1979 

National Cancer Institute 

CARCINOGENESIS 

Technical Report Series 

NO. 103 

BIOASSAY OF 

FENTHION 

FOR POSSIBLE CARCINOGENICITY 

CAS No. 55-38-9 

NCI-CG-TR-103 

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

Public Health Service 

National Institutes of Health 

,...,.-,«.;»,--¥ 

BIOASSAY OF
 

FENTHION
 

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) 79-1353
 
11

 
BIOASSAY OF
 

FENTHION
 

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
 

fenthion conducted for the Carcinogenesis Testing Program,
 

Division of Cancer Cause and Prevention, J National Cancer
 

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

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

determine whether selected environmental chemicals have the
 

capacity to produce cancer in animals. Negative results, in
 

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

than control animals, do not necessarily mean that the test
 

chemical is not a carcinogen, inasmuch as the experiments are
 

conducted under a limited set of circumstances. Positive results
 

demonstrate that the test chemical is carcinogenic for animals
 

under the conditions of the test and indicate that exposure to
 

the chemical is a potential risk to man. The actual 

determination of the risk to man from chemicals found to be 

carcinogenic in animals requires a wider analysis. 

CONTRIBUTORS: This bioassay of fenthion was conducted by Gulf
 

South Research Institute, New Iberia, Louisiana, initially under
 

direct contract to NCI and currently under a subcontract to
 

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

Testing Program.
 

The doses for the chronic study were selected by Drs. E. E.
 

Storrs (1) and 0. G. Fitzhugh (2,3). The principal investigator
 

was Mr. R. J. Wheeler (1). Chemicals were analyzed by Mr.
 

Wheeler and dosed feed mixtures by Mr. S. M. Billedeau (1). The
 

results of these analyses were reviewed by Dr. C. W. Jameson
 

(2). Histologic examination of animal tissues was performed by
 

Drs. R. A Ball (1) and B. Buratto (1), and the diagnoses included
 

in this report represent the interpretation of these pathologists.
 

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

Mason Research Institute (4). Statistical analyses were
 

performed by Dr. J. R. Joiner (2) and Ms. P. L. Yong (2), using
 

methods selected for the bioassay program by Dr. J. J. Gart (5).
 

ill
 
This report was prepared at Tracer Jitco (2) under the direction
 

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

Dr. L. A. Campbell, Director of the Bioassay Program; Dr. S. S.
 

Olin, Deputy Director for Science; Dr. J. F. Robens,
 

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

Mr. W. D. Reichardt, and Ms. L. A. Waitz, bioscience writers; and
 

Dr. E. W. Gunberg, technical editor, assisted by Ms. Y. E.
 

Presley and Ms. P. J. Graboske.
 

The following scientists at NCI (6) 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.vMorton H. Levitt,
 

Dr. Harry A. Milman, Dr. Thomas W. Orme, Dr. Sherman F. Stinson,
 

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

(1) Gulf South Research Institute, Atchafalaya Basin Laboratories,
 

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

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

Maryland.
 

(3) 4208 Dresden Street, Kensington, Maryland.
 

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

Rockville, Maryland.
 

(5) 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.
 

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

Prevention, National Cancer Institute, National Institutes of
 

Health, Bethesda, Maryland.
 

iv
 
SUMMARY
 

A bioassay of fenthion for possible carcinogenicitv was conducted
 

by administering the test chemical in feed to F344 rats and
 

B6C3F1 mice.
 

Groups of 50 rats of each sex and 50 mice of each sex were
 

administered fenthion in the diet at one of two doses, either 10
 

or 20 ppm, for 103 weeks and then observed for 0 to 2 additional
 

weeks. Matched controls consisted of groups of 25 untreated
 

animals of each species and sex. All surviving animals were
 

killed at 103 to 105 weeks.
 

The mean body weights and the survivals of the dosed animals were
 

essentially unaffected by administration of the test chemical
 

with the exception of the survival of the low-dose male mice,
 

which was significantly lower than that of the corresponding
 

matched control. Thus, most of the animals may have been able to
 

tolerate higher doses. Sufficient numbers of animals in all.
 

groups of rats and mice were at risk for development of
 

late-appearing tumors.
 

In the male and female rats and the female mice, no tumors
 

occurred at incidences that were significantly higher in dosed
 

groups than in control groups.
 

Tn the male mice, sarcomas, fibrosarcomas, or rhabdomyosarcomas
 

of the integumentary system occurred at incidences that were dose
 

related CP = 0.043). In direct comparisons of the incidences of
 

these tumors in the dosed groups with the incidence in the
 

control group, the P values of 0.048 and 0.028 for the low- and
 

high-dose groups, respectively, did not meet the Bonferroni
 

criterion of P = 0.025 for significance when multiple comparisons
 

are made (controls 0/25, low-dose 7/49 or 14%, high-dose 8/48 or
 

17%). However, the incidence of sarcomas and fibrosarcomas in
 

historical-control male B6C3F1 mice used in bioassays of other
 

chemicals tested at this same laboratory was 7/435 (1.6%), and no
 

rhabdomvosarcomas occurred in the historical-control male mice.
 

It is concluded that under the conditions of this bioassay,
 

fenthion was not carcinogenic for male or female F344 rats or for
 

female B6C3F1 mice. The increased incidence of sarcomas,
 

fibrosarcomas, and especially rhabdomvosarcomas of the
 

integumentary system in the male B6C3F1 mice suggested that the
 

test chemical was carcinogenic in these animals.
 
vi

 
TABLE OF CONTENTS
 

Page
 

I. Introduction 1
 

II. Materials and Methods 3
 

A. Chemical 3
 

B. Dietary Preparation 3
 

C. Animals 5
 

D. Animal Maintenance 5
 

E. Subchronic Studies 7
 

F. Chronic Studies 9
 

G. Clinical and Pathologic Examinations 9
 

H. Data Recording and Statistical Analyses 13
 

III. Results - Rats 19
 

A. Body Weights and Clinical Signs (Rats) 19
 

B. Survival (Rats) 21
 

C. Pathology (Rats) 21
 

D. Statistical Analyses of Results (Rats) 23
 

IV. Results - Mice 25
 

A. Body Weights and Clinical Signs (Mice) 25
 

B. Survival (Mice) 27
 

C. Pathology (Mice) 29
 

D. Statistical Analyses of Results (Mice) 31
 

V. Discussion 33
 

VI. Bibliography 37
 

APPENDIXES
 

Appendix A Summary of the Incidence of Neoplasms in
 

Rats Administered Fenthion in the Diet 39
 

Table Al Summary of the Incidence of Neoplasms in Male
 

Rats Administered Fenthion in the Diet 41
 

Table A2 Summary of the Incidence of Neoplasms in Female
 

Rats Administered Fenthion in the Diet 45
 

vii
 
Appendix B Summary of the Incidence of Neoplasms in Mice 

Administered Fenthion in the Diet 49 

Table Bl Summary of the Incidence of Neoplasms in Male 

Mice Administered Fenthion in the Diet 51 

Table B2 Summary of the Incidence of Neoplasms in Female 

Mice Administered Fenthion in the Diet 55 

Appendix C Summary of the Incidence of Nonneoplastic 

Lesions in Rats Administered Fenthion 

in the Diet 59 

Table Cl Summary of the Incidence of Nonneoplastic 

Lesions in Male Rats Administered Fenthion 

in the Diet 61 

Table C2 Summary of the Incidence of Nonneoplastic 

Lesions in Female Rats Administered Fenthion 

in the Diet 65 

Appendix D Summary of the Incidence of Nonneoplastic 

Lesions in Mice Administered Fenthion 

in the Diet 69 

Table Dl Summary of the Incidence of Nonneoplastic 

Lesions in Male Mice Administered Fenthion 

in the Diet 71 

Table D2 Summary of the Incidence of Nonneoplastic 

Lesions in Female Mice Administered Fenthion 

in the Diet 74 

Appendix E Analyses of the Incidence of Primary Tumors 

in Rats Administered Fenthion in the Diet 77 

Table El Analyses of the Incidence of Primary Tumors in 

Male Rats Administered Fenthion in the Diet.... 79 

Table E2 Analyses of the Incidence of Primary Tumors in 

Female Rats Administered Fenthion in the Diet.. 84 

Appendix F Analyses of the Incidence of Primary Tumors 

in Mice Administered Fenthion in the Diet 89 

viii
 
Table Fl Analyses of the Incidence of Primary Tumors in 

Male Mice Administered Fenthion in the Diet 91 

Table F2 Analyses of the Incidence of Primary Tumors in 

Female Mice Administered Fenthion in the Diet... 95 

Appendix G Analysis of Formulated Diets for 

Concentrations of Fenthion 99 

TABLES 

Table 1 Fenthion Subchronic Feeding Studies in Rats and 

Mice 8 

Table 2 Fenthion Chronic Feeding Studies in Rats 10 

Table 3 Fenthion Chronic Feeding Studies in Mice 11 

FIGURES 

Figure 1 Growth Curves for Rats Administered Fenthion 

in the Diet 20 

Figure 2 Survival Curves for Rats Administered Fenthion 

in the Diet 22 

Figure 3 Growth Curves for Mice Administered Fenthion 

in the Diet 26 

Figure 4 Survival Curves for Mice Administered Fenthion 

in the Diet 28 

ix
 

I. INTRODUCTION
 

Fenthion (CAS 55-38-9; NCI
 

C08651), the 0,0-dimethyl ester
 

of 0-(4-(methylthio)-m-tolylphosphorothioic acid, is one of the
 

organophosphate pesticides. It
 

Fenthion
 

was developed by G. Schrader and
 

E. Schegk and first marketed by
 

Farbenfabriken Bayer A.G. as an insecticide in 1957 (Spencer,
 

1973). This organophosphorus pesticide inhibits the enzyme
 

cholinesterase, thereby preventing the hydrolysis of
 

acetylcholine in insects and mammals. The effects of the
 

excessive accumulation of acetylcholine may be lethal to humans
 

if not treated (Murphy, 1975).
 

In recent years, this insecticide has been used in California for
 

the control of mosquitoes which are vectors of encephalitis
 

(Ayers and Johnson, 1976). Approximately 200,000 pounds of
 

fenthion were used in the United States in 1974, and an analysis
 

of use patterns showed that virtually all of the chemical was
 

sprayed over wetlands for insect control (Ayers and Johnson,
 

1976).
 
Fenthion is also applied topically to control warble grubs and
 

lice in beef and non-lactating cattle (Food and Drug
 

Administration, 1976), and it has been used for insect control in
 

food handling establishments (Environmental Protection Agency,
 

1973).
 

The acute oral LD for fenthion has been reported as 260 mg/kg
 

in the Sprague-Dawley male rat, 325 mg/kg in the Sprague-Dawley
 

female rat, 125 mg/kg in the CF1 male mouse, and 150 mg/kg in
 

the CF female mouse (DuBois and Kinoshita, 1964).
 

In other studies, fenthion given orally to male rats (strain not
 

specified) at 30 mg/kg for 13 weeks caused approximately 30%
 

mortality (Kimmerle, 1961), and when fed to male and female rats
 

(strain not specified) at 0.25-5.0 mg/kg for 3 months induced
 

mortality (percent not given) in the females at 5.0 mg/kg
 

(Shimamoto and Hattori, 1969). Metabolic products of fenthion
 

(sulfoxide, sulfone, oxygen analog, 0-sulfoxide, and 0-sulfone)
 

were found to be toxic in albino, Porton strain male rats by oral
 

administration (Francis and Barnes, 1963).
 

Fenthion was selected for study in the Carcinogenesis Testing
 

Program as a part of efforts to assess the carcinogenic potential
 

of certain pesticides.
 
II. MATERIALS AND METHODS
 

A. Chemical
 

Technical-grade fenthion was obtained in a single batch (Lot No.
 

