1979 

National Cancer Institute 

CARCINOGENESIS 

Technical Report Series 

NO. 157 

BIOASSAY OF 

METHYL PARATHION 

FOR POSSIBLE CARCINOGEN ICITY 

CAS No. 298-00-0 

NCI-CG-TR-157 

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

Public Health Service 

National Institutes of Health 

BIOASSAY OF
 

METHYL PARATHION
 

FOR POSSIBLE CARCINOGENICITY
 

Carcinogenesis Testing Program
 

Division of Cancer Cause and Prevention
 

National Cancer Institute
 

National Institutes of Health
 

Bethesda, Maryland 20014
 

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

Public Health Service
 

National Institutes of Health
 

DHEW Publication No. (NIH) 79-1713
 
ii

 
BIOASSAY OF
 

METHYL PARATHION
 

FOR POSSIBLE CARCINOGENICITY
 

Carcinogenesis Testing Program
 

Division of Cancer Cause and Prevention
 

National Cancer Institute
 

National Institutes of Health
 

FOREWORD: This report presents the results of the bioassay of
 

methyl parathion conducted for the Carcinogenesis Testing
 

Program, Division of Cancer Cause and Prevention, National Cancer
 

Institute (NCI), National Institutes of Health, Bethesda,
 

Maryland. This is one of a series of experiments designed to
 

determine whether selected chemicals have the capacity to produce
 

cancer in animals. A negative result, in which the test animals
 

do not have a greater incidence of cancer than control animals,
 

does not necessarily mean that a test chemical is not a
 

carcinogen, inasmuch as the experiments are conducted under a
 

limited set of circumstances. A positive result demonstrates
 

that a test chemical is carcinogenic for animals under the
 

conditions of the test and indicates that exposure to the
 

chemical is a potential risk to man. The actual determination of
 

the risk to man from chemicals found to be carcinogenic in
 

animals requires a wider analysis.
 

CONTRIBUTORS; This bioassay of methyl parathion was conducted by
 

the NCI Frederick Cancer Research Center (FCRC) (1), Frederick,
 

Maryland, operated for NCI (2) by Litton Bionetics, Inc.
 

The manager of the bioassay at FCRC was Dr. B. Ulland, the
 

toxicologist was Dr. E. Gordon, and Drs. R. Cardy and D. Creasia
 

compiled the data. Ms. S. Toms was responsible for management of
 

data, Mr. D. Cameron for management of histopathology, Mr. L.
 

Callahan for management of the computer branch, and Mr. R. Cypher
 

for management of the facilities. Mr. A. Butler performed the
 

computer services. Histopathologic evaluations for rats and mice
 

were performed by Dr. D. A. Willigan (3). The diagnoses included
 

in this report represent his interpretations.
 

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

Mason Research Institute (4). Statistical analyses were
 

performed by Dr. J. R. Joiner (5) and Ms. P. L. Yong (5), using
 

ill
 
methods selected for the bioassay program by Dr. J. J. Gart (6).
 

The chemicals used in this bioassay were analyzed at FCRC by Dr.
 

W. Zielinsky (1). The chemical analyses and narrative were
 

reviewed and approved by Dr W. Lijinsky (1).
 

This report was prepared at Tracor Jitco (5) under the direction
 

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

Dr. C. R. Angel, Acting Director of the Bioassay Program; Dr. S.
 

S. din. Deputy Director for Science; Dr. J. F. Robens,
 

toxicologist; Dr. R. L. Schueler, pathologist; Dr. G. L. Miller,
 

Ms. L. A. Waitz, Ms. M. S. King, and Mr. W. D. Reichardt,
 

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

assisted by Ms. Y. E. Presley.
 

The following scientists at NCI were responsible for evaluating
 

the bioassay experiment, interpreting the results, and reporting
 

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

J. Fielding Douglas, Dr. Richard A. Griesemer, Dr. Thomas E.
 

Hamm, Dr. William V. Hartwell, Dr. Morton H. Levitt, Dr. Harry A.
 

Milman, Dr. Thomas W. Orme, Dr. A. R. Patel, Dr. Sherman F.
 

Stinson, Dr. Jerrold M. Ward, and Dr. Carrie E. Whitmire.
 

(1)	 Frederick Cancer Research Center, P.O. Box B, Frederick,
 

Maryland.
 

(2)	 Carcinogenesis Testing Program, Division of Cancer Cause and
 

Prevention, National Cancer Institute, National Institutes of
 

Health, Bethesda, Maryland.
 

(3)	 Donald A. Willigan, Inc., 309 East Second Street, Bound
 

Brook, New Jersey.
 

(4)	 EG&G Mason Research Institute, 1530 East Jefferson Street,
 

Rockville, Maryland.
 

(5)	 Tracor Jitco, Inc., 1776 East Jefferson Street, Rockville,
 

Maryland.
 

(6)	 Mathematical Statistics and Applied Mathematics Section,
 

Biometry Branch, Field Studies and Statistics, Division of
 

Cancer Cause and Prevention, National Cancer Institute,
 

National Institutes of Health, Bethesda, Maryland.
 

iv
 
SUMMARY
 

A bioassay of methyl parathion for possible carcinogenicity was
 

conducted by administering the test chemical in feed to F344 rats
 

and B6C3F1 mice.
 

Groups of 50 rats of each sex were administered methyl parathion
 

at one of two doses, either 20 or 40 ppm, for 105 weeks. Matched
 

controls consisted of 20 untreated rats of each sex. All 

surviving rats were killed at the end of administration of the 

test chemical. 

Groups of 50 mice of each sex were administered methyl parathion
 

at one of two doses, initially either 62.5 or 125 ppm. These
 

doses were maintained for 102 weeks for the females; however, due
 

to decreased mean body weight gain in the dosed males, the low
 

and high doses for the males were reduced after 37 weeks to 20
 

and 50 ppm, respectively, and administration at the lowered doses
 

was continued for 65 weeks. The time-weighted average doses for
 

the male mice were 35 and 77 ppm, respectively, for the low- and
 

high-dose groups. Matched controls consisted of 20 untreated
 

mice of each sex. All surviving mice were killed at the end of
 

administration of the test chemical.
 

Mean body weights of the dosed male and female rats and mice were
 

lower than those of the corresponding controls throughout the
 

bioassay and were dose related. Survival was unaffected in both
 

species except for an increase in mortality in the high-dose
 

female rats, in which 46% of the animals were alive at the end of
 

the study.
 

No tumors occurred in any of the groups of rats or mice of either
 

sex at incidences that were significantly higher in the dosed
 

groups than in the corresponding control groups.
 

It is concluded that under the conditions of this bioassay,
 

methyl parathion was not carcinogenic for F344 rats or B6C3F1
 

mice of either sex.
 

v
 
vi

 
TABLE OF CONTENTS
 

Page
 

I. Introduction 1
 

II. Materials and Methods 5
 

A. Chemical 5
 

B. Dietary Preparation 5
 

C. Animals 6
 

D. Animal Maintenance 7
 

E. Subchronic Studies . 9
 

F. Chronic Studies 12
 

G. Clinical and Pathologic Examinations..... 15
 

H. Data Recording and Statistical Analyses 16
 

III. Results - Rats 23
 

A. Body Weights and Clinical Signs (Rats) 23
 

B. Survival (Rats) 23
 

C. Pathology (Rats) 26
 

D. Statistical Analyses of Results (Rats) 27
 

IV. Results - Mice 29
 

A. Body Weights and Clinical Signs (Mice) 29
 

B. Survival (Mice) 29
 

C. Pathology (Mice) 32
 

D. Statistical Analyses of Results (Mice) 33
 

V. Discussion 35
 

VI. Bibliography 37
 

APPENDIXES
 

Appendix A Summary of the Incidence of Neoplasms in
 

Rats Administered Methyl Parathion
 

in the Diet 39
 

Table Al Summary of the Incidence of Neoplasms in
 

Male Rats Administered Methyl Parathion
 

in the Diet 41
 

vii
 
Table A2 Summary of the Incidence of Neoplasms in 

Female Rats Administered Methyl Parathion 

in the Diet

Page 

 45 

Appendix B Summary of the Incidence of Neoplasms in 

Mice Administered Methyl Parathion 

in the Diet 49 

Table Bl Summary of the Incidence of Neoplasms in 

Male Mice Administered Methyl Parathion 

in the Diet 51 

Table B2 Summary of the Incidence of Neoplasms in 

Female Mice Administered Methyl Parathion 

in the Diet 55 

Appendix C Summary of the Incidence of Nonneoplastic 

Lesions in Rats Administered Methyl Parathion 

in the Diet 59 

Table Cl Summary of the Incidence of Nonneoplastic 

Lesions in Male Rats Administered Methyl 

Parathion in the Diet 61 

Table C2 Summary of the Incidence of Nonneoplastic 

Lesions in Female Rats Administered Methyl 

Parathion in the Diet 67 

Appendix D Summary of the Incidence of Nonneoplastic 

Lesions in Mice Administered Methyl 

Parathion in the Diet 73 

Table Dl Summary of the Incidence of Nonneoplagtic 

Lesions in Male Mice Administered Methyl 

Parathion in the Diet 75 

Table D2 Summary of the Incidence of Nonneoplastic 

Lesions in Female Mice Administered Methyl 

Parathion in the Diet 80 

Appendix E Analyses of the Incidence of Primary Tumors 

in Rats Administered Methyl Parathion 

in the Diet 85 

Table El Analyses of the Incidence of Primary Tumors 

in Male Rats Administered Methyl Parathion 

in the Diet 87 

viii
 
Table E2 Analyses of the Incidence of Primary Tumors 

in Female Rats Administered Methyl Parathion 

in the Diet 92 

Appendix F Analyses of the Incidence of Primary Tumors 

in Mice Administered Methyl Parathion 

in the Diet 97 

Table Fl Analyses of the Incidence of Primary Tumors 

in Male Mice Administered Methyl Parathion 

in the Diet 99 

Table F2 Analyses of the Incidence of Primary Tumors 

in Female Mice Administered Methyl Parathion 

in the Diet 105 

TABLES 

Table 1 Methyl Parathion Subchronic Feeding Studies 

in Rats 10 

Table 2 Methyl Parathion Subchronic Feeding Studies 

in Mice 11 

Table 3 Methyl Parathion Chronic Feeding Studies 

in Rats 13 

Table 4 Methyl Parathion Chronic Feeding Studies 

in Mice 14 

FIGURES 

Figure 1 Growth Curves for Rats Administered 

Methyl Parathion in the Diet 24 

Figure 2 Survival Curves for Rats Administered 

Methyl Parathion in the Diet 25 

Figure 3 Growth Curves for Mice Administered 

Methyl Parathion in the Diet 30 

Figure 4 Survival Curves for Mice Administered 

Methyl Parathion in the Diet 31 

ix
 

I. INTRODUCTION
 

Methyl parathion, 0,0-dimethyl
 

0(4-nitrophenyl)-phosphorothioate,
 

(CAS 298-00-0; NCI C02971) was o N -\ \-O-l»-OCH3
 I
 x OCH
 first marketed by Bayer AG in ''
 

1949, and today is manufactured
 

, . Methyl parathion
 

by at least four companies in
 

the United States (Ayers and
 

Johnson, 1976). It was the
 

leading organophosphate insecticide used in the United States in
 

1974, when usage reached 53 million pounds (Ayers and Johnson,
 

1976; EPA, 1975). Factors contributing to its widespread use
 

include its relatively low mammalian toxicity compared with
 

parathion (Gaines, 1969), its similar insecticidal activity to
 

that of parathion (Eto, 1974), its low phytotoxicity (Martin and
 

Worthing, 1977) and its suitability as a replacement for DDT
 

(EPA, 1975).
 

Methyl parathion is used in the agricultural industry (EPA, 1975)
 

as a contact and stomach poison with broad-spectrum insecticidal
 

activity and some efficacy against mites (EPA, 1975, Martin and
 

Worthing, 1977). It is sold as a wettable powder or emulsifiable
 
concentrate for foliage application. Several formulations
 

contain combinations of methyl parathion and ethyl parathion as
 

well as other registered pesticides. There are 62 crops on
 

which methyl parathion is registered for use (EPA, 1972 and
 

1974), but over 90% of the total volume used in 1974 was on
 

cotton (Ayers and Johnson, 1976). It is used to some extent in
 

California for mosquito control (EPA, 1975).
 

The duration of methyl parathion1s insecticidal activity ranges
 

from 2 to 4 weeks (Eto, 1974). Its persistence in soil, which
 

varies depending on soil type, temperature, moisture, and other
 

variables, has been studied in the laboratory and in the field.
 

The half-life of methyl parathion in the laboratory has been
 

reported to be as short as 3 to 11 days (King and McCarty, 1968)
 

and as long as 50 days (Baker and Applegate, 1970). In the
 

field, greater than 95% loss of the chemical occurred 30 days
 

from the time of application (Lichtenstein and Schulz, 1964).
 

More recent research has determined that much of what was
 

previously said to be "lost" actually is not recovered because it
 

has been bound to soil. When this is taken into account, the
 

half-life of methyl parathion is estimated to be 30 days
 

(Lichtenstein et al., 1977). Monitoring studies conducted in
 

areas devoted to cotton farming show that while residues are
 
apparent at the end of each growing season, they are not
 

detectable by the following planting season (Elliott, 1975).
 

The toxicity of methyl parathion for mammals, like that of other
 

organophosphorus insecticides, is due to inhibition of cholinesterase, and the symptoms include restlessness, muscular
 

twitchings, miosis, defecation, urination, lacrimation, incoordination, prostration, generalized muscular fibrillation,
 

convulsions, and death (EPA, 1975). Toxic symptoms may occur in
 

humans exposed to methyl parathion in manufacturing and agricultural operations, and protective standards have been established
 

(EPA, 1975). The average acute oral LD reported from several
 

laboratories for methyl parathion is 11 mg/kg body weight for
 

male rats, 16 mg/kg for female rats, and 18.5 mg/kg for grouped
 

male and female mice (EPA, 1975). In a three-generation (twolitter-per-generation) study in rats, methyl parathion at 30 ppm
 

in the diet reduced overall reproductive performance although
 

there was no consistent effect on individual parameters such as
 

number of stillbirths, physical structure of newborns, litter
 

size, weanling weights, or percentage survival to weaning; 10 ppm
 

methyl parathion in the diet had only sporadic effects on the
 

reproductive performance (EPA, 1975).
 
Although methyl parathion does not show great persistence in the
 

environment, residues do occur in food crops (EPA, 1975). For
 

this reason, and because of its extremely high level of
 

production and use, methyl parathion was selected for testing in
 

the Carcinogenesis Bioassay Program.
 
II. MATERIALS AND METHODS
 

A. Chemical
 

Methyl parathion (0,0-dimethyl 0(4-nitrophenyl)-phosphorothioate) was obtained from Monsanto as a brown semisolid. Its
 

purity was determined by gas-liquid chromatography to be 94.6%,
 

with one impurity greater than 1% and seven impurities less than
 

1%. The melting point was 33 to 34 C, and the refractive index
 

was 1.546 at 48.5 C; these values are consistent with the
 

melting point of 36 C and the refractive index of 1.552 at
 

48.5°C given in the literature (Eto, 1974). Elemental analysis
 

showed 36.6% carbon, 3.9% hydrogen, and 5.3% nitrogen
 

(theoretical: 36.5% C, 3.8% H, and 5.3% N).
 

The test material was stored at 5 C until used.
 

B. Dietary Preparation
 

Test diets containing methyl parathion were prepared every 1 to
 

1-1/2 weeks in 6- to 12-kg batches at the appropriate doses. A
 

known weight of the chemical was first mixed with an equal weight
 
of autoclaved Wayne® Sterilizable Lab Meal containing 4% fat
 

(Allied Mills, Inc., Chicago, 111.), using a mortar and pestle.
 

The mixing was continued with second and third additions of feed,
 

and final mixing was performed with the remaining quantity of
 

feed for a minimim of 15 minutes in a Patterson-Kelly
 

twin-shell blender. The diets were routinely stored at 5 C
 

until used.
 

C. Animals
 

Male and female F344 (Fischer) rats and B6C3F1 mice were obtained
 

as 4-week-old weanlings, all within 3 days of the same age, from
 

the NCI Frederick Cancer Research Center (Frederick, Md.). The
 

animals were housed within the test facility for 2 weeks and then
 

were assigned four rats of the same sex to a cage and five mice
 

of the same sex to a cage on a weight basis for each cage. The
 

male rats used in the chronic study weighed 90 to 105 g, averaging at least 100 g; the female rats, 80 to 95 g, averaging at
 

least 90 g; the male mice, 18 to 22 g, averaging at least 19.5 g;
 

and the female mice, 17 to 21 g, averaging at least 18.5 g.
 

Individual animals were identified by ear punch.
 
