National Cancer Institute 

CARCINOGENESIS 

Technical Report Series 

No. 10 

1977 

BIOASSAY OF 

DICHLORVOS 

FOR POSSIBLE CARCINOGENICITY 

CAS No. 62-73-7 

NCI-CG-TR-10 

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

Public Health Service 

National Institutes of Health 

BIOASSAY OF
 

DICHLORVOS
 

FOR POSSIBLE CARCINOGENICITY
 

Carcinogen Bioassay and Program Resources Branch
 

Carcinogenesis Program
 

Division of Cancer Cause and Prevention
 

National Cancer Institute
 

National Institutes of Health
 

Bethesda, Maryland 20014
 

DHEW Publication No. (NIH) 77-810
 

BIOASSAY OF
 

DICHLORVOS
 

FOR POSSIBLE CARCINOGENICITY
 

Carcinogenesis Program, Division of Cancer Cause and Prevention
 

National Cancer Institute
 

National Institutes of Health
 

CONTRIBUTORS: This report presents the results of the bioassay
 

of dichlorvos for possible carcinogenicity, 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, Incorporated, prime contractor for
 

the NCI carcinogen bioassay program.
 

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

Weisburger*»2 an(j R. R# Bates*; the doses were selected by Drs.
 

T. E. Shellenburger3»^, J. Η. Weisburger and R. R. Bates. Animal
 

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

Shellenburger, W. E. Greer3

, and H. P. Burchfield3, with the
 

technical assistance of Ms. D. H. Monceaux3

 and Mr. D.
 

Broussard3

. Necropsies were performed under the supervision of
 

Drs. E. Bernal3 and B. Buratto3. The histopathologic evaluation
 

was conducted at Experimental Pathology Laboratories by Dr. R. A.
 

Renne5,9 and Dr. J. Ferrell5

, and the diagnoses included in this
 

report represent the interpretation of these pathologists.
 

Pathologists at NCI and Tracor Jitco have reviewed selected
 

slides and concur with the overall pathologic evaluation of the
 

study.
 

Compilation of individual animal survival and summary tables was
 

performed by EG&G Mason Research Institute7

; pathology tables
 

were compiled at Experimental Pathology Laboratories5

; and
 

statistical analyses were performed by Dr. J. R. Joiner6

, using
 

methods selected for the bioassay program by Dr. J. J. Gart**.
 

iii
 
This report was prepared at Tracor Jitco^ under the direction of
 

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

toxicologist, Dr. J. F. Robens; the chemist, Dr. S. S. Olin; the
 

technical editor, Dr. E. W. Gunberg; and the technical writer,
 

Mr. W. D. Reichardt. The final report was reviewed by members of
 

the participating organizations^»*^,5,6#
 

^Carcinogen Program, Division 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.
 

3Gulf South Research Institute, Atchafalaya Basin Laboratories,
 

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

^Now with the National Center for Toxicological Research,
 

Jefferson, Arkansas.
 

^Experimental Pathology Laboratories (EPL), 17 Pine Street,
 

Herndon, Virginia.
 

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

Rockville, Maryland.
 

7

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

Rockville, Maryland.
 

Mathematical Statistics and Applied Mathematics Section, Field
 

Studies and Statistics, Division of Cancer Cause and
 

Prevention, National Cancer Institute, National Institutes of
 

Health, Bethesda, Maryland.
 

9Now with Battelle Pacific Northwest Laboratories,
 

Battelle Boulevard, Richland, Washington.
 

iv
 
SUMMARY
 

A bioassay for the possible carcinogenicity of technical-grade
 

dichlorvos was conducted using Osborne-Mendel rats and B6C3F1
 

mice· The test material was administered in the diet at two
 

concentrations for 80 weeks to groups of 50 animals of each
 

species and sex. The test animals were held for observation, and
 

surviving rats were killed at 110-111 weeks and surviving mice at
 

92-94 weeks from initiation of the study. Initial doses in both
 

species were not well tolerated and they were lowered after a few
 

weeks. Time-weighted average doses for both males and females
 

were 150 and 326 ppm for rats and 318 and 635 ppm for mice. The
 

matched controls consisted of 10 rats of each sex and 10 mice of
 

each sex; the pooled controls consisted of 60 rats of each sex,
 

100 male mice, and 80 female mice. All surviving rats were
 

killed at 106 to 109 weeks; surviving mice, at 92 to 94 weeks.
 

After the doses were reduced, no toxic signs directly attributable to the compound were observed. However, average weights of
 

high-dose animals were slightly depressed. Survival was not
 

dose-related in either species. Microscopic study of the tissues
 

of treated animals and matched and pooled controls revealed no
 

statistically significant increase in the incidence of tumors
 

attributable to exposure to dichlorvos in either animal species.
 

The significance of the three esophageal tumors in male and
 

female mice and of malignant fibrous histiocytomas in male mice
 

is unclear and there is insufficient evidence to indicate they
 

were associated with dichlorvos treatment. Thus under the
 

conditions of this study, dichlorvos was not demonstrated to be
 

carcinogenic.
 

TABLE J)F JCONTENTS
 

I. Introduction 1
 

II. Materials and Methods 3
 

A. Chemical 3
 

B. Dietary Preparation 3
 

C · Animals 5
 

D. Animal Maintenance 5
 

E. Subchronic Studies 6
 

F. Design of Chronic Studies 8
 

G. Clinical and Pathologic Examinations 11
 

11. Data Recording and .Statistical Analyses 12
 

III. Results - Rats 17
 

A· Body Weights and Clinical Signs (Rats) 17
 

B. Survival (Rats) 19
 

C. Pathology (Rats) 19
 

D. Statistical Analyses of Results (Rats) 23
 

IV. Results - Mice 27
 

A. Body Weights and Clinical Signs (Mice) 27
 

B. Survival (Mice) 27
 

C. Pathology (Mice) 29
 

D. Statistical Analyses of Results (Mice) 34
 

V. Discussion 37
 

VI. Bibliography 39
 

APJPEJNDD(ES
 

Appendix A Summary of the Incidence of Neoplasms in
 

Rats Fed Dichlorvos in the Diet 41
 

Table Al Proliferative Lesions of the Thyroid 43
 

Table A2 Other Proliferative Endocrine Lesions 44
 

vii
 
SfifiS
 

Table A3 Proliferative Lesions of the Reproductive 

System 45 

Table A4 Neoplasms of the Vascular and Hematopoietic 

Systems 47 

Table A5 Proliferative Lesions of the Digestive 

System 48 

Table A6 Proliferative Lesions of the Urinary 

Tract 49 

Table A7 Miscellaneous Proliferative Lesions 50 

Table A8 Analyses of the Incidence of Tumors at 

Specific Sites in Male Rats Fed 

Dichlorvos in the Diet 51 

Table A9 Analyses of the Incidence of Tumors at 

Specific Sites in Female Rats Fed 

Dichlorvos in the Diet 56 

Appendix Β Summary of the Incidence of Neoplasms in 

Mice Fed Dichlorvos in the Diet 61 

Table Bl Proliferative Lesions of the Digestive 

System 63 

Table B2 Primary Pulmonary Neoplasms 64 

Table B3

Table B4

 Neoplasms of the Vascular and 

Hematopoietic Systems

 Proliferative Lesions of the Endocrine 

System

 65 

 66 

Table B5 Proliferative Lesions of the Reproductive 

System 67 

Table B6 Neoplasms of the Integumentary System 68 

Table B7 Analyses of the Incidence of Tumors at 

Specific Sites in Male Mice Fed 

Dichlorvos in the Diet 69 

viii
 
Table B8 Analyses of the Incidence of Tumors at 

Specific Sites in Female Mice Fed 

Dichlorvos in the Diet 72 

Appendix C Summary of the Incidence of Nonneoplastic 

Lesions in Rats Fed Dichlorvos in the 

Diet 75 

Table C1 Summary of the Incidence of Nonneoplastic 

Lesions in Male Rats Fed Dichlorvos 

in the Diet 77 

Table C2 Summary of the Incidence of Nonneoplastic 

Lesions in Female Rats Fed Dichlorvos 

in the Diet 83 

Appendix D Summary of the Incidence of Nonneoplastic 

Lesions in Mice Fed Dichlorvos in the 

Diet 89 

Table D1 Summary of the Incidence of Nonneoplastic 

Lesions in Male Mice Fed Dichlorvos 

in the Diet 91 

Table D2 Summary of the Incidence of Nonneoplastic 

Lesions in Female Mice Fed Dichlorvos 

in the Diet 95 

TABLES 

Table 1 Design of Dichlorvos Chronic Feeding 

Studies in Rats 9 

Table 2 Design of Dichlorvos Chronic Feeding 

Studies in Mice 10 

FIGURES 

Figure 1

Figure 2

 Growth Curves of Rats Fed Dichlorvos 

in the Diet

 Survival Curves of Rats Fed Dichlorvos 

in the Diet

 18 

 20 

ix
 
Page 

Figure 3 Growth Curves of Mice Fed Dichlorvos in 

the Diet 28 

Figure 4 Survival Curves of Mice Fed Dichlorvos 

in the Diet 30 
I. INTRODUCTION
 

Dichlorvos, 2,2-dichlorovinyl diraethylphosphate, is an
 

organophosphate insecticide with contact and vapor action (Eto,
 

1974). It has been used widely for control of agricultural,
 

industrial, and domestic pests since the 1950's· Dichlorvos is
 

available in oil solutions, emulsifiable concentrations, and
 

aerosol formulations; the impregnation of dichlorvos in a
 

polyvinyl chloride base (pellets, strips, blocks, etc.) for
 

delayed release is a widely used method for the control of pests
 

in domestic and industrial situations (WHO/FAO, 1968; Stevenson,
 

1970).
 

Dichlorvos is registered as an anthelmintic to be administered
 

orally in swine, dogs, horses, cats, and puppies (CFR, 1976).
 

Topical application has been approved for beef and dairy cattle,
 

goats, sheep, swine, and chickens to control fleas, flies, and
 

mites. Dichlorvos has also been approved for use in barns and
 

chicken houses (WHO/FAO, 1968; EPA, 1973). Dichlorvos may be
 

applied in mushroom houses and in greenhouses where cucumbers,
 

radishes, lettuce, and tomatoes are grown (EPA, 1972, 1973).
 

Aerosols (0.5% dichlorvos) and strips are used domestically for
 

the control of ants, bedbugs, ticks, cockroaches, flies,
 

mosquitoes, silverfish, spiders, and wasps (WHO/FAO, 1968).
 

1 
Exposure to dichlorvos occurs by the inhalation of sprays or
 

vapors from impregnated resins, by skin contact, or orally as a
 

residue in food. The threshold limit value in workroom air as
 

adopted by the American Conference of Government Industrial
 

Hygienists (1971) is 1.0 rag/m3

; the acceptable daily intake has
 

been set at 0-0.004 ,mg/kg body weight (WHO/FAO, 1968).
 

Dichlorvos was selected for testing because of extensive use and
 

long-term human exposure.
 

2 
II. MATERIALS AND METHODS
 

A. Chemical
 

The dichlorvos used for this study was the technical-grade
 

material, Vapona®, obtained from Shell Chemical Co., Agricultural
 

Division, San Ramon, California. Analyses at Gulf South Research
 

Institute confirmed the manufacturer's specification of 94%
 

minimum purity. Analytical data include infrared, ultraviolet,
 

and nuclear magnetic resonance spectra, and thin-layer and gas-


liquid chromatograms. No attempt was made to identify
 

impurities. Dichlorvos was stored in its original container (a
 

clear, one-quart glass bottle) in a refrigerator at 4°C.
 

B. Dietary Preparation
 

All diets were formulated weekly using Wayne^ Lab-Blox animal
 

chow (Allied Mills; Chicago, Illinois) to which was added the
 

required amount of dichlorvos. The test compound was first
 

dissolved in a small amount of acetone, which was then added to
 

the feed. Corn oil was also added to the feed, primarily as a
 

dust suppressant, and the diets were mixed mechanically to assure
 

homogeneity and to allow for evaporation of the acetone. Final
 

diets, including the control diet, contained corn oil equal to 2%
 

3 
of the final feed weight. The corn oil was produced by Opelousas
 

Refinery Co., Opelousas, Louisiana.
 

The stability of dichlorvos in feed after 1, 4, and 7 days was
 

determined at -20°C, 4°C, and at room temperature by extraction
 

and quantitation of the test chemical remaining in 150 ppm, 300
 

ppm, and 600 ppm batches. The results indicated that the
 

stability of feed mixtures stored in sealed glass containers was
 

satisfactory at -20°C. At 4°C, analytical concentrations were
 

within 10% of the initial values after 7 days, but concentrations
 

dropped to approximately 30% of the original concentration after
 

.4 days at room temperature. Therefore, diet mixtures were stored
 

in a glass container at 0°C or lower, and the diet mixture in the
 

feed hoppers was changed daily.
 

During the chronic study, samples of the diet at each concentration were selected at intervals and analyzed for the concentration of test chemical. The analytical means and standard
 

deviations were:
 

150 ppm level (24 samples) = 147.4 + 5.4 ppm,
 

300 ppm level (28 samples) = 295.4 + 11.0 ppm,
 

600 ppm level (25 samples) = 594.0 +28.4 ppm.
 

4 
Water and the formulated diets were made available ad libitum to
 

the experimental animals.
 

C. Animals
 

Rats and mice of both sexes, obtained through contracts of the
 

Division of Cancer Treatment, NCI, were used in these tests. The
 

rats were Osborne-Mendel strain and were approximately the third
 

generation bred at Charles River Breeding Laboratories, Inc.,
 

Wilmington, Massachusetts, from animals originally procured from
 

Battelle Memorial Institute, Columbus, Ohio. All other rats used
 

for the pooled-control group were purchased directly from
 

Battelle Memorial. The mice were B6C3F1 hybrids obtained from
 

Charles River Breeding Laboratories, Inc. Upon arrival at the
 

laboratory all animals were quarantined for 6-19 days as a
 

laboratory-acclimation period and then assigned to each test
 

group.
 