4050284) from the Chemagro Division of Mobay Chemicals, Kansas
 

City, Missouri, and used during all phases of testing. Elemental
 

analyses for C, H, S, and P were consistent with GI_H1-D-PS^,
 

the molecular formula of fenthion. Thin-layer chromatography
 

showed a single spot. Gas-liquid chromatography (flame ionization
 

detector) showed no impurities. The infrared, ultraviolet, and
 

nuclear magnetic resonance spectra were consistent with those
 

shown by an analytical standard of fenthion. The technical-grade
 

fenthion as described above will be referred to as fenthion in
 

this report.
 

The bulk chemical was stored at 4 C.
 

B. Dietary Preparation
 

All diets were formulated weekly using Wayne® Lab Blox meal
 

(Allied Mills, Inc., Chicago, 111.) to which was added the
 
required amount of fenthion. The test compound was first
 

dissolved in a small amount of acetone (Mallinckrodt Inc., St.
 

Louis, Mo.) which was then added to the feed. Corn oil
 

(LouAna , Opelousas Refinery, Opelousas, La.) was also added to
 

the feed at 2% of the final feed weight, primarily as a dust
 

suppressant. The diets were mixed mechanically for not less than
 

25 minutes to assure homogeneity and to allow for evaporation of
 

the acetone. Diets for the control groups of animals also
 

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

The stability of fenthion in feed was tested by determining the
 

concentration of the compound in formulated diets at intervals
 

over a 7-day period. Diets containing 10 or 320 ppm fenthion
 

showed no significant change in fenthion concentration on
 

standing at ambient temperatures for this period. Formulated
 

diets were, therefore, stored at room temperature until used, but
 

not longer than 1 week.
 

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

diets, the concentration of fenthion was determined in randomly
 

selected batches of formulated diets at 8-week intervals during
 

the chronic studies. The results of these analyses are reported
 

in Appendix G. At each dietary concentration, the mean value
 
obtained was within 0.9% of the theoretical, and the coefficient
 

of variation was 6.74% or less.
 

C. Animals
 

F344 rats and B6C3F1 mice of each sex, obtained through contracts
 

of the Division of Cancer Treatment, NCI, were used in these
 

bioassays. The rats and mice were bred at and supplied by the
 

NCI Frederick Cancer Research Center, Frederick, Maryland. On
 

arrival at the laboratory, all animals were quarantined for 16
 

days, then assigned to dosed or control groups. The rats were 6
 

weeks of age and the mice were 7 weeks of age when placed on
 

study.
 

D. Animal Maintenance
 

All animals were housed in rooms in which the temperature ranged
 

from 22 to 24°C, and the relative humidity from 40 to 70%. The
 

air in each room was filtered through fiberglass filters (Air
 

Maze Incom International, Cleveland, Ohio), and room air was
 

changed 10 to 12 times per hour. Fluorescent lighting provided
 

illumination 10 hours per day, Food and tap water were available
 
ad libitum. Fresh feed was provided daily, and excess remaining
 

feed was discarded.
 

The rats were housed individually in hanging galvanized steel
 

mesh cages (Hoeltge, Inc., Cincinnati, Ohio), and the mice were
 

housed in polypropylene cages (Lab Products, Inc., Garfield,
 

N.J.) containing five females per cage or two or three males per
 

cage. Mouse cages were covered with polyester filter bonnets
 

(Lab Products, Inc.). The racks and cages for the rats were
 

sanitized every 2 weeks. The mouse cages were sanitized each
 

week. These cages and racks were washed in an industrial washer
 

at 82°C with Acclaim® detergent (Economics Laboratory, Inc.,
 

St. Paul, Minn.) and then rinsed. Absorbent Kimpak® cage
 

liners (Kimberly Clark Corp., Neenah, Wis.) were placed under the
 

rat cages and were changed three times per week. Absorb-dri
 

hardwood chip bedding (Lab Products, Inc.), used in the mouse
 

cages, was provided two times per week for males and and three
 

times per week for females. Filter bonnets were sanitized each
 

week. Feeder jars and water bottles were changed and sanitized
 

three times per week. Sipper tubes and stoppers were sanitized
 

two times per week.
 

The filter bonnets, feed jars, water bottles, sipper tubes, and
 

stoppers were washed in a Vulcan Autosan washer (Louisville, Ky.).
 
Cage racks for each species were rotated to a new position in the
 

room once per week; at the same time, each cage was moved to a
 

different row within the same column of a rack. Rats and mice
 

receiving fenthion were housed in separate rooms. Control and
 

dosed rats were housed on the same rack, whereas cages for control
 

and dosed mice were placed on separate racks in the same room.
 

E. Subchronic Studies
 

Subchronic feeding studies were conducted to estimate the maximum
 

tolerated doses (MTD's) of fenthion, on the basis of which two
 

concentrations (hereinafter referred to in this report as "low"
 

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

chronic studies. Groups of 10 males and 10 females of each
 

species were administered fenthion at one of several doses, and
 

groups of 10 control animals of each species and sex were
 

administered basal diet only. The period of administration of
 

the test chemical was 13 weeks, after which the animals were
 

killed and necropsied. Animals were weighed each week. Table 1
 

shows the number of animals that survived during the course of
 

administration and the week on study when the last death occurred.
 

The table also shows the mean body weights of the dosed animals
 

at week 13, expressed as percentages of mean body weights of
 
Table 1. Fenthion Subchronic Feeding Studies in Rats and Mice
 

Male Female 

Week on Week on 

Study Mean Weight Study Mean Weight 

when Last at Week 13 when Last at Week 13 

Dose Surviv­ Animal as % of Surviv- Animal as % of 

(ppm) al (a) Died Control al (a) Died Control 

Rats 

5 10/10 99 10/10 100
 

10 10/10 101 10/10 99
 

20 10/10 102 10/10 103
 

40 10/10 102 10/10 104
 

80 10/10 98 10/10 103
 

160 10/10 93 10/10 96
 

320 10/10 79 9/10 10 80
 

Mice
 

5 10/10 93 10/10 104
 

10 10/10 96 10/10 104
 

20 10/10 107 10/10 100
 

40 10/10 107 10/10 104
 

80(b) 10/10 104 10/10 100
 

160 10/10 96 10/10 104
 

320 10/10 107 10/10 100
 

(a) Number surviving/number in group.
 

(b) One animal (sex not recorded) showed enlargement of lymph nodes,
 

spleen, and liver. Histopathologic examination indicated a
 

reticulum-cell sarcoma, which appeared to be a coincidental lesion.
 
controls. Histopathologic findings are shown as footnotes to the
 

table.
 

In previous bioassays of organophosphorus chemicals at this
 

laboratory, chronic doses based on Subchronic tests were toxic.
 

Thus, doses for the chronic studies in both rats and mice were
 

set at relatively low concentrations (10 and 20 ppm).
 

F. Chronic Studies
 

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

feeding studies are shown in tables 2 and 3.
 

G. Clinical and Pathologic Examinations
 

All animals were observed twice daily. Clinical examination for
 

signs of toxicity and palpation for masses were performed each
 

month, and the animals were weighed every 2 weeks. Moribund
 

animals and animals that survived to the end of the bioassay were
 

killed using pentobarbitol and necropsied. Necropsies were also
 

performed on all animals found dead, unless precluded by
 

autolysis or severe cannibalization.
 
Table 2. Fenthion Chronic Feeding Studies in Rats
 

Sex and Initial Fenthion Time on Study
 

Test No. of Doses (b) Dosed Observed
 

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

Male
 

Matched-Control 25 0 105
 

Low-Dose 50 10 103 1-2
 

High-Dose 50 20 103 1-2
 

Female
 

Matched-Control 25 0 104-105
 

Low-Dose 50 10 103 2
 

High-Dose 50 20 103 2
 

(a) Rats were 6 weeks of age when placed on study.
 

(b) Test and control diets were available ad libitum.
 

10
 
Table 3. Fenthion Chronic Feeding Studies in Mice
 

Sex and Initial Fenthion Time on Study
 

Test No. of Doses (b) Dosed Observed
 

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

Male
 

Matched-Control 25 0 103-104
 

Female
 

Matched-Control 25- 0 103-104
 

Low-Dose 50 10 103 0-1
 

High-Dose 50 20 103 0-1
 

Low-Dose 50 10 103 0-1
 

High -Dose 50 20 103 0-1
 

(a) Mice were 7 weeks of age when placed on study.
 

(b) Test and control diets were available ad libitum.
 

11
 
The pathologic evaluation consisted of gross and microscopic
 

examination of major tissues, major organs, and all gross
 

lesions. The following tissues were examined microscopically:
 

skin, lungs and bronchi, trachea, bone and bone marrow, spleen,
 

lymph nodes, heart, salivary gland, liver, gallbladder (mice),
 

pancreas, stomach, small intestine, large intestine, kidney,
 

urinary bladder, pituitary, adrenal, thyroid, parathyroid,
 

mammary gland, prostate or uterus, testis or ovary, and brain.
 

Occasionally, additional tissues were also examined
 

microscopically. The different tissues were preserved in 10%
 

buffered formalin, embedded in paraffin, sectioned, and stained
 

with hematoxylin and eosin. Special staining techniques were
 

utilized when indicated for more definitive diagnosis. Blood
 

smears of all animals were routinely prepared.
 

A few tissues from some animals were not examined, particularly
 

from those animals that may have died early, been missing, or
 

been in advanced states of cannibalization or autolysis. 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.
 

12
 
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.
 

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
 

sections.
 

Probabilities of survival were estimated by the product-limit
 

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

report in the form of graphs. Animals were statistically
 

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

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

causes were not statistically censored. Statistical analyses for
 

13
 
a possible dose-related effect on survival used the method of Cox
 

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

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

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

except the departure from linearity test, which is only reported
 

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

The incidence of neoplastic or nonneoplastic lesions has been
 

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

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

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

the denominators included only those animals for which that site
 

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

(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
 

14
 
dose level. When results for a number of dosed groups (k) are
 

compared simultaneously with those for a control group, a
 

correction to ensure an overall significance level of 0.05 may be
 

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

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

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

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

where the Fisher exact P values are shown.
 

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

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

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

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

one-tailed 0.05 level of significance. Unless otherwise noted,
 

the direction of the significant trend is a positive dose
 

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
 

15
 
such an early tumor was found, comparisons were based exclusively
 

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

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

obtained, the standard procedures for analyses of the incidence
 

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

followed.
 

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

incidence of tumors. Curves of the proportions surviving without
 

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

The week during which an animal died naturally or was sacrificed
 

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

methods of comparing these curves were used for two groups;
 

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

groups. The statistical tests for the incidence of tumors which
 

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 to its control was calculated
 

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

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

16
 
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
 

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
 

17
 
the induction of tumors by the test chemical, which could not be
 

detected under the conditions of this test.
 

18
 
III. RESULTS - RATS
 

A. Body Weights and Clinical Signs (Rats)
 

Mean body weights of the male and female rats did not differ
 

appreciably from those of their respective controls at any time
 

during the bioassay (figure 1).
 

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

comparable to the controls in appearance and behavior. Clinical
 

signs were noted at a low incidence in both dosed and control
 

groups. These signs included loss of weight, rough hair coats,
 

and exudate from eyes; one low-dose female appeared to have
 

abdominal distention and had vaginal bleeding. During the second
 

year on study, clinical signs increased in frequency in both
 

dosed and control groups. These signs included rough and
 

discolored hair coats, loss of weight, pale mucous membranes,
 

poor food consumption, loose stools, discolored (dark) urine,
 

abdominal distention, vaginal bleeding, and tachypnea.
 

19
 
BgtfS38£8*f *6 

}

B 

3A 

a ,8B — 300­ ^­

i O 

LU Q g 

g 250­

>• 

Q 

O O 

CO 200­ 6 

Z 

u

<

l O

5 Q

MALE RATS 

O D MATCHED CONTROL j il O LOW DOSE 

A HIGH DOSE 

10 20 40 60 60 70 

TIME ON STUDY (WEEKS) 

13 300­

I­

(3 

2 250­

Q 

O 200­ m 

Ul 

5 150­

FEMALE RATS 

D MATCHED CONTROL 

O LOW DOSE 

A HIGH DOSE 

TIME ON STUDY (WEEKS) 

Figure 1. Growth Curves for Rats Administered Fenthion in the Diet 

20 
B. Survival (Rats)
 

The Kaplan and Meier curves estimating the probabilities of
 

survival for male and female rats administered fenthion in the
 

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

matched controls, are shown in figure 2. The result of the
 

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

significant in either sex.
 