D. Animal Maintenance
 

The animals were housed in polycarbonate cages (Lab Products,
 

Inc., Gar field, N.J.), 19 x 10-1/2 x 8 inches for the rats and
 

11-1/2 x 7-1/2 x 5 inches for the mice. The cages were suspended
 

from aluminum racks (Scientific Cages, Inc., Bryan, Tex.) and
 

were covered by nonwoven polyester-fiber 12-mil-thick filter
 

paper (Hoeltge, Inc., Cincinnati, Ohio). The bedding used was
 

Absorb-dri hardwood chips (Northeastern Products, Inc.,
 

Warrenburg, N.Y.). The feed was presterilized Wayne®
 

Sterilizable Lab Meal containing 4% fat provided ad libitum in
 

suspended stainless steel hoppers and replenished at least three
 

times per week. Water, acidified to pH 2.5, was supplied ad
 

libitum from glass bottles with sipper tubes (Lab Products, Inc.)
 

suspended through the tops of the cages.
 

The contaminated bedding was disposed of through an enclosed
 

vacuum line that led to a holding tank from which the bedding was
 

fed periodically into an incinerator. The cages were sanitised
 

twice per week and the feed hoppers twice per month at 82 to
 

88 C in a tunnel-type cagewasher (Industrial Washing Corp.,
 

Mataway, N. J.), using the detergents, Clout® (Pharmacal
 

Research Laboratories, Greenwich, Conn.) or Oxford D'Chlor
 

(Oxford Chemicals, Atlanta, Ga.). The glass bottles and sipper
 
tubes were sanitized at 82 to 88 C in a tunnel-type bottle
 

washer (Consolidated Equipment Supply Co., Mercersburg, Pa.)
 

three times per week, using a Calgen Commercial Division
 

detergent (St. Louis, Mo.). The racks for the cages were
 

sanitized at or above 82 C in a rack washer (Consolidated
 

Equipment Supply Co.) once per month, using the Calgen Commercial
 

Division detergent, and the filter paper was changed at the same
 

time.
 

The animal rooms were maintained at 22 to 24°C and 45 to 55%
 

relative humidity. Incoming air was passed through a filter of
 

65% efficiency and a bag filter of 95% efficiency at the intake,
 

and was expelled without recirculation through a "Z"-type
 

roughing filter of 30% efficiency and a bag system of 90 to 95%
 

efficiency at the exhaust (American Air Filters, Louisville, Ky.;
 

Mine Safety Appliances, Pittsburgh, Pa.). Room air was changed
 

15 times per hour. The air pressure was maintained negative to a
 

clean hallway and positive to a return hallway. Fluorescent
 

lighting was provided automatically on a 12-hour-per-day cycle.
 

Rats administered methyl parathion and their corresponding
 

controls were housed in the same room as rats on feeding studies
 

of the following chemicals:
 

(CAS 128-66-5) C. I. vat yellow 4 

(CAS 148-18-5) sodium diethyldithiocarbamate 

8 
Mice administered methyl parathion and their corresponding
 

controls were housed in the same room as mice on feeding studies
 

of the following chemicals:
 

(CAS 103-33-3) azobenzene
 

(CAS 128-66-5) C. I. vat yellow 4
 

(CAS 72-56-0) p,p'-ethyl-DDD
 

(CAS 20941-65-5) ethyl tellurac
 

(CAS 85-44-9) phthalic anhydride
 

(CAS 51-03-6) piperonyl butoxide
 

(CAS 86-06-2) 2,4,6-trichlorophenol
 

E. Subchronic Studies
 

Subchronic feeding studies were conducted to estimate the maximum
 

tolerated doses (MTD's) of methyl parathion, on the basis of
 

which two concentrations (referred to in this report as "low" and
 

"high" doses) were determined for administration in the chronic
 

studies. Groups of five rats and five mice of each sex were fed
 

diets containing methyl parathion at one of several doses for 7
 

weeks, followed by 1 week of observation, and groups of five
 

control animals of each species and sex were administered basal
 

diet only. Each animal was weighed twice per week. Tables 1 and
 

2 show the doses fed, the survival of animals in each dosed group
 

at the end of the study and the mean body weight of each dosed
 

group at week 7, expressed as a percentage of the mean body
 

weight of the corresponding controls. At the end of the 8 weeks,
 

9
 
Table 1. Methyl Parathion Subchronic Feeding Studies In Rats
 

Male Female 

Dose 

(ppm) Survival (a) 

Mean Weight 

at Week 7 

as % of 

Control Survival (a) 

Mean Weight 

at Week 7 

as % of 

Control 

0 5/5 100 5/5 100
 

10 5/5 101 4/5 102
 

20 5/5 97 5/5 95
 

30(b) 5/5 98 4/5 91
 

40(b) 5/5 98 4/5 87
 

50(b) 5/5 90 3/5 90
 

(a) Number surviving/number in group.
 

(b) Tissues of males and females examined microscopically were
 

essentially normal.
 

10
 
Table 2. Methyl Parathion Subchronic Feeding Studies in Mice
 

Male Female
 

Mean Weight Mean Weight
 

at Week 7 at Week 7
 

Dose as % of as % of
 

( ppm) Survival (a) Control Survival (a) Control
 

0 5/5 100 5/5 100
 

20 4/5 115 5/5 106
 

40 5/5 129 5/5 108
 

60 5/5 108 5/5 103
 

80 5/5 113 5/5 108
 

100 5/5 118 5/5 100
 

125(b) 5/5 96 5/5 96
 

250(b,c, d) 0/5 4/5 94
 

500(c,e) 0/5 0/5
 

(a) Number surviving/number in group.
 

(b) Histopathologic examination of males at 125 ppm and females at 250
 

ppm showed that all tissues were essentially normal.
 

(c) Clinical signs in both sexes at 250 and 500 ppm were rough hair
 

coat and arched back.
 

(d) At necropsy five males at 250 ppm had hemorrhage of the stomach.
 

(e) At necropsy three males and five females at 500 ppm had hemorrhage
 

of the stomach.
 

11
 
the animals were killed using C0_ and necropsied. The
 

footnotes to the tables include clinical and histopathologic
 

findings.
 

Ten percent depression in body weight was a major criterion for
 

the estimation of MTD's. The doses required to produce this
 

response were determined by the following procedure: first,
 

least squares regressions of mean body weights versus days on
 

study were used to estimate mean body weights of each of the
 

dosed groups at day 49. Next, probits of the percent weights of
 

the dosed groups at day 49 relative to weights of corresponding
 

control groups were plotted against the logarithms of the doses,
 

and least squares regressions fitted to the data were used to
 

estimate the doses required to induce 10% depression in weight.
 

The low and high doses for chronic studies were set at 20 and 40
 

ppm for rats and 62.5 and 125 ppm for mice.
 

F. Chronic Studies
 

The test groups, doses administered, and durations of the chronic
 

feeding studies are shown in tables 3 and 4. Due to decreased
 

mean body weight gain in the dosed male mice, the doses were
 

12
 
Table 3. Methyl Parathion Chronic Feeding Studies in Rats
 

Methyl 

Sex and Initial Parathion 

Test No. of in Diet (b) Time on Study 

Group Animals (a) (ppm) (weeks) 

Male 

Matched-Control 20 0 105 

Low-Dose 50 20 105 

High-Dose 50 40 105 

Female
 

Matched-Control 20 0 105
 

Low-Dose 50 20 105
 

High -Dose 50 40 105
 

(a) All animals were approximately 6 weeks of age when placed on
 

study.
 

(b) Test and control diets were provided ad libitum 7 days per
 

week.
 

13
 
Table 4. Methyl Parathion Chronic Feeding Studies in Mice
 

Methyl Time-weighted 

Sex and Initial Parathion Time on Average 

Test No. of in Diet (b) Study Dose (c) 

Group Animals (a) (ppm) (weeks) (ppm) 

Male 

Matched-Control 20 0 102 

Low-Dose 50 62.5 37 

20 65 35 

High-Dose 50 125 37 

50 65 77 

Female
 

Matched-Control 20 0 102
 

Low-Dose 50 62.5 102
 

High -Dose 50 125 102
 

(a) All animals were approximately 6 weeks of age when placed on
 

study.
 

(b) Test and control diets were provided ad libitum 7 days per
 

week.
 

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

z(no. of weeks receiving each dose)
 

14
 
reduced after week 37 to 20 ppm for the low-dose group and 50 ppm
 

for the high-dose group.
 

G. Clinical and Pathologic Examinations
 

All animals were observed twice daily. Observations for sick,
 

tumor-bearing, and moribund animals were recorded daily.
 

Clinical examination and palpation for masses were performed each
 

month, and the animals were weighed at least once per month.
 

Moribund animals and animals that survived to the end of the
 

bioassay were killed using CO- and necropsied.
 

The pathologic evaluation consisted of gross and microscopic
 

examination of major tissues, major organs, and all gross
 

lesions. The tiss'ues were preserved in 10% neutral buffered
 

formalin, embedded in paraffin, sectioned, and stained with
 

hematoxylin and eosin. The following tissues were examined
 

microscopically: skin, lungs and bronchi, trachea, bone marrow
 

(femur), spleen, lymph nodes (mesenteric and submandibular),
 

thymus, heart, salivary glands (parotid, sublingual, and
 

submaxillary), liver, pancreas, esophagus, stomach (glandular and
 

nonglandular), small and large intestine, kidney, urinary
 

bladder, pituitary, adrenal, thyroid, parathyroid, testis,
 

15
 
prostate, mammary gland, uterus, ovary, brain (cerebrum and
 

cerebellum), and all tissue masses. Peripheral blood smears were
 

also made for all animals, whenever possible.
 

Necropsies were also performed on all animals found dead, unless
 

precluded in whole or in part by autolysis or cannibalization.
 

Thus, the number of animals from which particular organs or
 

tissues were examined microscopically varies and does not
 

necessarily represent the number of animals that were placed on
 

study in each group.
 

H. Data Recording and Statistical Analyses
 

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

System (Linhart et al., 1974). The data elements include
 

descriptive information on the chemicals, animals, experimental
 

design, clinical observations, survival, body weight, and
 

individual pathologic results, as recommended by the
 

International Union Against Cancer (Berenblum, 1969). Data
 

tables were generated for verification of data transcription and
 

for statistical review.
 

16
 
These data were analyzed using the appropriate statistical 

techniques described in this section. Those analyses of the 

experimental results that bear on the possibility of 

carcinogenicity are discussed in the statistical narrative 

section. 

Probabilities of survival were estimated by the product-limit 

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

report in the form of graphs. Animals were statistically 

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

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

causes were not statistically censored. Statistical analyses for 

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

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

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

trend. One-tailed P values have been reported for all tests 

except the departure from linearity test, which is only reported 

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

The incidence of neoplastic or nonneoplastic lesions has been 

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

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

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

the denominators included only those animals for which that site 

17 
was examined histologically. However, when macroscopic
 

examination was required to detect lesions prior to histologic
 

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

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

denominators consist of the numbers of animals necropsied.
 

The purpose of the statistical analyses of tumor incidence is to
 

determine whether animals receiving the test chemical developed a
 

significantly higher proportion of tumors than did the control
 

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

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

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

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

compared simultaneously with those for a control group, a
 

correction to ensure an overall significance level of 0.05 may be
 

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

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

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

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

where the Fisher exact P values are shown.
 

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

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

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

18
 
of the dose-response curve is different from zero at the one-


tailed 0.05 level of significance. Unless otherwise noted, the
 

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

from linear trend.
 

A time-adjusted analysis was applied when numerous early deaths
 

resulted from causes that were not associated with the formation
 

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

first tumor was observed were excluded by basing the statistical
 

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

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

such an early tumor was found, comparisons were based exclusively
 

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

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

obtained, the standard procedures for analyses of the incidence
 

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

followed.
 

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

incidence of tumors. Curves of the proportions surviving without
 

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

The week during which an animal died naturally or was sacrificed
 

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

19
 
methods of comparing these curves were used for two groups;
 

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

groups. The statistical tests for the incidence of tumors which
 

used life-table methods were one-tailed and, unless otherwise
 

noted, in the direction of a positive dose relationship.
 

Significant departures from linearity (P less than 0.05, two-


tailed test) were also noted.
 

The approximate 95 percent confidence interval for the relative
 

risk of each dosed group compared with its control was calculated
 

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

relative risk is defined as p./p where p is the true
 

binomial probability of the incidence of a specific type of tumor
 

in a dosed group of animals and p is the true probability of
 

the spontaneous incidence of the same type of tumor in a control
 

group. The hypothesis of equality between the true proportion of
 

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

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

of unity represent the condition of a larger proportion in the
 

dosed group than in the control.
 

The lower and upper limits of the confidence interval of the
 

relative risk have been included in the tables of statistical
 

analyses. The interpretation of the limits is that in
 

20
 
approximately 95% of a large number of identical experiments, the 

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

control group would be within the interval calculated from the 

experiment. When the lower limit of the confidence interval is 

greater than one, it can be inferred that a statistically 

significant result (P less than 0.025 one-tailed test when the 

control incidence is not zero, P less than 0.050 when the control 

incidence is zero) has occurred. When the lower limit is less 

than unity, but the upper limit is greater than unity, the lower 

limit indicates the absence of a significant result while the 

upper limit indicates that there is a theoretical possibility of 

the induction of tumors by the test chemical, which could not be 

detected under the conditions of this test. 

21 
22

 
III. RESULTS - RATS
 

A. Body Weights and Clinical Signs (Rats)
 

Mean body weights of the dosed male and female rats were lower
 

than those of the corresponding controls, and were generally dose
 

related throughout the bioassay (figure 1). Corneal opacity was
 

observed in control and dosed groups. No other compound-related
 

clinical signs were recorded.
 

B. Survival (Rats)
 

Estimates of the probabilities of survival for male and female
 

rats administered methyl parathion in the diet at the doses of
 

this bioassay, together with those for the matched controls, are
 

shown by the Kaplan and Meier curves in figure 2. In male rats,
 

the result of the Tarone test for dose-related trend in mortality
 

is not significant. In females, the result of the Tarone test is
 

significant (P less than 0.001). An indicated departure from
 

linear trend is observed (P = 0.042) because of the relatively
 

steep increase in mortality observed in the high-dose female rats.
 

23
 
500­

D D ° ° A 

D D a fl 

D D

a

D D 

Q2 « g a

2 s § a 8 B H

 A A A 

°°'8 fi a 

H 

2 300­

UJ 

S 

o 

o 

10 

z 

ui 

S 

MALE RATS 

D MATCHED CONTROL 

O LOWDOSE 

A HIGH DOSE 

20 40 SO 60 70 

TIME ON STUDY (WEEKS) 

D 8 

SJ» « O 

O 

O 

a 

z 1i B a a a

A 8A A iA

an a o o o 

A A A 

D

O § 

A 

 A A A A A 

in 

S 

FEMALE RATS 

D MATCHED CONTROL 

O LOW DOSE 

A HIGH DOSE 

TIME ON STUDY (WEEKS) 

Figure 1. Growth Curves for Rats Administered Methyi Parathion in the Diet 

24 
0.80­

i-iM-i-i-CTi- •iMMMM.^-J

*?AvL... 

^''^tt 

( 

""I'LL - -i ": 1 

°O-­

3 

\ 

1 

u> 

O n en 

03 

0 

OC 

0.20­

0.10­

D

O

t\

MALE RA TS 

 MATCHED CONTROL 

 LOW DOSE 

 HIGH DOSE 

46 60 75 

TIME ON STUDY (WEEKS) 

A...... T>-­ . ""i"?>­ i 090 t o

A» 

'A--. *% » 080 ^ 

^"k 

& > A; 

> A 

a> ^.. A* • • ° a so­

^y •• ••• ^ 

5 0.40­

m 

0 

oc 

FEMALE R, \TS

 

0.20- D MATCHED CONTROL

 

O LOW DOSE 

0.10- £.i HIGH DOSE

 

0.00­

TIME ON STUDY (WEEKS) 

Figure 2. Survival Curves for Rats Administered Methyl Parathion in the Diet 

25 
In male rats, 39/50 (78%) of the high-dose group, 37/50 (74%) of
 

the low-dose group, and 17/20 (85%) of the control group lived to
 

the end of the bioassay. In females, 23/50 (46%) of the high-


dose group, 41/50 (82%) of the low-dose group, and 19/20 (95%) of
 

the control group lived to the end of the bioassay.
 

Sufficient numbers of rats of each sex were at risk for the
 

development of late-appearing tumors.
 

C. Pathology (Rats)
 

Histopathologic findings on neoplasms in rats are summarized in
 

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

are summarized in Appendix C, tables Cl and C2.
 

A variety of neoplasms were represented among the dosed and
 

control animals. Although a variety of benign and malignant
 

neoplasms occurred, each type has been encountered previously in
 

aged F344 rats. Moreover, the incidence of neoplasms by type and
 

site, also by test group and sex of animal appears to be without
 

relationship, and hence unattributable, to exposure to the test
 

chemical.
 

26
 
Nonneoplastic responses were also represented among both control
 

and dosed animals. Such lesions have also been encountered
 

previously and are considered to be similar to those commonly
 

observed in aging F344 rats.
 