D. Animal Maintenance
 

All animals were housed in temperature- and humidity-controlled
 

rooms. Incoming air was filtered through fiberglass air
 

conditioner filters which were changed monthly. The total air in
 

each room was changed 10-12 time per hour. The relative humidity
 

of the room air was maintained between 40% and 70% and the
 

temperature range was 22-24°C. Fluorescent lighting provided
 

5 
illumination 10 hours per day. Rats were housed individually in
 

hanging galvanized steel-mesh cages, and mice were in solid-


bottom and clear-sided polypropylene cages equipped with a
 

nonwoven polyester fiber-filter bonnet. Female mice were housed
 

five per cage, and males two or three per cage. Initially rats
 

were transferred to clean cages weekly; later in the study clean
 

cages were provided biweekly. Mice were transferred to clean
 

cages with filter bonnets weekly. Cages were cleaned two days
 

prior to use. Fresh bedding (Absorb-Dri®, Lab Products) was
 

provided two times a week for male mice and three times a week
 

for females. Feeder jars were changed daily, and excess feed was
 

discarded. Water bottles were changed and sterilized three times
 

per week. Animals 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.
 

Rats and mice receiving dichlorvos were housed in separate rooms
 

with their respective controls. No other animal was housed in
 

either room.
 

E. Subchronic Studies
 

Feeding studies were conducted to estimate the maximum tolerated
 

doses in order to determine the high and low concentrations
 

(hereinafter referred to as "high doses" and "low doses") to be
 

administered in the chronic study. The low dose given in the
 

6
 
chronic study is 1/2 the high dose. In these subchronic studies
 

dichlorvos was added to the animal feed at twofold increasing
 

doses, starting with 250 ppm and ending with 4,000 ppm for rats
 

and mice. Because there was no mortality in any treated group of
 

mice during the entire study, a second study was performed with
 

doses of 4,000 to 12,000 ppm. The compound was provided in feed
 

to experimental groups of five male and five female animals of
 

each species for 6 weeks, followed by a 2-week observation
 

period.
 

At 500 ppm none of the animals died, and there was only slight
 

reduction of weight gain. At 1,000 ppm the compound-fed animals
 

lost weight during the first and second weeks of the study but
 

returned to near normal weight expectation after that time. At
 

2,000 and 4,000 ppm all animals died during the study. The low
 

and high doses for rats were therefore set at 500 and 1,000 ppm.
 

Due to intense signs of toxicity observed in the high-dose rats
 

after initiation of the chronic study, the high-dose was reduced
 

to 300 ppm. The low-dose rats, started four weeks after the high
 

dose due to the inavailability of animals, were therefore placed
 

on study at 150 ppm as shown in table 1 (also see pp. 8 and 11,
 

below).
 

Mice receiving 4,000 ppm lost weight during the first week of the
 

study, and three of five female animals died; a fourth female of
 

7 
this group died during week 6. At 6,000 ppm and higher, all
 

animals died· The low and high doses for mice were set at 1,000
 

and 2,000 ppm.
 

F. Design of Chronic Studies
 

The design of the chronic studies, including both test animals and
 

their matched controls, is illustrated in tables 1 and 2.
 

The pooled controls consisted of the initial matched controls, 10
 

animals of each sex and species, for the studies of aldrin,
 

dieldrin, chlordane, dichlorvos, dimethoate, and heptachlor.
 

Because additional matched-control mice were started simultaneously with restarted treatment groups for some of these
 

compounds, the numbers of mice in the pooled-control groups vary.
 

The pooled controls for tests using rats consisted of 60 male and
 

60 female rats; for mice, 100 males and 80 females. Each of the
 

matched-control groups were housed in a separate room with its
 

respective treatment groups. All controls were placed on study
 

at 35 days of age except the matched-control rats for dichlorvos.
 

Because dichlorvos was the last bioassay of this series to be
 

started, there were slight differences in the ages of rats used
 

in the test. Due to the inability of the supplier to provide a
 

sufficient number of rats to start the entire test at one time,
 

one shipment of animals (the high-dose group and five matched
 

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

Sex and 

Treatment 

Grou£___ 

Initial 

No. of 

Animals 

Dichlorvos 

in Dieta 

(ppm) 

Time on Study 

Treated^Untreated0 

(weeks) (weeks) 

Time-Weighted 

Average Dosed 

(ppm) 

Male 

Matched-Control 5 0 0 110 

Low-Dose 50 150 

0 

80 

0 30 

150 

Matched-Control 5 0 0 110 

High-Dose 50 1,000 

300 

0 

3 

77 

0 30 

326 

Female 

Matched-Control 5 0 0 110 

Low-Dose 50 150 

0 

80 

0 30 

150 

Matched-Control 5 0 0 110 

High-Dose 50 1,000 

300 

0 

3 

77 

0 

30 

30-31 

326 

a

Doses were lowered because of toxic response.
 

b

Treatment periods at high and lowered dosages.
 

c

When diets containing dichlorvos were discontinued, treated
 

animals and their matched controls were fed control diets (2%
 

corn oil added) until termination.
 

d

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

Σ(no. of days receiving each dose)
 

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

Sex and 

Treatment 

Group ^ 

Initial 

No. of 

Animals 

Dichlorvos 

in Dieta 

(£pm) 

Time on Study 

Treated^Untreated0 

(weeks) (weeks) 

Time-Weighted 

Average Dose** 

(ppm) 

Male 

Matched-Control 10 0 0 92 

Low-Dose 50 1,000 

300 

0 

2 

78 

0 13 

318 

High-Dose 50 2,000 

600 

0 

2 

78 

0 14 

635 

Female 

Matched-Control 10 0 0 92 

Low-Dose 50 1,000 

300 

0 

2 

78 

0 12-13 

318 

High-Dose 50 2,000 

600 

0 

2 

78 

0 13-14 

635 

a

Doses were lowered because of toxic response.
 

"Treatment periods at high and lowered dosages.
 

c

When diets containing dichlorvos were discontinued, treated
 

animals and their matched controls were fed control diets (2%
 

corn oil added) until termination.
 

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

Σ(no. of days receiving each dose)
 

10
 
controls of each sex) was started on test at 43 days of age.
 

Four weeks later, a second shipment of animals (the low-dose
 

group and five additional control animals of each sex) was placed
 

on test at 36 days of age. Both shipments 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 probably no significant genetic drift influencing
 

the incidence of tumors.
 

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. Those animals appearing moribund at the time of
 

clinical examination were killed and necropsied.
 

The pathologic evaluation consisted of gross and microscopic
 

examination of all major tissues, organs, or gross lesions taken
 

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

The following tissues were routinely subjected to microscopic
 

examination: brain, pituitary, adrenal, thyroid, parathyroid,
 

trachea, esophagus, thymus, salivary gland, lymph nodes, heart,
 

lung, spleen, liver, kidney, stomach, pancreas, small intestine,
 

large intestine, urinary bladder, prostate or uterus, testis or
 

ovary, mammary gland, skin, and bone including marrow.
 

11
 
Occasionally, additional tissues were also examined
 

microscopically. The different tissues were preserved in 10%
 

buffered formalin, embedded in paraffin, sectioned, and stained
 

with hematoxylin and eosin. An occasional section was subjected
 

to special staining techniques for more definitive diagnosis.
 

A few tissues were not examined for some animals, particularly
 

for those that showed early deaths. Also, some animals were
 

missing, cannibalized, or Judged to be in such an advanced state
 

of autolysis as to precluded histopathologic interpretation·
 

Thus, the number of animals for which particular organs, tissues,
 

or lesions were examined microscopically, varies and does not
 

necessarily represent the number of animals that were placed on
 

experiment in each group.
 

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 included
 

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 (Berenblum, 1969). Data
 

tables were generated for verification of data transcription and
 

for statistical review.
 

12
 
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. Deaths due to accident or
 

scheduled deaths are treated as censored observations, and all
 

other deaths are uncensored. Statistical tests of differences in
 

survival between groups are compared using the method of Cox
 

(1972) for two groups and an extension of this method by Tarone
 

(1975) for more than two groups·
 

The incidence of neoplastic or nonneoplastic lesions is given as
 

the proportion of the number of animals bearing such lesions at a
 

specific anatomic site (numerator) to the number of animals
 

examined pathologically at that site (denominator). For the
 

organs and tissues in which most of the lesions appeared, the
 

denominators included only those animals for which such sites
 

were examined histologically. For tissues that required gross
 

observation for detection of lesions (e.g., skin or mammary
 

tumors), for lesions that appeared at several sites (e.g.,
 

lymphomas), or for tissues that were examined histologically only
 

when lesions were detected grossly, the denominators consisted of
 

the numbers of animals necropsied.
 

Statistical analysis of the incidence of tumors was made using
 

the Fisher exact test (Cox, 1970) to compare a control group to a
 

group of treated animals at each dose. In addition, the Armitage
 

13
 
and Cochran test for linear trend in proportions, with continuity
 

correction (Armitage, 1971), was used· This test, assuming a
 

linear trend, determined if the slope of the dose-response curve
 

was different from zero, at the (K05 level of significance· The
 

method also provided a calculation of the level of probability of
 

departure from linear trend.
 

A conservative adjustment, the Bonferroni inequality (Miller,
 

1966), was used for simultaneous comparison of several treated
 

groups with a control group. For the comparison of results
 

obtained with k different test doses with those for a control,
 

this correction requires a level of significance less than or
 

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

the 0.05 level. This adjustment was not made in the tables where
 

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

analysis when appropriate.
 

As an additional analysis, the exact 95% confidence interval for
 

the odds ratio (Gart, 1970) between each of the dose groups and
 

its control was calculated. The odds ratio is Pt(l~Pc)/Pc(*~Pt)
 

where pt is the true binomial probability of tumor in a treated
 

group of animals and pc is the true spontaneous probability of
 

tumor in a control group. The hypothesis of equality between the
 

true proportion of a specific tumor in a treated group and that
 

in a control group is expressed by an odds ratio of 1 (one).
 

14
 
Values in excess of 1 (one) represent the condition of a larger
 

proportion in the treated group than in the control. The entries
 

for confidence intervals in the statistical tables of this report
 

represent the conversion of each odds ratio to the difference in
 

probabilities, Pt~Pc> where Pt~Pc * 0 implies an odds ratio of 1
 

(one)·
 

15
 

III. RESULTS - RATS
 

A. Body Weights and Clinical Signs (Rats)
 

During the 3-week period that the high-dose animals were on test
 

at 1,000 ppm, intense signs of toxicity were observed, i.e.,
 

tremors, rough coat, diarrhea, and poor general appearance. When
 

the doses were reduced to 150 and 300 ppm, the appearance and
 

behavior of the treated rats during the first year of the study
 

generally were comparable to those of the controls.
 

The average weights of male and female high-dose rats were
 

consistently lower than the low-dose and matched-control groups
 

throughout the first year and one half of the study (see figure
 

1).
 

During the first year, adverse clinical signs were noted in both
 

treated and control groups at low or moderate incidence, with
 

gradually increasing frequency in treated animals during the
 

second year. These signs included rough hair coats, epistaxis,
 

hematuria, alopecia (generalized and/or localized), dark urine,
 

palpable masses, and bloating or abdominal distention. These
 

signs were evident in both treated and control groups but were
 

predominant in the high-dose female group. At terminaton of the
 

17
 
Figure 1, Growth Curves of Rats Fed Dichlorvos in<he Diet
 

18
 
study surviving animals in both treated and control groups
 

generally exhibited a poor physical condition.
 

. Surνiνa1 (Rats)
 

There was little difference in survival between the matched-


control group of male rats and the two dosed groups up to 105
 

weeks, at which time the matched-control group experienced a
 

proportionally severe loss. Seventy-six percent of the high-dose
 

males and 64% of the low-dose males survived for more than 105
 

weeks.
 

In the female rats, the matched-control group had the largest
 

proportion of deaths prior to the terminaton of the experiment.
 

Eighty-four percent of the high-dose females and 80% of the
 

low-dose females survived for over 105 weeks. There is no
 

statistical evidence of positive dose-related mortality. The
 

Kaplan and Meier survival curves for high-dose males and females
 

are comparable, as are those of low-dose males and females (see
 

figure 2).
 

C. Patholoj^y (Rats)
 

Histopathologic findings are tabulated in Appendix A, tables
 

A1-A7, covering neoplasms and other proliferative lesions, and in
 

Appendix C, tables CI and C2, covering nonneoplastic lesions.
 

19
 
Figure 2. Survival Curves of Rats Fed Dichlorvos in the Diet
 
Numerous inflammatory, degenerative, and proliferative lesions
 

commonly seen in aged rats occurred with approximately equal
 

frequency in the dichlorvos-fed and control rats. These included
 

focal hepatocytomegaly (table A5); chronic nephritis with
 

scarring, tubular dilatation and regeneration, and hyperplasia of
 

the transitional epithelium of the renal pelvis and the urinary
 

bladder (table A6); C-cell hyperplasia of the thyroid (table Al);
 

parathyroid hyperplasia (table A2); and endometrial hyperplasia
 

(table A3).
 

Several nonneoplastic lesions occurred more frequently in the
 

test rats than in the controls and could be related to exposure
 

to the test compound. These included aggregates of alveolar
 

macrophages in the lungs, interstitial fibrosis of the myocardium, and focal follicular-cell hyperplasia of the thyroid of
 

male rats (table Al).
 

Benign endocrine neoplasms occurred frequently in both test and
 

control rats (tables Al and A2). A lesser number of malignant
 

endocrine neoplasms were observed; pulmonary metastasis was
 

observed of one C-cell carcinoma (low-dose male) and one
 

pheochromocytoma (high-dose male).
 