In male rats, 40/50 (80%) of the high-dose group, 32/50 (64%) of
 

the low-dose group, and 21/25 (84%) of the matched-control group
 

were alive at week 103. In females, 32/50 (64%) of the high-dose
 

group, 38/50 (76%) of the low-dose group, and 16/25 (64%) of the
 

matched-control group were alive at week 103. 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.
 

21
 
i 

D^-if^ 

D±OT 

°0- •^ [3«

'A 1

c>-i A 

On 

Q 'A 

Q 

\, 

^

^ 

6-0 

1VAIA 

< 

D 

cn 

u. 

0 „ 5Aim S s « TM m 

0 

oc 

°­ 30­

MA 

D MAT 

O LOW 

A HIGH 

-E RAT 

:HED CON 

DOSE 

DOSE 

i 

TROL 

30 40 50 60 70

TIME ON STUDY (WEEKS) 

 80 90 100 110 

< 

cc 

O .50-­

>­

Im 

O 

cc 

O. 

I 

FEMALE RATS 

D MATCHED CONTROL 

O LOW DOSE 

A HIGH DOSE 

TIME ON STUDY (WEEKS) 

Figure 2. Survival Curves for Rats Administered Fenthion in the Diet 

22 
Neoplasms occurred with a comparable incidence among dosed and 

control animals. An exception to this was seen in C-cell 

adenomas of the thyroid, where there was an increased incidence 

of tumors in the low-dose female rats (12/48) as compared with 

the high-dose (4/46) and control (2/22) groups which were similar. 

A variety of common nonneoplastic lesions were encountered. The 

numbers of specific lesions were small, however, and they 

appeared to be unrelated to the administration of fenthion. 

Chronic inflammation of the submaxillary salivary gland occurred 

with a rather high incidence in dosed and control groups of both 

sexes. Viral inclusion bodies were not clearly evident. The 

inflammatory reaction was limited to the submaxillary gland and 

did not extend to the closely adjoining sublingual gland. These 

lesions were not considered to be compound related. 

Based on the histopathologic examination, fenthion was not 

carcinogenic in F344 rats under the conditions of this bioassay. 

D. Statistical Analyses of Results (Rats) 

Tables El and E2 in Appendix E contain the statistical analyses 

23 
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. 

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

dose-related trend in the incidence of interstitial-cell tumors 

of the testis is significant (P = 0.028), but the results of the 

Fisher exact test are not significant. Historical records for 

this strain of rats indicate spontaneous incidences of tumors at 

rates between 75 and 100%. A significant dose-related trend (P = 

0.036) in the negative direction is observed in the incidence of 

fibromas of the integumentary system in male rats and in the 

incidence of adenocarcinomas of the mammary gland in female rats, 

in which the incidence in the control group exceeds the 

incidences in the dosed groups. 

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

in the tables, the value of one is included; this indicates the 

absence of significant positive results. It should also be noted 

that each of the intervals has an upper limit greater than one, 

indicating the theoretical possibility of the induction of tumors 

by fenthion, which could not be detected under the conditions of 

this test. 
IV. RESULTS - MICE
 

A. Body Weights and Clinical Signs (Mice)
 

Mean body weights of the male and female mice did not differ
 

appreciably from those of their respective controls at any time
 

during the bioassay (figure 3).
 

During the first 4 months on study, the dosed animals were
 

generally comparable to the controls in appearance and behavior.
 

During the next 8 months, clinical signs were noted at a fairly
 

low incidence. These signs included alopecia, loss of weight,
 

and rough and discolored hair coats. Fighting was observed among
 

the male mice, but predominantly in the dosed groups. This
 

increased aggression resulted in traumatic conditions ranging
 

from genital mutilation to death and cannibalism, which persisted
 

until termination of the study. During the second year on study,
 

the incidence of clinical signs increased in the dosed animals.
 

These signs included pale mucous membranes, alopecia, tachypnea,
 

and abdominal distention. Some animals in all groups appeared
 

hyporeactive. A majority of the high-dose females exhibited a
 

yellow discoloration of the hair coat during the last 5 months.
 

25
 
o

n 

DO 

O 

a

8 

8 a A A n o on DDQOQ o o A D O QQOOOOOAQOQQfi D OQOQQOQQQnQDQ an onaananoAAA o aooo o on 

3D O AO ­ ­ O D A 

a 

m 20 A 

D

O

A

MALE MICE 

 MATCHED CONTROL 

 LOW DOSE 

 HIGH DOSE 

10 20 30 40 50 60 70

TIME ON STUDY (WEEKS) 

 80 90 100 110 

a an ana a oaa 

a n 8D8Qn28802g°00868D A

an n DAOAOA A 08 

a 

g

z 

< 

S 

20­ D

" a' 

na 

FEMALE MICE 

P MATCHED CONTROL 

O LOW DOSE 

A HIGH DOSE 

10 20 30 40 50 60 70

TIME ON STUDY (WEEKS) 

 80 90 100 

Figure 3. Growth Curves for Mice Administered Fenthion in the Diet 

26 
B. Survival (Mice) 

The Kaplan and Meier curves estimating the probabilities of 

survival for male and female mice administered fenthion in the 

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

matched controls, are shown in figure 4. The result of the 

Tarone test for positive dose-related trend in mortality in the 

three groups is not significant in either sex. In male mice, an 

indicated departure (P = 0.005) from linear trend is observed, 

because the high-dose animals survived longer than the low-dose 

animals. The result of the Cox test comparing the survival of 

the low-dose group with that of the control group in male mice is 

significant (P = 0.015), but the results of this test are not 

significant when the survival of the high-dose group is compared 

with that of the control group. 

In males, 38/50 (76%) of the high-dose group, 30/50 (60%) of the 

low-dose group, and 22/25 (88%) of the matched-control group were 

alive at week 103. In females, 41/50 (82%) of the high-dose 

group, 39/50 (78%) of the low-dose group, and 24/25 (96%) of the 

matched-control group were still alive at week 103. Sufficient 

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

late-appearing tumors. 

27 
J ^1 

% 

A- -

vl .90- iTl "L-L 0-. —a 

0--, 

A A 4­

Oi ^ A 

3 1

Ch 

A. 

-v ­

i 

BILIT

Y

OF SURVIVAL 

5

 •-" 

^n u

i 

6 

i g j3

<t

on 

O

DC a. 

MAL E MICE 

3 MATC HEDCON1 ROL 

D LOW JOSE 

2i HIGH DOSE 

10 20 30 40 50 60 70 80 90 100 110 

TIME ON STUDY (WEEKS) 

A A "C 

 A ­ A- - | • p — — ­1 1 A

 A 

A -CD -i-A .80­

Q 

OD 

i 

e 

VIVAL

3

OC .ou^ 

U> 

u. 

0 50 

t­

_J 

a." „„ PROBA

i S

FEM ALE Ml ;E 

D MAT :HEDCON TROL 

O LOW DOSE 

A HIGH DOSE 

0 10 20 30 40 50 60 70 80 90 100 110 

TIME ON STUDY (WEEKS) 

Figure 4. Survival Curves for Mice Administered Fenthion in the Diet 

28 
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 both dosed and
 

control animals. The majority were not thought to be compound
 

related. However, sarcomas of various types occurred with
 

greater frequency in dosed male mice than in the controls, as
 

follows:
 

Low High
 

Control Dose Dose
 

Skin and Subcutaneous
 

Tissue (25) (49) (48
 

Sarcoma, NOS 0 0 2 

Fibres ar coma 0 4 4 

Rhab domy os ar c oma 0 3 2 

In female mice, the only such tumor was a fibrosarcoma observed
 

in a low-dose animal. The integument was considered to be the
 

primary site for all of the primary sarcomas, NOS, and
 

fibrosarcomas. In the case of the rhabdomyosarcomas, the
 

skeletal muscle within the subcutaneous tissue appeared to be the
 

site of origin.
 

29
 
Histologically, differentiation was minimal to moderate among the 

various fibrosarcomas. Spindle-shaped fibroblastic elements were 

often arranged in a semi-whorled pattern with varying proportions 

of more primitive mesenchymal-type elements. Local invasiveness 

was readily apparent. In two cases, metastases occurred to the 

lungs and regional lymph node. 

The rhabdomyosarcomas were composed of large, pleomorphic, 

relatively undifferentiated cells. Anaplasia was the rule rather 

than the exception. Strap-shaped and multinucleated elements 

were occasionally encountered. Rudimentary cross-striations were 

found in a few cells in sections stained with hematoxylin and 

eosin; special stains were not employed. Attempts to find 

unequivocal cross-striations in neoplastic cells were complicated 

by the fact that the few striations observed were poorly 

developed at best, and also by the necessity of differentiating 

striations within remnants of pre-existing skeletal muscle fibers 

undergoing myolysis in the midst of encroaching neoplastic 

elements. One of these neoplasms metastasized to the regional 

lymph node and invaded the pararenal tissue. Spontaneous 

rhabdomyosarcomas are considered rare in mice; thus, the 

incidence of 5% for dosed males may represent a compound-related 

effect. 

30 
The histopathologic examination provided evidence for the
 

carcinogenicity of fenthion in male B6C3F1 mice, as there was a
 

compound-related increase in sarcomas of the skin and subcutis.
 

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 at an incidence of at least. 5%
 

in one or more than one group.
 

In male mice, the results of the Cochran-Armitage test for
 

dose-related trend in the incidence of animals with fibrosarcomas, sarcomas, or rhabdomyosarcomas of the integumentary
 

system are significant (P = 0.043). The Fisher exact comparison
 

of incidences between the low-dose and control groups shows a P
 

value of 0.048 and between the high-dose and control groups a P
 

value of 0.028. These two P values are above the 0.025 level
 

required for significance when the Bonferroni inequality
 

criterion is used for multiple comparisons. When the life-table
 

method, using times of observations of the tumors, is applied,
 

the result of the Tarone test is not significant. The historical
 

records of control male B6C3F1 mice at this laboratory indicate
 

31
 
an incidence of animals with sarcomas or fibrosarcomas of the
 

integumentary system of 7/435 (1.6%). The highest incidence of
 

these fibrosarcomas or sarcomas in the 27 male historical-control
 

groups at this laboratory was 4/25 (16%), but no rhabdomyosarcomas
 

are observed in the historical records for the control male or
 

female B6C3F1 mice. The incidences of animals with fibrosarcomas,
 

sarcomas, NOS, and rhabdomyosar comas in the low- and high-dose
 

groups of this study are 7/49 (14%) and 8/48 (17%), respectively.
 

These results suggest an association of these various types of
 

sarcomas with the administration of fenthion.
 

In female mice, the results of the Cochran-Armitage test for
 

positive dose-related trend in proportions and those of the
 

Fisher exact test comparing the incidences in the control group
 

with those in the dosed groups in the positive direction are not
 

significant at any site. Significant results in the negative
 

direction are observed in the incidence of papillary adenomas of
 

the thyroid in female mice, where the incidence in the control
 

group exceeds the incidences in the dosed groups. This negative
 

significance may be because the control animals lived longer than
 

the dosed animals.
 

32
 
V. DISCUSSION
 

Administration of fenthion to male and female F344 rats and
 

female B6C3F1 mice resulted in no appreciable toxicity at the
 

doses administered in this bioassay, since the mean body weights
 

and the survivals of the dosed animals were generally
 

unaffected. Among the male mice, 30/50 (60%) of the low-dose
 

group and 38/50 (76%) of the high-dose group, compared with 22/25
 

(88%) of the controls were alive at week 103 and the survival of
 

the low-dose group was significantly less than that of the
 

control group. Thus, animals other than male mice may have been
 

able to tolerate higher doses. However, fighting was observed
 

among the male mice, particularly among the dosed animals, and it
 

resulted in severe bite wounds and death. Sufficient numbers of
 

animals in all groups of rats and mice were at risk for the
 

development of late-appearing tumors.
 