Based on the histopathologic examination, there was no evidence
 

that methyl parathion was carcinogenic in F344 rats under
 

conditions of this bioassay.
 

D. Statistical Analyses of Results (Rats)
 

Tables El and E2 in Appendix E contain the statistical analyses
 

of the incidences of those primary tumors that occurred in at
 

least two animals of one group and at an incidence of at least 5%
 

in one or more than one group.
 

The results of the Cochran-Armitage tests for dose-related trend
 

in the incidence of tumors and the results of the Fisher exact
 

test comparing the incidences of tumors in the control and dosed
 

groups are not significant in the positive direction in either
 

sex.
 

27
 
Significant results in the negative direction are observed in the
 

incidences of animals with either liver, prostate, pituitary, or
 

mammary gland tumors. In females, this significance in the
 

negative direction may be accounted for by the early mortality of
 

the high-dose animals.
 

In each of the 95% confidence intervals for relative risk shown
 

in the tables, the value of one or less than one is included;
 

this indicates the absence of significant positive results. It
 

should also be noted that each of the intervals, except for the
 

incidence of mammary gland tumors in female rats, has an upper
 

limit greater than one, indicating the theoretical possibility of
 

tumor induction by methyl parathion, which could not be detected
 

under the conditions of this test.
 

28
 
IV. RESULTS - MICE
 

A. Body Weights and Clinical Signs (Mice)
 

Mean body weights of the high-dose male and female mice were
 

lower than those of the corresponding controls throughout the
 

bioassay (figure 3); mean body weights of the low-dose males were
 

decreased prior to lowering the dosage at week 38, while those of
 

the low-dose females were unaffected. No other compound-related
 

clinical signs were recorded.
 

B. Survival (Mice)
 

Estimates of the probabilities of survival for male and female
 

mice administered methyl parathion in the diet at the doses of
 

this bioassay, together with those for the matched controls, are
 

shown by the Kaplan and Meier curves in figure 4. The result of
 

the Tarone test for dose-related trend in mortality is not
 

significant in either sex.
 

29
 
60­

60­

0

O D D O D D « AA n oo n

" 

D O fTT D D 53PA 

/VyyVA/

Sp Q D oa" AA A O 40­ D

 ° OO , A . ^ A°A.

AO 

. 1- A A A A X D _ 0 a a ° UJ DDoBn

 A 

I 30- 000 A A ° A O 

0 L?°A .AA A

 

no « A

CD rr~A Z 

< 

UJ 4f* Dotes lowered for 20 E j W high- and low-dote male 

0 mice at week 38. 

AA MALE MICE 

D MATCHED CONTROL 

10­ O LOW DOSE 

A HIGH DOSE 

0 10 20 30 40 SO 80 70 80 90 100 11 

TIME ON STUDY (WEEKS) 

°8 nu o °Q SO- OD D ° Q 8 

n °a°° D D A

o A A rmf

 D o° A 

Cif ii tl^ uQ Q Q ~ _ O.. D A A 

Q r j . n/vA* A 5 40- /V jC» A /y\ /\ 

H D jftfA/W\'/\' /\ A^A ^ X 

O a ° A A HI 

S 8 ° A A A ^ 30­

Q A 0 nn°H CO g8Sns 

z 

< /T^T? 

UJ 

Z 20­

['ipp 

OQ FEMALE MICE 

A

 D MATCHED CONTROL 

10 O LOW DOSE ­

A HIGN DOSE 

0 ­

TIME ON STUDY (WEEKS) 

Figure 3. Growth Curves tor Mice Administered Methyl Parithiefl in the Diet 

30 
PROBABILITY OF SURVIVAL PROBABILITY OF SURVIVAL 

§ _ i M u » ( n a > - j o o ( o s

 g

s s s s s s s 

O O O O & O O O S 

0 • 

h 

1. 

1 d 

1 3 ' > o n — - ; OT • > 0 D — 

CO i r s m p 

If i ill

I n D S ^ 0 g m m

I S S S " 

n u 8- 8 5— H m

 H

c 

 0 

c 

p 

5 

s- d s­ 3 ^ 

S'5 I? 2 

m

Z 2§ 0 

3 * 09 

a " § 8 " 

3 i I 

m Si m 

• s (0 ,. — a- 

<7I 

3" ?-T S 

3­ 8- ^

F- s- 

1 

s M-l JT-9J1

" to ^fi 

r^

a 

5* 8 8­

i g 
In male mice, 43/50 (86%) of each dosed group and 16/20 (80%) of
 

the control group lived to the end of the bioassay. In females,
 

40/50 (80%) of each dosed group and 17/20 (85%) of the control
 

group lived to the end of the bioassay.
 

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

development of late-appearing tumors.
 

C. Pathology (Mice)
 

Histopathologic findings on neoplasms in mice are summarized in
 

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

are summarized in Appendix D, tables Dl and D2.
 

A variety of neoplasms were represented among the dosed and
 

control animals. Each type has been encountered previously in
 

the B6C3F1 hybrid mouse. Moreover, the incidence of neoplasms by
 

type and site, also by test group and sex of ,animal is without
 

relationship, and hence unattributable, to exposure to the test
 

chemical.
 

A variety of nonneoplastic responses are represented among both
 

control and dosed animals. Such lesions have been encountered
 

32
 
previously and are considered to be similar to those commonly
 

observed in aging B6C3F1 mice.
 

Based on the histopathologic examination, there was no evidence
 

that methyl parathion was carcinogenic in mice under conditions
 

of this bioassay.
 

D. Statistical Analyses of Results (Mice)
 

Tables Fl and F2 in Appendix F contain the statistical analyses
 

of the incidences of those primary tumors that occurred in at
 

least two animals of one group and an incidence of at least 5% in
 

one or more than one group.
 

The results of the Cochran-Armitage tests for dose-related trend
 

in the incidence of tumors and the results of the Fisher exact
 

test comparing the incidences of tumors in the control and dosed
 

groups are not significant in the positive direction in either
 

sex. However, significant results in the negative direction are
 

observed in the combined incidence of hepatocellular carcinoma
 

and adenoma in male mice and in the incidences of pituitary
 

tumors and of hematopoietic tumors in female mice.
 

33
 
In each of the 95% confidence intervals for relative risk, shown
 

in the tables, the value of one or less than one is included;
 

this indicates the absence of significant positive results. It
 

should also be noted that most of the intervals have an upper
 

limit greater than one, indicating the theoretical possibility of
 

the induction of tumors by methyl parathion, which could not be
 

detected under the conditions of this test.
 

34
 
V. DISCUSSION
 

Mean body weights of the dosed male and female rats and mice were
 

lower than those of the corresponding controls and were generally
 

dose related throughout the bioassay. Mortality was unaffected
 

in the rats or mice except for an increase in mortality in the
 

high-dose female rats in which 46% of the animals were alive at
 

the end of the study. Sufficient numbers of animals were at risk
 

for the development of late-appearing tumors.
 

No tumors occurred in any of the groups of rats or mice of either
 

sex at incidences that were significantly higher in the dosed
 

groups than in the corresponding control groups.
 

It is concluded that under the conditions of this bioassay,
 

methyl parathion was not carcinogenic for F344 rats or B6C3F1
 

mice of either sex.
 

35
 
36

 
VI. BIBLIOGRAPHY
 

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

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

Ayers, J. H. and Johnson, 0. H., Insecticides. In: Chemical
 

Economics Handbook, Stanford Research Institute, Menlo Park,
 

Calif., 1976, sec. 573.3003 E-F, 573.3007 G-H, 573.3007 N-0.
 

Baker, R. D. and Applegate, H. G., Effect of temperature and
 

ultraviolet radiation on the persistence of methyl parathion and
 

DDT in soils. Agron. J. £2(4):509-512, 1970. Cited in: Initial
 

Scientific and Minieconomic Review of_ Methyl Parathion,
 

Environmental Protection Agency, Office of Pesticide Programs,
 

Criteria and Evaluation Division, Washington, D.C., 1970.
 

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

Panel on Carcinogenicity o_f_ the Cancer Research Commission of
 

UICC, Vol. 2, International Union Against Cancer, Geneva, 1969.
 

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

Soc. 634:187-220, 1972.
 

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

1970, pp. 48-52.
 

Elliott, J., Monitoring of selected ecological components of the
 

environment in four Alabama counties. Hum. An int. Health, Proc.
 

Annu. Conf. 4:233-279, 1975.
 

Environmental Protection Agency, Initial Scientific and
 

Minieconimic Review o_f_ Methyl Parathion, U.S. Environmental 

Protection Agency, Office of Pesticide Programs, Criteria and 

Evaluation Division, Washington, D.C., 1975. 

Environmental Protection Agency, EPA Compendium o_f_ Registered
 

Pesticides, U. S. Government Printing Office, Washington, D.C.,
 

1974, sec. III-D-41.16 to III-D-41.17.1
 

Environmental Protection Agency, EPA Compendium of Registered
 

Pesticides, U. S. Government Printing Office, Washington, D.C.,
 

1972, sec. III-D-41.2 to III-D-41.15, III-D-41.18 to III-D-41.24,
 

III-D-41.27, III-D-41.29, III-D-41.32 to III-D-41.39.
 

37
 
Eto, M., Parathion-methyl, methyl parathion. In:
 

Organophosphorus Pesticides; Organic and Biological Chemistry,
 

CRC Press, Inc., Cleveland, Ohio, 1974, p. 242^
 

Gaines, T. B., Acute toxicity of pesticides, Toxicol. Appl.
 

Pharmacol. 14:515-534, 1969.
 

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

significance tests, confidence limits and adjustments for
 

stratification., Rev. Int. Stat. Inst. 39.: 148-169, 1971.
 

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

incomplete observations. J. Am. Statist. Assoc. 53:457-481, 1958.
 

King, P. and McCarty, P. L., A chromatographic model for
 

predicting pesticide migration in soils. Soil Sci. 106(4):
 

248-261, 1968.
 

Lichtenstein, E. P., Katan, J., and Anderegg, B. N., Binding of
 

"persistent" and "nonpersistent" l^C-labeled insecticides in an
 

agricultural soil. £. Agric. Food Chem. 25^1):43-47, 1977.
 

Lichtenstein, E. P. and Schulz, K. R., The effects of moisture
 

and microorganisms on the persistence and metabolism of some
 

organophosphorus insecticides in soils, with special emphasis on
 

parathion. J. Econ. Entomol. 57:618-627, 1964.
 

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

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

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

Martin, H. and Worthing, C. R., Parathion-methyl. In: Pesticide
 

Manual, British Crop Protection Council, London, 1977, p. 400.
 

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

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

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

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

induced by different numbers of administrations of benzo(a)
 

pyrene and ferric oxide. Cancer Res. 32_: 107 3-1081, 1972.
 

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

Biometrika 62(3):679-682, 1975.
 

38
 
APPENDIX A
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

RATS ADMINISTERED METHYL PARATHION IN THE DIET
 

39
 
40

 
TABLE A1.

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE RATS 

ADMINISTERED METHYL PARATHION IN THE DIET 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

ANIHALS INITIALLY IN STUD Y 20 50 50 

ANIHAL S NECROPS1ED 20 50 50 

ANIMALS EXAMINE D HIS1 COPATHOLOGICALLY 20 50 50 

INTEGUMENTAR Y SYSTEM 

*SKIN (20) (50) (50) 

PAPILLOMA , NOS 2 (4X) 2 (4X) 

SUUAMOUS CcLL CARCINOMA 1 (2X) 

KEHATOACANTHOM A 1 (2X) 

*SUBCUT TISSUE (20) (50) (50) 

ADENOCARCINOMA, NOS 1 (2X) 

FIBROMA 1 (5X) 1 (2X) 2 (H%) 

F1BEO SARCOMA 1 (2X) 1 (28) 

LIPOSARCOMA 1 (2») 

KtSPlRATORY SYS1EM 

fLUNG (20) (50) (50) 

ALVEOLAR/BRONCHIOLAR ADENOMA 2 (10X) 3 (6X) 3 (6X) 

ALVEOLAR/BHONCH10LAR CARCINOM A 1 (5%) 

FOLL1CULAR-CELL CARCINOMA , METAS 1 (2X) 

HBMATOPOIETIC SYSTEM 

"•MULTIPLE ORGANS (20) (50) (50) 

MALIGHAN T LYKPHOMA , NOS 2 (103S) 5 (10X) 3 (6X) 

MYELOMONOCYT1C LEUKEMIA 1 (5%) 

M3NOCYTIC LEUKEMI A 2 (4S) 1 (2X) 

*SPLEEN (20) (50) (49) 

MALIGNANT LYMPH OMA, NOS 1 

tTHYMU S (13) (37) (34) 

THYMOMA 1 

hEMANGIOB A 1 (3X) 

CIRCULATOR i SYSTtM 

» NUMBE R OF ANIMAL S KITH TISSUE .EXAMINED BIC80SCOPICALLY 

* NUMBE R OF ANIMAL S NECROPSIED 

41 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

i>I 6l.SU VE SYSTEM 

•SALIVARY GLAND 

FIBROMA 

MIXE D TUMOii, MALIGNAN T 

*LIVEfi 

HEPATOCELLULAR ADENOM A 

HtPATOCEILULAR CARCINOM A 

ISKALL INTESTIN E 

ADENOCARCINOMA, NOS 

tCOLON 

ADENOCARCINOKA , NOS 

U8INAH Y SYSTE M 

tKIDNE Y 

ADiNOCARClNOMA , NOS 

LIPOSABCOKA 

iiNDUCRINt SYSTEM 

•PITUITARY 

ADiNOMA , NOS 

ADENOCARCINOMA , NOS 

CHfiOMOPHObi ADENOM A 

ACIDOPHIL ADiNOM A 

«FAii£ENAL 

COBTICAI ADiNOM A 

PHEOCHROMOLYTOM A 

*THYfiOID 

OXYPHIL ADtNOMA 

FOLLICULAE-ChLL CARCINOMA 

C-CELL ADiNOM A 

C-CLLL CARCINOM A 

CYSTADENOMA, NOS 

PAPILLAR Y CYSTADENOBA , NOS 

tPANCREATIC ISLETS 

ISL£T-CiLL ADiNOBA 

* NUBBEfi OF ANIMAL S WITH TISSUE

* KUMBEfi OF ANIMALS NECEOPSIED 

MATCHED 

CONTROL LOW DOSE 

(20) (50) 

1 <5X) 1 (2*) 

(20) (U9) 

1 (5%) 

1 (5*) 

(20) (48) 

(19) (47) 

(20) (50) 

1 (5%) 

(20) (48) 

1 (5») 3 (6X) 

8 (40%) 8 (17*) 

(20) (50) 

3 (15%) 6 (12X) 

(20) (48) 

2 (4») 

1 (2X) 

1 (2*) 

(19) (45) 

_£_JJJS1_ .. __ « J[9ii

 EXAMINE D MICROSCOPICALLY 

HIGH DOSE 

(50) 

1

(50) 

(50) 

1

(45| 

1

(50) 

1

(50) 

5

1

8

1

(50) 

2

5

(49) 

1

1

2

1

1

(47) 

 (24) 

 (2X) 

 (2X) 

 (2)5) 

 (10X) 

 (2«) 

 (16S) 

(2%) 

 (4») 

 (10*) 

 (2X) 

 (2X) 

 (4X) 

 (2X) 

(2%) 

_. 2_J4J1_ 

42 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

KSPRODUCTIVk, SYSTEM 

*flAMMABY GLAND (20) (50) (50) 

PAPILLAR Y CYSTADENOCARCINOBA,NOS 1 (5«) 

FIBROADENOB A 

iPfiOSTAIE (20) (44)

 

PAPILLARY ADiNOBA 1 (554) 

ACINAB-C£LL ADtNOK A 2 (10*) 

JILSIIS (20) (50) (50) 

INTifiSTITIAL-CELL TUMOR 1 (5S) 8 (16i) 18 (36%) 

INT£RST11IAL-CELL TUMOR, BALIGNA 16 (80S) 32 (64*) 23 (46*) 

*SCHOTUfl (20) (50) (50) 

LIPOMA 1 (2*) 

NEfiVOU S SYSTfiB 

NON E 

SPECIAL Si,NSE ORGAN b 

*iiXTEENAL EAB (20) (50) (50) 

F1BROSARCOBA 1 (2«) 

aUSCULOSKELETA L SYSTEB 

NON E 

BOKI CAVITIES 

*Pi,RITONEUM (20) (50) (50| 

MiSOTHELIOBA, NOS 1 (2*) 

A LL OTHER SYSTEMS 

NONE 

> NUMBE R OF ANIMAL S WITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUfibER OF ANIMALS NECROPSIED 

43 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

ANIMA L DISPOSITION SUMMAR Y 

ANIMALS INITIALLY IN STUDY 20 50

 

NATURA L DiAIHo) 

MORIBUN D SACRIFICE 

SCHEDULE S SACRIFICE 

ACCIDENTALLY KILLED 

liRMINAL SAC&IFICE 1 7 37 39 

ANIMA L HISSING 

INCLUDtS AUTOLlZtL ANIMAL S 

IUMO B SUMMAR Y 

IOTAL ANIMALS hITH PKIMABY TUMORS * 20 48 48 

10TAL PRIMAk Y TUMORS 46 86 92 

TOTAL ANIMALS hITH BtNIGN TUMOBS 14 30 34 

TOTAL BEMG N TU MO-RS 23 41 54 

TOTAL ANIMAL S WIT H MALIGNAN T TUMORS 38 31 

TOTAL MALIGNAN T TUMOKS 23 44 38 

T01AL ANIMALS hITH SECONDARY TDHOES* 

IOTAL SiCONDAfiY TUMOfiS 

TOTAL ANIMAL S KIT H TUMOBS UNCiHTAIN-

BENIG N CR MALIGNAN T 

TOTAL UNCERTAI N TUMOBS 

TOTAL ANIMALS HUH TUMOfiS UNCifiTAIN-

PEIMABY OR ME1ASTATIC 

TOTAL UNCjiKIAIN TUMOHS 

* PklMAB Y TUMOfiS,: ALL TUM08S EXCEPT StCONDAflY TUMOfiS 

* SECONEABY TUMORS: METASTATIC TUMORS OB TUMORS INVASIVE INTO AN ADJACENT OfiGAH 
TABLE A2.