Proliferative lesions of the reproductive tract are summarized in
 

table A3. The overall incidence of tumors was low; the most
 

frequently observed lesions were endometrial stromal polyps and
 

21
 
endometrial hyperplasia. The incidence of mammary neoplasms is
 

also summarized in table A3. There was a relatively high
 

incidence of benign mammary neoplasms in both control and test
 

female rats· Table A4 summarizes the incidence of vascular and
 

hematopoietic neoplasms. The most frequently occurring tumor in
 

this category was hemangiosarcoma of the spleen, which occurred
 

only in male rats.
 

The incidence of proliferative lesions of the digestive system is
 

summarized in table A5. 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 glass11

 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 were large and contained 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 nodules was evident.
 

Nonneoplastic proliferative lesions were observed in the squamous
 

epithelium of the upper gastrointestinal tract of two test rats:
 

one focus of epithelial hyperplasia of the esophagus in a low22
 
dose male, and one focal area of acanthosis in the squamous
 

mucosa of the stomach in a low-dose female. No similar lesion
 

was observed in the esophagus or stomach of the control rats.
 

A low incidence of various other types of neoplasms was observed
 

in test and control rats with approximately equal frequency.
 

These included benign and malignant primary renal tumors (table
 

A6), malignant fibrous histiocytomas of the subcutis and of the
 

thoracic and abdominal viscera, lipomas, and one ependymoma of
 

the brain (table A7).
 

There were instances in this study, as noted above and in the
 

appendix tables A1-A7, where neoplastic or hyperplastic lesions
 

occurred only in test rats, or with increased frequency when
 

compared to control groups. In the judgment of the pathologist,
 

the nature, incidence, and severity of the lesions observed
 

provide no evidence of carcinogenic effect. For a summary of
 

nonneoplastic lesions in rats, see Appendix C.
 

D. StatIsticalwiAnalyses of Resultsw (Rats)
 

Appendix A, tables A8 and A9, contain the statistical analyses of
 

the proportions of rats with tumors, as well as the analyses of
 

those tumors which appeared in over 10% of the rats in a given
 

treated group. Since only 10 males and 10 females were in the
 

matched-control group for dichlorvos, matched-control groups from
 

23
 
studies of five other chemicals were combined for analyses and
 

designated as pooled controls. The resulting histopathologic
 

slides were evaluated by the same pathologist. No statistically
 

significant differences were found between the proportions of
 

tumors in the combined pooled-control groups and the proportions
 

of tumors in the matched controls.
 

The only tumor that occurred in a statistically significant
 

linear trend in proportions was malignant fibrous histiocytoma in
 

male rats (P « 0.018), which was observed in 2/58 (3%) of the
 

pooled controls, 4/48 (8%) of the low-dose, and 8/50 (16%) of the
 

high-dose animals. In the matched controls the proportion of
 

this neoplasm was 1/10 (10%), which exceeded that of the low-dose
 

males and was not statistically different from the proportion
 

seen in the high-dose males. This tumor was not observed in
 

significant numbers in the female rats.
 

Tests for linear trend were negative for the proportions of
 

tumors of the reproductive system and also for tumors of the
 

hematopoietic system in females. In male rats the proportions of
 

animals with some type of tumor, omitting tumors of the
 

reproductive system, showed a departure from linear trend (P =
 

0.01), and the Fisher exact test between the two matched controls
 

and the low-dose group had a probability level 0.024. This
 

24
 
represents a substantially larger proportion of tumors of the
 

pituitary in the pooled controls than in the low-dose male group.
 

On the basis of the variability of both the incidence and type of
 

spontaneous lesions and the lack of significant proportions of
 

tumors in the dosed groups compared with the matched controls, no
 

statistical significance can be attached to the incidence of the
 

tumors seen in the dichlorvos-fed rats in this study.
 

As an additional statistic, the 95% confidence interval was
 

calculated and entered in the tables. The implication of this
 

interval is that in 95/100 (95%) of a large number of
 

experiments, the true difference between the tumor rate for
 

treated groups of animals and the rate for the control groups
 

would be inside the interval calculated from the experiment. In
 

each of the intervals shown in the tables, zero is included; this
 

indicates the negative aspects of the results. It should also be
 

noted that each of the intervals has a positive endpoint indicating the theoretical possibility of tumor induction by dichlorvos
 

which could not be detected under the conditions of this test.
 

25
 

IV. RESULTS (MICE)
 

A. Bodfc Weights andCUnical^ Si^ns (Mice)
 

The average weights of the high-dose mice of both sexes were
 

generally lower after the initial growth phase than were the
 

weights of the low-dose and control groups (see figure 3).
 

Mice fed dichlorvos initially demonstrated severe signs of
 

toxicity: tremors, rough coat, diarrhea, and poor general
 

appearance. After doses were reduced the appearance and behavior
 

of the treated and control mice were generally comparable during
 

the first year of the study. Alopecia (generalized and/or
 

localized) and rough hair coats were noted in many treated
 

animals, particularly in the male groups, beginning at week 20
 

and persisting throughout the study.
 

After 50 weeks of treatment, bloating or abdominal distention was
 

observed in both treated and control groups except high—dose
 

females. From week 74 to termination of the study, many palpable
 

masses were observed.
 

B. Survival (Mice)
 

In male mice the low-dose and high-dose Kaplan and Meier survival
 

curves are comparable, whereas in female mice the curve of the
 

27
 
Figure 3. Growth Curves of Mice Fed Dichlorvos in the Diet
 

28 
low-dose gorup shows less probability of survival than that of
 

the high-dose group (see figure 4). There is no significant
 

dose-related trend in either sex. In the group with the poorest
 

survival, the low-dose female group, 74% of the animals lived to
 

90 weeks.
 

C. Pathology (Mice)
 

Histopathologic findings are tabulated in Appendix B, tables
 

B1-B6, covering neoplasms and other proliferative lesions, and in
 

Appendix D, tables Dl and D2, covering nonneoplastic lesions·
 

Several nonneoplastic proliferative or inflammatory lesions
 

occurred with approximately equal frequency in control and
 

dichlorvos-fed mice. These included a high incidence of
 

hyperplasia of the adrenal cortex in both sexes (table B4) and
 

cystic endometrial hyperplasia in female mice (table B5).
 

Proliferative lesions occurring in the digestive system are
 

summarized in table Bl. During initial microscopic examination
 

of tissues, several rather unusual proliferative lesions were
 

observed in the squamous epithelium of the esophagus in test
 

mice. These included two squamous-cell carcinomas (low-dose male
 

and high-dose female), and three cases of focal hyperplasia of
 

esophageal epithelium (two low-dose males and one high-dose
 

female). In addition, focal hyperplasia was observed in the
 

29
 
Figure 4. Survival Curves of Mice Fed Dichlorvos in the Diet
 
nonglandular epithelium of the stomach in a high-dose female
 

mouse. Since these lesions are rarely observed spontaneously in
 

laboratory mice, further examination of additional tissue
 

sections of esophagus and stomach was carried out. This involved
 

reexamination of all original slides from this study containing
 

sections of esophagus and preparation and examination of
 

additional sections of esophagus and stomach from paraffin blocks
 

and from the remaining formalin-fixed tissues. This additional
 

investigation, which included examination of multiple sections
 

from many animals, revealed one additional case of focal hyperplasia of esophageal epithelium (low-dose male) and resulted in
 

change of the diagnosis in the high-dose female from focal hyperplasia of esophageal epithelium to papilloma. The total number
 

of sections of esophagus and nonglandular stomach examined
 

microscopically was as follows: control males, 18; low-dose
 

male, 186.
 

Morphologically, the esophageal carcinoma observed in a low-dose
 

male was present as an uncircumscribed mass which protruded into
 

the lumen and extended into the submucosa but did not invade
 

adjacent muscularis or other tissues. The neoplasm was composed
 

of rows and nests of basophilic squamous epithelial cells interspersed with small amounts of loose stroma. Numerous mitotic
 

figures were visible, and several areas suggestive of pearl
 

formation were visible, although there was no well-keratinized
 

31
 
epithelium within the interior of the lesions. The carcinoma in
 

the high-dose female also protruded into the esophageal lumen,
 

and had similar cellular morphology; however, because of the
 

plane of section, the attachment of the lesion to adjacent
 

submucosa and epithelium was not visible; thus, it was impossible
 

to determine if the neoplasm invaded adjacent submucosa and
 

muscularis. The esophageal papilloma observed in one high-dose
 

female had some histologic similarities to the two carcinomas,
 

but had a lower mitotic rate, the thickness and the architecture
 

of the epithelium was more similar to adjacent normal epithelium,
 

and the lesion was pedunculated with a thin band of loose stroma
 

extending up into the protruding neoplasm. Also, no involvement
 

of adjacent submucosa was evident. Those esophageal and gastric
 

lesions classified as hyperplasia protruded slightly into the
 

lumen, but were not pedunculated. The epithelium was thicker and
 

slightly more basophilic than normal, but there were few mitotic
 

figures, and no evidence of involvement of adjacent submucosa.
 

In some cases, evidence of suppurative inflammation was present
 

in and around the area of hyperplasia.
 

The significance of these proliferative lesions observed in the
 

esophagus and stomach is difficult to assess. Although an
 

esophageal carcinoma was recently diagnosed in a control mouse of
 

the same strain in another NCI bioassay study, accurate figures
 

for spontaneous incidence may not be available at the present
 

32
 
time. The esophageal tumors did not, however, occur in statistically significant proportions in the present study, and,
 

despite the presumed rarity of such lesions in control animals,
 

there is insufficient information to establish association of the
 

tumors with dichlorvos treatment·
 

Hepatocellular carcinomas were observed rather frequently in both
 

test and control male mice, but were rare in females (table Bl).
 

Nodular hyperplasia of hepatocytes was an infrequent lesion in
 

both sexes.
 

There was a relatively low incidence of a wide variety of other
 

neoplasms in tissues examined from mice in this study, with no
 

obvious difference in incidence between test and control mice.
 

These included neoplasms of the lung (table B2), vascular and
 

hematopoietic systems (table B3), the endocrine system (table
 

B4), the reproductive system (table B5), and the skin (table B6).
 

There were instances in this study, as noted above and in
 

Appendix tables B1-B6, where neoplastic or hyperplastic lesions
 

occurred only in test mice, or with increased frequency when
 

compared with control groups. However, in the judgment of the
 

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

observed provide no clear evidence of carcinogenic effect.
 

33
 
D. Statistical Analyses of Results (Mice)
 

Appendix B, tables B7 and B8, contain the statistical analyses of
 

the proportions of mice with tumor as well as the analyses of
 

those tumors which appeared in over 10% of the mice in a given
 

treated group. Since only 10 males and 10 females were in the
 

control group specifically matched to dichlorvos, control groups
 

of chlordane (20 males, 20 females), dieldrin (20 males, 20
 

females), aldrin (20 males, 10 females), heptachlor (20 males, 10
 

females) and dimethoate (10 males, 10 females) were combined with
 

the subject control to increase the power of the test. These
 

controls were from the same supplier, were tested concurrently
 

over a year's span, and were evaluated by the same pathologists.
 

Although the number of male mice with tumors in the groups added
 

to the matched-control group to make up the pooled control was
 

28/81 (34%) compared with 1/10 (10%) in the matched-control
 

group, this difference is not statistically significant. The
 

Armitage test for linear trend in the proportions of the dosed
 

groups compared with either the pooled-control group or the
 

matched-control group resulted in probability levels above 0.10
 

for both male and female groups. In males, there was a departure
 

from linear trend ( β 0.028) when the matched controls were;
 

compared with the dosed groups, and the Fisher exact test of the
 

low dose versus the matched controls had a probability level of
 

34
 
0.054· This difference was not confirmed when the pooled-control
 

group was used.
 

The specific tumors which had the highest incidence in male mice
 

were alveolar/bronchiolar adenoma or carcinoma of the lung, and
 

hepatocellular carcinoma of the liver, but the incidences of
 

these types of tumors had no statistical significance when
 

compared with either control group. The predominant tumor in
 

female mice was malignant lymphoma, but this tumor appeared in
 

comparable proportions in all groups and no statistical significance could be found. There were no significant differences
 

between test and control groups in the age at observation of any
 

of these tumors. There is no statistical evidence in the data
 

that dichlorvos is carcinogenic for mice at the doses given.
 

As an additional statistic, the 95% confidence interval was
 

calculated and entered in the tables. The implication of this
 

interval is that in 95/100 (95%) of a large number of experiments, the true difference between the tumor rate for treated
 

groups of animals and the rate for the control groups would be
 

inside the interval calculated from the experiment. In each of
 

the intervals shown in the tables, zero is included; this
 

indicates the negative aspects of the results. It should also be
 

noted that each of the intervals has a positive endpoint indica35
 
ting the theoretical possibility of tumor induction by dichlorvos
 

which was not detected under the conditions of this test.
 

36
 
V. DISCUSSION
 

Dichlorvos is a member of the organophosphorous class of
 

pesticides whose predominant mode of toxicity is inhibition of
 

cholinesterase. No toxicity specifically characteristic of these
 

compounds was noted except in the early weeks of the study before
 

doses were lowered. However, general signs such as rough hair
 

coats, epistaxis, hematuria, alopecia, and dark urine in rats
 

were more pronounced among the treated animals in the second year
 

of the study. The compound was toxic at least to the high-dose
 

animals, since average weights of both high-dose rats and mice
 

were generally lower than were the weights of the low-dose and
 

control groups. Survival, however, was not significantly
 

affected by the administration of dichlorvos· Thus the study was
 

adequate under Bioassay guidelines to evaluate carcinogenicity in
 

rats and mice.
 

There were instances in this study where neoplastic or
 

hyperplastic lesions (e.g.,, malignant fibrous histiocytomas)
 

occurred only in certain test animals, or with increased
 

frequency in certain test animals as compared to controls. Most
 

of these lesions, however, occurred within the expected range of
 

variability and, in the judgment of the pathologist, were not
 

considered to be biologically significant. The significance of
 

37
 
the three esophageal tumors in treated mice is uncertain because
 

of insufficient information concerning the spontaneous incidence
 

of these lesions in mice, and lack of statistical significance
 

within this experiment.
 