In the male rats, interstitial-cell tumors of the testis occurred
 

at incidences that were dose related (P = 0.028); however, the
 

incidences of the tumors in the individual dosed groups were not
 

significantly higher than the incidence in the control group
 

(controls 18/24, low-dose 37/50, high-dose 45/49). Also, this
 

tumor is known to occur spontaneously at high incidences (70 to
 

33
 
100%) in F344 male rats. Thus, the occurrence of
 

interstitial-cell tumors of the testis in the dosed males of the
 

present bioassay cannot clearly be related to administration of
 

fenthion.
 

In the female rats and also in the female mice, no tumors
 

occurred at incidences that were significantly higher in dosed
 

groups than in control groups.
 

In the male mice, sarcomas, fibrosarcomas, or rhabdomyosarcomas
 

of the integumentary system occurred at incidences that were dose
 

related (P = 0.043). In direct comparisons of the incidences of
 

these tumors in the dosed groups with the incidence in the
 

control group, the P values of 0.048 and 0.028 for the low- and
 

high-dose groups, respectively, did not meet the Bonferroni
 

criterion of P = 0.025 for significance when multiple comparisons
 

are made (controls 0/25; low-dose 7/49, or 14%; high-dose 8/48,
 

or 17%). However, the incidence of sarcomas and fibrosarcomas in
 

historical-control male B6C3F1 mice used in bioassays of all
 

chemicals tested at this same laboratory was only 7/435 (1.6%),
 

and no rhabdomyosarcomas occurred in the historical-control male
 

mice. Thus, the increased incidence of sarcomas, fibrosarcomas,
 

or rhabdomyosarcomas of the integumentary system in the dosed
 

34
 
male mice of the present bioassay was associated with the
 

administration of the test chemical.
 

In a previously published study, when rats (strain not specified)
 

were administered diets containing 0, 2, 3, 5, 25, and 100 ppm
 

fenthion for 1 year, the dosed animals had no significant change
 

in general appearance, growth rate, food consumption, and gross
 

or microscopic appearance of tissues (Doull et al., 1963).
 

It is concluded that under the conditions of this bioassay,
 

fenthion was not carcinogenic for male or female F344 rats or for
 

female B6C3F1 mice. The increased incidence of sarcomas,
 

fibrosarcomas, and especially rhabdomyosarcomas of the
 

integumentary system in the male B6C3F1 mice suggested that the
 

test chemical was carcinogenic in these animals.
 

35
 
36

 
VI. BIBLIOGRAPHY
 

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

Economics Handbook, Stanford Research Institute, Menlo Park,
 

Calif., 1976, sec. 573.3002 W-X and 573.3007 G-H.
 

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

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

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

Panel of Carcinogenicity of the Cancer Research Commission of
 

UICC, International Union Against Cancer, Geneva, 1969.
 

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

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

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

1970, pp. 48-52.
 

Doull, J., Root, M., Cowan, N. J., Vesselinovitch, D., Fitch, F.
 

W., and Meskauskas, J., Chronic oral toxicity of Bayer 29493 to
 

male and female rats. Unpublished report submitted by
 

Farbenfabriken Bayer A.G., 1963, Cited in 1971 Evaluation of Some
 

Pesticides in Food, World Health Organization Pesticide Residue
 

Series No. 1, World Health Organization, Geneva, 1972. Food and
 

Drug Administration, 1976.
 

DuBois, K. P. and Kinoshita, F., Acute toxicity and anticholinesterase action of 0,0,-dimethyl 0- 4-(methylthio)-m- tolyl
 

phosphorothioate (DMTP; Baytex) and related compounds. Toxicol.
 

Appl. Pharmacol. 6^:86-95, 1964.
 

Environmental Protection Agency, Insecticides in food handling
 

establishments, Federal Register 38(154): 21685, 1973.
 

Food and Drug Administration, Opthalmic and topical dosage form
 

new animal drugs not subject to certification. CFR 21:143, 1976.
 

Francis, J. I. and Barnes, J. M., Studies on the mammalian
 

toxicity of fenthion. Bull. Wld Hlth Org. 2£:205-212, 1963.
 

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

significance tests, confidence limits and adjustments for
 

stratification. Rev. Int. Statist. Inst. 39(2):148-169, 1971.
 

37
 
Kaplan, E. L. and Meier, P., Nonparametric estimation from
 

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

Kimmerle, G., Subchronische oral versuche bei ratten mit S-1752 -


Wirkstoff. Unpublished report submitted by Farbenfabriken Bayer
 

A.G., 1961. Cited in 1971 Evaluations cy£ Some Pesticides in Food,
 

World Health Organization Pesticide Residue Series No. 1, World
 

Health Organization, Geneva, 1972.
 

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.
 

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

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

Murphy, S. D., Pesticides. In: Toxicology - The Basic Science of
 

Poisons, Casarett, L. J. and Doull, J., eds., Macmillan Publishing
 

Co., Inc., New York, 1975, pp. 408, 416-417.
 

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

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

by different numbers of administrations of benzo (a) pyrene and
 

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

Shimamoto, K. and Hattori, K., Chronic feeding of Baytex (0,0-dimethyl-o-(4-methylmercapto-3-methyl)phenyl-thiophosphate) in rats.
 

Acta Med. Univ. Kioto 40:163-71, 1969. Cited in 1971 Evaluations of
 

Some Pesticides ^n Food, World Health Organization Pesticide Residue
 

Series No. 1, World Health Organization, Geneva, 1972.
 

Spencer, E. Y., Fenthion. In: Guide to the Chemicals Used in Crop
 

Protection, University of Western Ontario, London, Ontario, 1973, p.
 

279.
 

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

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

World Health Organization, 1971 Evaluation of Some Pesticides in
 

Food, World Health Organization Pesticide Residue Series No. 1,
 

World Health Organization, Geneva, 1972.
 

38
 
APPENDIX A
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

RATS ADMINISTERED FENTHION IN THE DIET
 

39
 
40

 
TABLE A1. 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE RATS 

ADMINISTERED FENTHION IN THE DIET

 

MATCHED 

CONTROL LOW DOSE HIG H DOSE 

ACTUAL S INITIALL Y IK STUD Y 25 50 50 

ANIMAL S NECROP5IE D 25 50 49 

ANIMAL S EXAMINE D HISTOP ATHOLO GICAII Y 2 5 5 0 49 

INTEGUMENTAR Y SYSTE M 

*SKT N (25 ) (50) (49 ) 

PAPILLOMA , NOS 1 (2%) 

SQUAMO'J S CELL CARCINOM A 1 (4% ) 

*TBP?M R 2 (8% ) 

"?E SFTR AT3 P Y SYSTE M 

*IUNG (25) (49) (49) 

ALVEO I A D ./BRONCHTOLA R ADENOM A 1 (2% ) 

OSTEOSARCOMA , KETASTATIC 1 (2X ) 

H ^r^A'^'^PO^^'^1"^ C SY^TFF' 

*MULTIPL E DFGAN F (25) (50) (49 )

 

T.EUKEBT A,NO S 2 (8%) 1 (2% ) 

'WDI?FE?EliriA r ED LEJKEM.I A 1 (2% ) 

! YMPHOCYTT C IEUKEMI A 2 (4% ) 

MONOCYTI C LEUKEKI A 4 (16% ) 4 (8%) 8 (16% ) 

*SPLEEN' (25) (47 ) (49 )

 

HEMANGIOM A 1 (2%) 

C T"^ C 'I L A TO ^ Y SYSTE M 

IO N ? 

DIGESTIVE SYSTEM
 

(25) (49) (49)
 

NEOPLASTI C NODtJI E 

# NU1BE? . OF ANIMAL S WI m H TISSUE EXAMINE D MICROSCOPICALL Y 

* NUMSE 9 Of ANIMAL S "ECFOP^IED 

41 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

HEPATOCELLULA F CARCINOM A 1 (2%) 

HEMANGIOM A 1 (2%) 

#PANCREA ? (24) (47) (49) 

ACINAP-CEL L ADENOM A 1 (2% ) 

#JEJUNU M (24 ) (48) (48) 

ADENOCARCINO!"!A, NOS 1 (4% ) 

#CECU M (24 ) (47 ) (47) 

ADENOMATOU S POLYP, NOS 1 (2% ) 

URINAR Y SYSTE M 

#KIDNE Y (25) (49) (48) 

OSTEOSAFCOMA , METASTATIC 1 (2% ) 

ENDOCSINE SYSTEM 

•PITUITARY (25) (47) (44) 

CAP.CT NOMA,NO S 4 (9%) 

ADEM3MA , NOS 1 (2*) 

CHROMOPHOEE ADENO«A 9 (36%) 12 (26%) 9 (20%) 

«ADPENA L (25) (49) (49) 

CAPCTNOMA,NO S 1 (2%) 

PHEOCHRDMOCYTOM A 1 (2% ) 

tTHYROTD (23) (44) (27) 

T'OLLI CAPCINOM A 2 (5%) 

C-CELL ADENOM A 2 (9% ) 5 (11% ) 3 (11*) 

#PA*'CREA' T ' IC ISLET? : (24 ) (47 ) (49 ) 

TSLET-CELT, ADENC1 A 2 (8%) 1 (2%) 2 (4% ) 

REPRODUCTIV E SYSTE M 

*MAMMAR Y GLAN D (25) (50) (49 )

 

FIBROM A 1 (4% ) 1 (2% )

 

(24) (50) (49) 

._18_J75J1. ,_45_J9J«1 

# NUMBE R OF ANIKAL S WITH TISSUE EXAMINE D MICROSCOPICALL Y 

* NUMBE R O F ANIMAL S NECPOPSIE D 

42 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

NEF.VfHJ S SYSTE M 

*B?.AIN (25) (49 ) (49 ) 

FQUAMOU ? CEL L CARCINOMA , *1ETASTA 1 (2%) 

SPECIA L SENSE ORGAN ? 

*FA R (25 ) (50) (49 ) 

SQUAMOU S CELL CARCINOM A 1 (2% ) 

*EA R CANA L (25) (50) (49 ) 

PAPTLLOMA , NOS 1 (2X ) 

». USCiILriSKELKTA L SYSTE M 

NON E 

BOD Y CAVITIE S 

*PEFITONEU 1 (25) (50) (49 ) 

!«ESn^HELIOMA , NO S 1 (2 % ) 

f ESOTHET.TOHA , MALIGNAN T 1 (2*) 

*PLE!IRA (25) (50 ) (49 ) 

OSTEOSARCOH A 1 (2% ) 

A L T OTHER SYSTEMS 

NON E 

ANIMAL DISPOSITION SUMMARY
 

ANTMAL S INITIALL Y IN STUDY 25 50 50 

NATURA L DEATH S 3 4 2 

MORIBUN D SACRIFICE 1 14 12 

**SCHEDULED SACRIFICE 2 2 2 

ACCIDENTALL Y KILLE D 

TERMINA L SACRIFICE 19 30 34 

ANIMA L MISSIN G 

2L!NCLUDE?_AUTOLYZED_ANIMA_LS 

# NUMBE R OF ANIMAL S WIT H TISSUE EXAMINE D MICROSCOPICALL Y 

* NUMBE R OF ANIMAL S NECROPSIED 

Animals are in fact early terminal sacrifices, but appear as
 

scheduled sacrifices due to system interpretation.
 

