in the dichlorvos matched-control rats pooled
 

6 
Table 1. Design of Dimethoate Chronic Feeding Study in Rats and Mice
 

Experimental 

Design 

RATS 

Male 

Initial 

No. of 

Animals 

Dimethoate 

in Diet^ 

(ppm) 

Time 

Treated 

(weeks) 

on Study 

Untreated 

(weeks) 

Time-Weighted 

Average Dosee 

(ppm) 

Matched Control 10 0 0 114 

Low 50 250 

125 

0 

19 

61 

34-35 

155 

High 50 500 

250 

0 

19 

61 

33-34 

310 

Female 

Matched Control 10 0 0 114 

Low 50 250 

125 

0 

43 

37 

34-35 

192 

High 50 500 

250 

0 

43 

37 

33-34 

384 

MICE 

Mala 

Matched Control 10 0 0 94 

Low 50 250 

0 

69 

24 

250 

High 50 500 

0 

60 

34 

500 

Female 

Matched Control 10 0 0 94 

Low 50 250 

0 

80 

13 

250 

High 50 500 

0 

80 

14 

500 

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

Initially 1,000 and 500 ppm of dimethoate were fed to mice of each sex; these doses
 

were too toxic, however, and the mouse study was terminated and restarted as shown
 

in the table.
 c

Doses shown were toxic; therefore, doses for treated rats were lowered and fed at
 

.concentrations shown for the varying treatment periods indicated.
 

When diets containing dimethoate were discontinued, treated rats and their matched
 

controls were fed plain feed diets (without corn oil) for 8 weeks, then control
 

diets (2% corn oil added) for an additional 25 to 27 weeks. Mice received the control
 

diet until termination.
 e

Time-weighted average dose = Σ(dose in ppm χ no. of days at that dose).
 

£ Σ(no. of days receiving each dose)
 

Examination at necropsy subsequently revealed that 3 of 10 mice designated as male
 

matched controls were females.
 
for use as controls in the dimethoate study: (1) half of the
 

animals of each sex were started on test at 43 days of age and
 

half at 36 days of age; (2) they were obtained from the Charles
 

River Breeding Laboratories, Inc. and were the progeny (third
 

generation) of a group of Osborne-Mendel rats which were
 

purchased from the Battelle Memorial Institute, Columbus, Ohio.
 

Thus there was no significant genetic drift influencing the
 

incidence of tumors.
 

G· Clinical and Pathologic Examinations
 

All animals were observed for signs of toxicity twice daily, and
 

body weights were recorded at regular intervals until 110 weeks
 

for rats and 90 weeks for mice. All animals were palpated for
 

masses at each weighing. Those animals appearing moribund at the
 

time of clinical examination were killed and necropsied. In the
 

chronic study, the following 23 tissues and organs were taken
 

from killed animals and, where feasible, from animals found dead:
 

brain, pituitary, lymph nodes (cervical and mesenteric), thyroid,
 

parathyroid, salivary glands, lung, heart, diaphragm, stomach
 

(pylorus and fundus), duodenum, jejunum or ileum, large intestine, pancreas, adrenal, kidney (longitudinal and transverse),
 

liver, skin, entire gonads, urinary bladder, prostate or uterus,
 

and femur with marrow. Tissues were preserved in 10% buffered
 

formalin, embedded in paraffin, sectioned, routinely stained with
 

8
 
hematoxylin and eosin, and histologically examined. Selected
 

tissues were subjected to special staining techniques for more
 

definitive diagnosis.
 

The intent of the histologic examination was to evaluate all
 

organs, tissues, and gross lesions for every animal as specified
 

in the pathology protocol for the Bioassay Program. However,
 

occasional tissues were missing from some animals, and an occasional animal was missing or judged to be in such an advanced
 

state of autolysis as to preclude histopathologic interpretation
 

and was not preserved for such purposes.
 

H. Data Recording and Statistical Analyses
 

Pertinent data for 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, animal weight, and
 

individual pathologic results as recommended by the International
 

Union Against Cancer (UICC) (Berenblum, 1969). Data tables were
 

generated for statistical review and verification of data
 

transcription.
 

Statistical analysis of the incidence of tumors was made using
 

the Fisher exact test (Cox, 1970) to compare both the pooled
 

9
 
controls and the matched controls to treated animals at each dose
 

level. In addition, the Armitage and Cochran test for linear
 

trend in proportions with continuity correction (Armitage, 1971)
 

was used. This test, assuming a linear trend, determines if the
 

slope of the dose-response curve is different from zero (P <
 

0.05). The method also calculates the probability level of a
 

departure from linear trend.
 

A conservative adjustment, the Bonferroni inequality (Miller,
 

1966), was used for simultaneous comparisons of several
 

treatments with a control. For the comparison of k doses with a
 

control, this correction requires a significance level less than
 

or equal to 0.05/k for the overall comparison to be significant
 

at the 0.05 level. This adjustment was made in the tables where
 

the Fisher exact test results are shown and is discussed in the
 

analysis when appropriate. Thus, a corrected Ρ value < 0.05
 

would be deemed significant.
 

10
 
III. RESULT!* - RATS
 

A. Body Weights and Clinical Signs (Rats)
 

During the first year of the study the average gain in weight of
 

all treated rats, except the low-dose females, was less than that
 

of the matched controls (figure 1). During the second year the
 

average weight of the low-dose females was higher than that of
 

the matched controls. Throughout the study the average weight of
 

the high-dose females was less than that of the low-dose and
 

control females. There appeared to be a dose-related weight
 

depression in both low-dose and high-dose male rats throughout
 

the study.
 

During the first 4 months of the study the appearance and
 

behavior of the low-dose male and female rats generally were
 

comparable to those of the matched controls. During the first
 

week of the study the majority of the high-dose males and females
 

evidenced signs considered typical of organophosphate intoxication. The animals were generally hyperexcitable, and displayed
 

tremors and, occasionally, convulsions particularly in response
 

to acoustic stimuli. These tremors were accompained by depression of body weight and low consumption of food. Among the
 

high-dose male group the tremors increased during the second
 

week, although food consumption and body weights increased.
 

11
 
TIME ON STUDY (WEEKS) 

Figure 1. Growth Curves of Rats Fed Dimethoate in Diet
 

12 
After the second week the tremors were no longer observed. At
 

week 35, 80 to 90% of the treated rats, 60% of the male matched
 

controls, and 40% of the female matched controls evidenced
 

enlarging and protruding eyeballs with a developing opacity of
 

the corneal surface. In some cases there was a definite thickening of the palpebral conjunctival membranes. Two rats, one
 

high-dose female and one low-dose female, were killed for
 

diagnostic purposes at week 38 and found to have conjunctivitis
 

thought to be of viral origin. No deaths were attributed to this
 

condition; however, some rats became blind in one or both eyes.
 

Adverse clinical signs in all treatment groups were noted at a
 

low or moderate incidence during the second year of the study.
 

These signs included rough and discolored (yellow) hair coats,
 

alopecia, diarrhea, epistaxis, anemia, and tumors, as described
 

in the pathology narrative, below. A few of the high-dose rats
 

(male and female) evidenced dyspnea. Some treated females had
 

vaginal bleeding. Animals that survived to termination were
 

generally in poor physical condition.
 

B. Survival (Rats)
 

The survival data are presented in table 2 and figure 2. The two
 

female rats killed for diagnostic purposes during week 38 are
 

included in the data shown in figure 2. At termination there
 

appeared to be a dose-related effect with dimethoate, but this
 

13
 
TIME ON STUDY (WEEKS) TIME ON STUDY (WEEKS) 

Figure 2. Survival Curves of Rats Fed Dimethoate in Diet
 

14 
was obscured by the unusually large number of deaths in the male
 

control group.
 

Table 2. Dimethoate Chronic Feeding Study:
 

Number and Survival of Tumor-Bearing Rats
 

Percent Surviving**
 

(weeks)
 

Effective Number
 

Sex Dosage Groupa Number'* TBAC 52 78 115e
 

Μ Pooled Control 58 36 92 87 47
 Μ Matched Control 10 7 100 80 30
 Μ Low 50 23 98 96 72
 Μ High 49 24 92 82 58
 

F Pooled Control 60 43 97 95 73
 

F Matched Control 10 7 100 100 90
 

F Low 47 30 98 92 74
 

F High 45 21 88 67 51
 

a

See table 1 for actual dosage and for schedule of dosage
 

changes.
 

^Total number of rats initially placed on test minus the number
 

missing or autolyzed. "i
 c

Number of tumor-bearing rats.
 

"Denominator for survival percentages was the original number of
 

animals minus those killed for diagnostic purposes. No animals
 

were accidentally killed and none were missing.
 e

Study terminated at 115 weeks.
 

C. Pathology (Rats)
 

Histopathologic findings are tabulated in Appendix A. The
 

denominator for any particular tissue represents the number
 

examined, and does not necessarily represent the number of
 

animals that were placed on experiment in each group. The
 

15
 
numerator represents the number of animals bearing a given tumor;
 

percentages and Ρ values are also provided.
 

Numerous inflammatory, degenerative, and proliferative lesions,
 

commonly seen in aged rats, occurred with approximately equal
 

frequency in compound-treated and control animals· These
 

included hepatocytomegaly, biliary hyperplasia, chronic nephritis
 

with scarring, tubular dilatation and regeneration, C-cell
 

hyperplasia of thyroid, and testicular atrophy.
 

Several nonneoplastic lesions occurred more frequently in test
 

rats than in controls and may have been related to exposure to
 

the test compound. These included aggregates of alveolar macro-


phages in lung sections, interstitial fibrosis of myocardium,
 

focal cytomegaly of adrenal cortex, fatty metamorphosis of
 

hepatocytes, focal follicular-cell hyperplasia in thyroid
 

sections, and granulomas observed in the skin and subcutis of the
 

feet.
 