It should be noted that the confidence intervals for all tumor
 

sites in rats and mice, which were subjected to statistical
 

analysis, include a positive value; this incidates that the
 

possibility of tumorigenicity of dichlorvos is not precluded.
 

However, under the conditions of this study, dichlorvos was not
 

demonstrated to be carcinogenic in rats and mice.
 

38
 
VI. BIBLIOGRAPHY
 

Armitaee, P. Statistical Methods in Medical Research, John
 

Wiley and Sons, New York, 1971, p. 135.
 

Berenblum, I., Ed. Carcinogenicity Testing, UICC Technical
 

Report Series Vol. 2. International Union Against Cancer,
 

Geneva, 1969.
 

Code of Federal Regulations Vol. 21 526.600, 558.205, 1976.
 

Cox, D. R. Analysis of Binary Data, Hethuen, London, 1970, pp.
 

61-65.
 

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

Statistic. Soc. B. 34:187-220, 1972.
 

Documentation of the Threshold Limit Values for Substances in
 

Workroom Air, 3rd ed. American Conference of Governmental
 

Industrial Hygienists, Cincinnati, Ohio, 1971·
 

Environmental Protection Agency. Compendium of Registered
 

Pesticides. 1972, 1973, 1974.
 

Εto, M. Organophosphorus Pesticides: Organic and Biological
 

Chemistry, CRC Press, Cleveland, 1974.
 

Gart, J. J. Point and interval estimations of the common odds
 

ratio in the combination of 2 χ 2 tables with fixed
 

marginals. Biometrika 57:471-475, 1970.
 

Hayes, W. J., Jr. Toxicology of Pesticides, The Williams and
 

Wilkins Co., Baltimore, Maryland, 1975.
 

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

incomplete observations. J. Amer. Statist. Assn. 53:457­

481, 1958.
 

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

Peters, J. A. Carcinogenesis Bioassay Data System. J.
 

Comp. Biomed. Res. 7:230-248, 1974.
 

Mantel, Ν. Chi-square tests with one degree of freedom:
 

extensions of Mantel-Haenszel procedure. J. Am. Statist.
 

Assoc. 58:690-700, 1963.
 

39
 
Miller, R. G., Jr. Simultaneous Statistical Inference,
 

McGraw-Hill, New York, 1966.
 

Stevenson, D. E. Appraisal of the use of dichlorvos, with
 

particular reference to slow release generators. PANS 16 

(4), December 1970. 

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

Biometrika 62;679-682, 1975.
 

WHO/FAO, Evaluations of some pesticide residues in food. The
 

Monographs, Rome, Italy, 1968, 1967.
 

40
 
APPENDIX A
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS
 

IN RATS FED DICHLORVOS IN THE DIET
 

41
 

TABLE Al 

PROLIFERATIVE LESIONS OF THE THYROID 

MALE RATS FEMALE RATS 

Pooled Matched Low High Pooled Matched Low High 

Control Control Dose Dose Control Control Dose Dose 

Follicular-cell Adenoma 3/51 0/10 3/45 6/48 2/59 0/10 0/48 0/49 

(6%) (7%) (12.5%) (3%) 

Follicular-c ell 1/51 0/10 1/45 1/48 1/59 0/10 0/48 2/49 

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

Total Follicular-cell 4/51 0/10 4/45 7/48 3/59 0/10 0/48 2/49 

Neoplasms (8%) (9%) (15%) (5%) (4%) 

C-cell Adenoma 3/51 1/10 1/45 4/48 7/59 1/10 8/48 6/49 

(6%) (10%) (2%) (8%) (12%) (10%) (17%) (12%) 

C-cell Carcinoma 1/51 0/10 1/45 3/48 5/59 0/10 0/48 2/49 

(2%) (2%) (6%) (8%) (4%) 

Total C-cell Neoplasms 4/51 1/10 2/45 7/48 12/59 1/10 8/48 8/49 

(8%) (10%) (4%) (15%) (20%) (10%) (17%) (16%) 

Total Thyroid Neoplasms 8/51 1/10 6/45 14/48 15/59 1/10 8/48 10/49 

(16%) (10%) (13%) (29%) (25%) (10%) (17%) (20%) 

Follicular-cell 0/51 0/10 3/45 5/48 it/59 1/10 3/48 3/49 

Hyperplasia (7%) (10%) (7%) (10%) (6%) (6%) 

C-cell Hyperplasia 29/51 4/10 19/45 15/48 30/59 7/10 23/48 26/49 

(57%) (40%) (42%) (31%) (51%) (70%) (48%) (53%) 
TABLE A2
 

OTHER PROLIFERATIVE ENDOCRINE LESIONS
 

MALE RATS 

Pooled Matched Low High Pooled 

Control Control Dose Dose Control 

PITUITARY 

\denoma 14/48 4/8 5/44 9/46 23/51 

(29%) (50%) (11%) (20%) (45%) 

Carcinoma 2/48 0/8 0/44 0/46 0/51 

(4%) 

ADRENAL 

Cortical Adenoma 2/54 0/10 1/41 0/45 0/56 

(4%) (2%) 

Pheochromocytoma 1/54 0/10 0/41 1/45 0/56 

(2%) (2%) 

PANCREAS 

Islet-cell Adenoma 1/52 0/10 3/43 2/47 1/60 

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

PARATHYROID 

Adenoma 2/39 1/9 0/41 0/40 0/38 

(5%) (11%) 

Hyperplasia 5/39 1/9 6/41 8/40 3/38 

(13%) (11%) (15%) (20%) (8%) 

FEMALE
 

Matched
 

Control
 

2/9
 

(22%)
 

0/9
 

0/10
 

0/10
 

0/10
 

0/7
 

0/7
 

RATS
 

Low
 

Dose
 

18/45
 

(40%)
 

1/45
 

(2%)
 

0/46
 

2/46
 

(4%)
 

0/46
 

0/43
 

0/43
 

High
 

Dose
 

15/48
 

(31%)
 

1/48
 

(2%)
 

0/49
 

0/49
 

0/48
 

0/36
 

2/36
 

(5.5%)
 
___ ___ ___ TESTIS
 

Interstitial-cell Tumor
 

UTERUS
 

Endometrial Stromal
 

Polyp
 

Ln Endometrial Stromal
 

Sarcoma
 

Endometrial Hyperplasia
 

OVARY
 

Granulosa-cell Tumor
 

CLITORAL GLAND
 

Adenocarcinoma
 

TABLE A3
 

PROLIFERATIVE LESIONS OF THE REPRODUCTIVE SYSTEM
 

MALE RATS
 

Pooled Matched Low High Pooled
 

Control Control Dose Dose Control
 

0/58 0/10	 2/47 0/50
 

(4%)
 

— ~ 6/57
 

(11%)
 

— .
 0/57
 

——_
 1/57
 

(2%)
 

1/58
 

(2%)
 

— —	 1/60
 

(2%)
 

FEMALE
 

Matched
 

Control
 

2/9
 

(22%)
 

0/9
 

0/9
 

0/10
 

1/10
 

(10%)
 

RATS
 

Low
 

Dose
 

3/46
 

(6.5%)
 

0/46
 

4/46
 

(9%)
 

1/48
 

(2%)
 

0/48
 

High
 

Dose
 

2/49
 

(4%)
 

1/49
 

(2%)
 

4/49
 

(8%)
 

1/49
 

(2%)
 

0/50
 
TABLE A3

 

PROLIFERATIVE LESIONS OF THE REPRODUCTIVE SYSTEM 

(continued ) 

Pooled 

Control 

MAMMARY GLAND 

Carcinoma 0/58 

Fibroma 1/58 

(2%) 

Fibroadenoma 0/58 

Total Mammary Neoplasms 1/58 

(2%) 

High
 

Dose
 

2/50
 

(4%)
 

0/50
 

0/50
 

2/50
 

(4%)
 

Pooled
 

Control
 

2/60
 

(3%)
 

1/60
 

(2%)
 

8/60
 

(13%)
 

11/60
 

(18%)
 

FEMALE
 

Matched
 

Control
 

0/10
 

1/10
 

(10%)
 

1/10
 

(10%)
 

2/10
 

(20%)
 

RATS
 

Low
 

Dose
 

1/48
 

(2%)
 

5/48
 

(10%)
 

7/48
 

(15%)
 

13/48
 

(27%)
 

High
 

Dose
 

0/50
 

0/50
 

6/50
 

(12%)
 

6/50
 

(12%)
 

MALE RATS
 

Matched
 

Control
 

0/10
 

0/10
 

0/10
 

0/10
 

Low
 

Dose
 

0/48
 

1/48
 

(2%)
 

0/48
 

1/48
 

(2%)
 
TABLE A4
 

NEOPLASMS OF THE VASCULAR AND HEMATOPOIETIC SYSTEMS
 

MALE RATS	 FEMALE RATS
 

Pooled Matched Low High Pooled Matched Low High
 

Control Control Dose Dose Control Control Dose Dose
 

Sarcoma, N.O.S., Heart	 2/58 1/10 0/47 0/49 1/58 0/10 0/46 0/50
 

(3%) (10%) (2%)
 

Hemangiosarcoma, Spleen	 3/56 0/10 4/45 1/48 0/55 0/10 0/47 0/48
 

(5%) (9%) (2%)
 

Malignant Lymphoma	 1/58 0/10 0/48 2/50 2/60 1/10 0/48 0/50
 

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

For the purpose of this summary table, "malignant lymphoma" includes all types of lymphoma.
 
FEMALE
 

Matched
 

Control
 

1/10
 

(10%)
 

4/10
 

(40%)
 

0/7
 

0/9
 

RATS
 

Low
 

Dose
 

3/48
 

(6%)
 

14/48
 

(29%)
 

0/45
 

1/45
 

(2%)
 

High
 

Dose
 

1/49
 

(2%)
 

17/49
 

(35%)
 

0/44
 

0/47
 

LIVER NEOPLASMS
 

Neoplastic Nodule
 

OTHER PROLIFERATIVE LESIONS
 

Hepatocytomegaly
 

.p.
 

oo
 

ESOPHAGUS
 

Epithelial Hyperplasia
 

STOMACH
 

Acanthosis
 

TABLE A5
 

PROLIFERATIVE LESIONS OF THE DIGESTIVE SYSTEM
 

MALE RATS
 

Pooled
 

Control
 

2/58
 

(3%)
 

30/58
 

(52%)
 

0/20
 

0/53
 

Matched
 

Control
 

0/10
 

7/10
 

(70%)
 

0/6
 

0/9
 

Low
 

Dose
 

0/47
 

24/47
 

(51%)
 

1/37
 

(3%)
 

0/43
 

High
 

Dose
 

0/50
 

29/50
 

(58%)
 

0/46
 

0/44
 

Pooled
 

Control
 

5/60
 

(8%)
 

26/60
 

(43%)
 

0/21
 

0/57
 
TABLE A6 

PROLIFERATIVE LESIONS OF THE URINARY TRACT 

MALE RATS FEMALE RATS 

Pooled Matched Low High Pooled Matched Low High 

Control Control Dose Dose Control Control Dose Dose 

KIDNEY 

Hamartoma 0/57 0/10 2/47 0/50 1/58 1/9 0/47 0/48 

(4%) (2%) (11%) 

Malignant Mixed Tumor 0/57 0/10 0/47 1/50 1/58 0/9 0/47 1/48 

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

Total Renal Neoplasms 0/57 0/10 2/47 1/50 2/58 1/9 0/47 1/48 

(4%) (2%) (3%) (11%) (2%) 

Hyperplasia, Renal Pelvis 19/57 2/10 13/47 8/50 17/58 1/9 4/47 1/48 

(33%) (20%) (28%) (16%) (29%) (11%) (8.5%) (2%) 

URINARY BLADDER 

Epithelial Hyperplasia 12/51 5/10 24/44 8/41 8/52 1/8 9/39 3/46 

(23.5%) (50%) (55%) (19.5%) (15%) (12.5%) (23%) (6.5%) 
Lipoma
 

Malignant Fibrous
 

Histiocytoma
 

Ependymoma, Brain
 

TUNICA VAGINALIS
 

Mesothelioma
 

Mesothelial Hyperplasia
 

TABLE A7
 

MISCELLANEOUS PROLIFERATIVE LESIONS
 

MALE RATS
 FEMALE
 

Matched
 

Control
 

2/10
 

(20%)
 

0/10
 

0/10
 

——
 

Pooled
 

Control
 

1/58
 

(2%)
 

2/58
 

(3%)
 

0/57
 

0/58
 

0/58
 

Matched
 

Control
 

0/10
 

1/10
 

(10%)
 

0/10
 

0/10
 

0/10
 

Low
 

Dose
 

0/48
 

4/48
 

(8%)
 

0/47
 

1/47
 

(2%)
 

2/47
 

(4%)
 

High
 

Dose
 

0/50
 

8/50
 

(16%)
 

1/49
 

(2%)
 

0/50
 

1/50
 

(2%)
 

Pooled
 

Control
 

2/60
 

(3%)
 

1/60
 

(2%)
 

0/9
 

RATS
 

Low
 

Dose
 

1/48
 

(2%)
 

5/48
 

(10%)
 

0/46
 

——
 

High
 

Dose
 

0/50
 

1/50
 

(2%)
 

0/48
 
Table A8. Analyses of the Incidence of Tumors at Specific Sites in Male Rats Fed Dichlorvos in the Dieta
 

Topography: Morphology
 

Total Animals: All Tumors,
 

Omitting Reproductive System*5
 

 Values0
 

95% Confidence Interval (matched)d
 

95% Confidence Interval (pooled)d
 

Weeks to First Observed Tumor
 

Reproductive System: All Tumors^
 

 Values0
 

95% Confidence Interval (matched)"
 

95% Confidence Interval (pooled)^
 

Weeks to First Observed Tumors
 

Pooled
 

Control
 

37/58(0.64)
 

N.S.
 