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS 

ADMINISTERED METHYL PARATHION IN THE DIET 

" MATCHED 

CONTROL LOW DOSE HIGH DOSE 

ANIMALS INITIALLY IN STUDY 20 50 50 

ANIMALS NSCROfSIED 20 50 47 

ANIMALS EXAMINED HI STOP ATHOLOGI CALL Y 20 |50 47 

INTEGUMENTAR Y SYSIiM 

*SUBCUT TISSUE (20) (50) (47) 

FIbEOBA 1 (5%) 

FIBBOSABCOMA 1 (2X) 

LIPOBA 1 (5X) 

FIBROADilUOMA 1 (5%) 

RESPIRATORY SYSTEM 

*LUNG (20) (50) (47) 

SQUABOUS CEIL CARCINOMA, HEIASTA 1 (2*) 

ALVhOLAB/BttONCHIOLAR ADENOMA 5 (10*) 1 (2%) 

HtHAN«IOSARCOMA, HETASTATIC 1 (5X) 

UiMATOPOIETIC SYSTi-B 

*HULTIPLE OBGANS (20) (50) (47) 

HALIGNAN1 LYBPHOHA, NOS 1 (5%) 2 (4X) 

BYJiLOMONOCYTIC LEUKEBIA 1 (2%) 

HONOCYTIC LEUKEHIA 1 (2%) 3 (635) 

*SPLi£N (20) (50) (47) 

HEMANGIOSARCOHA, BE1ASTATIC 1 ( 5 % ) 

tBANDIBULA E L. MODE (20) (49) (47) 

h£HANGIC3ABCOBAi Mi.!A STATIC 1 (5%) 

CIBCULATOBY SYSILB 

* NUMBER OF ANIMALS HITH TISSDE EXAMINED MICROSCOPICALLY 

* NUMBER CF ANIMALS NECEOPSIED 

45 
1

TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED) __,_.__, _„_. _— __ ,— 

LUGESTIV.E SYSTEM 

tLIVEfi 

HEPATOCE1LULAR ADENOM A 

HEPATOCtlLULAK CARCINOM A 

UHINAB Y SYSTEM 

*KIi)N±. Y 

HEMANGIOSAHCCMA , ME1ASTATIC 

ENDOCRINE SYSTEM 

frPITUITARY 

CABCINOMA.NCS 

ADENOMA , NOS 

CHHOMOPHOEfl ADENOM A 

CHEOMOPHOBE CASCIHOMA 

JfADEENA L 

CORTICAL AD£t,OMA 

PHEOCHROMOCY10MA 

tlHYBOJE 

PAPILLARY CARCINOM A 

PAPILLAR Y ADiNOCARCINOM A 

C-CtLL ADENOMA 

C-CiLL CARCINOM A 

PAPILLAR Y CYSTADiiNOMA , NOS 

REPRODUCTIV E SYSTEM 

*MAHMAR Y GLAND 

FISBCADJiNOM A 

"VAGIN A 

SiiUAMOUS CELL CARCINOMA 

*U1ERUS 

ENDOMETEIA L SliOMAL POLYP 

i NUMB£ R OF AillMALS WITH TISSUE

* NUMBE R CF ANIMAL S NECEOPSIED 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

(20) 

2 (W%) 

(50) 

4 (8X) 

1 (2») 

(47) 

(20) 

1 (5») 

(50) (47) 

{20} 

10 (50%) 

2 (10S) 

(20) 

1 (5«) 

(20) 

1 (5%) 

1 (5*) 

(50) 

1 (i») 5 (10*) 

13 (26%) 

3 (6X) 

(50) 

2 (4») 

1 (2X) 

(49) 

1 (2%) 

1 (2X) 

.(47) 

15 

(47) 

(47) 

1 

(32 X) 

(2%) 

(20) 

5 (25%) 

(20) 

(20) 

4 J20»]_ 

(50) 

2 (4«) 

(50) 

(50) 

6_J12X1 

 EXAMINE D MICROSCOPICALLY 

(47) 

(47) 

1 

(46) 

4 

(2*) 

jm 

46 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

NihVQU S SYS1EM 

*bRAIN

CARCINOMA, NOS, METASXATIC

 (20) (50)

 1 (2*) 

 (47) 

SPECIAL SENSfi ORGAN S 

*i.YE

SiiUAMOUS CELL CARCINOM A

 (20) (50)

 1 (2%) 

 (47) 

BUSCULOSKELETAL SYSTEM 

*MANDIBLE

AMELOELAS10MA

*COSrOCHONDRAL SYNCH O

OSTEOSAiCOMA

 (20)

 (20)

 (50)

 (50)

 1 (2») 

 (47) 

1

 (47) 

(2%) 

bOU Y CAVITIES 

NON E 

ALL OTHEB SYSTEMS 

ThORA X 

HiMANGIOSAttCOMA 1 

ANIMAL LTSFCSITIGN SUMHAftY 

ANIMALS INITIALLY IN STUDY

NATURA L DEATHdl

MOBIBUN C SACRIFICE

SCHEDULED SACRIFICE 

ACCIDENTALL Y KILLED 

1EEMINAL SACRIFICE

ANIMA L MISSING 

 20

 1

 19

 50

 6

 3'

 41

 50 

 24 

3 

 23 

* NOMbi.8

* NUMBER

 OF ANIMALS

 OF ANIMALS

 WITH TISSUE

 NECEOPSIED 

 EXAMINE D MICROSCOPICALLY 

47 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

TUMO R SUMMAR Y 

X01AL ANIMALS KITH PRIMARY TUMORS* 18 33 20 

TOTAL PRIMARY TUMOES 31 51 27 

TOTAL ANIMALS WIT H BENIGN TUMOES 17 26 13 

TOTAL BENIG N TUHORS 26 39 21 

TOTAL ANIMALS Wllf a MALIGNANT TOHOES 4 10 5 

TOTAL MALIGNAN T TUMOKS 5 12 6 

TOTAL ANIMAL S hlTH SECONDARY TUMORS* 1 2 

TOTAL SECONDARY TUMOK S 4 2 

TOTAL ANIMALS HITH TUMORS UNCERTAINbENIG N CR MALIGNANT

 

TOTA L UNCERTAI N TUMORS

 

TOTAL ANIMAL S KITH TUMORS ONCERTAINPRIMAHY OR MEIASTAIIC

 

IOTAL UNCERTAIN TUMORS 

* £fi!MABY TUMORS: ALL TUflORS EXCEPT SECONDARY TUMORS 

* SECONEA8Y TUMORS : MilASTATIC TUMORS OR TUMOES INVASIVE INTO AN ADJACENT OBGAN 

48 
APPENDIX B
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

MICE ADMINISTERED METHYL PARATHION IN THE DIET
 

49
 
50

 
TABLE B1.

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE MICE 

ADMINISTERED METHYL PARATHION IN THE DIET 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

ANIMALS INITIALLY IN STUDY 20 50 50 

ANIMALS HISSING 1 

&&IMALS NECECfSIED 19 50 49 

ANIMALS EXAMINE D HISTOPATHOLOGICALLY 19 50 49 

INTEGUMENTAR Y SYSTEM 

*SKIN (19) (50) (49) 

KERATOACANTHOM A 1 (2%) 

FIBROSARCOMA, MET ASTATIC 1 (28) 

LIPOSARCOMA, METASTATIC 1 (28) 

*SUBCUT TISSUE (19) (50) (49) 

FIBHOSARCOMA 1 (28) 

LIPOSAECOMA 1 (2%) 

fiESPIfiATO£Y SYSTEM 

*LUN G (19) (50) (49) 

HEPATOCEILULAB CARCINOMA, METAST 1 (2*) 

ALVEOLAB/bRONCHIOLAB ADENOM A 1 (5X) 5 (10*) 5 (10%) 

ALVEOLAB/BfiONCHIOLAR CABCINOMA 5 (108) 3 (68) 

FIBfiOSARCOMA, MiTASTATIC 1 (2») 

ilPOSARCOMA, METASTATIC 1 (2%) 

HEMSNGICM A 1 (2%) 

hEMAIOPOIETIC SYSTiM 

*MULTIPiE OIGANS (19) (50) (49) 

MALIGNAN T LYMPKOHA, NOS 1 (58) 4 (8*) 2 (4%) 

MALIG.LYMPHOMA , HISTIOCYTIC TYPE 2 (4X) 

*HEMATCPOIETIC SYSTEM (19) (50) (49) 

MALIGNAN T LYHPHOMA , NOS 1 (555) 1 (28) 

tBONE MARHO W (19) (48) (48) 

SARCOMA, NOS, METAS1ATIC 1 (2%) 

(18) (48) (49) 

SAfiCOHA, NOS. MET ASIATIC ___________________________ 

* NU.MBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBE E CF ANIMAL S NJICEOPSIED 

51 
TABLE B1. MALE MICE: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

HEMANGICM A 1 (6%) 1 (2%) 1 (2«) 

Hi M AN GIO SARCOMA 1 (6%) 1 (2«) 

*LYHPH NOBE (17) (47) (48)

 

SARCOMA , NOS 1 (2%) 

MALlG.LYMPHOhA, HIST1OCYTIC TYPE 1 (2X)

 

» LIVES (19) (49) (49)

 

MALIG.LYMPHOMA , HISTIOCYTIC TYPE 1 (2XJ

 

CIRCULATOBY SYSTEM 

* HEART (19) (50) (49)

 

FIBBOSARCCMA, METASTATIC 1 (2*)

 

DIGESTIVE SYSTEM 

*LIVER (19) (49) (19) 

HEPATOCEILULAB ADENCM A 8 (42%) 12 (24S) 7 (14S) 

HEPATOCEILULAR CARCINOMA 2 <1«) 3 (6*) 6 (12%) 

SARCOMA, NOS, METASTATIC 1 Ctt) 

FIBBOSAKCOHA, MiiTASXATIC 1 (2X) 

LIPOSASCOMA, HETASTATJC 1 (2%) 

HEMANGIOM A 1 (2») 

Ht.H ANGICSAiCOMA 1 (5%) 

HtBANGIOSASCOMA, MtTASTATIC 1 (2X) 

AN G10 SARCOMA 1 (2X) 

*S10MACH (19) (»8) (49)

ADENOC A IN ADfcNOMATO U S POLYP 1 (2*) 

*ILtUM (19) (48) (47)

 

FIBBOSARCOMA, HETASIATIC ] (2%) 

URINARY SYSTEM 

#KIDNEY (19) (48) (49) 

LIPOSARCCM, METASTATIC 1 (2*) 

iNDOCEINE SYSTEM 

f AuHENA L (19) (43) (47) 

CORTICAL ADENOMA _ _ . _3_i16Xl 4 J9S1 _ 5 J11X1 

» NUMBE R OF AiilMALii WITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUHBEE CF ANIMALS NECflOPSIED 

52 
TABLE B1. MALE MICE: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

* THYROID (18) C*6) (48) 

FOIIICUIAR-CiLL CAJSCINOMA 1 (6S) 1 (2%) 

PAPILLARY CYSTADENOCAECINOMA.NOS 1 (2XJ 

*PANC£EATIC ISLETS (17) (45) (49) 

ISLET-CELL AD£NOMA 1 (6S) 3 (7S) 

kEPfiODUCTIVE SYSTEM 

*SEMINA1 VESICLE (19) (50) (49) 

PAPJLLABX CYSTADENOHA, NOS 1 (2X) 

*EPIDIEYHIS (19) (50) (49) 

LIPOSAECOHA, H£TASTATIC 1 (2%) 

N£fiVOUS SYST£B 

NONE 

SPECIAL SENSE ORGAN S 

*£Yi./LACRIMAL GLAN D (19) (50) (49) 

PAPILLAE i ADtNOH A 1 (535) 1 (2X) 3 (6X) 

aUSCULOSKELETAL SYSTEM 

*KIB (19) (50) (49) 

FIBBOSABC03A 1 (28) 

BOi)Y CAVITIES 

*MtSENTERY (19) (50) (49) 

FIEBOSAECOMA, HE1AS1ATIC 1 (2X) 

ALL OTHER SYSTEMS 

HON E 

t NUMBER CF ANIMAL S hlTH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBE B CF ANIMALS NECfiOPSIED 

53 
TABLE B1. MALE MICE: NEOPLASMS (CONTINUED) 

— -. —— ——— — — 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

ANIMAL DISPOSITION SUMMAR Y 

ANIMALS INITIALLY IN SIUD Y 20 50 50 

NATURA L DbAThal 3 7 7

 

BOBIBUNL SACRIFICE 

SCHtEULiC SACRIFICE 

ACCIDENTALLY KILLED 

IERMINA L SACRIFICE 16 43 43 

AN1HAL MISSING 1 

at INCLUDES AU10LY2tD ANIMALS 

IUMCR SUMMAR Y 

TOTAL ANIMALS HUH PEIMARY TUMORS* 13 31 28

 

IOTAL PRIMAR Y TUMOK S 22 1*9 39 

TOTAL ANIMALS fclTH BENIG N TUHORS 8 21 18 

TOTAL BEKIGN TUMORS 15 29 22

 

TOTAL ANIHALS WITH MAI1GNANT TUMORS 6 18 16 

TOTAL MALIGNAN T TUMORS 7 20 17 

TOTAL ANIMAL S ilTH SECONDARY TUMORS* 3 3 

10TAL SECONDARY TUMCRS 9 7 

10IAL ANIMALS HITh TUMORS UNCERTAIN ­

££NICN OR MALIGNANT 

1'OTAI UNCERTAIN TUMCfcS 

IOIAL ANIMAL S hITH TUHOKS UNCERTAIN -

PfilMARY Ofi MEIASTATIC 

TOTAL UNCERTAI N TUMCfiS 

* PRIMAR Y TUMORS: ALL TUMORS EXCEPT SiCOHDABY TUMOES 

* SECONDARY TUMORS: MEIASTAIIC TUMORS OR TUMORS INVASIVE INTO AN ADJACENT ORGA N 
TABLE B2.