The pituitary and thyroid were the most common primary sites of
 

neoplasia in both test and control rats. Primary tumors occurred
 

in the pituitary of 39/100 (39.0%) rats examined microscopically
 

from pooled-fcontrol male rats, 7/18 (38.8%) of matched-control
 

rats, and 47/171 (27.5%) of dimethoate-treated rats. While no
 

follicular-cell tumors occurred in the thyroid glands examined
 

microscopically from seven matched-control male rats, follicular16
 
cell tumors were observed in 4/51 (7.8%) pooled-control males and
 

in 9/92 male test rats, an incidence of 9.8%. In female rats,
 

the incidence of follicular-cell tumors was 3/59 (5.2%) in pooled
 

controls; 1/10 (10.0%) in matched controls; and 3/86 (3.4%) in
 

dimethoate-fed animals. The overall incidence of C-cell tumors
 

was much higher than that of follicular-cell tumors; however, no
 

difference in incidence was evident between the control and test
 

groups.
 

Microscopically, the follicular-cell adenomas appeared as
 

well-circumscribed, usually single, masses composed of enlarged
 

follicles lined by hyperbasophilic follicular cells. Follicular
 

cells were increased in number, either by papillary infolding of
 

simple cuboidal or columnar epithelium into the follicular lumen,
 

or by stratification of follicular cells surrounding the lumen.
 

There was distinct compression of surrounding normal thyroidal
 

parenchyma, usually with some evidence of fibrous encapsulation.
 

Follicular-cell lesions were classified as carcinoma based upon
 

the presence of anaplasia and histologic arrangement in
 

disorderly nests and/or sheets. Areas with papillary patterns
 

also occurred frequently. Fibrous stroma often intermingled
 

with, but did not encapsulate, the tumors. C-cell lesions were
 

classified as adenomas when the proliferating C-cells were in
 

nodular masses that widely separated thyroidal follicles and
 

distorted the normal follicular architecture. In the large, more
 

17
 
discrete nodular lesions, the proliferating C-cells were present
 

as interlacing bundles of elongated, spindling cells, rather than
 

exhibiting the polyhedral to spherical shape characteristic of
 

normal C-cells. When invasion of thyroid capsule, adjacent
 

tissues, or vessels occurred, the lesion was called C-cell
 

carcinoma.
 

No mammary gland tumor was observed in 10 matched-control male
 

rats necropsied; of 58 pooled-control males necropsied, one had a
 

fibroma. Among 99 male dimethoate-treated rats necropsied,
 

fibromas were observed in two animals from the low-dose group.
 

One fibroadenoma of the mammary gland was present in 10 matched-


control female rats necropsied; 8 fibroadenomas, 1 fibroma, and 2
 

adenocarcinomas of the' mammary gland occurred in 60 pooled-


control female rats necropsied: a total incidence of mammary
 

tumors of 18.3%. Among 47 female test rats necropsied from the
 

low-dose group, 7 had mammary tumors, an incidence of 14.8%.
 

These included five with fibroadenomas, one with a fibroma, and
 

one with an adenocarcinoma. In the high-dose female group, 4
 

mammary tumors occurred among 47 rats necropsied, an incidence of
 

8.5%. These included three with fibroadenomas and one with
 

fibroma.
 

A summary of proliferative hepatocytic lesions observed is
 

presented in Appendix A. These lesions appeared with approxi18
 
mately equal frequency in both the test and control groups.
 

Included under the classification of focal hyperplasia were foci
 

of hepatocytes with increased cytoplasmic basophilia and large
 

vesicular nuclei with prominent nucleoli. These foci did not
 

compress adjacent tissue and usually were less than 1 lobule in
 

diameter. Lesions classified as hepatocytomegaly consisted of
 

foci of enlarged hepatocytes, many of which contained large,
 

vesicular nuclei and numerous fine cytoplasmic vacuoles which
 

gave the cytoplasm a "ground glass" appearance. Distortion of
 

lobular architecture in these foci was minimal, and trabeculae
 

were continuous with adjacent normal hepatocytes. Lesions
 

classified as "neoplastic nodules" had similar cytologic
 

features, but usually were larger and contained more distinct
 

distortion of lobular architecture; trabeculae at the periphery
 

of these nodules were oriented perpendicular to trabeculae in
 

adjacent normal hepatic parenchyma. Compression of adjacent
 

parenchyma by the nodule was evident. Hepatocellular carcinoma
 

was diagnosed when the hepatocytic lesion contained areas of
 

complete loss of normal lobular architecture. The most frequent
 

abnormality in this type of lesion was the presence of widely
 

dilated sinusoidal spaces lined by rows or nests of hepatocytes
 

several cells thick, sometimes with papillary projections of
 

hepatocytes into the space. Pseudo-acinar formation and solid
 

sheets of hepatocytes were less frequently observed.
 

19
 
A low incidence of various other types of neoplasms which occur
 

in aged laboratory rats was observed in test and control groups
 

with approximately equal frequency. These included islet-cell
 

adenomas of the pancreas; hemangiomas and hemangiosarcomas of the
 

spleen and other organs; benign and malignant primary tumors of
 

kidney, the adrenal cortex, and male and female genitalia;
 

malignant fibrous histiocytomas of peritoneal surfaces and
 

subcutis; and gliomas of the brain. Bone marrow was examined,
 

and no differences were found between the test and matched-


control rats of either sex.
 

There were instances in this study where neoplastic or hyper-


plastic changes occurred only in test animals, or with increased
 

frequency when compared to control groups. In the experience of
 

the pathologist, however, the nature, incidence, and severity of
 

the lesions observed provided no evidence of a carcinogenic
 

effect.
 

For a summary of the incidence of nontumor pathology in rats
 

treated with dimethoate, see Appendix C.
 

D. Statistical Analyses of Results (Rats)
 

Data from various tissues were analyzed statistically and are
 

shown in Appendix A. Several statistics should be noted. The
 

incidence of thyroidal follicular-cell hyperplasia of the male
 

20
 
dimethoate-treated rats had a dose-related increase when compared
 

to the pooled controls, while pituitary adenomas had a
 

dose-related decrease in the female treated animal groups when
 

compared to the pooled-control group. None of these findings is
 

considered to have biological significance. Given the
 

variability of observed spontaneous incidence of these lesions in
 

this strain of rats among laboratories and the opposite and
 

inconsistent effects between female and male rats in this study,
 

these findings probably are not treatment related. The
 

dimethoate-treated animals have a significantly lower incidence
 

of hepatocytomegaly than the pooled-control groups. The
 

importance of this observation is difficult to evaluate. There
 

was no statistically significant increase in the incidence of
 

tumors in the treated group versus the control group based on
 

data from the histopathologic examination of the tissues.
 

21
 

IV. RESULTS - MICE
 

A. Body Weights and Clinical Signs (Mice)
 

In the first year of the study the average gain in weight of all
 

groups except the low-dose female mice was less than that of the
 

matched controls. In the second year the average gains in weight
 

in the treated groups were generally similar (see figure 3)·
 

During the first 4 months of the study the appearance and
 

b€ihavior of the treated mice (males and females) were generally
 

comparable to those of the matched controls with the exception of
 

the high-dose female group. Generalized tremors which appeared
 

to be accompanied by rapid heartbeats were observed in this group
 

at; week 16. There was no weight depression for the female
 

high-dose group at this time, although food consumption declined
 

slightly.
 

From week 48 to week 53 some of the low-dose males were noted to
 

have slight generalized tremors. During this period a weight
 

depression occurred, but the food consumption remained similar to
 

that of the control group.
 

At week 48 a majority of the high-dose males were observed to
 

have generalized tremors which appeared to be accompanied by
 

rapid heartbeats. These tremors persisted in some individual
 

23
 
TIME ON STUDY (WEEKS) 

Figure 3. Growth Curves of Mice Fed Dimethoate in Diet
 

24 
mice until termination but were not noted after week 48 for the
 

majority of the group. There was no appreciable change in weight
 

in this group from week 40 to week 60, although the consumption
 

of food remained within a normal range.
 

During the second year of the study adverse clinical signs such
 

as alopecia (generalized and/or localized), bloating or
 

abdominal distention, and tumors were observed in all treatment
 

groups. However, they were predominantly visible in the low-dose
 

males and females. The high-dose mice, especially the males, had
 

rough hair coats and, in some cases, hunched appearances.
 

Animals surviving at termination were generally in very poor
 

physical condition.
 

B · Survival (Mice)
 

The survival data are presented in table 3 and figure 4. The
 

data indicate that dimethoate had no effect on mouse survival
 

rates.
 

25
 
TIME ON STUDY (WEEKS) TIME ON STUDY (WEEKS) 

Figure 40 Survival Curves of Mice Fed Dimethoate in Diet
 

26 
Table 3. Dimethoate Chronic Feeding Study:
 

Number and Survival of Tumor-Bearing Mice
 

Percent Surviving^
 

Effective Number (weeks)
 

Sex Dosage Groupa Number^ TBAC 52 78 90e
 

Μ Pooled Control 96 31 94 92 85
 

Μ Matched Control 7 6 100 100 86
 

Μ Low 50 11 98 84 82
 

Μ High 50 11 96 96 92
 

F Pooled Control 80 14 96 90 83
 

F Matched Control 10 3 90 90 70
 

F Low 50 15 100 96 90
 

F High 49 12 96 94 90
 

a

See table 1 for actual dosage and for schedule of dosage
 

changes.
 

^Total number of mice initially placed on test minus number
 

missing or autolyzed.
 c

Number of tumor-bearing mice·
 

^Denominator for survival percentages was the original number of
 

animals placed on test. No animals were accidentally killed and
 

none were missing,
 e

Study terminated at 90 weeks.
 

C. Pathology (Mice)
 

At the beginning of the study there were 50 mice of each sex at
 

each dosage level and 10 female and presumably 10 male matched-


control mice. At necropsy, however, 3 of the 10 mice designated
 

as "male11

 matched controls were found to be females. Tissues
 

from these three mice were not included in the summary of the
 

histopathology data; there were, therefore, only seven
 

matched-control male mice in this study.
 

27
 
Histopathologic findings are tabulated in Appendix Β. The
 

denominator for any particular tissue represents the number
 

examined and does not necessarily represent the number of animals
 

that were placed on experiment in each group. The numerator
 

represents the number of animals bearing a given tumor; percentages and Ρ values are also provided.
 