43
 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

TUMO K SUMMAR Y 

"•CCnL ANIMAL S WITH PPJMAR Y TUMOKS * 25 49 48 

TOTAI PRIMAR Y TU10PS 42 78 77 

TOTAL ANIMAL S WITH BENIGN TUMORS 24 43 47 

^O^AL BENIG N TOM05S 34 60 64 

TO^A L ANIMAL S W I^K MALIGNAN T TUMOR S 7 16 1 1

 

^OTAL MALTGNAN T TUMOP S 8 17 1 1

 

TOTAL ANIMAL S WITH SECONDAR Y TUMORS* 2 

TOPA L SECONDAR Y TUMORS 3 

TO^AL ANIMAL S WITH *UMORS UNCERTAIN ­

BEVIG N OP HALTGNAK T 1 2

 

TOTA L UNCERTAI N Ttjpinps 1 2 

TOTAL ANIMAL S WITH TUMORS UNCERTAINPHIMAF Y 01? METASTATIC

 T OTA L UNCERTAI N ^UMOPS

 

* PRIMAR Y TUMORS : ALL TUMORS EXCEPT SECONDARY TUMORS 

# SECONDARY TUMOPS: METASTATIC TUMORS OR TUMOSS INVASIVE INTO AN ADJACENT ORGA N 

44 
TABLE A2. 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS 

ADMINISTERED FENTHION IN THE DIET 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

ANIHALS

ANIMALS

ANIMALS

 INITIALLY IN -5TUDY

 NECROPSIED

 EXAMINE D HISTOPATHOLOGICALLY

 25

 25

 25

 50

 50

 50

 50 

 49 

 49 

TNTEGUMENTAR Y SYSTEM 

*SKIH

PAPILLOMA , NOS

FIBEOSARCOMA

 (25) (50)

 1 (2«) 

1 (2% ) 

 (49) 

RESPIRATORY SYSTEM 

NONE 

HEMA^OPOIETIC SYSTEM 

*BULTIPLE ORGAN S

LEUKEMI A ,NOS

I YNPHOCYl'TC LEUKEMT A

MONOCYTIC LEUKEMI A

 (25)

 1

 2

 (4%)

 (8%)

 (50)

 1

 2

 (2%)

 (4% )

 (49) 

1 (2*) 

1 (2X ) 

9 (18%) 

*PPLEEV

ADENOCARCINOMA , NOS, METASTATIC

 (25)

 1 (4% ) 

 (49) (49) 

CIRCULATORY SYSTEM 

f'DM E 

DIGESTIVE SYSTEM 

tLIVE<!

NEOPLASTIC NODOLE

 (25)

 1 (4%) 

 (50) (49) 

#JEJUNU M

ADENOCAPCINOMA , NOS

 (24)

 1 (4«) 

 (49 ) (49) 

URINAR Y SYSTE M 

HOM E 

» NUMBE R

* NUMBE R

 OF

 OF

 ANIMAL S

 ANIMAL S

 WITH TISSUE

 NECF.OPSIED 

 EXAMINE D KICP.OSCOPICA LLY 

45 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE 

ENDOCRIN E SYSTE M 

• PITUITAR Y (25) (50) 

C4°" INOM A ,NOS 

ADENOMA , NO S 

CHROKOPHOBE ADENOM A 14 (56%) 20 (40%) 

• THYROI D (22) (48) 

FOLLICULAP.-CELL ADENOM A 

C-CELL ADENOM A 2 (9%) 12 (25%) 

• PANCREATI C ISLETS (25) (49)

 

TSLET-CEIL ADENOM A 

REPRODUCTIV E SYSTE M 

*1AMMAR Y GLAN D (25) (50) 

ADENOCARCINOM A , NOS 2 (8%) 

PAPILLAR Y ADENOCAFCINOM A 

FI B RO M. A 

I.IPOM A 1 (2% ) 

^TBR O ADENOM A 6 (12% ) 

(25) (49)

LEIOMYOSARCOM A 2 (4% ) 

El DO RETRIA L STRPNA l POLYP 2 (8%) 11 (22%) 

# UTERUS / EN DO KE^FIU M (25) (49)

 

ADENOCABCINOMA , NO S 1 (2% )

 

(25) (49) 

ADEVOCARCINOKA , NO S 1 (4%) 

GRANULOSA-CEL L CARCINOM A 1 (2%) 

NERVOU S SYSTEM 

NON E 

SPECIAL SENSE ORGANS
 

*EYELID (25) (50)

 

^IBROUS HTFTJOCYTOMA
 

# NUMBE ? OF ANIMAL S WI?H TISSUE EXAMINE D MICROSCOPICALL Y 

* NUMBS * P F ANIMAL S NECFOPSIED 

HIGH DOSE 

(48) 

2 (4% ) 

1 (2%) 

25 (52%) 

(46) 

1 (2% ) 

4 (9%) 

(49)

1 (2») 

(49) 

1 (2%) 

1 (2% ) 

1 (2% ) 

(46) 

1 (2% ) 

8 (17% ) 

(46) 

(48) 

(49) 

46 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

*EA P (25 ) (50) (49 ) 

FIB39PA 1 (I**) 

MUSC"LOSKELETAL SYSTEM
 

NONE
 

BODY CAVITIES 

*PEFI^ONEA L CAVIT Y (25) (50) (49) 

ADENOCARCINOMA , NOS, INVASIV E 1 (4« ) 

ALI OTHE? SYSTEMS
 

*tfULTIPLE ORGAN S (25) (50) (49 ) 

FIBROUS HISTIOCYTOMA, MALIGNAN T 1 (2%) 

("ESriTHELIOMA, MALIGNAN T 1 (2%) 

ANIMA L EISPOSITTON SUMKAS Y 

ANT1ALS INITIALLY T N STUDY 25 50 50 

NATURA L DEATHS) 1 1 2 

HOPIB0ID SACRIFICE 9 12 17 

**SCHEDULED SACRIFICE . 2 2 2 

ACCIDENTALLY KILLED 1 

TEPMINA L SACRIFICE 13 35 28 

ANIMA L MISSING 

§_!NCLUDES_AUIQLjrZED_ANTMALS_ 

f NUMBE R OF ANT1ALS WITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUNBE" OF ANIMAL S NECROPSIED 

**Animals are in fact early terminal sacrifices, but appear as 

scheduled sacrifices due to system interpretation. 

47
 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

TUMOP. SUMMAR Y 

TOTAI ANIMAL S WITH PRIMAR Y TUMORS * 18 UU 39 

TOTAL PRIMAR Y TUMOES 29 59 60 

TOTAL ANIMAL S WITH BENIGN TUMOR S 16 39 33 

TD^AL BENTGN TUMORS 20 51 U 3 

TOTAL ANIMAL S WITH MALIGNAN T TUMORS 6 8 16 

TOTAL MALIGNAN T TUMORS 8 8 17 

TOTAL ANIMAL S WITH SECONDARY TUMORS # 2 

TOTAL SECONDARY TUMORS 2 

TOTAL ANIMALS WITH TUMORS UNCEHTAIN-
 BEPtGN ?? MALIGNAN T 1 

TOTAL UNCERTAI N TUMORS 1 

TOTAL ANIMAL S WITH TUMORS UNCERTAIN­ PRIMAR Y OP METASTAPIC 

TOTAL UNCERTAI N 

* PRIMARY TUMORS: ALL TOHORS EXCEPT SECONDARY TUMORS 

# SECDSDA^ Y TUMORS : MErASPAri C TUMORS OR TUMORS INVASIV E INTO AN ADJACEN T ORGA N 

48 
APPENDIX B
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

MICE ADMINISTERED FENTHION IN THE DIET
 

49
 
50

 
TABLE B1.

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE MICE 

ADMINISTERED FENTHION IN THE DIET 

MATCHED 

CONTROL LOWD 

ASTMALS INITIALLY IN STUDY 25 50 

ANIMAL S NECUOFSIED 2 5 49 

ANIMAL S EXAMINE D HIS^OPATHOLOGTCALL Y 2 5 49 

INTETJMENTAR Y SYSTE M 

*SKTN (25) (49 ) 

P^PCOMA , NO17 

FIBROM A 1 (4X ) 

FIBHOSA?COM A 4 

*SUBCUT TISSUE (25) (49) 

SAKC3MA , NO S 

FIBROM A 

FIBS3SAPCOMA 

RHABDOKYOSARCOK A 3 

HESP T EATOH Y SYSTEM 

tLUP G ( 25) (48 ) 

ALVEOLAE/BRONCH I CLAP ADENOM A 2 (8%) 5 

PHABDDMYDPARCCM A , METASPAriC 

HSF.AT)?DIETIC SYSTE M 

*1ULTTPLE OBGAN S (25) (49)' 

("ALTO WAN T T.YMPHOMA , NOS 1 

rALTG.LYMPHOMA , LYMPHOCYTIC TYP E 1 (4% ) 3 

"ALTG.LYMPHOMA , HT?"IOCYTIC TYP E 

I,Y !". PH 0 CY TI C LEUKEMI A 1 

fi»ANULOCY T T C LEUKEMI A 1 

*AXTLLAP Y LYMP H NOD E (21 ) (43) 

FIBROSA^COM A , METASTATTC 1 

#INGUINA L LYMPH NODE (21) (43) 

PHABD0.1YOSARCOMA , METASTATIC 1 

CTPOTLATOT Y SYSTE M 

NONE 

# NUfBE^ OF AWTMAT.S WI^H TTSStJE EXAMINE D MICROSCOPICALLY 

* HUM3E T OF ANIMAL S 

OSE 

(8%) 

(6%) 

(10S) 

(2%) 

(6% ) 

(2%) 

(2X ) 

(2%) 

(2%) 

HIGH ! )OSE 

50 

48 

48 

(48) 

1 

1 

(48 ) 

1 

1 

3 

2 

(48 ) 

8 

1 

(48) 

1 

1 

(42 ) 

(42) 

(2X ) 

(2«) 

(2*) (25)

(6*) 

(4% ) 

(17*) 

(2«) 

(2%) 

(2*) 

51 
TABLE B1. MALE MICE: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

DIGESTIVE SYSTEM 

#LIVER (25) (49) (48) 

HEPATOCELLtlLAR ADENOM A 2 (4%) 4 (8*) 

H EP ATPCELIULAP. CARCINOM A 6 (24% ) 15 (31%) 13 (27% ) 

HEMANGIOSARCOB A 1 (2%) 

(24 ) (45) (42 ) 

ADENOMATOU S POLYP, NOS 1 (2% ) 

# JEJUNU M (24 ) (43 ) (40 ) 

ADENOMATOU S POLYP, NOS 1 (4% ) 

HRTNAR Y SYSTEM 

NON E 

ENDOCRIN E SYSTEM 

#PI^UITAPY (18) (35) (32) 

CH^OMOPHOBB ADENOM A 1 (3%) 

*ADRENA L (21) (48 ) (46 ) 

PHEOCHROMOCYTOM A 2 (4%) 1 (2*) 

#THY?OT D (23) (39) (35) 

PAPILLAR Y ADENOM A 1 (UK ) 

REPRODUCTIV E SYSTE M 

(23 ) (48) (45) 

SERTOLI-CELL TUMO R 1 (2S) 

NEFV^U S SYS^E*1 

NON E 

SPECIAL SENS E ORGAN S 

*EYE/LACHIMA L GLAN D (25) (49 ) (48) 

* NUMBE R OF ANIMAL S W^Tp TISSUE EXAMINE D KICFOSCOPICALLY 

* NUMBE R OF AWTKA1 S NECROPSTE D 

52 
TABLE B1. MALE MICE: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

M'l?a lLOSKELE r r A.t . SYSTE M 

NON E 

BODY CAVTTTE S 

*PET=I"'OVE!J«

?HA3DO»YOSASCOMA, ME^ASTATTC

 (25) (1*9)

 1 (2%) 

 (48 ) 

A LL OTHE R SYSTEM S 

NON E 

A M T K A L DISPOSITION SUMMAR Y 

ANIMAL S INITIALL Y IN STUD Y

NAT'J^A L DEATHS

M OP IB UN O SACRIFICE

**SCHEDULED SACPTFTCE

ACCIDENTALL Y KILLED

TERMINA L SACFIFICE

ANIMA L MTSSIHG 

 25

 3

 22

 50

 2

 20

 28

 ,

 50 

4 

 10 

1 

1 

 34 

D_AVIMALS 

# rO^-BE1?

* MJBBEK

 OF

 OF

 ANIMAL S

 ANIMALS

 WITH TISSU E

 NECPOPSIED 

 EXAMINE D MICEO 5COPICALLY 

Animal is in fact an early terminal sacrifice, but appears 

as a scheduled sacrifice due to system interpretation. 