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE MICE 

ADMINISTERED METHYL PARATHION IN THE DIET

 

-~' 

MATCHED 

CONTROL LOW OOSE HIGH DOSE 

AN IM AL S INITIALLY IN STUD Y 20 50 50 

ANIMALS MISSING 1 

A NX HALS NICBCfSlED 20 49 U8 

ANIMALS EXAMINE D HIS: COPATHOLOGICALLY 20 49 48 

INTi-GUHENlA B J SYSTi-M 

*SUBCU1 IISSUu (20) (49) (48) 

FIEBCSAECOH A 1 (2%} 1 (2») 

Hi U ANGIOSASCGMA 1 (2%) 

NEUBOFIEBGSABCOMA 1 (2X) 

KtSPlBAlGBY SYSTEM 

*LUN G (20) (49) (48) 

ALVECLAB/SBONCHIOLA B ADiNOMA 1 (2%) 1 (i.%)

ALVEOLAR/BBCNCH10LAE CABC1NOBA 2 (4X) 1 (2%) 

FIBEOSARCOHA, METASTATIC 1 (2X) 

LEIOHYOSABCOMA, flETASTATIC 1 (2%) 

HtSATOPOIETIC SYSTiM 

*BULTIPLE OBGAN S (20) (49) (43) 

MALIGNAN T LYMPHOMA, NOS 3 (15%) 10 (20X) 2 (4*) 

HALIG.LYMi'HOMA, HISTJ.OCYTIC TYPE 1 12%) 3 (6X) 

GEANULOC11IC LEUKEMI A 1 (5%) 

*iONE MAEEO H (20) (49) (48)

 

HEflANGIOH A 1 (5%) 

tSPLEEN (20) (49) (47)

 

HEHANGICSAECOMA 1 (2%)

 

MALIGNAN T LXMPHCHA , NOS 2 (10%) 

tfiESENTZEIC L. NOD E (19) (49) (47)

 

AD£MOCABCINGtU, NOS, METASTATIC 1 (2%)

 

*S1'CMACH (2U) (48) (48)

 

JjA_ljG_.L_YBP.HptlA. HISIIOCYl'IC TY PE l_J2jil_ 

t NUMBE R CF ANIMAL S WIT H TISSUE EXAMINE D HICBOSCOPICALLY 

* NUMBE E CF ANIMALS NiCBCPSIED 

55 
TABLE B2. FEMALE MICE: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

tlHYHU S (14) (30) (34)

 

THYBOM A 1 (3»)

 

MALIGNAN T LYMPHOMA , NO S 2 (14%)

 

CihCULAlOR Y SYSTEM 

NON E 

UllSiSTIVE SYSI£fi 

*L1VER (20) (48) 

HEtATOCEllULA R ADiNCM A 1 (5*) 3 (6«) 2 (4S) 

HiPATOCElLULAR CAECINOMA 1 (2%) 

HivM ANGIOSARCOJJ A 

•SIOBACH (20) (48) (48) 

S^UAMOUS CuLI CARCINOMA 1 (2%) 

Ai-iiNOCAcClNOMA, NOS 1 (2%) 

*DUODtM « (20) (49) (46)

 

aDiNCCABCINCKA, NOS 1 (2») 

URiNAh Y SYSTE M 

*Kli(NEY (20) (49) (<*8)

 

HEHANGIOMA 1 (2*) 

tNtjOCEINE SYSIbM 

•PITUITARY (17) (45) (44) 

ADiNCflA, NOS 1 (2%) 1 (2%) 

CHaOMOI>HOB£ AD£NOM A 4 (245S) 4 (9X) 

• ADRENA L (20) (49) (48) 

CORTICAL ADENOMA 2 (10%) 1 (2X) 1 (2S) 

•IHYfiOIE (20) (47) (46)

 

fOLUCULAR-CELL ADhKOM A 1 ( 5S)

 

PAPILLARY CYSTADENOflA, NOS 1 (2*)

 

*PANCR£AIIC ISLETS (18) (46) ("2)

 

ISLiT-CELL ADiNOMA 1 .(6X1.

 

* NUMBE E OF ANIMALS WITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBEB OF ANIMALS NECEOPSIED 

56 
TABLE B2. FEMALE MICE: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

ajSPBODUCIIVi. SYS1EH 

*MAMBAE Y GLAND (20) (49) (48) 

ADENOCARCINOMA, NOS 3 (61) 1 (2«) 

«UT£BUS (20) (48) (45) 

JENDOM£TBZAL STfiCMAL POLYP 3 (1%) 

HiMANGIOMA 1 (2%) 

H EM AN GIO SARCOMA 1 (2%) 

tOVAR Y (17) (48) (47) 

PAP11IAEY CYSXADENOBA , NOS 1 (2%) 

lEBATOMA, BENIGN 1 (2*) 

HtMANGIOM A 1 (2%) 

NERVOU S SYSTEM 

NON E 

SPECIAL SENSE ChGANS 

*EYVLACRI8A1 GLAN D (20) (49) (48) 

PAPILLAR Y ADJ.NOMA 1 (2*) 

PAPILLARY CYS'IABENOCAkCINOMA,NO S 1 (2S) 

hUSCULOSKELE'IA L bYSTE M 

NON E 

dOD Y CAVITIES 

*ABEOMINA L CAVIT Y (20) (49) (48) 

LEIOHYOSAhCOKA 1 (2%) 

*P±,EITONEU« (20) (49) (48)
 

MtSQTHELIOMA, NOS 1 (2%)
 

ALL OIH£R SYSIiHS 

NONE 

* NUKBEfi OP ANIMAL S HITH TISSUE EXAMINE D HICBOSCOPICALLY 

* NUMBE R OF ANIMALS NECRCPSIED 

57 
TABLE B2. FEMALE MICE: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

*NIMAL DISPOSITION SUMMAR Y 

ANIMALS INITIALLY IN SIUDY 20 50 50

 

NATDKA L Ui-ATBd) 3 10 7 

MOBJEUN D SACRIFICE 2

 

SCHErULJcL SACRIFICE 

ACCIDENTALLY KILLiD 

TERMINAL SACRIFICE 17 40 4Q 

ANIMA L MISSING 1

 

a) INCLUDES AUIOLYZiD ANIMAL S 

JUKC6 SUflHAE Y 

TOTAL ANIMAL S WIT H PRIMAR Y TUMORS* 14 30 20

 

TOTAL PRIMAR Y TUMOK S 18 42 22

 

TOTAL ANIMAL S WIT H BENIGN TUMORS 7 13 8 

TOTAL BEMGN TUMOES 10 17 9 

TOTAL ANIMALS WIT H MAIIGNAN T TUMORS 8 22 11 

TOTAL MALIGNANT TUMORS 8 25 12 

TOTAL ANItiALS HUH SECONDARY TUMORS* 2 1 

TOTAL SECONDAR Y TUMORS 2 1 

TOTAL ANIMALS WITH TUMOHS UNCERTAINBENIGN CE MALIGNAN T 1

 

TOTAL UNCERTAIN TUMCRS 1 

TOTAL ANIMALS WITH TUMORS UNCERTAINPRIMARY OB M£1ASTATIC

 

IOTAL UNCERTAI N TUMCRS 

* PRIMAR Y TUMOHS: ALL TUMORS EXCEPT SECONDARY TUMORS 

* SECONDARY 1UMOBS: M±.1ASTAIIC TUMORS OR TUMORS INVASIVE INTO AN ADJACENT ORGAN 

58 
APPENDIX C
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS
 

IN RATS ADMINISTERED METHYL PARATHION IN THE DIET
 

59
 
60

 
TABLE C1.

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE RATS 

ADMINISTERED METHYL PARATHION IN THE DIET 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

ANIHALS INITIALLY IN STUD Y 20 50 50 

ANIHALS NECECPSIED 20 50 50 

ANIHALS EXAMINE D HISTOPATHOLOGICALLY 20 50 50 

INTEGUMENTARY SYSTiM 

*SKIN (20) (50) (5i) 

£PID£BMAI INCLUSION CYST 2 (431) 

ULCEH, CHRONIC 1 (2X) 

KKSPIfiATOR Y SYS1EM 

*LUNG (20) (50) (50) 

iMPHYSEHA, NOS 1 (2%) 

HYPEEPLASIA, ADENOMATOU S 1 (2%) 

HYPESPLASIA, ALV20LAH EPITHELIUM 1 (5X) 

»LUNG/ALVEOLI (20) (50) (50) 

EDEMA , NOS 1 (2X) 

hilBAIOPOIETIC SYSTEM 

»BON£ MA SHOW (20) (50) (50) 

HYPJiBPLASIA, HEMATOPOIETIC 2 (10*) 3 (6») 

#SPLEEN (20) (50) (49) 

HEMATOPOIESIS 1 (2X) 6 (12X) 

SWANDIBULA H L. NODn (20) (50) (50) 

LYMPHANGiECTASIS 6 (30%) 6 (12X) 3 (6S) 

CONGESTION. NOS 2 (4%) 3 (6*) 

FIBBOSIS 1 (2«) 

PL ASM ACYlOSiS 1 (2«) 

HYPEBPLAS1A, RETICU1UM CELL 1 (2X) 1 (2») 

HYPJiBPLASIA, LYMPHOIL- 1 (5») 4 (8») 1 (2%) 

#PANCBEATIC L.NODt (20) (50) (50) 

* NUMBE B Cf ANIMAL S HITh TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBER CF ANIMALS NECEOPS1ED 

61 
TABLE C1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE 

*MES£NTERIC L. NOOt, (20) (50) 

LYKPHANGIiCTASI S 1 (5%) 

CONGESTION, NOS 1 (2X) 

i-DiMA, NOS 1 (2«) 

HEMORBHAG E 1 (2%) 

ATROPHY, NOS 1 (5%) 1 (2*) 

HYPEBPLASiA, EETICULU M CELL 3 (6X) 

HYPtKPLASIA, LYMPHOI D 2 (48) 

ITHYMU S (U) (37) 

HEMORRHAG E 

ATROPHY , NOS 13 (100S5) 29 (78X) 

CIRCULATOR Y SISItM 

«HEAB1 (20) (50) 

FIBROSIS, FOCAL 1 (2X) 

FIBROSIS, DIFFUSE 1 (2X) 

*hi,AaT/ATkIUM (20) (50)

 

THROMBOSIS, NOS 

fcMYOCABBIUM (20) (50) 

INFLAMMATION , NCS 

INFLAMMATION , CHBONI c 14 (70X) 35 (70X) 

FIBBOSIS 1 (5%) 

*PANCR£ATIC AitTERY, (20) (50)

 

HYPEBTROPhY , NOS 1 (5%)

 

SYSTtM 

• SALIVAR Y GLAND (20) (50)

 

FIBROSIS, DIFFUSE 

tLIVER (49) 

fIBBOSIS 12 (60X) 17 (35*) 

NECEOSIS, NOS 3 (6») 

NECfiOSIS, COAGULAT1VE 1 (2J) 

LIPOIDOSIS 2 (4X) 

ANGIECTAS1S 

*Li Vi.fi/Cf, NT BXLOBU LA fl (20) (49)

 

HI EC EOS IS^,, NOS_ 

* NUMoE R OF ANIMAL S WIT H TISSUE EXAMINE D MICROS COP 1CALL! 

* NUMBEB OF ANIMAL S NEC60PSIED 

HIGH DOSE 

(50) 

2 (4S) 

5 (10S) 

(34) 

2 <6S) 

21 (62 X) 

(50) 

(50) 

1 (2X) 

(50) 

1 (2X) 

19 (388) 

(50) 

(50) 

1 (2») 

(50) 

6 (12X) 

1 (2%) 

3 (6X) 

2 (4X) 

(50) 

62 
TABLE C1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE 

LIFCIDOSIS 

tLXVEB/EEBIPOBIA L (20) (49)

 

XIPOIDOSIS 1 (5X)

 

JLIVEB/HEPAIOCYIES (20) (49) 

CYTCPLASMIC V ACUOIIZAIIGN 12 (60%) 25 (51%)

 

HYPiBPLASIA, NOS 15 (75X) 16 (33J)

 

IBXLE EUCT (20) (49)

HYPZHPLASIA, NOS 17 (85X) 38 (78S)

 

# PANCREA S (19) (45)

 

INFLAMMATION, CHBONIC 1 (5«) 1 (2%)

 

PflBIABTEBITIS 2 (118) 7 (16X)

 

*PANCBIATIC ACINU S (19) (45)

 

AIBOPHY , FOCAL 1 (2*)

 

tSICMACH (20) (48)

 

UYPEBPLAS1A, EPITHELIAL 1 (2X)

 

*SJiALL INTiSIINE (20) (48)

 

HYPEBPLASIA, LYBPHOID 

*DUGDtNUM (20) (48)

 

ULCIB, NOS 1 (2*)

 

ifUUGDi^A L MUCOSA (20) (48)

 

NECROSIS, NOS 1 (2X)

 

#ILEU M (20) (48)

 

ULCER, CHEONIC 1 (5*)

 

UtflNAB Y SYSTEM 

*KIUNEY (20) (50)

1NFLABHATION, CHSONIC 16 (30%) 34 (68/4)

 

INFLAMMATION , CHBONIC FOCAL 

NEPHBOPAIH Y 3 (6S)

 

*KItNEY/COEIiX (20) (50) 

CYST, NOS 

yiBBOSIS, DIFFUSE , , __ ^ . _ 1 J2X1_ _. 

* NUHBfiB OF ANIHALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* iiUMBEB OF ANIKALS NECEOPSIED 

HIGH DOSE 

1 (2%) 

(50) 

(50) 

11 (22X) 

3 (6X) 

(50) 

35 (70X) 

(47) 

2 (4») 

3 (6X) 

(47) 

1 (2X) 

(50) 

(50) 

1 (2X) 

(50) 

(50) 

(50) 

(50)

22 (44%) 

1 (2%) 

12 (24S) 

(50) 

1 (2%) 

63 
TABLE C1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) _ __________ ——_«_ __ 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

* KI L> Ni V GL 0 Hi, KU LU S 

NEPHROPATH Y 

(20) (50) 

3 (6*) 

(50) 

1 (2*) 

tUilNABY BLABDhR (20) (46) (50) 

EtOSION 1 (2») 

*U. BLABCEB/MULOSA (20) (46) (50) 

NECBOSIS, NOS 1 (2X) 

hMuOOiINE SYSTEM 

#PITUITAB Y (20) (48) (50) 

CYST, NOS 

HEMORRHAGIC CYST 

hYPBBPLASiA, NOS 

2

2

 (1035) 

 (10%) 2

1

 (4») 

 (2*) 

2 (4X) 

1 (255) 

HYPERPLASIA, FOCAL 2 (4*) 

iAUEENA L (20) (50) (50) 

ANGIECIASIS 5 (10X) 3 (6K) 

tAUBENAL COB1EX 

LJPCIDOSIS 

HYPERPLASIA, NOS 

(20) 

2 (10X) 

(50) 

4 (8X) 

2 (4X) 

(50) 

1 (2*) 

*ADB£NA1 MEEULLA (20} (50) (50) 

HYPEHPLASIA, NOS 1 (5X) 

#THY20IE 

FOLLICULAK CYST, NOS 

HYPERPLASIA, C-CELL 

(20) 

2 (10*) 

2 (10%) 

(48) 

2 (4S) 

C*9) 

2 (4*) 

1PABATHYROXE 

HYPJcRPLASIA, NOS 

(2) (8)

1 (13*) 

(14) 

fiiPBODUCTIVE SYSTEH 

*«AH«ARY GLAN D 

GAL AGIO CfiLE 

(20) 

2 (10*) 

(50) 

2 (4«) 

(50) 

5 (12S) 

HYP£fiPLASIA,

LACTATION 

 NOS 

1 (5*) 

1 (2X) 

1 (2X) 

*PfiOSTATE (20) (44) (48) 

INFLAMHATIOM, SOPPUBATIVE . _ _1 J2I1 _ J-J231 

# NUMBE E OP ANIMALS WITH TISSUE EXAHINE D MICBOSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

64 
TABLE C1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE 

INFLAMMATION,

INFLAMMATION,

ATROPHY , NOS 

 ACUTE 

 ChBONIC 

1 (5*) 

1 (5%) 

11 (55%) 

3

1

25

 (7*) 

(2%) 

 (57*) 

HYPERPLASIA, NOS 1 (5*) 

HYPERPLASIA, EPITHELIAL 1 (2*) 

HYPERPLASIA, FOCAL 

tIESTIS 

ATROPHY , NOS 

(20) 

1 (5%) 

(50) 

2 (4*) 

HYPEBPLASIA, INTERSTITIAL CELL 

•TESTIS/TUBULE (20) (50) 

DEGiNEBATION, NOS 1 (2X) 

*iPIDICYMIS (20) (50) 

LIPOGBANULOMA 

NERVOU S SYSTEM 

NONE 

SPECIAL SENSE ORGANS 

*EYE (20) (50) 

CATARACT 14 (70%) 16 (32H) 

*EYE ANTEEIO K CHAMBER (20) (50) 

HEMORRHAGE 1 (5%) 

*£Yt/CCENEA (20) (50) 

CALCIFICATION, FOCA1 1 (5%) 

*EY£BALL TUNICA VASCU (20) (50) 

INFLAMMATION , NOS 6 (30%) 

INFLAMMATION , ACUTi 1 (2*) 

INFLAMMATION , ACUTE/CHRONIC 

INFLAMMATION, CHHONIC 

*EYiyfiETINA (20) (50) 

ATROPHY , NOS 13 (65%) 16 (32*) 

flUSCULOSKELETAL SYSTEM 

*BONE (20) (50) 

FIBROUS PSTj,Oi)ISIHQ£HY_ 

# NUMBE R OF ANIMALS WITH TISSUE EXAMINED MICfiOSCOPICALLY 

* NUMBE R OF ANIMALS NECEOPSIED 

,—_—_..— __—__ 

HIGH DOSE 

6 (13*) 

11 (23*) 

2 (4*) 

2 C*«) 

(50) 

2 (tX) 

1 <2X) 

(50) 

(50) 

1 (2*) 

(50)

7 (14*) 

(50) 

(50) 

(50) 

1 (2*) 

1 (2X) 

1 (2X) 

(50) 

6 (12*) 

(50) 

65 
TABLE C1.MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

bOi)¥ CAVITIES 

NON E 

ALL CIHEE SYSIEKS 

NONE 

SPECIAL MORPHOLOG Y SUMMAR Y 

NONE 

« NUHB£B OF ANIMAL S KITH TISSUE EXAMINED MICROSCOPICALLY 

* NUHBEB CF ANIMALS NECEOPSIED 

66 
TABLE C2.

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE RATS 

ADMINISTERED METHYL PARATHION IN THE DIET

 