Several nonneoplastic proliferative or inflammatory conditions
 

occurred with approximately equal frequency in control and
 

dimethoate-treated mice. These included lymphoid hyperplasia of
 

the spleen, purulent inflammation of the ovary and endometrium,
 

endometrial hyperplasia, and nodular hyperplasia of the liver.
 

Adrenocortical hyperplasia occurred frequently in all male mice,
 

but at a higher incidence in treated animals.
 

The most commonly occurring neoplasm in male mice was hepatocellular carcinoma. There were 8/50 (16%) among low-dose males and
 

6/50 (12%) among high-dose males, compared with 4/7 (5 7%) in
 

matched controls and 17/92 (18%) in pooled controls. Female mice
 

had a much lower incidence of this neoplasm; no primary hepatic
 

tumor was observed in livers examined histologically from 99
 

female dimethoate-treated mice. Among matched controls the
 

incidence was 1/10 (10%) and among pooled controls 3/78 (4%).
 

The term "hepatocellular carcinoma" was used for proliferative
 

lesions of the livers in mice which, in the judgment of the
 

28
 
pathologist, had the potential for progressive growth, invasion,
 

and metastasis, and for causing death of the host. This judgment
 

was based upon the cytologic and histologic features of the
 

neoplasms and the knowledge that lesions with the same
 

morphologic characteristics have exhibited malignant biologic
 

behavior. The hepatocellular carcinomas observed in the various
 

test and control groups comprised the full spectrum of morphology
 

of this entity. The tumors varied from those composed of well-


differentiated hepatocytes with a relatively uniform arrangement
 

to those which were very anaplastic and poorly differentiated
 

with numerous mitotic figures. Various types of hepatocellular
 

carcinomas described in the literature were seen, including those
 

with an orderly cord-like arrangement of neoplastic cells, those
 

with a glandular pattern resembling adenocarcinoma, and those
 

composed of sheets and nests of highly anaplastic cells intermingled with widely dilated sinusoids.
 

Malignant lymphoreticular tumors were the most common tumors in
 

female mice. The majority of lymphoreticular neoplasms observed
 

were classified as malignant lymphomas. There were 7/50 (14%)
 

among low-dose females and 4/49 (8%) among high-dose females,
 

compared with 2/10 (20%) in matched controls and 8/79 (10%) in
 

pooled controls. One mast-cell sarcoma was observed in a
 

low-dose female mouse; this neoplasm was in the liver, spleen,
 

and bone marrow and was composed of ovoid cells with central
 

29
 
nuclei and numerous small cytoplasmic granules which stained
 

metachromatically with toluidine blue and Giemsa stains. One
 

hemangiosarcoma of the spleen occurred in a high-dose female
 

mouse.
 

Several benign pulmonary epithelial tumors, classified as
 

alveolar/bronchiolar adenomas to indicate possible sites of
 

origin, occurred in both test and control groups. One
 

alveolar/bronchiolar carcinoma occurred in a low-dose male mouse.
 

This tumor metastasized to the bronchial lymph node and heart.
 

Of the primary endocrine tumors, follicular-cell adenomas of the
 

thyroid were the most frequent, occurring with approximately
 

equal frequency in test and control groups. One cortical carcinoma and one pheochromocytoma occurred in adrenals examined from
 

45 high-dose female mice; no adrenal tumor was observed in any
 

other group.
 

Other tumors observed in tissues examined from mice in this study
 

included fibrosarcomas of the skin in the male mice only (1/92
 

pooled controls, 1/7 matched controls, 1/50 low-dose, and 1/50
 

high-dose males); one carcinoma of the rete testis in a high-dose
 

male mouse; one leiomyosarcoma of the vagina in a low-dose female
 

mouse; two endometrial stromal polyps of the uterus; one papillary adenoma; and one thecoma of the ovary.
 

30
 
There were instances in this study where neoplastic or
 

hyperplastic lesions occurred only or with increased frequency in
 

test animals when compared to control groups. In the experience
 

of the pathologist, however, the nature, incidence, and severity
 

of the lesions observed provide no clear evidence of a
 

carcinogenic effect.
 

For a summary of the incidences of nontumor pathology inmice
 

treated with dimethoate, see Appendix D.
 

D. Statistical Analyses of Results (Mice)
 

Selected tissue data were analyzed statistically, and the results
 

are shown in Appendix B. Several statistics are of interest,
 

including pulmonary neoplasms and adrenocortical hyperplasia
 

where one sex of the mouse had a higher incidence of lesions than
 

the pooled controls. Neither of these findings is considered to
 

have biological significance on the basis of the variability of
 

observed spontaneous incidences in this strain and the opposite
 

and inconsistent effects between male and female animals. Data
 

from the histopathologic examination of tissues revealed no
 

significant difference in the incidence of tumors among the
 

dimethoate-treated mice and their controls.
 

31
 

V. DISCUSSION
 

Dimethoate is a member of the organophosphorus class of
 

pesticides whose predominant mode of toxicity is inhibition of
 

cholinesterase. Toxicity characteristic of these compounds was
 

evident in the animals in this bioassay. Early in the study
 

tremors and hyperexcitability were observed in both male and
 

female rats. In mice, tremors also were noted in both sexes, but
 

at a later point in the study. Other clinical signs could not
 

definitely be related to treatment. The toxicity of dimethoate
 

may have affected the survival of test animals, since among rats
 

fewer of the high-dose than low-dose animals survived to
 

termination. However, the significance of this observation is
 

not clear, since survival was lowest in the 10 male matched-


control rats.
 

There were instances in this study where neoplastic or hyper-


plastic lesions occurred only in test animals, or with increased
 

frequency as compared to controls. However, these instances are
 

not statistically significant, and they are not considered to be
 

biologically significant. Thus, under the conditions of this
 

study, dimethoate was not carcinogenic. This bioassay did
 

provide an acceptable test for carcinogenicity under the general
 

guidelines of the Bioassay Program since maximum doses were used
 

33
 
and these animals survived to an age at which tumors could have
 

developed.
 

These conclusions differ from those of Gibel et al. (1973), who
 

suggested that dimethoate may have carcinogenic properties.
 

Because these investigators did not report in detail either their
 

methods or their results, it is not possible to compare their
 

data with the present study. In addition, their use of different
 

strains of test animals, namely the Wistar rats and the AB mouse,
 

may be significant.
 

34
 
VI. BIBLIOGRAPHY
 

Armitage, P. 1971. Statistical Methods in Medical Research, p.
 

135.	 J. Wiley & Sons, New York.
 

Berenblum, I., ed. 1969. Carcinogenicity Testing. UICC Technical
 

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

Geneva.
 

Chemical Economics Handbook. 1969. Chemical Information
 

Services, Stanford Research Institute, Menlo Park,
 

California.
 

Cox, D.R. 1970. Analysis of Binary Data, p. 62. Methuen and
 

Co., Ltd., London.
 

Gibel, W., Lohs, Kh., Wildner, G.P., Ziebarth, D., and Stieglitz,
 

R. 1973. Experimental study on carcinogenic, hematotoxic,
 

and hepatotoxic activity of organic phosphorus pesticides.
 

Arch. Geschwulstforsch. 41:311-328 (translated from German).
 

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

Peters, J.A. 1974. Carcinogenesis bioassay data system. J.
 

Comp. Biomed. Res. 7^:230-248.
 

Martin, H., ed. 1971. Pesticide Manual, 2nd edition, p. 90.
 

British Crop Protection Council.
 

Miller, R.G., Jr. 1966. Simultaneous Statistical Inference, p.
 

8. McGraw-Hill, New York.
 

Sontag, J., Page, N., and Saffiotti, U. 1976. Guidelines for
 

Carcinogen Bioassay in Small Rodents. NCI Carcinogenesis
 

Technical Report Series No. 1. National Cancer Institute,
 

NIH, PHS, U.S. DHEW Publication No. (NIH) 76-801. U.S.
 

Government Printing Office, Washington, D.C.
 

U.S.	 Environmental Protection Agency. 1975. Tolerances and
 

exemptions from tolerances for pesticide chemicals in or on
 

raw agricultural commodities - dimethoate. Federal Register
 

40 (206):49575.
 

35
 

APPENDIX A
 

SUMMARY OF THE INCIDENCE OF TUMORS AND
 

PROLIFERATIVE LESIONS IN RATS
 

FED DIMETHOATE IN THE DIET
 

37
 

39
 

Appendix A. Summary of the Incidence of Tumors and Proliferative
 

Lesions in Rats Fed Dimethoate in the Diet
 

Anatomic Site Pooled Matched Pooled Matched 

and/or Control Control Low-Dose High-Dose Control Control Low-Dose High-Dose 

Body System Males Males Males Males Females Females Females Females 

Digestive System0 

Neoplastic Nodule 2/58 0/10 1/49 0/48 5/60 1/10 1/47 4/44
 

(3%) (2%) (8%) (10%) (2%) (9%)
 

 ValuesC N.S. N.S. N.S. N.S. N.S. N.S. N.S. N.S.
 

Hepatocellular Carcinoma 1/58 0/10 0/49 1/48 0/60 0/10 0/47 1/44
 

(2%) (2%) (2%)
 

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

Total Liver Neoplasms	 3/58 0/10 1/49 1/48 5/60 1/10 1/47 5/44
 

(5%) (2%) (2%) (8%) (10%) (2%) (11%)
 

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

Other Lesions of Liver
 

Focal Hyperplasia A/58 0/10 1/49 2/48 1/60 0/10 0/47 0/44
 

(7%) (2%) (4%) (2%)
 

 Values °
 N.S. N.S. N.S. N.S. N.S. N.S. N.S. N.S.
 

Hepatocytomegaly 30/58 5/10 19/49 12/48 26/60 5/10 4/47 12/44
 

(52%) (50%) (39%) (25%) (43%) (50%) (8.5%) (27%)
 

 Values ° .003N/.818 .096N/.830 .252N/.752N .008N/.234N .020N/.001 .560/.001 .000N/.010N .122N/.306N
 

Small Intestine
 

Adenocarcinoma 0/52 0/8 0/48 1/45 0/56 0/10 0/46 0/37
 

(2%)
 

 Values °
 N.S. N.S. N.S. N.S. N.S. N.S. N.S. N.S.
 