 - 0.010
 

2/58(0.03)
 

N.S.
 

Matched
 

Control
 

6/10(0.60)
 

N.S.
 

59
 

0/10(0)
 

N.S.
 

.....
 

Low
 

Dose
 

20/48(0.43)
 

 = 0.024*(N)
 

(-0.50,0.21)
 

(-0.40,0.01)
 

76
 

3/48(0.06)
 

N.S.
 

(-0.18,1.00)
 

(-0.06,0.10)
 

110
 

High
 

Dose
 

33/50(0.66)
 

N.S.
 

(-0.26,0.43)
 

(-0.17,0.21)
 

42
 

2/50(0.06)
 

N.S.
 

(-0.18,1.00)
 

(-0.06,0.09)
 

72
 
Table A8. Analyses of the Incidence of Tumors at Specific Sites in Male Rats Fed Dichlorvos in the Dieta
 

(continued)
 

Topography: Morphology
 

Thyroid: Follicular-cel] L
 

Adenoma or Carcinoma^
 

 Values0
 

95% Confidence Interval (matched)d
 

95% Confidence Interval (pooled)d
 

Weeks to First Observed Tumor
 

ho
 

Hematopoietic System:
 

Malignant Lymphoma^
 

 Values0
 

95% Confidence Interval (matched)d
 

95% Confidence Interval (pooled)d
 

Weeks to First Observed Tumor
 

Pooled
 

Control
 

4/51(0.08)
 

N.S.
 

1/58(0.02)
 

N.S.
 

Matched
 

Control
 

0.10(0)
 

N.S.
 

—
 

0.10(0)
 

N.S.
 

Low
 

Dose
 

4/45(0.09)
 

N.S.
 

(-0.19,1.00)
 

(-0.10,0.12)
 

86
 

0/48(0)
 

N.S.
 

(-1.00,0.02)
 

103
 

High
 

Dose
 

7/48(0.15)
 

N.S.
 

(-0.17,1.00)
 

(-0.08,0.18)
 

110
 

2/50(0.04)
 

N.S.
 

(-0.15,1.00)
 

(-0.04,0.06)
 

102
 
Table A8. Analyses of the Incidence of Tumors at Specific Sites in Male Rats Fed Dichlorvos in the Dieta
 

(continued)
 

Topography: Morphology
 

Pituitary: Chromophobe
 

Adenoma or Carcinoma*5
 

 Values0
 

Departure from Linear Trend
 

95% Confidence Interval (matched)d
 

95% Confidence Interval (pooled)d
 

in Weeks to First Observed Tumor
 

u>
 

Thyroid: C-cell Adenoma
 

or Carcinoma*5
 

 Values0
 

95% Confidence Interval (matched)d
 

95% Confidence Interval (pooled)d
 

Weeks to First Observed Tumor
 

Pooled Matched 

Control Control 

16/48(0.33) 4/8(0.50) 

N.S. N.S. 

 = 0.045 = 0.013 

80 

4/50(0.08) 1/10(0.10) 

N.S. N.S. 

106 

Low
 

^ Jto£e_ _ „
 

5/44(0.11)
 

 = 0.011*(N)
 

 = 0.023**(N)
 

(-0.73,-0.02)
 

(-0.35,-0.03)
 

85
 

2/45(0.04)
 

N.S.
 

(-0.26,0.06)
 

(-0.11,0.07)
 

110
 

High
 

Dose
 

9/46(0.20)
 

N.S.
 

N.S.
 

(-0.67,0.07)
 

(-0.30,0.06)
 

110
 

7/48(0.15)
 

N.S.
 

(-0.29,0.16)
 

(-0.08,0.18)
 

110
 
54
 

Table A8. Analyses of the Incidence of Tumors at Specific Sites in Male Rats Fed Dichlorvos in the Dieta
 

(continued)
 

Topography: Morphology
 

Pancreatic Islet: Islet-cell
 

Adenoma*5
 

 Values0
 

95% Confidence Interval (matched)d
 

95% Confidence Interval (pooled)d
 

Weeks to First Observed Tumors
 

Pooled
 

Control
 

1/52(0.02)
 

N.S.
 

80
 

Matched
 

Control
 

0/10(0)
 

N.S.
 

—
 

Low
 

Dose
 

3/43(0.07)
 

N.S.
 

(-0.18,1.00)
 

(-0.04,0.09)
 

76
 

High
 

Dose
 

2/47(0.04)
 

N.S.
 

(-0.16,1.00)
 

(-0.04,0.063)
 

110
 

Multiple Organs: Malignant 

Fibrous Histiocytoma" 2/58(0.03) 1/10(0.10) 4/48(0.08) 8/50(0.16) 

 Values0 = 0.018 N.S. N.S. N.S. 

95% Confidence Interval (matched)d 

95% Confidence Interval (pooled)d 

(-0.30,0.10) 

(-0.05,0.11) 

(-0.29,0.17) 

(0.00,0.19) 

Weeks to First Observed Tumor 59 86 61 

a

Treated groups received time-weighted average doses of 150 and 327 ppm in feed. 

^Number of tumor-bearing animals/number of animals examined at site (proportion). 
Table Α8· Analyses of the Incidence of Tumors at Specific Sites in Hale Rats Fed Dichlorvos in the Dieta
 

(continued)
 

c

Beneath the proportions for the matched and pooled-control groups are the probability levels (P values) for
 

the Cochran-Armitage test for dose-related trend in proportions when Ρ is below 0.10; otherwise, N.S. (not
 

significant is indicated. Beneath the proportions for the treated groups are the Ρ values for the Fisher
 

exact (conditional) test for the comparison of the treated groups with the matched-control group (*) and the
 

pooled-control group (**) when Ρ is below 0.05; otherwise, N.S. is indicated.
 

(N) A negative trend results from a lower proportion in the treated group than in the matched or pooled-


control group.
 

^95% confidence interval of the difference in proportions of treated group and matched or pooled control
 

group.
 
Table A9. Analyses of the Incidence of Tumors at Specific Sites in Female Rats Fed Dichlorvos in the Dieta
 

56 

Pooled
 

To £O g rap hy ^ ,,^ο,^Ρΐί^ί^,,δΧ Control
 

Total Animals: All Tumors,
 

Omitting Reproductive System" 38/60(0-63)
 

 Values0 N.S.
 

95% Confidence Interval (matched)d
 

95% Confidence Interval (pooled)d
 

Weeks to First Observed Tumor
 

Reproductive System: All Tumorsb 19/60(0.32)
 

 Values0 N.S.
 

95% Confidence Interval (matched)d
 

95% Confidence Interval (pooled)d
 

Weeks to First Observed Tumors
 

Hatched
 

Control
 

8/10(0.80)
 

N.S.
 

60
 

5/10(0.50)
 

 = 0.026(N)
 

60
 

Low
 

Dose
 

34/48(0.71)
 

N.S.
 

(-0.56,0.02)
 

(-0.12,0.26)
 

92
 

17/48(0.35)
 

N.S.
 

(-0.50,0.21)
 

(-0.15,0.23)
 

99
 

High
 

Dose
 

30/50(0.60)
 

N.S.
 

(-0.41,0.19)
 

(-0.22,0.16)
 

48
 

10/50(0.20)
 

N.S.
 

(-0.63,0.05)
 

(-0.28,0.07)
 

110
 
57
 

Table A9. Analyses of the Incidence of Tumors at Specific Sites in Female Rats Fed Dichlorvos in the Dieta
 

(continued)
 

Pooled Matched Low High 

Topography: Morphology Control Control Dose Dose w_ L r _ 

Thyroid: Follicular-cell 

Adenoma or Carcinomab 3/59(0.05) 0/10(0) 0/48(0) 2/49(0.04) 

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

95% Confidence Interval (matched)d — (-0.16,1.00) 

95% Confidence Interval (pooled)d (-1.00,0.03) (-0.08,0.07) 

Weeks to First Observed Tumor — — 110 

Hematopoietic System: 

Malignant Lymphomab 2/60(0.03) 1/10(0.10) 0/48(0) 0/50(0) 

 Valuesc N.S. = 0.034(N) N.S. N.S. 

Departure from Linear Trend N.S. = 0.020(N) N.S. N.S. 

95% Confidence Interval (matched)d (-1.00,0.01) (-1.00,0.05) 

95% Confidence Interval (pooled)d (-1.00,0.03) (-1.00,0.03) 

Weeks to First Observed Tumor 110 92 N 
58
 

Table A9. Analyses of the Incidence of Tumors at Specific Sites in Female Rats Fed Dichlorvos in the Dieta
 

(continued)
 

Topography: Morphology 

Pooled 

Control 

Matched 

Control 

Low 

Dose 

High 

Dose 

Pituitary: Chromophobe 

Adenoma or Carcinomab 23/51(0.45) 2/9(0.22) 19/45(0.42) 16/48(0.33) 

 Valuesc N.S. N.S. N.S. N.S. 

95% Confidence Interval (matched)d (-0.22,0.42) (-0.30,0.33) 

95% Confidence Interval (pooled)d (-0.24,0.19) (-0.31,0.09) 

Weeks to First Observed Tumor 106 92 105 

Thyroid: C-cell Adenoma 

or Carcinomab 12/59(0.20) 1/10(0.10) 8/48(0.17) 8/49(0.16) 

 Valuesc N.S. N.S. N.S. N.S. 

95% Confidence Interval (matched)d (-0.28,0.18) (-0.28,0.18) 

95% Confidence Interval (pooled)d (-0.19,0.13) (-0.19,0.12) 

Weeks to First Observed Tumor 110 92 110 
Table A9. Analyses of the Incidence of Tumors at Specific Sites in Female Rats Fed Dichlorvos in the Dieta
 

(continued)
 

Topography: Morphology 

Pooled 

Control 

Matched 

Control 

Low 

Dose 

High 

Dose 

Multiple Organs: Malignant 

Fibrous Histiocytoma" 1/60(0.02) 0/10(0) 5/48(0.10) 1/50(0.02) 

 Valuesc N.S. N.S. N.S. N.S. 

Departure from Linear Trend - 0.016 N.S. N.S. N.S. 

95% Confidence Interval (raatched)d (-0.20,1.00) (-0.09,1.00) 

95% Confidence Interval (pooled)d (-0.02,0.12) (0.03,0.04) 

Weeks to First Observed Tumor 92 48 

a

Treated groups received time-weighted average doses of 150 and 327 ppm in feed.
 

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

c

Beneath the proportions for the matched and pooled-control groups are the probability levels (P values) for the
 

Cochran-Armitage test for dose-related trend in proportions when Ρ is below 0.10; otherwise, N.S. (not significant) is indicated. Departure from linear trend is noted beneath the Ρ value for dose-related trend when Ρ is
 

below 0.05. Beneath the proportions for the treated groups are the Ρ values for the Fisher exact (conditional)
 

test for the comparison of the treated groups with the matched-control group (*) and the pooled-control group
 

(**) when Ρ is below 0.05; otherwise, N. S. is indicated.
 

(N) A negative trend results from a lower proportion in the treated group than in the matched or pooled-control
 

group.
 

d

95% confidence interval of the difference in proportions of treated group and matched or pooled-control group.
 

APPENDIX B
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS
 

IN MICE FED DICHLORVOS IN THE DIET
 

61
 

LIVER
 

Hepatocellular Carcinoma
 

Nodular Hyperplasia
 

OS STOMACH
 00 Squamous Epithelial
 

Hyperplasia
 

ESOPHAGUS
 

Squamous-cell Carcinoma
 

Papilloma
 

Epithelial Hyperplasia
 

TABLE Bl
 

PROLIFERATIVE LESIONS OF THE DIGESTIVE SYSTEM
 

MALE MICE
 

Pooled Matched Low High Pooled
 

Control Control Dose Dose Control
 

17/92 0/10 12/49 7/50 3/78
 

(18%)	 (24%) (14%) (4%)
 

3/92 0/10	 0/49 1/50 1/78
 

(3%)	 (2%) (1%)
 

0/90 0/10	 0/50 0/49 0/77
 

0/27 0/10	 1/47 0/46 0/16
 

(2%)
 

0/27 0/10	 0/47 0/46 0/16
 

0/27 0/10	 3/47 0/46 0/16
 

(6%)
 

FEMALE
 

Matched
 

Control
 

0/9
 

0/9
 

0/9
 

0/8
 

0/8
 

0/8
 

MICE
 

Low
 

Dose
 

0/47
 

0/47
 

0/46
 

0/45
 

0/45
 

0/45
 

High
 

Dose
 

0/49
 

3/49
 

(6%)
 

1/48
 

(2%)
 

1/41
 

(2%)
 

1/41
 

(2%)
 

0/41
 
TABLE B2
 

PRIMARY PULMONARY NEOPLASMS
 

MALE MICE FEMALE 

Pooled 

Control 

Matched 

Control 

Low 

Dose 

High 

Dose 

Pooled 

Control 

Matched 

Control 

Alveolar/Bronchiolar 

Carcinoma 

0/91 0/10 1/47 

(2%) 

0/49 0/79 0/9 

Alveolar/Bronchiolar 

Adenoma 

6/91 

(7%) 

0/10 6/47 

(13%) 

5/49 

(10%) 

0/79 0/9 

Total Primary 

Pulmonary Neoplasms 

6/91 

(7%) 

0/10 7/47 

(15%) 

5/49 

(10%) 

0/79 0/9 

MICE
 

Low
 

Dose
 

0/47
 

1/47
 

(2%)
 

1/47
 

(2%)
 

High
 

Dose
 

0/46
 

1/46
 

(2%)
 

1/46
 

(2%)
 
TABLE B3
 

NEOPLASMS OF THE VASCULAR AND HEMATOPOIETIC SYSTEMS
 

MALE MICE	 FEMALE MICE
 

Pooled Matched Low High Pooled Matched Low High
 

Control Control Dose Dose Control Control Dose Dose
 

Malignant Lymphoma	 5/92 1/10 1/50 2/50 8/79 1/9 6/49 3/50
 

(5%) (10%) (2%) (4%) (10%) (11%) (12%) (6%)
 

Hemangiosarcoma 0/92 0/10	 1/50 0/50 0/79 0/9 0/49 1/50
 

(2%) (2%)
 

Hemangioma 0/92 0/10	 1/50 0/50 0/79 0/9 0/49 0/50
 

(2%)
 

a

For purposes of this summary table, "malignant lymphoma11 includes lymphosarcoma, reticulum cell sarcoma,
 

and all "types11

 of malignant lymphoma.
 