ANIHAL S INITIALLY IN STUDY 

ANIMALS NtCEOESILU 

ANIMALS EXAMINE D HISTOPATHOLOGICALLY 

INTEGUMENTAR Y SYSTEM 

NONE 

KESPIRATOBY SYSiEM 

#LUNG/BBCNCHU S 

GRANULOMA , FOBEIGN BODY 

*LUNG /BRONCHIOLE 

HYPEBPLASIA, ADENOMATOUS 

*LUNG 

HYPER EMI A 

£i)£MA, NOS 

HEMORRHAGE 

BHONCHOPNEUMONIA, NOS 

PNEUMONIA , ASPIflATION 

HYPERPLASIA, ADENOMATOUS 

HYPEBPLASIA, ALVEOLAR iPITHELIUM 

HfcMAlOPOIETIC SYSTEM 

*BONE MABRO M 

HYPCPLASIA, NOS 

HYPEBPLASIA, HE OATOPOIETIC 

•SPLEEN 

FIB RO SIS, MULTI FOCAL 

SIDEROSJS 

HEM ATOPOIESIS 

*MANDIBULAfi L. NOD£ 

LYMPHANGIECTASIS 

» NUMBE B OF ANIMALS HITH 1ISSUE

* NUMBEB CF ANIMALS NECfiOPSIED 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

20 50 50 

20 50 47 

20 50 47 

(20) (50) (47) 

1 (2%) 

(20) (50) (47) 

1 (2%) 

(20) (50) (47) 

4 (9%) 

3 ((>%)

4 (9%) 

1 (2%) 

1 (2%) 

3 (6%) 

1 (2*) 

(20) (50) (47) 

1 (2%) 

1 (5*) 

(20) (50) (47) 

1 (2%) 

1 (5%) 

1 (2*) 

(20) (49) (47) 

1 (2%\ 

 EXAMINED MICROSCOPICALLY 

67 
TABLE C2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

INFLAMMATION, ACUTE 

HYPKRPLASJ.A, LYMPHOID 

IHESENTEBIC L. NODE 

H£BOBBHAGE 

PIGHENTA1ION, NOS 

HYPE1PLASIA, NOS 

HYPEBPLASIA, LYMPHOIJD 

*THYMUS 

HYPBBEMIA 

HEMORRHAGE 

ATROPHY , NOS 

HYPEHPLAS1A, LYHPHOID 

#THYHIC MEEULLA 

HEMORRHAG E 

CIRCULATOfiY SYSTEM 

tHEABT 

FIBBOSIS, FOCAL 

•HEABT/ATRIUM 

THROMBOSIS, NOS 

tflYOCAEDIUM 

INFLAMMATION, CHRONIC 

F1BEOSIS 

OEGENEBAli-ON, NOS 

NECROSIS, NOS 

*AOBTA 

INFLAMMATION , FOCAL 

iHEPATIC SINUSOID 

HYPERPLASIA, NOS 

DIGESTIVE SYSTEM 

»SALIVARY GIAN D 

FIBBOSIS, DIFFUSE 

ATROPHY, NOS 

* NUHBi,fi OF ANIMALS WITH TISSUE

* NUMBER OF ANIMALS NECROPSIED 

— — i— — — — — 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

1 (5*) 1 (2«) 

1 <5X) 1 (2X) 

(20) (49) (47) 

1 (2*) 

1 (2») 

1 (255) 

1 (5%) 1 (2*) 

(20) (1*6) (39) 

1 (3*) 

1 (2%) 4 (10X) 

19 (95XJ 24 (52*) 

1 (2*) 

(20J (46) (39) 

1 (3*) 

(20) (50) (47) 

1 12%) 

(20) (50) (47) 

1 (2%) 

(20) (50) (47) 

11 (5555) 15 (30*) 

2 (4X) 

1 (255) 

1 (2%) 

(20) (50) (47) 

1 (2%) 

(20) (50) (47) 

1 (2*) 

(20) t<*9)

 (46) 

1 (5%) 

2 («!_ 

 iiXAMINfiD MICROSCOPICALLY 

68 
TABLE C2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

HIGH DOSE 

(47) 

1 (2%) 

1 (2X) 2 (4%) 

12 (26X) 

1 (2X) 

1 (2*) 

(47) 

(47) 

(47) 

(44) 

(44) 

(47) 

(47) 

1 (2%) 

(47) 

(47) 

3 (6S) 

(47) 

_ _ 1_J2*1_ 

f LIVES 

INFLAHBATION, G RANULOMASOUS 

1NFLABBA1ION, NECEO GRA N 

FIBBOSIS 

NtCROSIS, NOS 

LIPOJCDOSJS 

BASOPHILIC CYTO CHANGE 

FOCAL CELLULAR CHANGE 

HYPERPLASIA, NOS 

tLIVER/PERIPORTAL 

LIPOIEOSIS 

*LIV.EB/HEPA10CYIES 

NLCBOSIS, NCS 

CYTOPLASB1C VACUOLIZATIC N 

HYPEBPLAS1A, NOS 

tBILE DUCT 

HYPERPLASIA , NOS 

*PANCfl.EAS 

1NFLAMBA2ICN. CHBONIC 

* PANCREATIC ACINU S 

ATROPHY , FOCAL 

*S1'CKACH 

INFLABBAT10N, CHRONIC 

KGASTRIC BUCOSA 

ULCER, NCS 

*COLON 

NiBATODIASIS 

URINAR Y SYSTEM 

*KJ.CNEY 

HYDRONEPHiiOSIS 

INFLABMA1ION, CHBONIC 

NEPHROPAIH Y 

#KICNiY/CCBIEX 

CYSI ^ NOS 

* NUMBES OF ANIMALS WIT H TISSUE

» NUMBEB OF ANIBALS NECBOPSIED 

MATCHED 

CONTROL 

(20) 

1 (5») 

1 (5X) 

1 (5S) 

(20) 

(20) 

2 (10») 

18 (90S) 

(20) 

9 (45%) 

(20) 

1 (5%) 

(20) 

(20) 

1 (5%) 

UO) 

(^0) 

(20) 

1 (5») 

4 (20S) 

(20) 

LOW DOSE 

(50) 

1 (2») 

2 (4») 

1 (2X) 

1 (2X) 

6 (12%) 

2 (4S) 

(50) 

1 (2*) 

(50) 

1 (2») 

32 (64X) 

(50) 

12 (24%) 

(50) 

1 (2») 

(50) 

1 (2X) 

(50) 

(50) 

2 (US) 

(48) 

1 (2X) 

(50) 

2 (4S) 

2 (4*) 

(50) 

 EXABINiD MICROSCOPICALLY 

69 
TABLE C2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

DEGiNiRAlICN, NGS 1 (2«) 

#KI£NEY/GLCME#UiUS (20) (50) (47)

 

NtPHKOPATH * 1 (5%) 1 (2%)

 

iNUOCfilNE SYSTEM 

IPITUITABY (20J (50) (47) 

CYST, NOS 1 (5%) 7 (14X) 2 (4X) 

HEHOBBHAGIC CYS1 2 (4X) 

HYPLBPLASIA, CHBOMOPHOBE-CELL 1 (2») 

tADEENA L (20) (50) (47)

 

ANGIECTASI 3 2 («)

 

*Ai,Bi,NAl./CAFSOL£ (20) (50) (47) 

FIBBOSIS 1 (2«) 

#ADBiNA L COBTEX (20) (50) (47)

 

CYST, NOS 1 (5%)

 

LIPOIDOSIS 1 (5%) 2 (4X)

 

hYPtEPLASIA, _NO S 7 (35%) 4 (8X)

 

tttflfiiNAL MEEULLA (20) (50) (47) 

LYMPHCCY1CSIS 1 (28) 

*TnYBOIE (20) (49) (47) 

F01IICUIAE CYST, NCS 1 (2X) 

hYPEBPLASIA, C-CEL1 1 (531) 7 ( 1 4X ) 1 (2K) 

it PRODUCTIVE bYSILH 

*flAMflAH Y GLANi) (20) (50) (47) 

GALACTOCELE 11 (55%) 4 (8X) 3 (6X) 

HYPEEPLASIA, CYSTIC 1 (2%) 

LACTATIO N 1 (2X) 1 (2X) 

•UTEEUS (20) (50) (46)

 

HYDBOMETE A 2 (4X)

 

LlPOGSANUIOflA 1 <5X )

 

*Ul£BUS/ENDCBi,TRIUB (20) (50) (46) 

CYSI,. NOS „ 3 J15S1 . 1 (2X) 1_J2S1_ 

* NUKBE B CF ANIBALS WITH TISSUE EXAMINE D HICBOSCOP1CALLY 

* NUMBE R CF A SI HA IS NECfiCPSIED 

70 
TABLE C2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

IBFLABBA1ION, VESICULAR 1 (2X) 1 (2%) 

HYPERPLASIA, SOS 1 (2%) 

•UXEttUS/BYCMiTRIUB (20) (50) (46) 

HEBGBBHAGE 1 (5%) 

tOVARY (20) (50) (46) 

CORPUS 1UTEUB CYSI 1 (2X) 

NfcfiVOUS SISTEfl 

tCEBEBBAL VENSRICLE (20) (50) (47) 

EILATATIGN, NOS 1 (2*) 1 (2%) 

*BhAIN (20) (50) (47) 

ATBOPHY, PRESSURE 1 (5%) 

iPiiCIAL SENSE 06GANS 

**YE (20) (50) (47) 

CATARACT 3 (6») 2 (4%) 

*iYE/HETINA (20) (50) (47) 

ATROPHY, NOS 4 (8%) 

DYSPLASIA, NOS 1 (2«) 

*iYE/CEYSTAlLINt LENS (20) (50) (47) 

DEGENLHA1ION, NOS 1 (2%) 

KUSCULOSKELE1AL SYS1£M 

iiONE 

BOUY CAVITIES 

NONi, 

ALL 01H£B SYSTEMS 

AuIPOSE TlSSUt 

LI gCGRA SULPHA 1 

* NUM3E K Of ANIMAL S MITH TISSUE EXAMINE D BICEOSCOPICALLY 

* NUBBER CF AKIMALS NECEOPSIED 

71 
TABLE C2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

SPECIAL HCBEHOLOGY SUMMABY 

NO L1SIOS REPORTED

AUf C/NECBGPSY/HISTO PtRF

AUTCLYSIS/NC NECBOPSY

* SUMBEB CF ANIflALS HUH TISSUE

* NUHBEB CF AJttMAIS NECBOPSIfiD 

 EXAHIN£D MICBOSCOPICA1LY 

1

 1

 5 

2 

3 

72 
APPENDIX D
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS
 

IN MICE ADMINISTERED METHYL PARATHION IN THE DIET
 

73
 
74

 
TABLE 01.

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE MICE 

ADMINISTERED METHYL PARATHION IN THE DIET 

HIGH DOSE 

50 

49 

49 

(49) 

1 (2X) 

1 (2X) 

(49) 

1 (2X) 

(49) 

(49) 

(48) 

1 (2X) 

(49) 

14 (29%) 

2 (4S.) 

(48) 

1 (2%) 

(48) 

2 J4&1 

ANIMALS IMTIALLY IN STUDY 

ANIMALS HISSING 

ANIMALS NECBOPSIiD 

ANIMALS EXAMINED HI STOPATHOLOGICALL Y 

INTEGUMENTAB Y SYSTEM 

*SKIN 

CYST, NOS 

EPIDERMAL INCLUSION

SEBACEOUS CYST 

ABSCESS, CHBONIC 

*SUBCUT TISSUE

 

ABSCESS, CHBONIC 

HESPIBAI08Y SYSIiM 

•LUNG 

INFLAMMATION, FOCAL 

 CYST 

HYPEBPLASIA, ALVEOLAE EPITHELIOH 

* LUNG/ALVEOLI 

iDiMA, NCS 

HIS1IOCY30SIS 

HEBATOPOIBTIC SYSTEM 

»BONi. MABfiO H 

HYPEBPLASIA, HEMATOPOIE1IC 

*SPL£EN 

HYPEBPLASIA, LYMPHOI D 

HEMATOPOIESIS 

*LYMP H NODt 

GfiANUIOMA, NOS 

fHANDIBULA S L. NODE 

HYPfBPLASIA, LYMPHCID 

* NUflBtE OF ANIMALS WITH TISSUE

* NUMB£B OF ANIMALS NECBOPSIED 

MATCHED 

CONTROL LOW DOSE 

20 50 

1 

19 50 

19 50 

(19) (50) 

1 (5%) 

1 (5») 1 (2%) 

(19) (50) 

1 (5%) 

(19) (50)

1 (2S) 

1 (5%) 1 (2») 

(19) (50) 

1 (5%) 

1 (2X) 

(19) (48) 

(18) (48)

7 (39%) 17 (35%) 

1 (2%) 

(17) (47) 

(17) (47) 

7 J15X1 

 EXAMINED MICBOSCOPICALLY 

75 
TABLE D1. MALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

HEMATCFOIESIS 1 (2%) 

*MES±,NTERIC L. NODi (17) (47) (48) 

CONGESTICN , NOS 2 (12%) 2 (4%) 

HLMORBHAGE 1 (6%) 3 (6%) 7 (15%) 

INFLAMMATION , NOS 3 (6%) 

INFLAMMATION , ACUTE 2 (4%) 

INFLAMMATION , ACUT E HjiMOBRHAGIC 1 (2%) 

LYMPHOI D DEPLETION 3 (6%) 

hYPERPLASIA , RETICULU M CELL 3 (18%) 1 (2%) 3 (6%) 

HYPERPLASIA , LYMPHOI D 2 (12%) 15 (32%) 13 (27%) 

HEM ATOPOIESIS 8 (47%) 12 (26%) 

4THYMU S (12) (35) (35) 

ATROPHY , NO S 8 (67%) 32 (91%) 30 (86%) 

HYPEBPLASIA, LYMPHOI D 1 (8%) 1 (3») 

CIRCULATOR Y SYSTEM 

#Rj.Ghl VENTRICLE (19) (50) (49)

 

THROMBOSIS, NOS 1 (2%)

 

DIGESTIVE SYSTE M 

*LIVEfi (19) (49) (49) 

LYMPHOCYTIC INFLAMMATOR Y INFILTR 1 (2%) 

INFARCT, NOS 1 (5%) 

LIPOIDOSIS 2 (4%) 3 (6%)

HYPERTROPHY , FOCA L 1 (2%) 

»LIVER/HEPAIOCY1ES (19) (49) (49) 

LIPCIBOSIS 1 (5%) 1 (2%) 

CYTOPLASKIC VACUCLIZATIO N 1 (2X) 2 (4S) 

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

*GALLB1AEDER (19) (50) (49) 

HYPERPLASIA , EPITHELIAL 1 (2*) 

POLYP 1 (2%) 

*MUCOSA OF GALLBLADDE (19) (50) (49) 

CYS1, NOS 1 (5%)

 

»STOMACH (19) (48) (49) 

HYPifiPLA SIA, EPITHELIAL 1 I5%1

 

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

* NUMBE R CF ANIMAL S NtCROPSI£D 

76 
TABLE 01. MALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

•GASTHIC FUNDU S (19) (48) (49)

 

HYPiBPLASIA, EPITHELIAL 1 (2»)

 

*PiYERS PATCH (19) (48) (47) 

INFLAMMATION , ACUTE 1 (2X) 

HYPifiPLASIA, LYHPHOID 1 (2%) 1 (2») 

URINAR Y SYSTEM 

JtKIDNtY (19) (48) (49) 

HYERONEPHfiOSI S 1 (2%) 1 (2%) 

LYMPHOCY1IC INFLABBATOfiY INFILTR 1 (5X) 4 (8X) 

INFARCT, HiALtD 1 U*) 

*KIENiY/CCETiX (19) (48) (49) 

CYST, NOS 2 (4X) 

*K1ENEY/EELVIS (19) (48) (49) 

INFLAMMATION , SUPPURATIVE 1 (2X)

 

INFLAHMA1ION, ACUIE 1 (5%)

 

HYPEfiPLASIA, EPITHELIAL 1 (2«)

 

*URINA£Y BLADDif c (18) (44) (44)

 

INFLAMMATION, NOS 1 (2»)

 

iNDOCfilNE SYSTEM 

tPIIUITARY (15) (42) (45)

 

CYST, NOS 2 (13X) 1 (2*)

 

tADBENA L COfiTEX (19) (43) (47) 

HYPIEPLASIA, NOS 1 (5*)

 

*ACB£NAL MEEULLA (19) (43) (47) 

HYPIBPLASIA, NOS 1 (28)

 

•TUYEOIE (18) (46) (48) 

FOLL1CULAB CYST, NOS 1 (2%) 

riYPEBPLASIA, FOLLICULAR-CELL 2 (4X) 

tPANCRJEATJC ISLETS (17) (45) (49) 