?Low— and high-dose male and female rats received "time-weighted average doses" of 155, 310, 192, and 384 ppm, respectively.
 

Number of tumor-bearing animals/number of animals examined at site, and (%).
 

°Beneath the untreated controls incidence is the probability level for the Armitage test for positive dose-related trend in proportions when it is
 

below 0.10 (otherwise N.S. - not significant) and its departure statistic (P value/departure value).
 

Beneath the dosed group incidence is the corrected probability level for the Fisher exact test for comparison of that dosed group with the control
 

groups when it is below 0.10 (otherwise N.S. - not significant).(P value for pooled controls/P value for matched controls).
 

 = negative trend.
 
Appendix A. (Rats, continued)
 

Anatomic Site Pooled Matched Pooled Matched 

and/or Control Control Low-Dose High-Dose Control Control Low-Dose High-Dose 

Body System Males Males Males Males Females Females Females Females 

Urinary Tractb 

Kidney 

Tubular-Cell Adenoma 

 Values0 

3/57 

(5%) 

N.S. 

1/9 

(11%) 

N.S. 

0/50 

N.S. 

0/48 

N.S. 

0/58 

N.S. 

0/10 

N.S. 

0/47 

N.S. 

0/45 

N.S. 

Hamartoma 

 Values0 

0/57 

N.S. 

0/9 

N.S. 

0/50 

N.S. 

1/48 

(2%) 

N.S. 

1/58 

(2%) 

N.S. 

0/10 

N.S. 

0/47 

N.S. 

1/45 

(2%) 

N.S. 

Malignant Mixed Tumor 

 Values0 

0/57 

N.S. 

0/9 

N.S. 

1/50 

(2%) 

N.S. 

0/48 

(2%) 

N.S. 

1/58* 

(2%) 

N.S. 

0/10 

N.S. 

0/47 

N.S. 

1/45 

(2%) 

N.S. 

Total Renal Neoplasms 

 Values0 

3/57 

(5%) 

N.S. 

1/9 

(11%) 

N.S. 

1/50 

(2%) 

N.S. 

1/48 

(2%) 

N.S. 

2/58 

(3%) 

N.S. 

0/10 

N.S. 

0/47 

N.S. 

2/45 

(4%) 

N.S. 

-Ρ* Ο 

Hyperplasia, 

Renal Pelvis 

 Values0 

19/57 

(33%) 

.016N/.026 

1/9 

(11%) 

.114/.549 

6/50 

(12%) 

.016N/N.S. 

11/48 

(22%) 

.338N/N.S. 

17/58 

(29%) 

.095N/.544 

2/10 

(20%) 

N.S. 

9/47 

(19%) 

.332N/N.S. 

8/45 

(18%) 

.27ON/N.S. 

Urinary Bladder 

Epithelial Hyperplasia 

 Values0 

12/51 

(23.5%) 

.203N/.098 

2/8 

(25%) 

.534/.154 

4/45 

(9%) 

N.S. 

7/42 

(17%) 

N.S. 

8/53 

(15%) 

.062N/.308 

1/9 

(11%) 

N.S. 

2/42 

(5%) 

N.S. 

2/38 

(5%) 

N.S. 

*This neoplasm was diagnosed as a liposarcoma at microscopic examination. Several months following submission of the data from this study, a decision
 

was made following consultation with pathologists from NCI and Tracor Jitco to classify tumors of this type as malignant mixed tumors of kidney.
 

Therefore, this neoplasm should be included in summary of incidence of malignant mixed renal tumors.
 
41
 

Appendix A. (Rats, continued) 

Anatomic Site 

and/or 

Body System 

Pooled 

Control 

Males 

Matched 

Control 

Males 

Low-Dose 

Males 

High-Dose 

Males 

Pooled 

• Control 

Females 

Matched 

Control 

Females 

Low-Dose 

Females 

High-Dose 

Females 

Endocrine System 

Thyroid 

Follicular-Cell 

Adenoma 

 Values0 

3/51 

(6%) 

N.S. 

0/7 

N.S. 

4/47 

(8.5%) 

N.S. 

3/45 

(7%) 

N.S. 

2/59 

(3%) 

N.S. 

1/10 

(10%) 

N.S. 

2/46 

(4%) 

N.S. 

0/39 

N.S. 

Follicular-Cell 

Carcinoma 

 Values0 

1/51 

(2%) 

N.S. 

0/7 

N.S. 

0/47 

N.S. 

2/45 

(4%) 

N.S. 

1/59 

(2%) 

N.S. 

0/10 

N.S. 

1/46 

(2%) 

N.S. 

0/40 

N.S. 

Total Follicular-Cell 

Neoplasms 

 Values0 

4/51 

(8%) 

N.S. 

0/7 

N.S. 

4/47 

(8.5%) 

N.S. 

5/45 

(11%) 

N.S. 

3/59 

(5%) 

N.S. 

1/10 

(10%) 

.088N/.706 

3/46 

(6.5%) 

N.S. 

0/40 

N.S. 

C-cell Adenoma 

 Values0 

3/51 

(6%) 

N.S. 

1/7 

(14%) 

N.S. 

7/47 

(15%) 

N.S. 

2/45 

(4%) 

N.S. 

7/59 

(12%) 

N.S. 

2/10 

(20%) 

N.S. 

8/46 

(17%) 

N.S. 

4/40 

(10%) 

N.S. 

C-cell Carcinoma 

 Values0 

1/51 

(2%) 

N.S. 

0/7 

N.S. 

1/47 

(2%) 

N.S. 

2/45 

(4%) 

N.S. 

5/59 

(8%) 

N.S. 

1/10 

(10%) 

N.S. 

3/46 

(6.5%) 

N.S. 

2/40 

(5%) 

N.S. 

Total C-cell Neoplasms 

 Values0 

4/51 

(8%) 

N.S. 

1/7 

(14%) 

N.S. 

8/47 

(17%) 

N.S. 

4/45 

(9%) 

N.S. 

12/59 

(20%) 

N.S. 

3/10 

(30%) 

N.S. 

11/46 

(24%) 

N.S. 

6/40 

(15%) 

N.S. 

Total Thyroid Neoplasms 

 Values0 

8/51 

(16%) 

N.S. 

1/7 

(14%) 

N.S. 

12/47 

(26%) 

N.S. 

9/45 

(20%) 

N.S. 

15/59 

(25%) 

.164N/.193 

4/10 

(40%) 

.036N/.720 

14/46 

(30%) 

N.S. 

6/40 

(15%) 

N.S. 
42
 

Appendix A. (Rats, continued) 

Anatomic Site Pooled Matched Pooled Matched 

and/or Control Control Low-Dose High-Dose Control Control Low-Dose High-Dose 

Body System Males Males Males Males Females Females Females Females 

Follicular-Cellu 

Hyperplasia 0/51 0/7 4/47 7/45 4/59 0/10 1/46 0/40 

(8.5%) (16%) (7%) (2%) 

 Values0 .003/.776 .116/.863 .098/N.S. .008/N.S. N.S. N.S. N.S. N.S. 

C-cell Hyperplasia 29/51 5/7 21/47 23/45 30/59 5/10 22/46 14/40 

(57%) (71%) (45%) (51%) (51%) (50%) (48%) (35%) 

 Values0 N.S. N.S. N.S. N.S. .069N/.606 N.S. N.S. N.S. 

Other Endocrine Tissues 

Pituitary 

Adenoma 14/49 1/8 13/46 9/41 23/51 5/10 15/45 8/39 

c (29%) (12.5%) (28%) (22%) (44%) (50%) (33%) (20.5%) 

 Values N.S. N.S. N.S. N.S. .012N/.817 .039N/.787 .374N/.524N .030N/.146N 

Carcinoma 2/49 1/8 0/46 1/41 0/51 0/10 1/45 0/39 

(4%) (12.5%) (2%) (2%) 

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

Adrenal 

Cortical Adenoma 2/55 0/9 0/49 0/44 0/56 0/8 1/46 1/43 

(4%) (2%) (2%) 

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

Cortical Carcinoma 1/54 0/9 1/49 1/44 0/56 0/8 1/46 1/43 

(2%) (2%) (2%) (2%) (2%) 

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

Pancreas 

Islet-Cell Adenoma 1/52 0/7 1/49 3/44 1/60 1/10 4/46 0/42 

(2%) (2%) (7%) (2%) (10%) (9%) 

 Values0 N.S. N.S. N.S. N.S. N.S. N.S. N.S. N.S. 
43
 

Appendix A. (Rats, continued) 

Anatomic Site 

and/or 

Body System 

Pooled Control 

Males 

Matched 

Control 

Males 

Low-Dose 

Males 

High-Dose 

Males 

Pooled 

Control 

Females 

Matched 

Control 

Females 

Low-Dose 

Females 

High-Dose 

Females 

Reproductive System" 

Testis 

Interstitial-Cell Tumor 

 Values0 

0/58 

N.S. 

0/10 

N.S. 

2/50 

(4%) 

N.S. 

1/49 

(2%) 

N.S. 

Uterus 

Endometrial Stromal 

Polyp 

 Values0 

6/57 

(11%) 

N.S. 

1/9 

(11%) 

N.S. 

1/46 

(2%) 

N.S. 

3/44 

(7%) 

N.S. 

Squamous-Cell Carcinoma 

 Values0 

0/57 

N.S. 

0/9 

N.S. 

0/46 

N.S. 

1/44 

(2%) 

N.S. 

Ovary 

Granulosa-Cell Tumor 

 Values0 

1/58 

(2%) 

N.S. 

1/10 

(10%) 

N.S. 

0/45 

N.S. 

0/40 

N.S. 

Mammary Gland 

Adenocarcinoma 

 Values0 

0/58 

N.S. 

0/10 

N.S. 

0/50 

N.S. 

0/49 

N.S. 

2/60 

(3%) 

N.S. 

0/10 

N.S. 