53
 
TABLE B1.MALE MICE: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

"UMO H SUMMAR Y 

TOTAL ANIMAL S WIT H PRIMAR Y TUMORS * 1 0 35 26 

TOTAL PPTIURY TUMOFS 12 40 39 

TOTA L ANIMAL S WIT H BENIG N TUMORS « 10 16

 

TOTAL BENIGN TUWOH S 5 11 16

 

TO^AL ANIMAL S WITH MAITGNAN T TUMORS 7 28 20 • "OTAL MALIGNAN T TUMOF S 7 29 23 

TOTAL ANIMAL S WITH SECONDARY TUMORSt 2 1 

TOTAL SECONDAR Y TUMORS 3 1 

TOTAL ANIMAL S WITH TUMORS UNCERTAINBENIGN OR MALIGNAN T

 

TOTAL UNCERTAI N TUMOES

 

"•OTAL ANIMAL S WIT H TI'MORS UNCERTATNFRJMAH Y OR METASTATIC

 

TOTAL UNCERTAI N TUMORS 

* PRIMAR Y TUMORS : AIL TUMORS EXCEFT SECONDARY TU!iDRS 

* SECONDAR Y TUMORS: METASTATIC TUMORS OR TUMORS INVASIVE INTO AN ADJACENT ORGAJt 

54 
TABLE B2.

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE MICE 

ADMINISTERED FENTHION IN THE DIET 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

ANIMALS INITIALLY IN STUDY 25 50 50 

ANTMAL S NECRCPSIED 24 47 50 

ANIMALS EXAMINE D HISTOPATHOLOGICALLY 24 47 50 

INTEGUMENTAR Y SYSTEM 

*SKIN (24) (47) (50)

 

FIBPOSARCOMA 1 (2*)

 

RESPIRATOR Y SYSTEM 

ILUNG (24) (46) (50) 

ALVEOLAR/BRONCHIOLA R ADENOM A 2 (8X) 3 (7%) 3 (6X) 

ALVEOLAR/BRONCHIOLAP CARCINOMA 1 (4X) 

HEMATOPOIETIC SYSTEM 

*MULTIPLE ORGAN S (2«) (47) (50) 

MALIGNAN T LYMPHOMA, NOS 1 (2X) 

MALIG . LYMPHOMA , LYKPHOCYTIC TYP E tt (17X) 6 (13X) 12 (24X) 

MALIG . LYMPHOMA , HISTIOCYTIC TYP E 2 (4«) 

#SPLEEN (24) (t5) (48)

 

HEMANGIOSARCOMA , METASTATIC 1 (2«)

 

CALIG. LYMPHOM A , UNDIFFER-T YPE 1 <2X )

 

MALIG . LYMPHOMA , LYMPHOCYTIC TYP E 1 (4S)

 

JtMANDIBULA R L. ROEE (21 ) (46) (43)

 

MALTG. LYMPHOMA , LYMPHOCYTIC TYPE 1 (5X) 

#LIVEB (24 ) (47) (50)

 

MALTG . LYMPHOMA , LYMFHOCYTIC TYPE 2 (4S)

 

#KIDNE Y (23) (47) (48) 

MALIG . LYMPHOMA , LYMPHOCYTIC TYPE 1 (2X) 

CIRCULATOR Y SYSTE M 

*BL"OD VESSEL (24) (47) (50) 

___ _ HEMANGIOSARCOM A _____________________ _ 

# VUMBE S OF ANIMAL'S WTTH ^ISSUE EXAMINE D MICROSCOPICALLY 

* NUMBE R OF ANIMAL S NECPOPSIED 

55 
•• 

TABLE B2. FEMALE MICE: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

DIGESTIVE SYSTEM 

tLIVEE (24) (47) (50) 

HEPAIOCELLULAF ADENOM A 1 (2*) 

HEPATOCELLULAR CABCINOSA 2 (8%) 4 (9X) 1 <2X ) 

H EM AN GTD SARCOM A 2 (4X) 

#STOMACH (24) (44) (41) 

ADENOMATOU S POLYP, NOS 1 (2%) 

URINAR Y SYSTEM 

NONE 

ENDOCRINE SYSTEM 

*PITUITARY (21) (37) (42) 

ADENOMA , NOS 1 (3X) 3 (7«) 

CHROMOPHOBE ADENOM A 1 (3%) 

ACIDDPHIL ADENOM A 1 (3«) 1 (2*) 

f ADRENA L (23) (45) (46) 

PHEOCHROMOCYTOMA 1 (2*) 

#THYROID (21) (42) (40)

 

PAPILLAR Y ADENOM A 3 (14*) 

REPRODUCTIV E SYSTEM 

*MAMMAR Y GLAN D (24) (47) (50) 

ADENO CARCINOMA , NOS 2 (i*X) 

FIBRO ADENOM A 1 (4%) 1 (2%) 2 (4% ) 

# UTERUS (19) (45) (40) 

FIBROMA 1 (3«) 

H EM ANGIDM A 1(5% ) 

fOVAR Y (24) (40) (43) 

GRANOLOSA-CEL L TUMOR 1 (2%) 

TERATOMA , BENIGN 1 (2%) 

NERVOUS SYSTEM 

NON E 

# NUMBER OF ANIMAL S WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMAL S NECPOPSIED 

56 
TABLE B2. FEMALE MICE: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

SPECIAL SENSE OPGANS 

*EYE/LACRIMAL GLAN D (24) (47) (50) 

ADENOMA , NOS 2 (4X ) 

MU5CULOSKELETA L SYSTEM 

MOKE 

BODY CAVITIES 

NONE 

A LL OTHEP SYSTEMS 

*MULTIPLE ORGANS (21*) (47) (50) SARCOMA , NOS 1 (2%) FIBROSARCOMA 1 (4%)

 

RHABDOMYOSARCOM A 1 (2%) 

ANIMA L DISPOSITION STJMHA5Y 

ANIMALS INITIAILY IN STUDY 25 50 50 

NATURA L DEATHS 1 4 3 

MORIBUN D SACRTFTCE 1 8 6 

SCHEDULED SACRIFICE 

ACCIDENTALLY KILLED 

TERMINAL SACRIFICE 23 38 41 

ANIMA L MISSING 

®_INC.LUDES_AUTOLYZED_ANJMALS 

# NUMBER OF ANIMALS WITH TISSttE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMAL S NECPOPSIED 

57 
TABLE B2. FEMALE MICE: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

TUMOR SUMMAR Y 

TOTAL ANIMAL S WITH PRIMAR Y rtJMORS * 12 22 24 

TOTAL PRIMAPY TUMORS 18 29 32 

TOTAL ANIMAL S WITH BENIGN TUMORS 6 6 14 

TOTAL BENIGN TUMORS 7 7 16 

TOTAL ANIMAL S WITH MALIGNAN T TUMORS 9 20 15 

•POTAL MALIGNAN T TUMORS 11 22 15 

TOTAL ANIMALS WITH SECONDARY TUMORSf 1 

TOTAL SECONDARY TUMORS 1 

TOTAL ANIMAIS WITH TUMORS UNCERTAINBEPIGN OB MALIGNAN T 1 

TOTAL UNCERTAI N TUMORS 1 

TOTAL ANIMALS WITH TUMORS UNCERTAINPRIMAR Y OR METASTATIC

 

TOTAL UNCERTAI N TUMORS 

* PRIMARY TUMORS : ALL TUMORS EXCEPT SECONDARY TUMORS 

t SECONDAR Y TUMOPS: METASTAHIC TUMORS OR TUMORS INVASIVE INTO AN ADJACENT OBGAN 

58 
APPENDIX C
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS
 

IN RATS ADMINISTERED FENTHION IN THE DIET
 

59
 
60

 
TABLE C1.

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE RATS 

ADMINISTERED FENTHION IN THE DIET 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

ANIMAL S INITIALLY IN STUDY 25 50 50 

ANIMAL S NECHOPSIED 25 50 49 

ANIMAL S EXAMINE D HISTCPA'HOLOGICALLY 25 50 49 

INTEGUMENTAR Y SYSTEM 

*SKTN (25) (50) (49) 

CYST, NOS 1 ( U % ) 

EPIDERMA L INCLUSION CYST 1 (2X) 

MULTIPLE CYSTS 1 (4«) 

*SUBCUT TISSUE (25) (50) (49) 

EPIDERMA L INCLUSION CYST 1 (2% ) 

NODULE 1 (2%) 

RESPIRATOR Y SYSTEM 

*LUNG (25) (49) (49) 

HYPERPLASIA, ADENOMATOUS 1 (2%) 

HEMA-^OPOIETIC SYSTE M 

fSPLEEV (25) (47) (49) 

FIBROSIS, FOCAL 1 (2%) 1 (2*) 

IHFA8CT, NOS 2 

tSPLENIC RED PULP (25) (47) (49) 

FIBROSIS 1 (2%) 

*MESENTEFIC L. NODE (23) (47) (47) 

CYST , NOS 1 (2%) 

INFLAMMATION , CHRONIC 1 (4%)

 

CIRCULATORY SYSTEM 

«HE A?T/ATi=IUM (25) (50) (49) 

THROMBUS^ORGANIZED 1_ 

# NUMBER OF ANIMAL S WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBE R OF ANIMAL S NECBOPSIED 

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

#AUFICULA R APPENDAGE 

THROMBUS , ORGAN T Z E D 

#MYOCAHDIU M 

FIBROSIS, FOCAL 

FI BED SIS, MULPIFOCAL 

DIGESTIVE SYSTEM 

#SALIVAR Y GLAN D 

INFLAMMATION , CHRONIC 

tSUBMAXILLAR Y GLAN D 

INFLAMMATION , ACUTE/CHRONIC 

INFLAMMATION , CHRONIC 

#LIVER 

METAMORPHOSIS FATTY 

FDCAI, CELLULAR CHAN3E 

*BII.E DUCT 

INFLAMMATION , CHRONIC

 

HYPEHPLASIA, NOS 

HYPERPLASIA , FOCAL 

tPANCREAS 

PERIASTERITIS 

tPANCREATIC ACINUS 

ATROPHY , FOCAL 

#STOMACH 

HLCEH , NOS 

ULCER, ACUTE 

*GA?TRIC SUBMUCOS A 

EDEMA , NOS 

#CECUM 

POLYPOID HYPERPLASTA 

URINAR Y SYSTE M 

tKIDNEY 

INFLAMMATION ^ CHRONIC 

* NUMBER OF ANIMAL S WI^H TISSUE

* NUM3ER OF ANIMAL S NECFOPSIED 

MATCHED 

CONTROL LOW DOSE 

(25) (50) 

1 (2%) 

(25) (50) 

1 (2X) 

(24) (48) 

1 (4X) 

(24) (48) 

2 (4%) 

13 (54X) 13 (27%) 

(25) (U9 ) 

3 (6X) 

(25) (50) 

1 (2% ) 

2 (4X ) 

(24) (47) 

(24) (47) 

1 (2*) 

(23) (46) 

1 (2%) 

(23) (46) 

2 (9%) 

(24) (47) 

1 (2X) 

(25) (49) 

Ji_ n2xi__ . 39 180*1 

 EXAMINED MICROSCOPICALLY 

HIGH DOSE 

(49) 

(49) 

1 (2X) 

(48) 

1 (2X) 

(48) 

11 (23%) 

(49) 

1 (2*) 

(49) 

1 (2%) 

1 (2X) 

(49) 

1 (2X) 

(49) 

(49) 

1 (2X) 

(49) 

(47) 

(48) 

40 J83X1 

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

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

fUPISAR Y BLADDE R (24 ) (46) (44 ) 

INFLAMMATION , ACUTE 1 (2% ) 

ENDOCRINE SYSTEM 

(25) (47) (44 ) 

MULTIPLE CYSTS 1 (2%) 

HEMORRHAG E 3 (7*) 

HYPERPLASIA, FOCAL 1 (2X) 2 (5S) 

tADFENA L (25) (49) (49) 

DEGENERATION, CYSTIC 1 (2X) 

#ADRENA L MEDULL A (25) (49 ) (49) ­

HYPERPLASIA , NODULAP 3 (6%)

 

(23) (44) (27) 