HYFEfiPLASiA. NOS 4 J9X1 **_J8S1 

* NUHBEfi OF ANIMALS ilTH TISSUE EXAMINED MICROSCOPICALLY * NUflBEB OF ANIHALS NECEOPSIED 

77 
TABLE D1. MALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED
 

CONTROL LOW DOSE HIGH DOSE
 

RiPBODUCTIVE SYSTEM 

*MABHABY G1AND (19) (50) (49)

 

GALAC1OCELE 1 (2S)

 

*PBEPUTIAL G1AND (19) (50) (49)

 

DILATATION, NOS 1 (2%)

 

JFPBOSXATI (17) (46) (46)

 

INFLABBAIION, CHBONIC 1 (6X)

 

tPEOSIAIIC GLAN D (17) (46) (46) 

faYPEBPLASIA, NOS 1 (2%) 

*S£MINAL VESICLE (19) (50) (49) 

DILATATION, NOS 6 (32%) 31 (62X) 16 (33*) 

CYS1, NOS 1 (2%) 

LIPOGBANULOM A 1 (2*) 

*EPIDIDYBIS (J9) (50) (49) 

GRANULOMA , NOS 1 (2%) 1 (2%) 

NEBVOU S SJSTEH 

IBBAIN (18) (47) (48) 

COBEOEA AHYLACEA 3 (17S) 8 (17i) 4 (8») 

SPiLlAL StNSE OEGAN S 

*£YE/CCRNEA (19) (50) (49) 

JNFLAHMAIION. uHRONIC 1 (2X) 

*EYE/LACBIflAL G1AND (19) (50) (49) 

HYPLBPLASIA , NOS 1 (2%) 

flUSCULO SKELETAL SYSli.M 

NON E 

oODY CAVIIIES 

*HiSENT£BY (19) (50) (49) 

* NUMBE E OF AMZHALS HU H TISSUE EXAMINE D MICBOSCOP1CALLY 

* NUBBEfi OF ANIBAL S NECBOPSIED 

78 
TABLE 01. MALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

ALL OTHER SYSliMS 

Ai/IPOSE TISSUE 

LIPOGHANULOM A 

MORPHOLOGY SUHBAK Y 

ANIBAI MISSING/NO NECBOPSY 

AU10LYSI5/NO NiCKOPSY 

* NUHBEf i CF ANIHALS WIT H TISSUE EXAMINi-D KICEOSCOPICALLY 

* NUMBEf c CF ANIKA1S NEC6OPSIED 

79 
TABLE 02.

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE MICE 

ADMINISTERED METHYL PARATHION IN THE DIET 

— ———— —— 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

ANIMAL S INITIALLY I N SILL Y 20 50 50 

ANIMALS MISSING 1 

ANIMAL S NECEOPSliD 20 49 48 

ANIMALS EXAMINE D HI STO PATHOLOGICALLY 20 49 48 

INTEGUMENTAR Y SYS1EM 

*SKIN (20) (49) (48) 

SEBACEOUS CYST 1 (2%) 

INFLAMMATION , ACUTE/CriRONIC 1 (2%) 

ALOPECIA 1 (2X) 

HESP1HATORY SYSIiM 

(LUN G (20) (49) (48) 

HYPE8PLASIA , ALVEOLA R EPITHELIUM 1 (2X) 

HIST10CYIOSIS 1 (2%) 

HEMAIOPOIETIC SYSTEM 

*BONE MARBO W (20) (49) (48) 

HYPE6PLAS1A, HEMAIOPOIETIC 1 (2%) 1 (2%) 

HYPEfcPLASIA, iRYTHECID 1 (2%) 

tSPLiEN (20) (49) (47) 

INFLAMMATION , ACUT E 1 (28) 

INFLAMMATION , FOCAL GRANULOMATO U 1 (2%) 

ADHESION, NOS 1 (2X) 

hYPERPLASIA , LYMPHOID 8 (40») 12 (24X) 13 (28S) 

htflATOPOItSIS 1 (5S) 5 (10X) 1 (2«) 

tLYMP H NCCt (19) (49) (47) 

IHBOMBOSiS, NOS 1 (2%) 

• HANDIBU1A E L. NOD E (19) (49) (47) 

HEMCEEHAGI C CYS1 1 (2*) 

INFLAMMATION , ACUT E 1 (2%) 

LYMPjiOID DEPLETION 1 12%\ 

S NUMBE R OF ANIMALS WIT H TISSUE EXAMINED MICROSCOPICALLY 

* NUMBEfi OF ANIMAL S NtCROPSIED 

80 
TABLE D2. FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

HYEEBELASIA , BEHCULUM CELL 1 (2%) 

HYPEBPLAS1A, LYMPHOI D 1 (5%) 6 (12X) 3 (6«) 

*flESENTEBIC L. NODE (19) (49) (47) 

HEMCEBHAG E 1 (2%) 1 (2») 

LYMPHOID utPLETION 1 (2X) 

HYPEEPLASIA , RETICULUf l CELL 2 (4») 1 (2*) 

HYPERPLASIA, LYHPHOID 4 (2156) 9 (18*) 10 (2U) 

H EM ATOPOIESIS 3 (16») 

*XHYMUS (14) (30) (34) 

HEBOEEHAG E 1 (3%) 

ATROPHY , NOS 7 (50%) 16 (53X) 29 (85%) 

HYPERPLAS1A, LYMPhOI D 2 (7X) 

CIRCULATORY SYSliM 

*HEAB1 (20) (49) (48) 

DEGENERATION , GBANULA R 1 (2%) 

iilGiSTIVE SYSTEM 

*SALIVARY GIAN D (20) (47) (47) 

LYMPHOCY1IC INFLAMMATOR Y INFILTR 1 (5«) 3 (6X) 2 (4») 

HYi>£RPLASIA, LYMPHOID 1 (2*) 

iLXVEfi (20) (49) (48) 

LYHPHCCYTIC INFLAMBATOR Y INFILTR 2 (10S) 4 (8S) 

INFLAMMATION , GBANULCMATOU S 1 (5%) 

GBAMULOMA , NOS 1 (5X) 

INFLAMMATION , FOCAL GSANULOHATOU 1 (2») 

NECROSIS, FOCAL 1 (2») 

NECROSIS, COAGULATIVx. 1 (2%) 

L1POIDOSIS 1 (5%) 1 12%) 

LYBPHOCYTOSIS 1 (2X) 

*LIV£E/HEPAIOCYTES (20) (49) (48)

 

NECROSIS, NOS 1 (5X)

 

*GALLBLAEDifi (20) (49) (48)

 

HYPEBPLASIA, EPITHELIAL 1 (2%) 

•PANCREAS (18) (46) (42) 

CILATATICM/DUCIS 

* MUBBEB OP AM1MALS WITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBEfi Cl AMIHALS NECBOPSIED 

81 
TABLE 02. FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

- • "~— '-' '— "~ ­ 7 "-­" "" '—— —~— —"— — •' 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

INFLAHHA1ION. CHRONIC 1 (2X) 

•PANCREATIC

ATfiOPHY ,

 ACINUS 

 BOS 

(18) (46) (<*2) 

1 (2%) 

*SIOHACH 

INFLAKHAXION ,

PERJABTEBITIS 

 ACUTE 

(20) 

1 (5X) 

(48) (48) 

1 (2X) 

#GASIRIC BUCOSA 

CYST, NOS 

(20) (48) 

1 (2%) 

(48) 

IGASTEIC SEBOSA 

INF1ABBA1ION, CHRONIC 

(20) 

1 (5X) 

(48) (48) 

*PEYERS FA TCh 

HYPERP1ASIA, LYMPHOID 

(20) 

1 (5%) 

(49) (46) 

1 (2X) 

UHINABY SYSTEfl 

* KIDNEY 

LYBPHOCYTiC INFLABHATORY

PifiJUBIERITIS" 

INFARCT, HEALED 

PLASBACY20SIS 

HYPtRPLASIA, LYMPHOID 

 INFILIR 

(20) 

6 (30S) 

(49) 

4 (8%) 

1 (2X) 

1 (2%)

1 (2*) 

1 (2X) 

(48) 

1 (2*) 

*KIDN£Y/GIOfliBUI.US 

NEPHBOPA1HY 

(20) 

1 (5X) 

(49) (48) 

1 (2%) 

*K1LN£Y/IELVIS 

LYBPHCCY1IC INFLABBA10RY INFILTR 

(20) (49) (48) 

1 (2%) 

*UtIUABY BLACCiE 

1YBEHCCYTIC INFLABBATOR Y

INFLAHMATION , CH2ONIC 

HYPERP1ASIA, LYBPHOIC 

 INFILTR 

(19) (45) 

3 (7X) 

2 (4») 

(43) 

1

1

 (2X) 

 (2X) 

fiNlJOCRIN£ SYSTEM 

#PI1UI1ARY 

CYST, NOS 

(") (45) (44) 

1 (2») 

tADRENA L 

CYS1, NOS 

(20) (49) 

1 J211 __. (48) 

f NUBBEf i Cf ANIMALS WITH TISSUE

* NUMBE R OF ANIHAL S NECEOPSIED 

 EXAMINE D HICEOSCOPICALLY 

82 
TABLE D2. FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

INFLAHMAIICN, CHRONIC 1 (5X) 

HEMATOPOIiSIS 1 (5») 

tADfiENAL CO 61 EX (20) (49)

 

CYST, NOS 

HYPERPLASIA, NOS 

*ThYROID (20) (47)

CYSTIC FOLLICLES 1 (2*) 

HYPERPLA-SIA, FOLLICULAR-CELL 

tPANCHEATIC ISLETS (18) (46) 

HYPIkPLASIA, NOS 1 (2») 

BEPRODOCTIVE SYSTEM 

* MAMMAR Y GLAN D (20) (49)

 

GALACTOCELE 

METAPLASIA, SQUAMOU S 

LACTATION 

tUIERUS (20) (48)

HY CEO MET 6A 3 (15%) 3 (6X) 

HYPERPLASIA, STBOMA1 

*UTEBUS/ENDCM£TfcIUn (^0) (48) 

CYSI, NOS 

HYPBRPLASIA, NOS 3 (15K) 5 (10S) 

HYPiRPLASIA, CYSTJ.C 14 (70%) 31 (65*) 

tOVARY/PABOVABIA N (20) (48)

 

INFABCT, NOS 

»OVABY (17) (48) 

CYST, NOS 3 (6K) 

FOLLICULAR CYSI, NOS 2 (12S) 8 (17«) 

HEMORKHAG1C CYSI 3 (6*) 

ATROPHY, NOS 15 (88%) 25 (52«) 

*OVARY/FOLLICLE (17) (48) 

HEMORRHAG E 1 (2*) 

HEMORBHAGIC CYST 1 (2X) 

NtfiVOU S SYSTEM 

*BfiAIN (18) (49) 

PfcBIVASCULAR CUFFING 1 12%} 

* NUHBE B OF ANIMALS WIT H TISSUE EXAMINED HICROSCOPICALLY 

* NUMBER OF A til HA IS NECBOPSIED 

(48) 

1 (2X) 

1 (2K) 

(46) 

1 (2%) 

(42) 

(48) 

1 (2%) 

1 (2%) 

1 (2X) 

(45) 

3 (7X) 

1 (2S) 

(45) 

3 (7%) 

15 (33%) 

16 (36 X) 

(45) 

1 (2X) 

(47) 

5 (11*) 

28 (60S) 

(47) * 

1 (2X) 

(48) 

83 
TABLE D2. FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

CORPORA AflYLACEA 2 (11%) 5 (10%) 

SPECIAL SENSE ORGAN S 

NONE 

MUSCULOSK£LETAL SYSTEM 

*BONE

RESORPTION

 (20) (49)

 1 (2%) 

 (48) 

*JOINT

OSTEOARTHRITIS

 (20) (49) (48) 

1 (2%) 

faODY CAVITIES 

*ABDOHINAL CAVITY

LIECG6ANIU.OMA

 (20) (49) (48) 

1 (2%) 

*PERITONEUfl

mrtAMSATlON, ACOTL

 (20) (49) (48) 

1 (2%) 

*H£SiNTEBY

HEBOEBHAGJC CYST

 (20) (49) (48) 

1 (2%) 

ALL OXHEB SYSTEMS 

ADIPOSE TJSSUi. 

LIPCGEANULOM A 1 1 1 

SPECIAL MCBPHOLOGY SUBHAR Y 

ANIMAL HISSING/SO NECROPSY

AUIOLYSIS/NO NECROPSY

« NUWBifi CF ANIMAL S HUH USSUE

* NUMBE R OF ANIMALS NECROPSIED 

 hXAMINED MICROSCOPICALLY 

1

 1 

1 

84 
APPENDIX E
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS
 

IN RATS ADMINISTERED METHYL PARATHION IN THE DIET
 

85
 
86

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

Administered Methyl Parathion in the Diet (a)
 

Topography: Morphology


Lung: Alveolar/Bronchiolar
 

Carcinoma or Adenoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


c»
 

Hematopoietic System:
 

Lymphoma or Leukemia (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor 

Matched
 

 Control
 

 2/20 (10)
 

 N.S.
 

 105
 

 3/20 (15)
 

 N.S.
 

88 

Low
 

Dose
 

3/50 (6)
 

N.S.
 

0.600
 

0.076
 

6.860
 

105
 

8/50 (16)
 

N.S.
 

1.067
 

0.295
 

5.813
 

90 

High
 

Dose
 

3/50 (6)
 

N.S.
 

0.600
 

0.076
 

6.860
 

105
 

4/50 (8)
 

N.S.
 

0.533
 

0.102
 

3.410
 

102 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats
 

Administered Methyl Parathion in the Diet (a)
 

(continued)
 

Topography: Morphology


Liver: Hepatocellular Carcinoma
 

or Adenoma (b)


P Values (c,d)


Departure from Linear Trend (e)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

oo
 Weeks to First Observed Tumor


oo
 

Pituitary: Adenoma,
 

or Adenocarc inoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched
 

 Control
 

 2/20 (10)
 

 P = 0.025 (N)
 

 P = 0.044
 

 105
 

 9/20 (45)
 

 N.S.
 

83
 

Low High
 

Dose Dose
 

0/49 (0) 0/50 (0)
 

N.S. N.S.
 

0.000 0.000
 

0.000 0.000
 

1.372 1.345
 

—
 —
 

11/48 (23) 15/50 (30)
 

N.S. N.S.
 

0.509 0.667
 

0.242 0.346
 

1.197 1.478
 

41 104
 
09 

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

Administered Methyl Parathion in the Diet (a)
 

(continued)
 

Topography ; Morphology
 

Adrenal: Pheochromocytoma (b)
 

P Values (c,d)
 

Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Thyroid: C-cell Carcinoma
 

or Adenoma (b)
 

P Values (c,d)
 

Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched
 

Control
 

3/20 (15)
 

N.S.
 

105
 

0/20 (0)
 

N.S.
 

Low
 

Dose
 

6/50 (12)
 

N.S.
 

0.800
 

0.195
 

4.615
 

100
 

3/48 (6)
 

N.S.
 

Infinite
 

0.261
 

Infinite
 

105
 

High
 

Dose
 

5/50 (10)
 

N.S.
 

0.667
 

0.147
 

4.014
 

105
 

3/49 (6)
 

N.S.
 

Infinite
 

0.255
 

Infinite
 

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

Administered Methyl Parathion in the Diet (a)
 

(continued)
 

Topography: Morphology


Pancreatic Islets: Islet-cell
 

Adenoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


Prostate: Acinar-cell
 

Adenoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


Matched
 

 Control
 

 2/19 (11)
 

 N.S.
 

 105
 

 2/20 (10)
 

P = 0.027 (N)
 

 105
 

Low High 

Dose Dose 

4/45 (9) 2/47 (4) 

N.S. N.S. 

0.844 0.404 

0.136 0.032 

8.864 5.318 

95 104 

0/44 (0) 0/48 (0) 

N.S. N.S. 

0.000 0.000 

0.000 0.000 

1.524 1.400 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats
 

Administered Methyl Parathion in the Diet (a)
 

(continued) 

Topography; Morphology 

Matched 

Control 

Low 

Dose 

High 

Dose 

Tescis: Interstitial-cell 

Tumor (b) 17/20 (85) 40/50 (80) 41/50 (82) 

P Values (c,d) N.S. N.S. N.S. 

Relative Risk (f) 

Lower Limit 

Upper Limit 

0.941 

0.781 

1.291 

0.965 

0.802 

1.310 

Weeks to First Observed Tumor 88 41 80 

(a) Dosed groups received 20 or 40 ppm.
 

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

(c) Beneath the incidence of tumors in the control group is the probability level for the Cochran-


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

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

the comparison of that dosed group with the matched-control group when P is less than 0.05;
 

otherwise, not significant (N.S.) is indicated.
 

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

(e) The probability level for departure from linear trend is given when P is less than 0.05 for
 

any comparison.
 