1/47 

(2%) 

N.S. 

0/47 

N.S. 

Fibroma 

 Values0 

1/58 

(2%) 

N.S. 

0/10 

N.S. 

2/50 

(4%) 

N.S. 

0/49 

N.S. 

1/60 

(2%) 

N.S. 

0/10 

N.S. 

1/47 

(2%) 

N.S. 

1/47 

(2%) 

N.S. 
Appendix A. (Rats, continued) 

Anatomic Site Pooled Matched Pooled Matched 

and/or Control Control Low-Dose High-Dose Control Control Low-Dose High-Dose 

Body System Males Males Males Males Females Females Females Females 

Fibroadenoma ° 0/58 0/0 0/50 0/49 8/60 1/10 5/47 3/45 

(13%) (10%) (11%) (6%) 

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

Total Mammary Neoplasms 1/58 0/0 2/50 0/49 11/60 1/10 7/47 4/47 

(2%) (4%) (18%) (10%) (15%) (8.5%) 

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

Vascular and Hematopoietic 

Tissues 

Hemangioma 0/58 0/10 0/50 1/49 0/60 0/10 0/47 0/47 

(2%) 

 Values 0 N.S. N.S. N.S. N.S. N.S. N.S. N.S. N.S. 

Hemangiosarcoma 3/56 3/10 1/50 2/49 0/60 0/10 1/47 0/47 

(5%) (30%) (2%) (4%) (2%) 

 Values0 N.S. .046N/.003 N.S./.026N N.S./.060N N.S. N.S. N.S. N.S. 

^Malignant Lymphoma 1/58 0/10 0/50 1/49 2/60 0/10 0/47 0/47 

(2%) (2%) (3%) 

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

*Includes all types. 
Appendix A. (Rats, continued) 

Pooled Pooled Anatomic Site Control Control Low-Dose High-Dose Control Control Low-Dose High-Dose 

and/or Males Males Males Males Females Females Females Females 

Miscellaneous Neoplasms'5 

Trichoepithelioma 0/58 0/10 0/50 1/49 0/60 0/10 0/47 0/47 

(2%) 

 Values0

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

Lipoma 1/58 1/10 1/50 1/49 2/60 0/10 0/47 0/47 

(2%) (10%) (2%) (2%) (4%) 

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

Osteosarcoma, Skull 0/58 0/10 1/50 0/49 0/60 0/10 0/47 0/47 

(2%) 

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

Malignant Fibrous 2/58 1/10 1/50 2/49 1/60 0/10 1/47 0/47 

Histiocytoma (3%) (10%) (2%) (4%) (2%) (2%) 

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

Glioma 1/57 0/9 0/49 1/48 0/59 0/10 1/47 0/45 

(2%) (2%) (2%) 

 Values0 

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

Alveolar/Bronchiolar 0/58 0/10 0/48 0/48 0/58 0/10 1/47 0/45 

Carcinoma (2%) 

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

APPENDIX B
 

SUMMARY OF THE INCIDENCE OF TUMORS AND
 

PROLIFERATIVE LESIONS IN MICE
 

FED DIMETHOATE IN THE DIET
 

47
 

49


Appendix Β. Summary of the Incidence of Tumors and Proliferative
 

Lesions in Mice Fed Bimethoate in the Diet
 

Anatomic Site Pooled Matched Pooled Matched 

and/or Control Control Low-Dose High-Dose Control Control Low-Dose High-Dose 

Body System Males Males Males Males Females Females Females Females 

Digestive System 

Liver Neoplasms
 

Hepatocellular
 

Carcinoma 17/92 4/7 8/50 6/50 3/78 1/10 0/50 0/49
 

(18%) (57%) (16%) (12%) (4%) (10%)
 

 Values0 .191N/.886 .024N/.043 N.S. N.S. N.S. N.S. N.S. N.S.
 

Nodular Hyperplasia 3/92 0/7 3/50 5/50 1/78 0/10 2/50 2/49
 

(3%) (6%) (10%) (1%) (4%) (4%)
 

 Values .076/.840 .223/.852 N.S. .204/N.S. N.S. N.S. N.S. N.S.
 

Hepatocytomegaly 0/92 0/7 2/50 1/50 1/78 1/10 0/50 4/49
 

(4%) (2%) (1%) (10%) (8%)
 

 Values0 N.S. N.S. N.S . N.S. .0376/.0889 N.S. N.S. ,144/N.S.
 

Salivary Gland
 

Fibrosarcoma 0/88 0/6 1/50 0/49 0/77 0/10 0/50 0/49
 

(2%)
 

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

Low-dose and high-dose mice received 250 and 500 ppm of dimethoate in the diet, respectively.
 

Number of tumor-bearing animals/number of animals examined at site, and (%).
 

Beneath the untreated controls incidence is the probability level for the Armitage test for positive dose-related trend in proportions when it is
 

below 0.10 (otherwise N.S. - not significant) and its departure statistic (P value/departure value).
 

Beneath the dosed group incidence is the corrected probability level for the Fisher exact test for comparison of the dosed group with the control
 

groups when it is below 0.10 (otherwise N.S. - not significant).(P value for pooled controls/P value for matched controls).
 

 = negative trend.
 
Appendix B. (Mice, continued) 

Anatomic Site Pooled Matched Pooled Matched 

and/or Control Control Low-Dose High-Dose Control Control Low-Dose High-Dose 

Body System Males Males Males Males Females Females Females Females 

Endocrine System 

Thyroid 

Follicular-Cell 1/79 1/6 0/47 1/46 1/72 0/10 3/46 1/41 

Adenoma (1%) (17%) (2%) (1%) (6.5%) (2%) 

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

Follicular-Cell 0/79 0/6 2/47 1/46 1/72 0/10 0/46 1/41 

Hyperplasia (4%) (2%) (1%) (2%) 

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

Adrenal 

Cortical Carcinoma 0/88 0/7 0/47 0/48 0/78 0/10 0/46 1/45 

(2%) 

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

Pheochromocy toma 0/88 0/7 0/47 0/48 0/78 0/10 0/46 1/45 

(2%) 

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

Adrenocortical 27/88 3/7 35/47 38/48 19/78 0/10 0/46 0/45 

Hyperplasia (31%) (43%) (74%) (79%) (24%) 

P Values0 .000/.020 .102/.212 .000/.202 .000/.122 .000N/.026 N.S. .000N/N.S. .000N/N.S. 
Appendix B. (Mice, continued)
 

Matched
 

and/or Control Control Low-Dose High-Dose Control Control Low-Dose High-Dose
 

Body System Males Males ' Males
 

Anatomic Site Pooled Matched Pooled
 

Males Females Females Females Females
 

Pulmonary
 

Lung
 

0/10 0/49 0/48
 

Carcinoma (2%)
 

Alveolar/Bronchiolar 0/91 0/7 1/50 0/48 0/79
 

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

Alveolar/Bronchiolar 6/91 4/7 1/50 1/48 0/79 0/10 4/49 5/48
 

Adenoma (7%) (57%) (2%) (2%) (8%) (10%)
 

.121N/.483 .005N/.000 .310N/.000N .336N/.002N .007/.413 .246/.630 .040/N.S. .014/N.S.
 Values0
 

Total Primary 6/91 4/7 2/50 1/48 0/79 0/10 4/49 5/48
 

Pulmonary Neoplasms (8%) (57%) (4%) (2%) (8%) (10%)
 

.158N/.897 .001N/.000 .640N/.002N .336N/.002N .007/.414 .246/.630 .040/N.S. .014/N.S.
 Values0
 

Vascular and Hematopoietic
 

Malignant Lymphoma* 5/92 0 11 0/50 2/50 8/79 2/10 7/50 4/49
 (5%) (4%) (10%) (20%) (14%) (8%)
 

 Values0 N.S. N.S. .220N/N.S. N.S. N.S. N.S.
 N.S. N.S.
 

Mast-Cell Sarcoma 0/92 0/7 0/50
 0/50 0/79 0/10
 1/50 0 /49
 

(2%)
 

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

Hemangiosarcoma, Spleen 0/90 0/7 0/50 0/50 0/77 0/9
 0/50 1/49
 

0 (2%)
 Values N.S. N.S. N.S.
 N.S. N.S. N.S. N.S.
 N.S.
 

*For purposes of this summary table, "malignant lymphoma" includes lymphosarcoma, reticulum cell sarcoma, and all "types" of malignant lymphoma.
 
Anatomic Site
 

and/or
 

Body System
 

Reproductive System
 

Vagina
 

Leiomyosarcoma
 

 Values0
 

Uterus
 

Endometrial Stromal
 

Polyp
 

 Values C
 

Endometrial Hyperplasia
 

 Values0
 

Ovary
 

Papillary Adenoma
 

 Values °
 

Thecoma
 

 Values °
 

Testis
 

Carcinoma, Rete Testis
 

 Values C
 

Appendix B. (Mice, continued) 

Pooled Matched 

Control Control Low-Dose High-Dose 

Males Males Males Males 

0/90 0/7 0/49 1/48 

(2%) 

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

Pooled
 

Control
 

Females
 

0/79
 

N.S.
 

1/78
 

(1%)
 

N.S.
 

27/78
 

(35%)
 

.006N/.434
 

0/73
 

N.S.
 

0/73
 

N.S.
 

Matched
 

Control
 

Females
 

0/10
 

N.S.
 

1/9
 

(11%)
 

N.S.
 

0/9
 

.409/.226
 

0/10
 

N.S.
 

0/10
 

N.S.
 

Low-Dose
 

Females
 

1/50
 

(2%)
 

N.S.
 

0/50
 

N.S.
 

10/50
 

(20%)
 

.112N/.328
 

0/46
 

N.S.
 

0/46
 

N.S.
 

High-Dose
 

Females
 

0/49
 

N.S.
 

0/48
 

N.S.
 

9/48
 

(19%)
 

.084N/.372
 

1/45
 

(2%)
 

N.S.
 

1/45
 

(2%)
 

N.S.
 