TABLE B4
 

PROLIFERATIVE LESIONS OF THE ENDOCRINE SYSTEM
 

THYROID
 

C-cell Carcinoma
 

Follicular-cell
 

Adenoma
 

Follicular-cell
 

Hyperplasia
 

ADRENAL
 

Cortical Adenoma
 

Adrenocortical
 

Hyperplasia
 

PITUITARY
 

Chromophobe Adenoma
 

Pooled
 

Control
 

0/79
 

1/79
 

(1%)
 

0/79
 

0/88
 

27/88
 

(31%)
 

0/70
 

MALE MICE FEMALE 

Matched Low High Pooled Matched 

Control Dose Dose Control Control 

0/8 0/49 0/50 0/72 0/9 

0/8 1/49 0/50 1/72 0/9 

(2%) (1%) 

0/8 1/49 1/50 1/72 1/9 

(2%) (2%) (1%) (11%) 

0/10 1/50 0/49 0/78 0/9 

(2%) 

7/10 34/50 28/49 19/78 9/9 

(70%) (68%) (57%) (24%) (100%) 

0/9 0/46 0/44 0/58 0/8 

MICE
 

Low
 

Dose
 

0/43
 

1/43
 

(2%)
 

3/43
 

(7%)
 

0/43
 

41/43
 

(95%)
 

0/39
 

High
 

Dose
 

1/44
 

(2%)
 

0/44
 

0/44
 

0/47
 

47/47
 

(100%)
 

2/42
 

(5%)
 
TABLE B5 

PROLIFERATIVE LESIONS OF THE REPRODUCTIVE SYSTEM 

MALE MICE FEMALE MICE 

Pooled 

Control 

Matched 

Control 

Low 

Dose 

High 

Dose 

Pooled 

Control 

Matched 

Control 

Low 

Dose 

High 

Dose 

UTERUS 

Endometrial Stromal 

Polyp 

Endometrial Hyperplasia 

1/78 

(1%) 

27/78 

(35%) 

0/9 

5/9 

(55·5%) 

1/45 

(2%) 

37/45 

(82%) 

0/49 

37/49 

(75.5% 

OVARY 

Adenocarcinoma 0/73 0/8 1/40 

(2.5%) 

0/45 
TABLE B6 

NEOPLASMS OF THE INTEGUMENTARY SYSTEM 

Pooled 

Control 

MALE MICE 

Matched 

Control 

Low 

Dose 

High 

Dose 

Pooled 

Control 

FEMALE 

Matched 

Control 

MICE 

Low 

Dose 

High 

Dose 

SKIN 

Tr ichoepi thel ioma 0/92 0/10 0/50 0/50 0/79 0/9 1/49 

(2%) 

0/50 

00 
69
 

Table B7. Analyses of the Incidence of Tumors at Specific Sites in Male Mice Fed Dichlorvos in the Dieta
 

Topography: Morphology
 

Total Animals: All Tumorsb
 

 Values0
 

Departure from Linear Trend
 

95% Confidence Interval (matched)d
 

95% Confidence Interval (pooled)d
 

Weeks to First Observed Tumor
 

Pooled Matched Low High 

Control Control Dose Dose 

29/92(0.32) 1/10(0.10) 21/50(0.42) 14/50(0.28) 

N.S. N.S. * 0.050** N.S. 

N.S. = 0.028 N.S. N.S. 

(-0.06,0.44) (-0.19,0.30) 

(-0.02,0.32) (-0.20,0.14) 

78 65 33 

Lung: Alveolar/Bronchiolar 

Adenoma or Carcinomas^ 6/91(0.07) 0/10(0) 7/47(0.15) 5/49(0.10) 

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

95% Confidence Interval (matched)d 

(-0.16,1.00) (-0.19,1.00) 

95% Confidence Interval (pooled)d 

(-0.03,0.19) (-0.06,0.14) 

Weeks to First Observed Tumors — 65 94 
Table B7. Analyses of the Incidence of Tumors at Specific Sites in Male Mice Fed Dichlorvos in the Dieta
 

(continued) 

Topography: Morphology 

Pooled 

Control 

Matched 

Control 

Low 

Dose 

Liver: 

Hepatocellular Carcinomab 17/92(0.18) 0/10(0) 12/49(0.24) 

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

95% Confidence Interval (matched)d (-0.24,1.00) 

95% Confidence Interval (pooled)d (-0.09,0.022) 

Weeks to First Observed Tumor — 78 

Hematopoietic System:
 

Malignant Lymphoma^ 5/92(0.05) 1/10(0.10) 1/50(0.02)
 

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

95% Confidence Interval (matched)^ (-0.20,0.04)
 

95% Confidence Interval (pooled)d (-0.65,0.05)
 

Weeks to First Observed Tumor 78 90
 

a

Treated groups received time-weighted average doses of 317 and 635 ppm in feed.
 

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

High
 

_^Dose,
 

7/50(0.14)
 

N.S.
 

(-0.17,1.00)
 

(-0.17,0.10)
 

94
 

2/50(0.04)
 

N.S.
 

(-0.26,0.06)
 

(-0.07,0.07)
 

33
 
Table B7. Analyses of the Incidence of Tumors at Specific Sites in Male Mice Fed Dichlorvos in the Dieta
 

(continued)
 

c

Beneath the proportions for the matched and pooled-control groups are the probability levels (P values) for tin
 

Cochran—Armitage test for dose-related trend in proportions when Ρ is below 0.10; otherwise, N.S. (not significant) is indicated. Departure from linear trend is noted beneath the Ρ value for dose-related trend when Ρ ii
 

below 0.05· Beneath the proportions for the treated groups are the Ρ values for the Fisher exact (conditional)
 

test for the comparison of the treated groups with the matched-control group (*) and the pooled-control group
 

(**) when Ρ is below 0.05; otherwise N.S. is indicated.
 

(N) A negative trend results from a lower proportion in the treated gorup than in the matched or pooled-control
 

group.
 

d

95% confidence interval of the difference in proportions of treated group and matched or pooled-control group.
 
Table B8. Analyses of the Incidence of Tumors at Specific Sites in Female Mice Fed Dichlorvos in the Diet a 

72
 

Topography: Morphology
 

Total Animals: All Tumors**
 

 Values0
 

95% Confidence Interval (matched)**
 

95% Confidence Interval (pooled)d
 

Weeks to First Observed Tumor
 

Lung: Alveolar/Bronchiolar
 

Adenoma or Carcinomas^
 

 Values0
 

95% Confidence Interval (matched)d
 

95% Confidence Interval (pooled)d
 

Weeks to First Observed Tumors
 

Pooled
 

Control
 

14/79(0.18)
 

N.S.
 

0/79(0)
 

N.S.
 

Matched
 

Control
 

1/9(0.11)
 

N.S.
 

92
 

0/9(0)
 

N.S.
 

Low
 

Dose
 

11/49(0.22)
 

N.S.
 

(-0.29,0.24)
 

(-0.10,0.20)
 

38
 

1/47(0.02)
 

N.S.
 

(-0.10,1.00)
 

(-0.01,1.00)
 

93
 

High
 

___Dose
 

8/50(0.16)
 

N.S.
 

(-0.32,0.18)
 

(-0.15,0.14)
 

78
 

1/46(0.02)
 

N.S.
 

(-0.10,1.00)
 

(-0.01,1.00)
 

93
 
Table B8. Analyses of the Incidence of Tumors at Specific Sites in Female Mice Fed Dichlorvos in the Diet a 

(continued) 

Pooled Matched Low High
 

Topography: Morphology Control ^ Control Dose Dose
 

Liver:
 

Hepatocellular Carcinoma^ 3/78(0.04) 0/9(0) 0/47(0) 0/49(0)
 

 Values0 

 = 0.085(N) N.S. N.S. N.S.
 

95% Confidence Interval (matched)d
 — —


95% Confidence Interval (pooled)d (-1.00,0.02) (-1.00,0.02)
 

Weeks to First Observed Tumor
 — — —
 

u> 

Hematopoietic System:
 

Malignant Lymphomab 8/79(0.10) 1/9(0.11) 6/49(0.12) 3/50(0.06)
 

 Valuesc N.S. N.S. N.S. N.S.
 

*
 

95% Confidence Interval (matched)^ (-0.34,0.14)
 (-0.32,0.06)
 

95% Confidence Interval (pooled)d (-0.09,0.14) (-0.12,0.06)
 

Weeks to First Observed Tumor 92 77 78
 

a

Treated groups received time-weighted average doses of 317 and 635 ppm in feed.
 

"Number of tumor-bearing animals/number of animals examined at site (proportion).
 
Table B8. Analyses of the Incidence of Tumors at Specific Sites in Female Mice Fed Dichlorvos in the Dieta
 

(continued)
 

c

Beneath the proportions for the matched and pooled-control groups are the probability levels (P values) for the
 

Cochran—Armitage test for dose-related trend in proportions when Ρ is below 0.10; otherwise, N.S. (not significant) is indicated· Departure from linear trend is noted beneath the Ρ value for dose-related trend when Ρ is
 

below 0.05. Beneath the proportions for the treated groups are the Ρ values for the Fisher exact (conditional)
 

test for the comparison of the treated groups with the matched-control group (*) and the pooled-control group
 

(**) when Ρ is below 0.05; otherwise, N.S. is indicated.
 

(N) A negative trend results from a lower proportion in the treated group than in the matched or pooled-control
 

group.
 

^95% confidence interval of the difference in proportions of treated group and matched or pooled-control group.
 
APPENDIX C
 

SUMMARY OF THE INCIDENCE
 

OF NONNEOPLASTIC LESIONS IN RATS
 

FED DICHLORVOS IN THE DIET
 

75
 

TABLE CI 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS 

IN MALE RATS FED DICHLORVOS IN THE DIET 

AHIHALS IHITIALLT IV STUDY
 

AHIHALS NBCROPSIED
 

AIIHALS BXAHIIBD HISTOPATHOLOGICALLY
 

AHIHALS WITH TUMORS
 

INTEGUHBHTARY SYSTEM
 

SUBCUT TISSUE
 

PERIARTERITIS
 

RESPIRATORY SYSTEH
 

TRACHEA
 

IVFLAHHATIOH CHROVIC
 

LU1G/BRO1CHIOLE
 

HYPERPLASIA EPITHELIAL
 

LONG
 

EHPHYSEHA
 

ATELECTASIS
 

CONGESTION
 

IVFLAHHATIOH IVTERSTITIAL
 

ALVEOLAR HACROPHAGES
 

HYPERPLASIA ALVEOLAR-CELL
 

LUVG/ALVEOLI
 

EDEHA
 

IHFLAHHATION SUPPURATIVE
 

CIRCULATORY SYSTEH
 

ATRIUH
 

THROHBOSIS
 

HYOCARDIUH
 

IIFLAHHATIOH
 

IMFLAMHATIOH FOCAL
 

FIBROSIS
 

HECROSIS DIFFUSE
 

COHTROL
 

10
 

10(100%)
 

to
 

 (60%)
 

1 (10%)
 

1
 

1
 

3 (30%)
 

1
 

1
 

1
 

LOW DOSE
 

50
 

48(100%)
 

47
 

20 (42%)
 

21 (44%)
 

1
 

1
 

20
 

1
 

1
 

2
 

14
 

3
 

3
 

1
 

2
 

17 (35%)
 

1
 

1
 

16
 

16
 

1
 

HIGH DOSE
 

50
 

50(100%)
 

50
 

33 (66%)
 

1 (2%)
 

1
 

1
 

9 (18%)
 

1
 

1
 

8
 

1
 

7
 

1
 

1
 

16 (32%)
 

13
 

1
 

12
 

77
 
TABLE CI MALE RATS: NONNEOPLASTIC LESIONS (CONT.)

 

ENDOCARDIUM
 

FIBROSIS
 

AORTA
 

CALCIFICATION
 

CORONARY ARTERY
 

CALCIFICATION
 

PULHONARY ARTERY
 

HYPERPLASIA
 

LEFT GASTRIC ARTERY
 

CALCIFICATION
 

HESENTERIC ARTERY
 

IMFLAHHATION
 

PERIARTERITIS
 

DIGESTIVE SYSTEM
 

LIVER
 

INFLAMMATION SUPPURATIVE
 

FIBROSIS FOCAL
 

PERIARTERITIS
 

HBCROSIS FOCAL
 

METAMORPHOSIS FATTY
 

REPATOCYTOHBGALY
 

AHGIECTASIS
 

LIVER/CETCRILOBULAR
 

NECROSIS FOCAL
 

BILE DUCT
 

DILATATION
 

INFLAMMATION
 

FIBROSIS
 

HYPERPLASIA
 

PANCREAS
 

HEMORRHAGE
 

CONTROL
 

1
 

1
 

1
 

1
 

1
 

1
 

1
 

9 (90%)
 

7
 

1
 

7
 

t
 

1
 

1
 

1
 

2
 

78
 

LOW DOSE
 

6
 

6
 

3
 

3
 

3
 

3
 

1
 

1
 

35 (73%)
 

28
 

t
 

3
 

24
 

6
 

21
 

6
 

2
 

21
 

4
 

HIGH DOSE
 

2
 

2
 

3
 

3
 

43 (86%)
 

32
 

1
 

1
 

29
 

2
 

22
 

2
 

4
 

22
 

7
 

1
 
TABLE CI MALE RATS: NONNEOPLASTIC LESIONS (CONT.)