HYPERPLASIA , C-CELL 1 (>4%) 

f'HYROID FOLLICLE (23) (44) (27)

 

HYPERPLASIA , CYSTIC 1 (2X)

 

REPRODUCTIVE SYSTEM 

*MA«MAR Y GLAN D (25) (50) (49) 

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

(24) (50) (49) 

ATROPHY , NOS 3 (6X) 

NERVOUS SYSTEM 

tBRAI N (25) (49) (49)

 

MALACI A 1 (2X) 

SPECIAL SENSE ORGAN S 

*EAP (25) (50) (49)

 

EPIDERMAL INCLUSION CYST 1 (2X)

 

MUSCULOSKELETAL SYSTEM 

NONE 

t NUMBER OF ANIMAL S HITH TISSOE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMAL S NECROPSIED 

63 
TABLE C1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

BODY CAVITIES 

*PERITONEUM (25) (50) (U9 ) 

INFLAMMATION , CHRONIC FOCAL 1 (2«) 

NECROSIS, FAT 1 (2*) 

*MESENTERY (25) (50) (49) 

NECROSIS. FAT 1 (2%) 

ALL OTHER SYSTEMS
 

NONE
 

SPECIAL MORPHOLOGY SUMMARY 

NO LESION REPORTED 1 

AUTOLYSIS/NO NECROPSY 1 

# NUMBER OF ANIMALS WITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

64 
TABLE C2. 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE RATS 

ADMINISTERED FENTHION IN THE DIET 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

ANIMAL S INITIALLY IN STUDY 25 50 50 

ANIMAL S NECROFSIED 25 50 49 

ANIMAL S EXAMINE E PISTOPATHOLOGICALLY 25 50 49 

INT EGUMEV'AR Y SYSTE M 

*SKTN (25) (50) (49) 

MULTIPLE CYSTS 1 (2%) 

.RESPIRATOR Y SYSTEM 

#I,UNG (25) (50) (49) 

BRONCHOPNEUMONI A ACUT E SOPPURATI 1 (4X) 

HEMATOPOIETIC SYSTEM 

#SPLEEN (25) (49) (49) 

FIBROSIS, FOCAL 1 (4«) 

CIfiC"LATOP.Y SYSTEM 

NONE 

DIGESTIVE SYSTEM 

fSA!IVA*Y GLAN D (24) (48) (48) 

INFLAMMATION , ACUTE/CHRONIC 2 (4«) 

#SUBMAXILLAR Y GLAN D (24) (48) (48) 

INFLAMMATION , CHRONIC 6 (25%) 16 (33%) -11 (23X) 

#LIVE* (25) (50) (49) 

INFLAMMATION , CHRONIC FOCAL 1 (2%) 

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

DEGEN.ERATIONJ L _GRANULAR 

f NUMBE R OF ANIMAL S W I^H TISSUE EXAMINE D HICBOSCOPICALLY 

* NUMBER OF ANIMAL S NECROPSIED 

65 
TABLE C2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE 

NECROSIS, FOCAL 1 (2%) 

METAMORPHOSI S FATTY 1 (2% ) 

tSTOMACH (23) (49)

 

ULCER, ACUT E 2 (4%) 

URINAR Y SYSTEM 

tKIDNEY (25) (49)

 

HYDRONEPHROSIS 1 (2%)

 

INFLAMMATION , CHRONIC 8 (32%) 22 (45*) 

CALCIFICATION, MET A3 TA P 1C 1 (2% )

 

ENDOCRINE SYSTEM 

tPITUITARY (25) (50)

 

CYST, NOS 4 (8%) 

HEMORRHAG E 5 (20%) 8 (16%)

 

HYPERPLASIA , NOS 2 (4% )

 

HYPERPLASIA, FOCAL 1 (2%) 

fTHYROID (22) (48) 

HYPERPLASIA , C-CELL 

HYPERPLASIA , FOI, LICIT LA R- CELL 1 (2% ) 

REPRODUCTIVE SYSTEM 

*MAMMAR Y GLAN D (25) (50)

 

DYSPLASIA, NOS 8 (32%) 13 (26%)

 

*MAM«AR Y LOBULE (25) (50)

 

RYPEBPLASIA , NOS 2 (8%) 5 (10*)

 

#UTERUS/ENDOMETPIUM (25) (49)

 

HYPERPLASIA, CYSTIC 

#OVAH Y (25) (49)

 

NECROSIS, FAT 1 (H%) 1 (2%)

 

NERVOU S SYSTE M 

tBRAIN (24) (50) 

HYDROCEPHAUISj. NOS . __ 1 12%1 „ 

# NUMBER OF ANIMAL S WI^H TISSUE EXAMINE D MICROSCOPICALL Y 

* NUMBER OF ANIMAL S NICF.OPSIED 

HIGH DOSE 

2

(49) 

(49) 

23

(48) 

1

5

1

(46 ) 

1

(49) 

14

(49) 

1

(46) 

1

(48) 

1

(48) 

 (4%) 

 (47% ) 

(2%) 

 (10%) 

(2%) 

 (2% ) 

 (29%) 

 (2*) 

 (2») 

 (2») 

66 
TABLE C2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

INFAP.CT, NOS 1 (2%) 

SPECIAL SENSE ORGAN S 

NON E 

MUSCULOSKELETA L SYSTEM 

NOM E 

BODY CAVITIES 

*ABDOMINAL CAVITY

NECROSIS, FAT

*PE*ITONEUN

NECROSIS, FAT

^PERITONEA L CAVIT Y

NECROSIS, FA"1

*MEPENTER Y

NECROSIS, FAT

 (25)

 (25)

 1 (4%) 

 (25)

 (25)

 1 (4S) 

 (50)

 (50)

 (50)

 (50)

 (49) 

1 ( 2%) 

 (49) 

 (49) 

1 (2%) 

 (49) 

ALI OTHER SYSTEMS 

OMEN^U" ! 

NECROSIS, FAT 1 1 

SPECIAL MORPHOLOGY SUMMAR Y 

N O LESION REPORTED

ACCIDENTA L DEA^H

 3 1 4 

1 

# NUMBE R

* N.UMBEP

 OF

 OF

 ANIMALS

 ANIMAL S

 WITH TISSUE

 NECEOPSIED 

 EXAMINE D MICROSCOPICALLY 

67 
68

 
APPENDIX D
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS
 

IN MICE ADMINISTERED FENTHION IN THE DIET
 

69
 
70

 
TABLE D1. 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE MICE 

ADMINISTERED FENTHION IN THE DIET 

MATCHED 

CONTROL LOWOOSE HIGH DOSE 

ANIMAL S INITIALLY IN STUDY 25 50 50 

ANIMALS NECROPSIED 25 49 US 

ANIMAL S EXAMINE D HISTOPATHOLOGICAI.LY 25 1*9 48 

INTEGUMENTAR Y SYSTEM 

*SKIN (25) (49) (48) 

ABSCESS, NOS 2 (4X) 2 (4X) 

ULCER, CHPONIC 1 (4%) 

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

•RESPIRATORY SYSTEM 

#LUNG (25) (48) (48) 

ATELECTASIS 1 (2X) 

INFLAMMATION , FOCAL GRANULOMATO U 1 (2%) 

HEMATOPOIETIC SYSTEM ' 

tSPLEEN (25) (48) (48) 

HYPERPLASIA, FOLLICULAR-CELL 2 (4«) 

HEMATOPOIESIS 1 (2%) 

#SPLENIC SINUSOIDS (25) (48) (48) 

HYPERPLASIA, NOS (2X)

 

tMANDIBOLAR L. NODE (21) (43) (42) 

HYPEHPLASIA, NOS 1 (2X)

 

tBESENTEPIC L. NODE (21) (43) (42)

 

HYPERPLASIA, NOS 1 (2X) 

HYPERPLASIA, LYMPHOID 1 (5X) 

HEMATOPOIESIS 1 (2%)

 

CIRCULATORY SYSTEM 

*PULMONARY ARTERY (25) (49) (48)

 

HYPERT5QPHIt_FOCftL 

t NUMBER OF ANIMALS HITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

71 
TABLE D1. MALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

DIGESTIVE SYSTEM 

#LIVEE (25) (49) (48) TNFARCT, NOS 1 (2*) 

INFARCT, ACUTE 1 (2X) 

METAMOPPHOS7S FATTY 1 (2*) 

FOCAL CELLULAR CHANGE 1 (2*) 1 (2*) 

*PANCREA S (25) (48) 

CYSTIC EUCTS 1 (2X) 

#STOMACH (24 ) (45) 

HYPEBPLASIA , NOS 1 (28) 

tPEYERS PATCH (24) (43) (40) 

HYPERPLASIA , LYMPHOI D 2 (5X) 

URINAR Y SYSTEM 

*KIDNE Y (25) (49) (48) 

INFLAMMATION, CHRONIC 1 (2%) 

HYPERPLASIA , LYMPHOID 1 (2% ) 1 (2%) 

tURTNAR Y BLAEEE R (22) (44) (41) 

ATYPIA , NOS 1 (2%) METAPLASIA , SQUAMOUS 1 (5%) 1 (2%) 

ENDOCRINE SYSTEM 

SADFESA L CORTEX (21) (48) (46) LIPOIDOSIS 1 (2%)

 

#ADRENA L MEDULLA (21 ) (48) (46) HYPERPLASIA , NOS 1 (5%) 

REPRODUCTIVE SYSTEM 

VONE 

NEFVOU S SYSTEM 

NON E 

f NUMBE R 3F ANIMAL S WITH TISSU E EXAMINE D MICRO SOPICALLY 

* NUMBER OF ANIMALS NECFOPSIED 

72 
TABLE 01. MALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

SPECIAL SENSE ORGANS 

NONE 

MUSCULOSKELETAL SYSTEM 

NONE 

BODY CAVITIES 

NONE •_ — — ••— —•• — «•. — — _M1___«><W»«WIVW— W_«MM_K___.»___ V »«._W«W M MW«VBWMHW«AB « « ^^ 0>b O> «» * _M ^. ^« _ _ •w • 

A LL OTHER SYSTEMS 

*MULTIPLE ORGANS (25) (49) (US ) 

HYPERPLASIA, LYMPHOID 2 («*) 

HEMATOPOIESIS 1 (U%) 

SPECIAL MORPHOLOGY SUMMARY
 

NO LESION REPORTED 13 7 16
 

ACCIDENTAL DEATH 1
 

AUTDLYSTS/NO NECROPSY 1 1
 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECPOPSTED
 

73
 
TABLE 02. 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE MICE 

ADMINISTERED FENTHION IN THE DIET 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

ANIMALS INITIALLY II! STUDY 25 50 50 

ANIMAL S NECPOFSIED 24 HI 50 

ANIMAL S EXAMINE D HTSTOPATHOLOGICALLY 24 47 50 

INTEGUMENTAR Y SYSTEM 

NON E 

TJESP.TSATORY SYSTEM 

*LUNG (24) (46) (50) 

CONGESTION, NOS V (2X) 

INFLAMMATTON , INTERSTITIAL 1 (2*) 

RYPERPLASIA, LYMPHOID 1 (2K) 

lEHATJPOTE^IC SYSTEM 

fSPLEEN J24 ) (45) (48) 

HEMOSIDEROSIS 1 (4*) 

HYPEHPtASTA , LYMPHOID 2 (8K) 1 (2%) 2 (4») 

HEMATOPOIESTS 2 

CIRCULATORY SYSTEM 

*HEART (24) (47) (50) 

PERIARTERITIS 1 (2«) 

*COP.ONARY APTER Y (24) (47) (50) 

DEGEVERATION, NOS 1 <2X) 

HYPERPLASIA , NOS 1 (2%) 

*HEPATIC ARTER Y (24) (47) (50)

 

PER^VASCULITIS 1 (2%) 

NECR3SIS , NOS 1 (2%) 

DIGESTIVE SYSTEM 

*IIVER (24) (47) (50) 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

74 
TABLE D2. FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

NECROSIS, COAGULATIVE 

INFAPCT, NOS 

METAMORPHOSIS FATTY 

FOCAL CELLULAR CHANG E 

tLIVER/CENTRILOBULAR 

NECROSIS, NOS 

tPANCREAS 

CYSTIC DUCTS 

tSTOMACH 

ATYPIA , NOS 

UHTNAR Y SYSTEM 

tKIDNEY 

HYP'ERPLASIA, LYMPHOID 

tURINARY BLADDER 

HYPERPLASIA, LYMPHOI D 

ENDOCRINE SYSTEM 

tPITUITARY 

HYPERPLASIA , NOS 

fADRENA L CORTEX 

HEMORRHAG E 

LIPOIDOSIS 

REPRODUCTIVE SYSTEP! 