Appendix B. (Mice, continued) 

Anatomic Site Pooled Matched Pooled Matched 

and/or Control Control Low-Dose High-Dose Control Control Low-Dose High-Dose 

Body System Males Males Males Males Females Females Females Females 

b Integumentary System 

Skin 

Fibrosarcoma 1/92 1/7 1/50 1/50 0/79 0/10 0/50 0/49 

(1%) (14%) (2%) (2%) 

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

APPENDIX C
 

SUMMARY OF THE INCIDENCE OF
 

NONTUMOR PATHOLOGY IN RATS
 

FED DIMETHOATE IN THE DIET
 

55
 

TABLE C1
 

SUMMARY OF THE INCIDENCE OF NONTUMOR PATHOLOGY
 

IN MALE RATS FED DIMETHOATE IN THE DIET
 

ANIMALS INITIALLY IN STUDY
 

AHIMALS NECROPSIED
 

ANIMALS EXAMINED HISTOPATHOLOGICALLY
 

AHIMALS WITH TUMORS
 

INTEGUMENTARY SYSTEM *
 

SKIN
 

INFLAMMATION SUPPURATIVE
 

INFLAMMATION GRANULOMATOUS
 

IHFLAMMATION FOCAL GRANOLOMATOUS
 

INFLAM SUPPURATIVE GRANULAMATOUS
 

GRANULATION TISSUE
 

HYPERPLASIA EPITHELIAL
 

RESPIRATORY SYSTEH
 

TRACHEA
 

INFLAMMATION CHRONIC
 

LUNG
 

FOREIGN BODY
 

EHPHYSEHA
 

CONGESTION
 

EDEMA
 

HEMORRHAGE
 

FOREIGN-BODY PNEUMONIA
 

ABSCESS
 

ALVEOLAR RACSOPHAGES
 

HYPERPLASIA ALVEOLAR-CELL
 

LUNG/ALVEOLI
 

INFLAMMATION SUPPURATIVE
 

CALCIFICATION
 

CIRCULATORY SYSTEH
 

MYOCARDIUM
 

INFLAMMATION
 

CONTROL
 

10
 

10 (100%)
 

10
 

7 (70%)
 

1 (10%)
 

1
 

1
 

LOW DOSE HIGH DOSE
 

50 50
 

50(100%) 49(100%)
 

50 49
 

23 (46%) 24 (49%)
 

5 (10%) 5 (10%)
 

5 5
 

1
 

α
 3


2
 

1
 

2 3
 

17 (34%) 22 (45%)
 

1
 

1
 

17 21
 

1 1
 

1
 

1
 

1
 

3
 

1
 

1
 

15 14
 

4 1
 

1 2
 

1 2
 

24 (48%) 20 (41%)
 

23 19
 

1 1
 

57
 
TABLE CI MALE RATS: NONTUMOR PATHOLOGY (CONT.)

 

HYOCARDIUH (CONT.)
 

INFLAHHATION FOC1L
 

FIBROSIS
 

FIBROSIS FOCAL
 

DEGENERATION
 

CALCIFICATION
 

ENDOCARDIUH
 

FIBROSIS
 

AORTA
 

CALCIFICATION
 

HESENKRIC ARTERI
 

PERIARTERITIS
 

DIGESTIVE SYSTBH
 

SALITART GLAND
 

IHFL1HHATIOH FOCAL
 

IHFLABHATION FOCAL GRAHULOHATOUS
 

LIVER
 

CONGESTION
 

INFLAHHATION FOC1L
 

HETAHORPROSIS FATTY
 

HEPATOCYTOHEGALT
 

ANGIECTASIS
 

HEHATOPOIESIS
 

LIVER/HBPATOCYTES
 

HYPERPLASIA FOCAL
 

BILE DUCT
 

INFLAHHATION
 

FIBROSIS
 

HYPERPLASIA
 

PANCREAS
 

INFLAHHATION ACUTE SUPPURATIVE
 

CONTROL
 

7 (70%)
 

6
 

5
 

1
 

1
 

2
 

1
 

2
 

58
 

LOW DOSE
 

22
 

1
 

1
 

2
 

2
 

1
 

1
 

2
 

2
 

3* (68%)
 

2
 

1
 

1
 

21
 

1
 

1
 

19
 

1
 

1
 

1
 

12
 

2
 

11
 

2
 

1
 

HIGH DOSE
 

2
 

16
 

2
 

6
 

6
 

25 (51%)
 

1
 

1
 

18
 

2
 

t
 

12
 

4
 

2
 

2
 

8
 

3
 

1
 

6
 
TABLE C1 MALE RATS: NONTUMOR PATHOLOGY (CONT.)

 

PANCREAS (CO IT.)
 

FIBROSIS FOCAL
 

PANCREATIC ACINUS
 

ATROPHY
 

ATROPHY FOCAL
 

STOHACR
 

ABSCESS
 

GASTRIC HOCOSA
 

HULTIPLE CTSTS
 

CALCIFICATIOf
 

SHALL I1TESTIHB
 

IHFLAHHATIOV FOCAL GRANULOHATOUS
 

URINARY STSTEH
 

KIDNEY
 

INFLAHHATION CHRONIC
 

KIDIEY/CORTEX
 

CAST
 

CTTOPLASHXC VACUOLIZATION
 

REIAL TOBULE
 

PIGHENTATION
 

HYPERPLASIA DIFFUSE
 

KIDIEY/PELVIS
 

CALCULUS
 

INPLAHHATION
 

HYPERPLASIA EPITHELIAL
 

URINARY BLADDER
 

CALCULUS
 

CONTROL
 

9 (90%)
 

6
 

6
 

2
 

1
 

1
 

2
 

t
 

1
 

3
 

t
 

LOW DOSE
 

1
 

2
 

1
 

1
 

1
 

1
 

3
 

3
 

t
 

1
 

45 (90%)
 

44
 

44
 

t
 

1
 

7
 

3
 

6
 

5
 

2
 

HIGH DOSE
 

1
 

t
 

35 (71%)
 

30
 

30
 

2
 

1
 

t
 

11
 

2
 

1
 

11
 

12
 

6
 

59
 
TABLE CI MALE RATS: NONTUMOR PATHOLOGY (CONT.)
 

URIRARY BLADDER (COW Τ.)
 

HYPERPLASIA EPITHELIAL
 

EHDOCRIWE SI STEP!
 

PITUITARY
 

HYPERPLASIA CHROHOPHOBE-CELL
 

ADRElfAL CORTEX
 

CYTOHS6ALY
 

THYROID
 

(JLTIHOBRAICHIAL CYST
 

CYSTIC FOLLICLES
 

HYPERPLASIA C-CELL
 

HYPERPLASIA FOLLICULAR-CELL
 

PARATHYROID
 

HYPERPLASIA
 

PAMCHEATIC ISLETS
 

HYPERPLASIA
 

HBHATOPOIETIC SYSTBH
 

SPLEEI
 

HEB0RRHA6S
 

FIBROSIS
 

FIBROSIS FOCAL
 

HEHOSIDBROSIS
 

HYPERPLASIA RETICULUH-CELL
 

HEHATOPOIESIS
 

LYHPH BODE
 

HYPERPLASIA RETICULUH-CELL
 

LYMPHOID HYPERPLASIA
 

COITROL
 

2
 

5 (50%)
 

5
 

5
 

2
 

2
 

1 <*0%)
 

1
 

1
 

LOW DOSE
 

4
 

33 (66%)
 

2
 

2
 

3
 

3
 

25
 

1
 

21
 

4
 

8
 

8
 

1
 

1
 

6 (12%)
 

6
 

1
 

5
 

1
 

1
 

HIGH DOSE
 

7
 

32 (65%)
 

3
 

3
 

8
 

8
 

27
 

3
 

2
 

23
 

7
 

1
 

1
 

1
 

1
 

9 (18%)
 

8
 

1
 

1
 

2
 

1
 

α
 

3
 

2
 

2
 

60
 
TABLE C1 MALE RATS: NONTUMOR PATHOLOGY (CONT.)

 

REPRODUCTIVE SYSTBH
 

PROSTATE
 

INFLAMMATION
 

INFLAMMATION SUPPURATIVE
 

INFLAMMATION GRAMULOHATOUS
 

HYPERPLASIA EPITHELIAL
 

TESTIS
 

PERIARTERITIS
 

ATROPHY
 

TUNICA VAGINALIS
 

HYPERPLASIA MESOTHELIAL
 

HERVOUS SYSTEH
 

BRAIN/MENINGBS
 

INFLAMMATION FOCAL GRANULOMATOUS
 

BRAIN
 

CORPORA AMYLACEA
 

MUSCULOSKELETAL SYSTEM
 

BONE
 

OSTEOPOROSIS
 

SKELETAL HUSCLE
 

INFLAMMATION SUPPURATIVE
 

INFLAMMATION GRANULOMATOUS
 

SPECIAL SENSE ORGANS
 

EYE
 

SYNECHIA ANTERIOR
 

EYE/CILIARY BODY
 

INFLAMMATION
 

CONTROL
 

9 (90%)
 

1
 

1
 

9
 

9
 

2 (20%)
 

1
 

1
 

1
 

1
 

LOW DOSE
 

41 (82%)
 

9
 

2
 

7
 

1
 

41
 

2
 

41
 

1 (2%)
 

1
 

1
 

2 (4%)
 

1
 

1
 

1
 

1
 

HIGH DOSE
 

36 (?3%J
 

10
 

8
 

2
 

35
 

1
 

35
 

2
 

2
 

1 (2%)
 

1
 

1
 

1 (2%)
 

1
 

1
 

1
 

t
 

6L
 
TABLE C1 MALE RATS: NONTUMOR PATHOLOGY (CONT.) 