PANCREAS (COIT.)
 

FIBROSIS
 

PERIARTERITIS
 

PANCREATIC ACIIOS
 

ATROPHT
 

ESOPHAGUS
 

HYPERPLASIA EPITHELIAL
 

GASTRIC flUCOSA
 

CALCIFICATIOIT
 

GASTRIC BOSCULARIS
 

CALCHTCATIOH
 

URINARY SYSTSH
 

KIDNEY
 

PYELONEPHRITIS SUPPURATIVE
 

INFLANATION CHRONIC
 

PERIARTERITIS
 

KIDNEY/CORTEX
 

CYST
 

KIDNEY/HSDULLA
 

NECROSIS
 

KIDNEY/PELVIS
 

DILATATION
 

INPLAHBATION SUPPURATIVE
 

HYPERPLASIA EPITHELIAL
 

URETER
 

HYPERPLASIA EPITHELIAL
 

URINARY BLADDER
 

CALCULUS
 

INFLAHHATION CHRONIC
 

CONTROL
 

1
 

1
 

2
 

2
 

1
 

1
 

10 (100%)
 

10
 

11
 

2
 

2
 

4
 

2
 

LOW DOSE
 

2
 

3
 

4
 

4
 

1
 

1
 

1
 

1
 

2
 

2
 

42 (88%)
 

36
 

36
 

1
 

1
 

1
 

1
 

13
 

2
 

13
 

24
 

4
 

HIGH DC
 DOSE
 

3
 

4
 

12
 

12
 

40 (809
 

38
 

1
 

38
 

1
 

9
 

1
 

1
 

8
 

1
 

1
 

10
 

2
 

5
 
TABLE C1 MALE RATS: NONNEOPLASTIC LESIONS (CONT.)

 

URINARY BLADDER (COHT·)
 

HYPERPLASIA EPITHELIAL
 

HYPERPLASIA RESOTHELIAL
 

BETA PL AS11 SQUAROUS
 

URETHRA
 

CALCULUS
 

HYPERPLASIA EPITHELIAL
 

ENDOCRINE SYSTEH
 

PITUITARY
 

HYPERPLASIA CHROHOPHOBE-CELL
 

ADRENAL
 

NECROSIS FAT
 

CYTOHEGALY
 

ANGIECTASIS
 

ADRENAL CORTEX
 

CYTOREGALY
 

HYPERPLASIA FOCAL
 

THYROID
 

ULTIHOBRANCHIAL CYST
 

CYSTIC FOLLICLES
 

HYPERPLASIA
 

HYPERPLASIA C-CELL
 

HYPERPLASIA FOLLICULAR-CELL
 

PARATHYROID
 

HYPERPLASIA
 

PANCREATIC ISLETS
 

HYPERPLASIA
 

HEHATOPOIETIC SYSTEH
 

SPLEEN
 

FIBROSIS FOCAL
 

CONTROL
 

4
 

5 (50%)
 

2
 

2
 

4
 

1
 

1
 

1
 

LOW DOSE
 

24
 

1
 

t
 

1
 

3? (65%)
 

4
 

4
 

2
 

1
 

1
 

4
 

3
 

t
 

25
 

t
 

4
 

1
 

3
 

5
 

5
 

3 (6%)
 

3
 

HIGH DOSE
 

8
 

t
 

1
 

t
 

1
 

31 (62%)
 

4
 

4
 

1
 

1
 

6
 

6
 

20
 

3
 

4
 

15
 

5
 

8
 

8
 

1
 

1
 

5 CtOXj
 

4
 

t
 

80
 
TABLE CI MALE RATS: NONNEOPLASTIC LESIONS (CONT.)
 

SPLEEI (COHT.)
 

HYPERPLASIA RETICULUΗ-CELL
 

HEMATOPOIESIS
 

CERVICAL LTHPH BODE
 

LTHPHOID HYPERPLASIA
 

REPRODUCTIVE SYSΤEH
 

PROSTATE
 

IVFLAHHATIOR SUPPURATIVE
 

IIPLABHATIOH GRANULOMATOUS
 

IHFLAH SUPPURATIVE GRANULOMATOUS
 

HYPERPLASIA EPITHELIAL
 

HBTAPLASIA SQOAHOUS
 

PROSTATIC DUCT
 

DEPOSIT10I OP CRYSTALS
 

TESTIS
 

PERIARTERITIS
 

ATROPHY
 

HYPERPLASIA HESOTHELIAL
 

TUVICA VAGINALIS
 

HYPERPLASIA HESOTHELIAL
 

EPIDIDYMIS
 

IIFLAHHATIOH GRANULOMATOUS
 

HERVOUS SYSTEH
 

BRAI*
 

HYDROCEPHALUS
 

PIVEAL BODY
 

CORPORA AHYLACEA
 

COfTROL
 

5 (50%)
 

2
 

2
 

1
 

1
 

5
 

1
 

6
 

LOW DOSE
 

3
 

43 (90%}
 

5
 

3
 

2
 

t
 

41
 

41
 

3
 

3
 

t (2%>
 

1
 

1
 

HIGH DOSE
 

1
 

2
 

1
 

1
 

40 (80%)
 

12
 

11
 

1
 

1
 

1
 

38
 

4
 

37
 

1
 

1
 

1
 

2 (4%)
 

2
 

2
 

81
 
TABLE CI MALE RATS: NONNEOPLASTIC LESIONS (CONT.)
 

UUSCUL0S1CE1.ETAL SYSTEM
 

ΒΟΙΕ
 

FIBROUS OSTEODYSTROPHY
 

SPECIAL SEISE ORGAIS
 

IOIR
 

ALL OTHER SYSTEHS
 

HOLTIPLE 0R6A1S
 

ARTERIOSCLEROSIS
 

CALCIFICATION
 

ADIPOSE TISSUE
 

IIFLAHHATIOI ACUTE
 

WO LESIOV REPORTED
 

AUTOLYSIS/VBCROPSY PERF/IO HISTO
 

AUTOLYSIS/Ι HSCROPSY PBRFORHBD
 

AIIHAL DISPOSITIOV SUHHARY
 

AVIHALS IIITIALLY II STUDY
 

IATURAL DEATH*
 

HORIBUID SACRIFICE
 

SCHEDULED SACRIFICE
 

ACCIDENTALLY KILLED
 

TBRHIIAL SACRIFICE
 •IMCLODES 1UTOLYZED AIIHALS
 

COITROL
 

t (10X)
 

t
 

1
 

10
 

1
 

7
 

2
 

LOW DOSE
 

t (2XJ
 

1
 

1
 

1 (2%)
 

t
 

1
 

1
 

t
 

2
 

50
 

6
 

T4
 

30
 

HIGH DOSE
 

1 (2X)
 

1
 

1
 

t
 

50
 

6
 

7
 

37
 

32
 
TABLE C2 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS
 

IN FEMALE RATS FED DICHLORVOS IN THE DIET
 

AN I HALS INITIALLY II STUDY
 

AHIHALS IECROPSIED
 

ANIMALS EXAMINED HISTOPATHOLOGICALLY
 

ANIMALS WITH TUHORS
 

INTEGUMENTARY SYSTEM
 

HOVE
 

RESPIRATORY SYSTEM
 

TRACHEA
 

IBFLAHHATIOB SUPPURATIVE
 

INFLAHHATION FOCAL CHROHIC
 

LUNG/BROWCHIOLE
 

INFLAHHATION SUPPURATIVE
 

LUHG
 

FOREIG1-BODY PβBUMONIA
 

ABSCESS
 

IHFLAB SUPPURATIVE 6RAVULARAT0US
 

ALVEOLAR MACROPHAGES
 

HYPERPLASIA ALVEOLAR-CELL
 

LUNG/ALVEOLI
 

IHFLAHHATION SUPPURATIVE
 

CIRCULATORY SYSTEH
 

HYOCARDIUf!
 

INFLAHHATION
 

FIBROSIS
 

ENDOCARDIUM
 

FIBROSIS
 

DIGESTIVE SYSTEH
 

SALIVARY GLAND
 

CALCULUS
 

CONTROL
 

10
 

10(100%)
 

10
 

8 (80%)
 

1 (10%)
 

1
 

1
 

1
 

4 (40%)
 

83
 

LOW DOSE
 

50
 

48(100%)
 

48
 

34 (71%)
 

23 (48%)
 

23
 

1
 

1
 

22
 

3
 

1
 

1
 

19 (40%)
 

19
 

2
 

19
 

4
 

4
 

36 (75%)
 

1
 

t
 

HIGH DOSS
 

50
 

50(100%)
 

50
 

30 (60%)
 

25 (50%)
 

2
 

1
 

1
 

2
 

2
 

25
 

3
 

1
 

21
 

3
 

16 (32%)
 

16
 

1
 

15
 

1
 

1
 

41 (82%)
 
TABLE C2 FEMALE RATS: NONNEOPLASTIC LESIONS (CONT.)
 

SALIVARY GLAND (COHT·)
 

CYSTIC DUCTS
 

FIBROSIS
 

CALCIFICATION
 

LIVER
 

PERIARTERITIS
 

NECROSIS FOCAL
 

HETABOHPHOSIS FATTY
 

HEPATOCYTOHEGALY
 

AHGIECTASIS
 

BILE DOCT
 

INFLAHBATION
 

HYPERPLASIA
 

PAHCREAS
 

ECTOPIA
 

FIBROSIS
 

PAHCREATIC DUCT
 

DILATATION
 

INFLABHATION GRANULOMATOUS
 

HYPERPLASIA EPITHELIAL
 

PABCREATIC ACIIOS
 

ATROPHY
 

S TO AC Η
 

EPIDERHAL INCLUSION CYST
 

ULCER
 

IHFLAHHATION ACUTE
 

ACANTHOSIS
 

LARGE INTESTINE
 

PERIARTERITIS
 

URINARY SYS TEH
 

KIDNEY
 

INFLABHATION CHRONIC
 

CONTROL
 

4
 

1
 

4
 

1
 

2
 

1
 

2
 

9 (90%)
 

8
 

8
 

LOW DOSE
 

1
 

Τ
 

1
 

T9
 

4
 

14
 

2
 

24
 

4
 

23
 

2
 

2
 

6
 

6
 

2
 

1
 

1
 

29 (60%Τ
 

20
 

20
 

HIGH DOSE
 

26
 

t
 

10
 

17
 

25
 

7
 

24
 

5
 

1
 

4
 

1
 

1
 

1
 

1
 

11
 

11
 

1
 

1
 

1
 

1
 

1
 

28 (56%f
 

27
 

27
 
TABLE C2 FEMALE RATS: NONNEOPLASTIC LESIONS (CONT.)
 

KIDHEY/PBLVIS
 

CALCULUS
 

INFLAHHATIOH SUPPURATIVE
 

HYPERPLASIA EPITHELIAL
 

URIHARY BLADDER
 

HYPERPLASIA EPITHELIAL
 

ENDOCRINE SYSTEH
 

PITUITARY
 

HYPERPLASIA CHROHOPHOBE-CELL
 

ADRENAL
 

AHGIECTASIS
 

ADRENAL CORTEX
 

CYTOREGALY
 

HYPERPLASIA FOCAL
 

A1GIECTASIS
 

THYROID
 

ULTIHOBRANCHIAL CYST
 

CYSTIC FOLLICLES
 

ATROPHY
 

HYPERPLASIA C-CELL
 

HYPERPLASIA FOLLICULAR-CELL
 

PARATHYROID
 

HYPERPLASIA
 

PANCREATIC ISLETS
 

HYPERPLASIA
 

HEHATOPOIBTIC SYSTEH
 

SPLEBH
 

FIBROSIS FOCAL
 

CONTROL
 

2
 

1
 

1
 

1
 

1
 

7 (70%}
 

1
 

1
 

2
 

1
 

1
 

7
 

1
 

7
 

1
 

2 (20%)
 

2
 

LOW DOSE
 

4
 

3
 

1
 

α
 

9
 

9
 

33 (69%)
 

5
 

5
 

13
 

8
 

1
 

6
 

25
 

1
 

1
 

23
 

3
 

10 (21%)
 

10
 

1
 

HIGH DOSE
 

2
 

2
 

1
 

3
 

3
 

36 (72%)
 

1
 

1
 

1
 

1
 

α
 

6
 

1
 

10
 

27
 

1
 

1
 

26
 

3
 

2
 

2
 

2
 

2
 

7 (1M)
 

7
 

1
 

85
 
TABLE C2 FEMALE RATS: NONNEOPLASTIC LESIONS (CONT.)
 

SPLEEN (COW Τ.)
 

PERIARTERITIS
 

HEHOSIDEROSIS
 

HYPERPLASIA RETICOLUH-CELL
 

HEHATOPOISSIS
 

REPRODOCTITE SYSTEB
 

UTEROS
 

HYDROBETRA
 

UTEROS/EWDOHETRI0H
 

CIST
 

HYPERPLASIA
 

HYPERPLASIA FOCAL
 

HYPERPLASIA CYSTIC
 

OVARY
 

CYST
 

FOLLICULAR CYST
 

HYPERPLASIA EPITHELIAL
 

NERVOUS SYSTEH
 

BRAIN
 

GLIOSIS
 

MUSCULOSKELETAL SYSTEH
 

HO HE
 

SPECIAL SEVSE ORGANS
 

HOIE
 

86
 

CONTROL
 

2
 

1 (10%)
 

1
 

1
 

LOW DOSE
 

3
 

6
 

6 (13%)
 

5
 

1
 

1
 

1
 

2
 

1
 

1
 

HIGH DOSE
 

t
 

2
 

1
 

4
 

TO (20%)
 

3
 

3
 

4
 

4
 

3
 

2
 

t
 

t (2%)
 

t
 

1
 
TABLE C2 FEMALE RATS: NONNEOPLASTIC LESIONS (CONT.)
 