(f) The 95% confidence interval of the relative risk between each dosed group and the control group.
 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats 

Administered Methyl Parathion in the Diet (a) 

Matched Low High 

Topography: Morphology Control Dose Dose 

Lung: Alveolar /Bronchiolar 

Adenoma (b) 0/20 (0) 5/50 (10) 1/47 (2) 

P Values (c,d) N.S. N.S. N.S. 

Departure from Linear Trend (e) P TM 0.037 

Relative Risk (f) Infinite Infinite 

Lower Limit 0.525 0.023 

Upper Limit Infinite Infinite 

VO Weeks to First Observed Tumor — 93 105 

to 

Hematopoietic System: 

Leukemia or Lyaphome (b) 1/20 (5) 3/50 (6) 4/47 (9) 

P Values (c,d) N.S. N.S. N.S. 

Relative Risk (f) 1.200 1.702 

Lower Limit 0.106 0.186 

Upper Limit 61 . 724 81.978 

Weeks to First Observed Tumor 105 101 86
 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Administered Methyl Parathion in the Diet (a)
 

(continued)
 

Topography: Morphology


Liver: Hepatocellular
 

Carcinoma or Adenoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


VO
 

w

 Pituitary: Adenoma or
 

Carcinoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


Matched
 

 Control
 

 2/20 (10)
 

P = 0.046 (N)
 

 105
 

 12/20 (60)
 

P = 0.021 (N)
 

 105


Low
 

Dose
 

5/50 (10)
 

N.S.
 

1.000
 

0.184
 

10.007
 

105
 

22/50 (44)
 

N.S.
 

0.733
 

0.465
 

1.331
 

 93


High
 

Dose
 

0/47 (0)
 

N.S.
 

0.000
 

0.000
 

1.429
 

—
 

15/47 (32)
 

P = 0.031 (N)
 

0.532
 

0.312
 

1.031
 

 97
 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Administered Methyl Parathion in the Diet (a)
 

(continued)
 

Matched
 

Topography: Morphology Control
 

Mammary Gland: Fibroadenoma (b) 5/20 (25)
 

P	 Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


Uterus: Endometrial Stromal
 

Polyp (b)


P	 Values (c,d)


Relative Risk (Matched
 

Control) (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

P = 0.001 (N)
 

 105
 

 4/20 (20)
 

 N.S.
 

105
 

Low	 High
 

Dose Dose
 

2/50 (4) 0/47 (0)
 

P = 0.018 (N) P = 0.002 (N)
 

0.160	 0.000
 

0.017	 0.000
 

0.900	 0.332
 

105
 —
 

6/50 (12) 4/46 (9)
 

N.S.	 N.S.
 

0.600	 0.435
 

0.164	 0.092
 

2.659	 2.148
 

105 86
 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Administered Methyl Parathion in the Diet (a)
 

(continued)
 

(a) Dosed groups received 20 or 40 ppm.
 

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

(c) Beneath the incidence of tumors in the control group is the probability level for the Cochran-


Armitage test when P is less than 0.05; otherwise, not significant (N.S.) is indicated.
 

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

test for the comparison of that dosed group with the matched-control group when P is less than
 

0.05; otherwise, not significant (N.S.) is indicated.
 

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

(e) The probability level for departure from linear trend is given when P is less than 0.05 for
 

any comparison.
 VO
 

(f) The 95% confidence interval of the relative risk between each dosed group and the control
 

group.
 
96

 
APPENDIX F
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS
 

IN MICE ADMINISTERED METHYL PARATHION IN THE DIET
 

97
 
98

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

Administered Methyl Parathion in the Diet (a)
 

Matched Low
 

Topography: Morphology Control Dose
 

Lung: Alveolar/Bronchiolar
 

Carcinoma (b) 0/19 (0) 5/50 (10)
 

P Values (c,d) N.S. N.S.
 

Relative Risk (f) Infinite
 

Lower Limit 0.501
 

Upper Limit Infinite
 

Weeks to First Observed Tumor 84
 

40

 Lung: Alveolar/Bronchiolar
 

Carcinoma or Adenoma (b) 1/19 (5) 10/50 (20)
 

P Values (c,d) N.S. N.S.
 

Relative Risk (f) 3.800
 

Lower Limit 0.613
 

Upper Limit 160.949
 

Weeks to First Observed Tumor 102 84
 

High
 

Dose
 

3/49 (6)
 

N.S.
 

Infinite
 

0.243
 

Infinite
 

102
 

8/49 (16)
 

N.S.
 

3.102
 

0.470
 

134.436
 

102
 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice
 

Administered Methyl Parathion in the Diet (a)
 

(continued)
 

Matched Low
 

Topography: Morphology Control Dose
 

Hematopoietic System:
 

Lymphoraa (b) 2/19 (11) 8/50 (16)
 

P Values (c,d) N.S. N.S.
 

Relative Risk (f) 1.520
 

Lower Limit 0.348
 

Upper Limit 13.949
 

Weeks to First Observed Tumor 97 96
 

o
 

o
 

Liver: Hepatocellular
 

Carcinoma (b) 2/19 (11) 3/49 (6)
 

P Values (c,d) N.S. N.S.
 

Relative Risk (f) 0.582
 

Lower Limit 0.074
 

Upper Limit 6.640
 

Weeks to First Observed Tumor 84 102
 

High
 

Dose
 

3/49 (6)
 

N.S.
 

0.582
 

0.074
 

6.640
 

6/49 (12)
 

N.S.
 

1.163
 

0.237
 

11.202
 

102
 

23 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice
 

Administered Methyl Parathion in the Diet (a)
 

(continued)
 

Topography ; Morphology
 

Liver: Hepatocellular
 

Carcinoma or Adenoma (b)
 

P Values (c,d)
 

Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

All Sites: Hemang iosar coma (b)
 

P Values (c,d)
 

Departure from Linear Trend (e)
 

Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched


Control


10/19 (53)


P = 0.034 (N)


84


2/19 (11)


N.S.


P = 0.033
 

102
 

 Low
 

 Dose
 

 14/49 (29)
 

 N.S.
 

0.543
 

0.294
 

1.152
 

 102
 

 0/50 (0)
 

 N.S.
 

0.000
 

0.000
 

1.278
 

High
 

Dose
 

12/49 (24)
 

P = 0.028 (N)
 

0.465
 

0.241
 

1.018
 

102
 

1/49 (2)
 

N.S.
 

0.194
 

0.003
 

3.563
 

102
 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice
 

Administered Methyl Parathion in the Diet (a)
 

(continued)
 

Matched Low
 

Topography: Morphology Control Dose
 

All Sites: Hemangioma 1/19 (5) 3/50 (6)
 

P Values (c,d) N.S. N.S.
 

Relative Risk (f) 1.140
 

Lower Limit 0.101
 

Upper Limit 58.635
 

Weeks to First Observed Tumor 102 102
 

All Sites: Hemangios arcoma
 

o
 or Hemangioma (b) 3/19 (16) 3/50 (6)
 

ro
 

P Values (c,d) N.S. N.S.
 

Relative Risk (f) 0.380
 

Lower Limit 0.057
 

Upper Limit 2.658
 

Weeks to First Observed Tumor 102 102
 

High
 

Dose
 

1/49 (2)
 

N.S.
 

0.388
 

0.005
 

29.845
 

102
 

2/49 (4)
 

N.S.
 

0.259
 

0.024
 

2.118
 

102
 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice
 

Administered Methyl Parathion in the Diet (a)
 

(continued)
 

Matched Low
 

Topography; Morphology Control Dose
 

Adrenal: Cortical Adenoma (b) 3/19 (16) 4/43 (9)
 

P Values (c,d) N.S. N.S.
 

Relative Risk (f) 0.589
 

Lower Limit 0.113
 

Upper Limit 3.737
 

Weeks to First Observed Tumor 102 102
 

o
 Pancreatic Islets: Islet-cell
 

Adenoma (b) 1/17 (6) 3/45 (7)
 

u>
 

P Values (c,d) N.S. N.S.
 

Relative Risk (f) 1.133
 

Lower Limit 0.101
 

Upper Limit 58.167
 

Weeks to First Observed Tumor 102 102
 

High
 

Dose
 

5/47 (11)
 

N.S.
 

0.674
 

0.150
 

4.039
 

102
 

0/49 (0)
 

N.S.
 

0.000
 

0.000
 

6.484
 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice
 

Administered Methyl Parathion in the Diet (a)
 

(continued)
 

Topography! Morphology 

Matched 

Control 

Low 

Dose 

High 

Dose 

Eye/Lacrimal Gland:

Adenoma (b) 

 Papillary 

1/19 (5) 1/50 (2) 3/49 (6) 

P Values (c,d) N.S. N.S. N.S. 

Relative Risk (f) 

Lower Limit 

Upper Limit 

0.380 

0.005 

29.260 

1.163 

0.103 

59.809 

Weeks to First Observed Tumor 102 102 102 

(a) Dosed groups received time-weighted average doses of 35 or 77 ppm.
 

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

(c) Beneath the incidence of tumors in the control group is the probability level for the Cochran-


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

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

the comparison of that dosed group with the matched-control group when P is less than 0.05;
 

otherwise, not significant (N.S.) is indicated.
 

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

(e) The probability level for departure from linear trend is given when P is less than 0.05 for
 

any comparison.
 

(f) The 95% confidence interval of the relative risk between each dosed group and the control group.
 
Table F2. Analyses of the Incidence of Primary Tumors in Female Mice
 

Administered Methyl Parathion in the Diet (a) 

Matched Low High 

Topography: Morphology Control Dose Dose 

Lung: Alveolar/Bronchiolar 

Carcinoma or Adenoma (b) 0/20 (0) 3/49 (6) 2/48 (4) 

P Values (c,d) N.S. N.S. N.S. 

Relative Risk (f) Infinite Infinite 

Lower Limit 0.255 0.128 

Upper Limit Infinite Infinite 

Weeks to First Observed Tumor — 102 102 

Hematopoietic System: 

Lymphoma or Leukemia (b) 8/20 (40) 12/49 (24) 5/48 (10) 

P Values (c,d) P = 0.004(N) N.S. P = 0.008(N) 

Relative Risk (f) 0.612 0.260 

Lower Limit 0.286 0.081 

Upper Limit 1.499 0.799 

Weeks to First Observed Tumor 97 91 82 
Table F2. Analyses of the Incidence of Primary Tumors in Female Mice
 

Administered Methyl Parathion in the Diet (a)
 

(continued) 

Topography; Morphology 

Matched 

Control 

Low 

Dose 

High 

Dose 

All Sites: Hemangiomas (b) 1/20 (5) 3/49 (6) 0/48 (0) 

P Values (c,d) N.S. N.S. N.S. 

Relative Risk (f) 

Lower Limit 

Upper Limit 

1.224 

0.108 

62.958 

0.000 

0.000 

7.780 

Weeks to First Observed Tumor 102 102 — 

All Sites: Hemang ios arcoma
 

or Hemang i oma (b ) 1/20 (5) 5/49 (10) 2/48 (4)
 

P Values (c,d) N.S. N.S. N.S.
 

Relative Risk (f) 2.041 0.833
 

Lower Limit 0.254 0.047
 

Upper Limit 94.440 48.155
 

Weeks to First Observed Tumor 102 102 101
 
Table F2. Analyses of the Incidence of Primary Tumors in Female Mice
 

Administered Methyl Parathion in the Diet (a) 

(continued) 

Matched Low High 

Topography: Morphology Control Dose Dose 

Liver: Hepa to cellular 

Carcinoma or Adenoma (b) I/ 20 (5) 4/49 (8) 2/48 (4) 

P Values (c,d) N.S. N.S. N.S. 

Relative Risk (f) 1.633 0.833 

Lower Limit 0.179 0.047 

Upper Limit 78. 704 48.155 

Weeks to First Observed Tumor 102 93 102 

Pituitary: Adenoma (b) 4/17 (24) 5/45 (11) 1/44 (2) 

P Values (c,d) P = 0.010 (N) N.S. P = 0.019 (N) 

Relative Risk (f) 0.472 0.097 

Lower Limit 0.120 0.002 

Upper Limit 2.166 0.902 

Weeks to First Observed Tumor 102 100 82 
Table F2. Analyses of the Incidence of Primary Tumors in Female Mice
 

Administered Methyl Parathion in the Diet (a)
 

(continued)
 

Matched Low High
 

Topography: Morphology Control Dose Dose
 

Adrenal: Cortical Adenoma (b) 2/20 (10) 1/49 (2) 1/48 (2)
 

P Values (c,d) N.S. N.S. N.S.
 

Relative Risk (f) 0.204 0.208
 

Lower Limit 0.004 0.004
 

Upper Limit 3.754 3.830
 

Weeks to First Observed Tumor 102 102 102
 

Mammary Gland:
 

00 

o Adenocarcinoma (b) 0/20 (0) 3/49 (6) 1/48 (2)
 

P Values (c,d) N.S N.S. N.S.
 

Relative Risk (f) Infinite Infinite
 

Lower Limit 0.255 0.023
 

Upper Limit Infinite Infinite
 

Weeks to First Observed Tumor 102 83
 
Table F2. Analyses of the Incidence of Primary Tumors in Female Mice
 

Administered Methyl Parathion in the Diet (a)
 

(continued)
 

Matched Low High 

Topography ; Morphology Control Dose Dose 

Uterus: Endometrial Stromal 

Polyp (b) 0/20 (0) 0/48 (0) 3/45 (7) 

P Values (c,d) N.S. — N.S. 

Relative Risk (f) — Infinite 

Lower Limit 0.278 — Upper Limit — Infinite 

Weeks to First Observed Tumor 102 

(a) Dosed groups received 62.5 or 125 ppm.
 

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

(c) Beneath the incidence of tumors in the control group is the probability level for the Cochran-


Armitage test when P is less than 0.05; otherwise, not significant (N.S.) is indicated.
 

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

test for the comparison of that dosed group with the matched-control group when P is less than
 

0.05; otherwise, not significant (N.S.) is indicated.
 

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

(e) The probability level for departure from linear trend is given when P is less than 0.05 for
 

any comparison.
 

(f) The 95% confidence interval of the relative risk between each dosed group and the control
 

group.
 
110

 
Review of the Bioassay of Methyl Parathion* for Carcinogenicity
 

by the Data Evaluation/Risk Assessment Subgroup
 

of the Clearinghouse on Environmental Carcinogens
 

December 13, 1978
 

The Clearinghouse on Environmental Carcinogens was established
 

in May, 1976, in compliance with DHEW Committee Regulations and the
 

Provisions of the Federal Advisory Committee Act. The purpose of
 

the Clearinghouse is to advise the Director of the National Cancer
 

Institute on the Institute's bioassay program to identify and evaluate
 

chemical carcinogens in the environment to which humans may be exposed.
 

The members of the Clearinghouse have been drawn from academia, industry,
 

organized labor, public interest groups, and State health officials.
 

Members have been selected on the basis of their experience in carcinogenesis or related fields and, collectively, provide expertise in
 

chemistry, biochemistry, biostatistics, toxicology, pathology, and
 

epidemiology. Representatives of various Governmental agencies participate as ad hoc members. The Data Evaluation/Risk Assessment Subgroup
 

of the Clearinghouse is charged with the responsibility of providing
 

a peer review of reports prepared on NCI-sponsored bioassays of chemicals
 

studied for carcinogenicity. It is in this context that the below critique is given on the bioassay of Methyl Parathion.
 

The reviewer for the report on the bioassay of Methyl Parathion
 

agreed with the conclusion that the compound was not carcinogenic
 

under the conditions of test. After a brief description of the experimental design, he said that no data were given on the stability
 

and content of the compound in the diet mix and that the size of the
 

matched control groups was too small. He added, however, that the
 

shortcomings were not significant. Based on the results of the study,
 

the reviewer said that Methyl Parathion would not appear to pose a
 

risk of cancer for human beings. He moved that the report on the
 

bioassay of the compound be accepted as written. The motion was
 

seconded and approved without objection.
 

Clearinghouse Members Present:
 

Arnold L. Brown (Chairman), University of Wisconsin Medical School
 

Joseph Highland, Environmental Defense Fund
 

William Lijinsky, Frederick Cancer Research Center
 

Henry Pitot, University of Wisconsin Medical Center
 

Verne A. Ray, Pfizer Medical Research Laboratory
 

Verald K. Rowe, Dow Chemical USA
 

Michael Shimkin, University of California at San Diego
 

111
 
Louise Strong, University of Texas Health Sciences Center
 

Kenneth Wilcox, Michigan State Health Department
 

Subsequent to this review, changes may have been made in the
 

bioassay report either as a result of the review or other reasons.
 

Thus, certain comments and criticisms reflected in the review may
 

no longer be appropriate.
 

•&U.S. GOVERNMEN T PRINTIN G OFFICE : I 97 9-28 I - 2 t 7 / 3 07 2
 

112
 

DHEW Publication No. (NIH) 79-1713