CONTROL LOW DOSE HIGH DOSE
 

IRIS 1
 

INFLAMMATION 1
 

EYE/CRYSTALLINE LE»S 1
 

DEGENERATION 1
 

ALL OTHER SYSTEMS 1 (10%J 8 (16%)
 

RULTIPLE ORGANS 1 6
 

PERIARTERITIS 6
 

ARTERIOSCLEROSIS 1 2
 

ARTERIAL CALCIFICATION 1
 

CALCIFICATION 1 2
 

PERITONEUM 1
 

INFLAMMATION 1
 

ADIPOSE TISSUE 1
 

INFLARFfATION GRANULOHATOT7S 1
 

NO LESION REPORTED 1
 

AOTOLYSIS/NO NECROPSY PERFORMED 1
 

ANIHAL DISPOSITION SUMMARY
 

AIIMALS INITIALLY IN STUDY to 50 50
 

NATURAL DEATH* 3 4 6
 

MORIBUND SACRIFICE 4 10 15
 

SCHEDULED SACRIFICE
 

ACCIDENTALLY KILLED
 

TERMINAL SACRIFICE 3 36 29
 

•INCLUDES AUTOLYZED ANIMALS
 

• SYSTEM PERCENTAGES ARE BASED ON BUMBER OF ANIMALS NECROPSIBD.
 

62
 
TABLE C2 

SUMMARY OF THE INCIDENCE OF NONTUMOR PATHOLOGY
 

IN FEMALE RATS FED DIMETHOATE IN THE DIET
 

ABIKALS INITIALLY I STUDY
 

ANIHALS NSCROPSIED
 

ANIMALS EXAHINED HISTOPATHOLOGICALLY
 

AHIHALS WITH TUHOFS
 

INTEGUHENTARY SYSTEH *
 

SKIN
 

INFLAHHATION SUPPURATIVE
 

INFLAHHATIOH GRANULOHATOUS
 

RESPIRATORY SYSTEM
 

TRACHEA
 

FOREIGN BODY
 

INFLAHHATION CHRONIC
 

LUHG/BROHCHIOLE
 

INFLAHHATION SUPPURATIVE
 

LUNG
 

ATELECTASIS
 

COHGESTION
 

BDEKA
 

REHORRBAGE
 

FOREIGN-BODY PHEUHOHIA
 

ALVEOLAR MACROPHAGES
 

HYPERPLASIA ALVEOLAR-CELL
 

LUNG/ALVEOLI
 

IWFLAHHATIOI SUPPURATIVE
 

CIRCULATORY SYSTEH
 

RYOCARDIUH
 

FIBROSIS
 

FIBROSIS FOCAL
 

EWDOCARDIUR
 

FIBROSIS
 

CONTROL
 

10
 

10(100%)
 

10
 

7 (70%)
 

2 (20%)
 

1
 

1
 

2
 

2
 

2 (20%)
 

2
 

2
 

1
 

1
 

LOW DOSE
 

50
 

47(100%)
 

47
 

30 (64%)
 

2 (4%)
 

2
 

2
 

16 (34%)
 

1
 

1
 

15
 

1
 

14
 

1
 

1
 

1
 

15 (32%)
 

14
 

14
 

2
 

2
 

HIGH DOSE
 

50
 

47(100%}
 

45
 

21 (45%)
 

3 (6%)
 

3
 

1
 

2
 

21 (45%)
 

1
 

1
 

21
 

4
 

1
 

1
 

5
 

16
 

9 (19%)
 

8
 

6
 

2
 

1
 

1
 

63
 
TABLE C2 FEMALE RATS: NONTUMOR PATHOLOGY (CONT.)

 

MESENTERIC ARTERY
 

PERIARTERITIS
 

DIGESTIVE SYSTEM
 

SALIVARY GLAND
 

CALCULUS
 

FIBROSIS POCAL
 

LIVER
 

NECROSIS FOCAL
 

HETABORPHOSIS FATTT
 

HEPATOCTTOHEGALT
 

ANGIECTASIS
 

LIVER/CENTRILOBULAR
 

NECROSIS FOCAL
 

BILE DUCT
 

DILATATION
 

INFLAMMATION
 

HYPERPLASIA
 

PANCREAS
 

INFLAMMATION CHRONIC
 

FIBROSIS
 

PERIARTERITIS
 

PANCREATIC ACINOS
 

ATROPHY
 

ESOPHAGUS
 

DILATATION
 

STOMACH
 

ULCER FOCAL
 

INFLAMMATION ACUTE SUPPURATIVE
 

GASTRIC HUSCULARIS
 

HYPERPLASIA
 

CONTROL
 

6 (60%)
 

5
 

5
 

1
 

3
 

1
 

3
 

LOW DOSE
 

1
 

1
 

26 (55%)
 

1
 

1
 

1
 

15
 

1
 

7
 

4
 

4
 

12
 

3
 

5
 

7
 

5
 

1
 

4
 

1
 

4
 

4
 

3
 

2
 

1
 

HIGH DOSE
 

22 (47%)
 

1
 

1
 

18
 

1
 

6
 

12
 

4
 

1
 

1
 

3
 

2
 

2
 

2
 

2
 

1
 

1
 

64
 
SHALL INTESTINE
 

ULCER FOCAL
 

COLON
 

ULCER FOCAL
 

URINARY SYSTEM
 

KIDHET
 

IHFLAHHATION CHRONIC
 

KIDHBY/HEDULLA
 

CONGESTION
 

KIDNEY/PELTIS
 

CALCULUS
 

INFLAHHATION SUPPURATIVE
 

INFLAHHATION CHROMIC
 

HYPERPLASIA EPITHELIAL
 

URINARY BLADDER
 

IHFLAHHATION DIFFUSE
 

INFLAHHATION CHRONIC
 

HYPERPLASIA EPITHELIAL
 

D.	 BLADDER/HUCOSA
 

HEHORRHAGE
 

ENDOCRINE SYSTEM
 

PITUITARY
 

HYPERPLASIA CHROHOPHOBE-CELL
 

ADRENAL
 

ATROPHY
 

ANGIECTASIS
 

TABLE C2 FEMALE RATS: NONTUMOR PATHOLOGY (CONT.) 

CONTROL
 

7 (70%)
 

6
 

6
 

2
 

1
 

2
 

1
 

1
 

7 (70%)
 

LOW DOSE
 

1
 

1
 

1
 

1
 

30 (6<!%)
 

26
 

26
 

11
 

7
 

1
 

1
 

9
 

2
 

2
 

33 (70%)
 

3
 

3
 

6
 

1
 

5
 

HIGH DOSE
 

20 (43%)
 

16
 

16
 

1
 

1
 

9
 

2
 

2
 

1
 

8
 

3
 

1
 

1
 

2
 

1
 

1
 

22 (47%)
 

3
 

3
 

1
 

1
 

65 
TABLE C2 FEMALE RATS: NONTUMOR PATHOLOGY (CONT.) 

COHTROL LOW DOSE HIGH DOSE
 

ADREIAL CORTEX 1 11 8
 

CYT0HE6ALY 1 10 6
 

HYPERPLASIA POCIL 2
 

AIGIECTASIS 2 1
 

THYROID 6 24 15
 

ULTIHOBRAICHIAL CYST 1 2 1
 

CYSTIC FOLLICLES 1
 

HYPERPLASIA C-CELL 5 22 14
 

HYPERPLASIA FOLLICITLAR-CELL 1
 

PARATHYROID 1
 

HYPERPLASIA t
 

PAWCREATIC ISLETS 1 1
 

ffYPERPLASIA 1 1
 

HEHATOPOIETIC SYSTBH 3 (30%) 4 (9%) 6 (13%)
 

SPLEEI 3 4 6
 

FIBROSIS 1 1
 

HEBOSIDEROSIS 2 1 1
 

ATROPHY 1
 

LYBP13OID HYPERPLASIA 1
 

HEHATOPOIESIS 2 5
 

LYHPH IODE t
 

LTHPHOID HYPERPLASIA 1
 

REPRODUCTIVE SYSTBH 4 (9%) 10 (21%)
 

HABRARY GLA1D 4
 

HYPERPLASIA 3
 

HYPERPLASIA FOCAL 1
 

TESTIS 1
 

ATROPHY 1
 

66
 
TABLE C2 FEMALE RATS: NONTUMOR PATHOLOGY (CONT.)

 

UTERUS
 

HEMORRHAGE
 

UTERUS/ENDOMETRIUH
 

INFLAMMATION SUPPURATIVE
 

HYPERPLASIA
 

HYPERPLASIA CYSTIC
 

METAPLASIA SQUAMOUS
 

NERVOUS SYSTEM
 

NONE
 

MUSCULOSKELETAL SYSTEM
 

NONE
 

SPECIAL SENSE ORGANS
 

EYE/CORNEA
 

INFLAMMATION CHRONIC
 

EYE/CILIARY BODY
 

PIBROSIS
 

EYE/CRYSTALLINE LE»S
 

DEGENERATION
 

BYE/CONJUNCTIVA
 

INFLAMMATION CHRONIC
 

EYB/LACRIMAL GLAND
 

INFLAMMATION CHRONIC
 

EYE/LACRIHAL DUCT
 

METAPLASIA SQUAMOUS
 

CONTROL LOW DOSE HIGH DOSE
 

1
 

1
 

3 6
 

1 1
 

1
 

2 3
 

2 3
 

2 (4%>
 

1
 

1
 

1
 

1
 

1
 

1
 

1
 

1
 

1
 

1
 

1
 

1
 

67 
TABLE C2 FEMALE RATS: NONTUMOR PATHOLOGY (CONT.)

 

ALL OTHER STSTERS
 

MULTIPLE ORGANS
 

PERIARTERITIS
 

NO LESION REPORTED
 

AUTOLYSIS/NECROPSY PERF/NO HISTO
 

AUTOLYSIS/NO HECROPST PERFORHED
 

ANIHAL DISPOSITION SUHHARY
 

ANIBALS INITIALLY IN STUDY
 

NATURAL DEATH*
 

RORIBUND SACRIFICE
 

SCHEDULED SACRIFICE
 

ACCIDENTALLY KILLED
 

TERMINAL SACRIFICE
 

«INCLUDES AUTOLYZED ANIHALS
 

CONTROL
 

10
 

1
 

9
 

LOW DOSE HIGH DOSE
 

1 (2%)
 

1
 

1
 

4
 

2
 

3 3
 

50 50
 

5 13
 

9 12
 

36 25
 

• SYSTEM PERCENTAGES ARE BASED ON NUMBER OF ANIHALS NECROPSIED.
 