ILL OTHER STSTEHS
 

BORE
 

MO LESIOH REPORTED
 

AUTOLYSIS/Ϊ IECROPSY PERFORRED
 

AMIHAL DISPOSITIOI SUHHARY
 

AHIHALS IIITIALLY IH STUDY
 

VATURAL DEATH*
 

HORIB0ID SACRIFICE
 

SCHEDULED SACRIFICE
 

ACCIDEWTALLY KILLED
 

TERHIIAL SACRIFICE
 

«INCLUDES AUTOLYZED ANIBALS
 

COITROL LOW DOSE HIGH DOSE 

1 

2 

to 50 50 

3 2 

5 7 6 

5 <IO 42 

87
 

APPENDIX D
 

SUMMARY OF THE INCIDENCE
 

OF NONNEOPLASTIC LESIONS IN MICE
 

FED DICHLORVOS IN THE DIET
 

89
 

TABLE D1
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS
 

IN MALE MICE FED DICHLORVOS IN THE DIET
 

ANIHALS IIIΤΙALLY II STUDY
 

ANIMALS IECROFSIED
 

ANIHALS EXAMINED HISTOPATHOLOGICALLY
 

AHIHALS WITH TUMORS
 

INTEGUHBITARY SYSTEH
 

SKIM
 

INFLAMMATION FOCAL CHRONIC
 

RESPIRATORY SYSTEM
 

LUNG
 

INFLAMMATION INTERSTITIAL
 

BRONCHOPNEUMONIA SUPPURATIVE
 

HYPERPLASIA ALVEOLAR-CELL
 

CIRCULATORY SYSTEH
 

HEART
 

PERIARTERITIS
 

DEGEBERATIOH
 

COROHARY ARTERY
 

INFLAMMATION
 

MESENTERIC ARTERY
 

INFLAMMATION
 

RSIAL ARTERY
 

INFLAMMATION
 

DIGESTIVE SYSTSH
 

LITER
 

INFLAMMATION CHRONIC
 

INFLAMMATION FOCAL CHRONIC
 

INFLAMMATION CHROVIC DIFFUSE
 

CONTROL
 

10
 

10(100%}
 

10
 

1 (10%)
 

1 (10%)
 

1
 

1
 

1 (10%)
 

1
 

1
 

2 (20%)
 

2
 

1
 

1
 

91
 

LOW DOSE
 

50
 

50(100%)
 

50
 

21 (a 2%)
 

1 (2%)
 

1
 

1
 

3 (6%)
 

3
 

1
 

1
 

2
 

1 (2%)
 

1
 

1
 

1
 

1
 

1
 

1
 

5 (10%)
 

1
 

HIGH DOSE
 

50
 

50(100%)
 

50
 

14 (28%)
 

1 (2%)
 

1
 

1
 

3 (6%)
 

3
 

3
 

1 (2%)
 

1
 

1
 

5 (10%)
 

3
 

1
 

1
 
TABLE D1 MALE MICE: NONNEOPLASTIC LESIONS (CONT.)
 

LIVER (CONT.)
 

PERIVASCULAR CUFFING
 

HYPERPLASIA NODULAR
 

AHGIECTASIS
 

LIVER/CAUDATE LOBS
 

NECROSIS
 

LIVER/HBPATOCYTES
 

HYPERTROPHY FOCAL
 

PANCREAS
 

INFLAMMATION ACUTE
 

INFLAMMATION FOCAL CHROMIC
 

PANCREATIC ACINUS
 

ATROPHY
 

ESOPHAGUS
 

HYPERPLASIA EPITHELIAL
 

URINARY SYSTEM
 

KIDNEY
 

INFLAMMATION CHRONIC
 

PERIARTERITIS
 

RENAL TUBULE
 

CYTOPLASMIC VACUOLIZATION
 

ENDOCRINE SYSTEM
 

ADRENAL CORTEX
 

CYTOMEGALY
 

HYPERPLASIA
 

THYROID
 

INFLAMMATION ACUTE FOCAL
 

CONTROL
 

1
 

1
 

1
 

1 (10%)
 

t
 

1
 

7 (70%J
 

7
 

7
 

92
 

LOW DOSE
 

1
 

1
 

1
 

ι
 

1
 

3
 

3
 

15 (30%}
 

15
 

15
 

36 (72%)
 

35
 

6
 

34
 

2
 

1
 

HIGH DOSE
 

1
 

2
 

1
 

1
 

20 (40%)
 

20
 

19
 

1
 

30 (60%)
 

28
 

3
 

28
 

2
 
TABLE D1 MALE MICE: NONNEOPLASTIC LESIONS (CONT.)
 

THYROID (CONT.) 

PERIARTERITIS 

HYPERPLASIA FOLLICULAR-CELL 

PARATHYROID
 

CYST
 

HEMATOPOIETIC SYSTEM 

BONE MARROW 

HYPOPLASIA 

HYPERPLASIA HEMATOPOIETIC 

SPLEEN 

CONGESTΙΟΙ 

HYPERPLASIA RBTICULOH-CBLL 

HEBATOPOIESIS 

LYHPH HODE 

HYPERPLASIA RETICULUH-CBLL 

LYHPHOID HYPERPLASIA 

HEHATOPOIESIS 

ftEPRODUCTITE SYSTEH 

TESTIS
 

SPERHATOGEHIC GRANULOHA
 

ATROPHY
 

ATROPHY FOCAL
 

NERVOUS SYSTBH 

HONE 

MUSCULOSKELETAL SYSTEH 

NONE 

CONTROL LOV DOSE HIGH DOSE 

1 

1 1 

Τ 

t 

2 (20%} * (8%) 4 (8%) 

2 1 

1 

1 1 

2 2 2 

1 

1 2 

2 

2 2 

1 t 

1 

1 

1 (10%) 1 (2%i 3 (6%) 

1 1 3 

t 

2 

1 1 

93
 
TABLE D1 MALE MICE: NONNEOPLASTIC LESIONS (CONT.)
 

SPECIAL SEISE ORGANS
 

IOIE
 

ALL OTHER SISTERS
 

PERITONEUM
 

IHFLAHHATION ACUTE
 

IWFLABHATION ACUTE NECROTIZING
 

HESEHTERY
 

PERIARTERITIS
 

90 LESIOI REPORTED
 

ANIHAL DISPOSITION SUHHARY
 

AVIHALS INITIALLY IN STUDY
 

NATURAL DEATH*
 

H0RIBU1D SACRIFICE
 

SCHEDULED SACRIFICE
 

ACCIDENTALLY KILLED
 

TERHIVAL SACRIFICE
 •INCLUDES AUTOLYZED ANIHALS
 

CONTROL LOW DOSE HIGH DOSE
 

1 

1 

1 

t 

1 

t 3 5 

10 50 50 

1 

α 3 

9 U6 47 

94
 
TABLE D2

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS 

IN FEMALE MICE FED DICHLORVOS IN THE DIET 

AHIHALS IHITIAXLY IR STUDY
 

AHIHALS MISSING
 

AHIHALS HECROPSIBD
 

AHIHALS EXAHIHBD HISTOPATHOLOGICALLY
 

AHIHALS WITH TUHORS
 

INTBGUHENTARY STSTBH
 

NONE
 

RESPIRATORY STSTEH
 

LUNG
 

INFLAMMATION IHTERSTITIAL
 

HYPERPLASIA ALVEOLAR-CELL
 

CIRCULATORY SYSTEM
 

HEART
 

PERIARTERITIS
 

MYOCARDIUM
 

INFLAMMATION FOCAL
 

INFLAMMATION FOCAL CHRONIC
 

DIGESTIYE SYSTBH
 

LIVER
 

INFLAMMATION FOCAL
 

INFLAMMATION SUBACUTE
 

INFLAMMATION FOCAL CHROHIC
 

CYTOPLASHIC VACUOLIZATION
 

HYPERPLASIA HODULAR
 

LIVER/HBPITOCYTES
 

HYPERTROPHY FOCAL
 

BILE DUCT
 

INFLAMMATION FOCAL CHROHIC
 

PANCREAS
 

PERIARTERITIS
 

CONTROL
 

10
 

9(100%)
 

9
 

1 (11X)
 

95 

LOW DOSE
 

50
 

1
 

49(100%)
 

47
 

11 (22%J
 

1 (2%)
 

1
 

1
 

2 (4%)
 

2
 

2
 

9 (18%)
 

4
 

1
 

3
 

1
 

2
 

2
 

2
 

2
 

HIGH DOSB
 

50
 

50(100%)
 

49
 

8 (16%)
 

1 (2%)
 

1
 

1
 

2 (4%)
 

2
 

2
 

1
 

1
 

13 (26%)
 

9
 

2
 

4
 

1
 

3
 

1
 

1
 
TABLE D2 FEMALE MICE: NONNEOPLASTIC LESIONS (CONT.) 

CONTROL
 

PANCREATIC DOCT
 

CIST
 

PANCREATIC ACINUS
 

ATROPHY
 

ESOPHAGUS
 

HYPERPLASIA EPITHELIAL
 

STOHACH
 

INFLAMMATION SUBACUTE
 

HYPERPLASIA EPITHELIAL
 

S.INTESTIHE/HUCOSA
 

AMYLOIDOSIS
 

URINARY SYSTEM
 

KIDNEY 1
 

MINERALIZATION 1
 

INFLAMMATION CHRONIC
 

PERIARTERITIS
 

RENAL TUBULE
 

MINERALIZATION
 

URINARY BLADDER
 

PERIARTERITIS
 

ENDOCRINE SYSTEM 9 (100%)
 

PITUITARY
 

HYPERPLASIA CHROHOPHOBE-CKLL
 

ADRENAL
 

INFLAMMATION ACUTE
 

HYPERPLASIA
 

96
 

LOW DOSE
 

2
 

2
 

1
 

1
 

7 (14%)
 

6
 

6
 

1
 

1
 

41 (84%)
 

3
 

3
 

HIGH DOSE
 

1
 

1
 

2
 

2
 

1
 

1
 

τ
 1
 

1
 

16 (32%)
 

15
 

14
 

1
 

1
 

1
 

47 (94%)
 

2
 

1
 

1
 
TABLE D2 FEMALE MICE: NONNEOPLASTIC LESIONS (CONT.)

 

RIGHT ADRENAL GLAND
 

HYPERPLASIA
 

ADRENAL CORTEX
 

CYTOMEGALY
 

HYPERPLASIA
 

HYPERPLASIA CYSTIC
 

THYROID
 

CYSTIC FOLLICLES
 

PERIARTERITIS
 

HYPERPLASIA FOLLICULAR-CELL
 

HEMATOPOIETIC SYSTEH
 

BONE HARROW
 

HYPERPLASIA HEMATOPOIETIC
 

SPLEEN
 

HYPERPLASIA RETICULUM-CELL
 

LYHPHOID HYPERPLASIA
 

LYMPH NODE
 

LYHPHOID HYPERPLASIA
 

REPRODUCTIVE SYSTEH
 

EXOCERYIX
 

HYPERPLASIA
 

UTERUS/EIDOHETRRIH
 

IIFLAHHATION SUPPURATIVE
 

INFLAHHATIOR ACUTE
 

HYPERPLASIA CYSTIC
 

OVARY
 

CYST
 

COHTROL
 

9
 

9
 

1
 

t
 

5 (56%)
 

5
 

5
 

LOW DOSE
 

40
 

1
 

39
 

1
 

3
 

1
 

3
 

7 (14%)
 

3
 

3
 

4
 

2
 

2
 

2
 

2
 

40 (82%)
 

1
 

1
 

39
 

1
 

2
 

37
 

to
 

HIGH DOSE
 

3
 

3
 

43
 

43
 

2
 

1
 

1
 

3 (6%)
 

2
 

2
 

1
 

1
 

40 (80%)
 

39
 

2
 

37
 

8
 

3
 

97
 
TABLE D2 FEMALE MICE: NONNEOPLASTIC LESIONS (CONT.)

 

OVARY (COHT.)
 

FOLLICULAR CYST
 

HEMATOCYST
 

INFLAMMATION SUPPURATIVE
 

NERVOUS SYSTBH
 

BRAIH/MENINGES
 

PERIVASCULAR CUPFIHG
 

BRAIN
 

IHFLAMMATION FOCAL CHROMIC
 

MUSCULOSKELETAL SYSTEM
 

NONE
 

SPECIAL SENSE ORGANS
 

NONE
 

ALL OTHER SYSTEMS
 

PERITONEUM
 

IHFLAMMATIOH ACUTE
 

MESENTERY
 

PERIARTERITIS
 

NO LESIOH REPORTED
 

AUTOLYSIS/HECROPSY PBRF/HO HISTO
 

AUTOLYSIS/HO NECROPSY PERFORMED
 

ANIMAL DISPOSITION SUMMARY
 

ANIMALS INITIALLY IH STUDY
 

HATURAL DEATH*
 

MORIBUHD SACRIFICE
 

SCHEDULED SACRIFICE
 

ACCIDEHTALLY KILLED
 

TERMINAL SACRIFICE
 

MISSIHG
 

•INCLUDES AUTOLYZED AHIHALS
 

COHTROL LOV DOSE
 

7
 

2
 

1
 

1 

3 

2 

10 

1 

50 

7 

6 

9 36 

1 

98 

U. S. GOVERNMENT PRINTING OFFICE : 1977

HIGH DOSE
 

3
 

1
 

1
 

2 (4%)
 

1
 

1
 

t
 

^ (8«
 

2
 

2
 

2
 

2
 

1
 

1
 

50
 

3
 

5
 

42
 

 241-161/3080 

DHEW Publication No. (NIH) 77-810