68
 
APPENDIX D
 

SUMMARY OF THE INCIDENCE OF
 

NONTUMOR PATHOLOGY IN MICE
 

FED DIMETHOATE IN THE DIET
 

69
 

TABLE 01 

SUMMARY OF THE INCIDENCE OF NONTUMOR PATHOLOGY 

IN MALE MICE FED DIMETHOATE IN THE DIET 

ANIMALS INITIALLY IN STUDY
 

AMIMALS NECROPSIED
 

AMIMALS EXAMIMED HIST0PATHOLOGICALLY
 

AHIMALS WITH TOBORS
 

IMTEGOBENTARY SYSTEB*
 

SKIN
 

ULCER FOCAL
 

INFLAMMATION NECROTIZING
 

HYPERPLASIA EPITHELIAL
 

ACANTHOSIS
 

RESPIRATORY SYSTEM
 

LUNG
 

EMPHYSEMA
 

INFLAMMATIOI FOCAL
 

IMFLAMMATIOW FOCAL CHRONIC
 

HYPERPLASIA ALVEOLAR-CELL
 

CIRCULATORY SYSTEH
 

MYOCARDIUM
 

MINERALIZATION
 

DIGESTIVE SYSTEM
 

LIVER
 

INFLAMMATION CHRONIC
 

NECROSIS FOCAL
 

CYTOPLASBIC VACUOLIZATION
 

HEPATOCYTOMEGALY
 

HYPERPLASIA MODULAR
 

MODULAR HYPERPLASIA
 

CONTROL
 

7
 

7(100%)
 

7
 

6 (86%)
 

1 («*)
 

1
 

1
 

1 (14%)
 

LOW DOSE
 

50
 

50(100%)
 

50
 

11 (22%)
 

3 (6%)
 

3
 

1
 

1
 

1
 

1
 

3 (6%)
 

3
 

2
 

1
 

8 (16%)
 

6
 

1
 

2
 

3
 

HIGH DOSE
 

50
 

50(100%)
 

50
 

11 (22%)
 

1 (2%>
 

1
 

1
 

t (2%)
 

1
 

1
 

1
 

8 (16%)
 

7
 

1
 

1
 

1
 

1
 

4
 

1
 

71
 
TABLE D1 MALE MICE: NONTUMOR PATHOLOGY (CONT.)

 

BILE DUCT
 

IBFLAHUTIOB CBBOIXC
 

PABCREAS
 

IBFLAHEATIOI FOCAL CHRONIC
 

PAICREATIC DUCT
 

CTST
 

PABCBEATIC ICIBOS
 

1TBOPHT
 

ATBOPHT FOCAL
 

LARGE IBTESTXBE
 

•EHATODIASIS
 

ORIBARY STSTEH
 

BOBE
 

EBBOCBIBE STSTEB
 

ADRE1AL COBTSX
 

HYPERPLASIA
 

THTBOID
 

HTPEBPLASIA FOLLICOLAR-CELL
 

CYSTIC FOLLICLES
 

HEBATOPOIETXC STSTEH
 

SPLEBB
 

LIHPHOID HYPERPLASIA
 

BEBATOPOXESXS
 

LYRPfl BODE
 

AIGIECTASIS
 

COHTROL
 

1
 

1
 

1
 

1
 

3 (43%)
 

3
 

3
 

1 (1W)
 

1
 

1
 

72
 

LOW DOSE
 

1
 

1
 

1
 

1
 

36 (72%)
 

35
 

35
 

3
 

2
 

1
 

2 (4%)
 

2
 

1
 

1
 

HIGH DOSE
 

1
 

1
 

1
 

1
 

t
 

1
 

39 (78%)
 

38
 

38
 

1
 

1
 

2 (4%)
 

1
 

1
 

1
 

1
 
TABLE D1 MALE MICE: NONTUMOR PATHOLOGY (CONT.)

 

COHTROL LOW DOSE 

REPRODUCTIVE SISTER 

SEHIHAL TBSICLE 

DISTEHTIOH 

3 (6%) 

1 

1 

TESTIS 

ATROPHY 

ATROPHY FOCAL 

2 

2 

EPIDIDYMIS 

IHFLAHHATIOH CHROHIC 

HBR?OUS SYSTEH 

HOIS 

MUSCULOSKELETAL SYSTSH 

HOHS 

SPECIAL SEHSB 0R6AHS 

HOHE 

ALL OTHER SYSTEMS 

BPICARDIUH 

IHFLAHHATIOV CHROHIC 

HO LESIOH REPORTED 1 5 

AHIHAL DISPOSITION SUHHARY 

AHIHALS INITIALLY IH STUDY 

HATURAL DEATH* 

HORIBUHD SACRIFICE 

SCHEDULED SACRIFICE 

ACCIDEHTALLY KILLED 

TERHIHAL SACRIFICE 

7 

1 

6 

50 

3 

6 

41 

•IICLUDES AUTOLYZED AHIHALS 

HIGH DOSE
 

2 (4X)
 

1
 

1
 

1
 

1
 

1 (2%)
 

1
 

1
 

3
 

50
 

2
 

2
 

46
 

• SYSTEM PERCEHTAGES ARE BASED ON NUMBER OF ANIMALS NECROPSIED.
 

73
 
TABLE D2
 

SUMMARY OF THE INCIDENCE OF NONTUMOR PATHOLOGY
 

IN FEMALE MICE FED DIMETHOATE IN THE DIET
 

ANIHALS INITIALLY IN STUDY
 

ANIMALS NECROPSIED
 

ANIHALS EIAHΙΝKD HISTOPATHOLOGICALLY
 

ANIHALS WITH TUHORS
 

INTEGUHENTARY SYSTBH
 

NONE
 

RESPIRATORY SYSTEH
 

HOME
 

CIRCULATORY SYSTEH *
 

HEART
 

PERIARTERITIS
 

HYOCARDIUH
 

INFLAHHATION SUPPURATIVE
 

DIGESTIVE SYSTEH
 

LIVER
 

INFLAHHATION FOCAL
 

LYHPHOCYTIC INFLAH INFILTRATE
 

INFLAHHATION SUPPURATIVE
 

GRANULOHA
 

NECROSIS FOCAL
 

HEPATOCYTOHEGALY
 

HYPERPLASIA NODULAR
 

HEHATOPOIESIS
 

SHALL INTESTINE
 

LIHPHOID HYPERPLASIA
 

CONTROL
 

10
 

10(100%)
 

10
 

3 (30%)
 

1 (10%)
 

1
 

1
 

LOW DOSE
 

50
 

50(100%)
 

50
 

15 (30%)
 

1 (2%)
 

1
 

1
 

1
 

1
 

7 (14%)
 

6
 

1
 

1
 

1
 

2
 

1
 

1
 

1
 

HIGH DOSE
 

50
 

49(100%)
 

49
 

12 (24%)
 

8 (16%)
 

8
 

2
 

1
 

1
 

1
 

4
 

2
 

74
 
TABLE D2 FEMALE MICE: NONTUMOR PATHOLOGY (CONT.)
 

URINARY SYSTEM
 

KIDNEY
 

HYDRONEPHROSIS
 

GLOMERULOSCLEROSIS
 

KIDHEY/CORTEX
 

LYMPHOCYTIC INFLAM INFILTRATE
 

ENDOCRINE SYSTEH
 

THYROID
 

PERIARTERITIS
 

HYPERPLASIA FOLLICULAR-CELL
 

HEHATOPOIETIC SYSTEM
 

SPLEEN
 

LYMPHOID HYPERPLASIA
 

HEMATOPOIESIS
 

LYMPH NODE
 

CYST
 

INFLAMMATION GRANULOMATOUS
 

AMYLOIDOSIS
 

CERVICAL LYMPH NODE
 

CYST
 

REPRODUCTIVE SYSTEH
 

UTERUS/BNDOHETRIUH
 

CYST
 

INFLAMMATION
 

INFLAMMATION SUPPURATIVE
 

HYPERPLASIA
 

HYPERPLASIA CY5TIC
 

CONTROL
 

9 (90%)
 

9
 

7
 

2
 

75
 

LOW DOSE
 

5 (10%)
 

2
 

1
 

Τ
 

3
 

3
 

1 (2%)
 

1
 

1
 

7 (14%)
 

4
 

2
 

2
 

2
 

2
 

1
 

1
 

43 (86%)
 

42
 

29
 

2
 

3
 

3
 

7
 

HIGH DOSE
 

3 (6%)
 

3
 

3
 

1 (2%)
 

1
 

1
 

3 (6%)
 

2
 

2
 

2
 

1
 

1
 

39 (80%)
 

35
 

26
 

1
 

8
 
TABLE 02 FEMALE MICE: NONTUMOR PATHOLOGY (CONT.) 

CONTROL LOW DOSE HIGH DOSE
 

OVARY 3 5 2
 

FOLLICULAR CYST 3 t
 

INFLAMMATION 2
 

INFLAMMATION SUPPURATIVE 3 1 1
 

OVARY/SEROSA 3 6
 

CYST 2 6
 

HULTIPLE CYSTS 1
 

1ERVOUS SYSTEH
 

HONE
 

MUSCULOSKELETAL SYSTEH
 

RONE
 

SPECIAL SENSE ORGANS
 

NONE
 

ALL OTHER SYSTEHS
 

NONE
 

NO LESION REPORTED 4 7
 

AUTOLYSIS/NO NECROPSY PERFORMED 1
 

ANIHAL DISPOSITION SUMMARY 

ANIMALS INITIALLY IN STUDY

NATURAL DEATH* MORIBUND SACRIFICE

SCHEDULED SACRIFICE 

ACCIDENTALLY KILLED 

TERMINAL SACRIFICE

 10

 2

 7

 1 

 50

 4

 45

1 

 50 

2 

3 

 45 

•INCLUDES AUTOLYZED ANIMALS
 

• SYSTEM PERCENTAGES ARE BASED ON NUMBER OF ANIMALS NECROPSIED.
 

* U. S. GOVERNMENT PRINTING OFFICE : 1977 241-161/3009 

76 

DHEW Publication No. (NIH) 77-804