*BAtfMAR Y GLAND 

GALACTOCELE 

DYSPLASIA, NOS 

fUTERUS 

HYDROMETRA 

#UTEHOS/ENDOMETRIUM 

HYPERPLASIAX CYSTIC 

MATCHED 

CONTROL LOW DOSE 

1 <2X ) 

1 (4X) 1 (2X) 

1 12%) 

(24) (47) 

1 (2X ) 

(22) 

1 (5X) 2 (4X) 

(24) (44) 

(23) (47) 

1 (4X) 5 (11X) 

(18) <<n> 

(21) (37) 

1 (3X) 

(23) (45) 

1 (2X) 

(24) (47) 

1 (2X) 

(19) 

1 (2*) 

(19) (45) 

1 J2X1 

HIGH DOSE 

1 (2X ) 

1 (2X) 

(50) 

(48) 

2 (4X ) 

(41)

1 (2%) 

(48) 

1 (2*) 

(39) 

(42) 

(46) 

2 (4X) 

(50) 

1 (2X) 

(40) 

(40) 

# NUMBER OF ANIMALS WITH TISSUE EXAMIHED MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

75 
TABLE 02. FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED)

 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

tOVAR Y (24) (40) (43) 

CYST, NOS 1 (4%) 2 (5%) 3 (7X) 

NIBVOUS SYSTE M 

NONE _•..•_.-_.._•.__.».,..•.•.«_.»__«_...*•_«•*«*•»« — w«w««M«<WMJMWl4MU«AM« W i i > «w«WM____MM«_K«»«_MMMi»«a>w.iBii» a 

SPECIAL SENSE ORGANS 

*EYE/LACRTMA L -GLAN D (24) (47) (50) 

HYPERPLASI A , AEENOWATOIJ S 1 (2%) 

MUSCt'LOSKE'LETA L SYSTE M 

*STEBNI!M (24) (47) (50) 

CiSTEOPOROSTS 1 (2%) 

BODY CAVITIES 

NONE 

A LL OTHER SYSTEMS 

• "MULTIPLE ORGANS (24) (47) (50) 

HYPERPLASIA , LYMPHOI D 1 ( 4«) 3 (555) 2 (4%) 

SPECTAL MORPHOLOG Y SUMMAR Y 

NO LESION REPORTE D 8 9 16 

AUTOLYSIS/NO NECROPSY 1 3 

tt NUMBE R OF ANIMAL S WITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBER OF ANIMAL ? NECROP3IED 

76 
APPENDIX E
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS IN
 

RATS ADMINISTERED FENTHION IN THE DIET
 

77
 
78

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

Administered Fenthion in the Diet (a)
 

Matched Low
 

Topography: Morphology Control Dose
 

Integumentary System: Fibroma of the
 

Skin (b) 2/25 (8) 0/50 (0)
 

P Values (c,d) P = 0.036(N) N.S.
 

Relative Risk (f) 0.000
 

Lower Limit 0.000
 

Upper Limit 1.685
 

Weeks to First Observed Tumor 103
 

VO
 —
 

Hematopoietic System: Leukemia (b) 6/25 (24) 9/50 (18)
 

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

Relative Risk (f) 0.750
 

Lower Limit 0.275
 

Upper Limit 2.317
 

Weeks to First Observed Tumor 98 77
 

High
 

Dose
 

0/49 (0)
 

N.S.
 

0.000
 

0.000
 

1.718
 

—
 

8/49 (16)
 

N.S.
 

0.680
 

0.238
 

2.154
 

96 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats
 

Administered Fenthion in the Diet (a)
 

(continued)
 

Topography: Morphology


Pituitary: Carcinoma, NOS (b)


P Values (c,d)


Departure from Linear Trend (e)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

00
 

o Weeks to First Observed Tumor


Pituitary: Chromophobe Adenoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched
 

 Control
 

 0/25 (0)
 

 N.S.
 

 P=0.015
 

—
 

 9/25 (36)
 

 N.S.
 

73
 

Low
 

Dose
 

4/47 (9)
 

N.S.
 

Infinite
 

0.506
 

Infinite
 

80
 

12/47 (26)
 

N.S.
 

0.709
 

0.328
 

1.668
 

79
 

High
 

Dose
 

0/44 (0)
 

•"—
 

—
 

9/44 (20)
 

N.S.
 

0.568
 

0.237
 

1.418
 

84 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats
 

(continued)
 

Topography: Morphology


Thyroid: Follicular-cell
 

Carcinoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


oo
 

Thyroid: C-cell Adenoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Administered Fenthion in the Diet (a)
 

Matched Low
 

 Control Dose
 

 0/23 (0)	 2/44 (5)
 

 N.S.	 N.S.
 

Infinite
 

0.159
 

Infinite
 

—	 104
 

 2/23 (9)	 5/44 (11)
 

 N.S.	 N.S.
 

1.307
 

0.238
 

13.047
 

103 64
 

High
 

Dose
 

0/27 (0)
 

—
 

E
 

—
 

3/27 (11)
 

N.S.
 

1.278
 

0.161
 

14.236
 

103 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats
 

Administered Fenthion in the Diet (a)
 

(continued)
 

Matched Low
 

Topography ; Morphology Control Dose
 

Pancreatic Islets: Islet-cell
 

Adenoma (b) 2/24 (8) 1/47 (2)
 

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

Relative Risk (f) 0.255
 

Lower Limit 0.005
 

Upper Limit 4.703
 

Weeks to First Observed Tumor 98 96
 oo
 

to
 

Testis: Interstitial-cell Tumor (b) 18/24 (75) 37/50 (74)
 

P Values (c,d) P = 0.028 N.S.
 

Relative Risk (f) 0.987
 

Lower Limit 0.755
 

Upper Limit 1.405
 

Weeks to First Observed Tumor 98 86
 

High
 

Dose
 

2/49 (4)
 

N.S.
 

0.490
 

0.038
 

6.476
 

94
 

45/49 (92)
 

N.S.
 

1.224
 

0.966
 

1.521
 

83
 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats
 

Administered Fenthion in the Diet (a)
 

(continued)
 

(a) Dosed groups received 10 or 20 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 (N) indicates a lower incidence in a dosed group than in the control group.
 

(e) The probability level for depa-ture 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 Fenthion in the Diet (a)
 

Matched Low High
 

Topography: Morphology Control Dose Dose
 

Hematopoietic System: Leukemia (b) 3/25 (12) 3/50 (6) 11/49 (22)
 

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

Relative Risk (f) 0.500 1.871
 

Lower Limit 0.073 0.560
 

Upper Limit 3.524 9.741
 

Weeks to First Observed Tumor 85 70 94
 

oo
 

Pituitary: Chromophobe Adenoma (b) 14/25 (56) 20/50 (40) 25/48 (52)
 

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

Relative Risk (f) 0.714 0.930
 

Lower Limit 0.438 0.596
 

Upper Limit 1.277 1.586
 

Weeks to First Observed Tumor 79 79 76
 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Administered Fenthion in the Diet (a)
 

(continued)
 

Matched Low High
 

Topography; Morphology Control Dose Dose
 

Thyroid: C-cell Adenoma (b) 2/22 (9) 12/48 (25) 4/46 (9)
 

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

Departure from Linear Trend (e) P - 0.022 (N)
 

Relative Risk (f) 2.750 0.957
 

Lower Limit 0.697 0.152
 

Upper Limit 23. 940 10.075
 

oo
 

Ul Weeks to First Observed Tumor 105 104 102
 

Mammary Gland: Fibroadenoma (b) 1/25 (4) 6/50 (12) 1/49 (2)
 

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

Relative Risk (f) 3.000 0.510
 

Lower Limit 0.399 0.007
 

Upper Limit 134.975 39.258
 

Weeks to First Observed Tumor 105 86 84
 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Administered Fenthion in the Diet (a)
 

(continued)
 

Topography: Morphology


Mammary Gland: Adeno carcinoma, NOS (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


00


o\
 Uterus: Endometrial Stromal Polyp (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched
 

 Control
 

 2/25 (8)
 

P = 0.036 (N)
 

 90
 

 2/25 (8)
 

 N.S.
 

83
 

Low
 

Dose
 

0/50 (0)
 

N.S.
 

0.000
 

0.000
 

1.685
 

—
 

11/49 (22)
 

N.S.
 

2.806
 

0.687
 

24.758
 

74
 

High
 

Dose
 

0/49 (0)
 

N.S.
 

0.000
 

0.000
 

1.718
 

—
 

8/46 (17)
 

N.S.
 

2.174
 

0.484
 

19.975
 

44 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Administered Fenthion in the Diet (a)
 

(continued)
 

(a) Dosed groups received 10 or 20 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 (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.
 
88

 
APPENDIX F
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS IN
 

MICE ADMINISTERED FENTHION IN THE DIET
 

89
 
6

 0
Table Fl. Analyses of the Incidence of

Administered Fenthion in

 Primary Tumors

 the Diet (a) 

 in Male Mice 

Topography: Morphology

Matched 

 Control 

Low 

Dose 

High 

Dose 

Integumentary System: Fibres ar coma (b) 0/25 (0) 4/49 (8) 4/48 (8) 

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

Relative Risk (f) 

Lower Limit 

Upper Limit 

Infinite 

0.486 

Infinite 

Infinite 

0.496 

Infinite 

Weeks to First Observed Tumor — 89 92 

vo 

Integumentary System: 

Rhabdomyosarcoma (b) 0/25 (0) 3/49 (6) 2/48 (4) 

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

Relative Risk (f) 

Lower Limit 

Upper Limit 

Infinite 

0.315 

Infinite 

Infinite 

0.158 

Infinite 

Weeks to First Observed Tumor 61 68 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice 

Administered Fenthion in the Diet (a) 

(continued) 

Topography: Morphology

Matched 

 Control 

Low 

Dose 

High 

Dose 

Integumentary System: Fibres ar coma, 

Sarcoma, NOS, or 

Rhabdomyosarcoma (b) 0/25 (0) 7/49 (14) 8/48 (17) 

P Values (c,d) P = 0.043 P = 0.048 P = 0.028 

Relative Risk (f) 

Lower Limit 

Upper Limit 

Infinite 

1.018 

Infinite 

Infinite 

1.223 

Infinite 

kO 

N> Weeks to First Observed Tumor — 61 68 

Lung: Alveolar/Bronchiolar 

Adenoma (b) 2/25 (8) 5/48 (10) 8/48 (17) 

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

Relative Risk (f) 

Lower Limit 

Upper Limit 

1.302 

0.235 

13.059 

2.083 

0.463 

19.178 

Weeks to First Observed Tumor 104 78 92 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice
 

Administered Fenthion in the Diet (a)
 

(continued)
 

Matched Low
 

Topography: Morphology Control Dose
 

Hematopoietic System: Lymphoma
 

or Leukemia (b) 1/25 (4) 6/49 (12)
 

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

Relative Risk (f) 3.061
 

Lower Limit 0.407
 

Upper Limit 137.655
 

Weeks to First Observed Tumor 104 69
 VO
 

Liver: Hepatocellular Carcinoma (b) 6/25 (24) 15/49 (31)
 

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

Relative Risk (f) 1.276
 

Lower Limit 0.548
 

Upper Limit 3.582
 

Weeks to First Observed Tumor 82 84
 

High
 

Dose
 

2/48 (4)
 

N.S.
 

1.042
 

0.058
 

60.184
 

101
 

13/48 (27)
 

N.S.
 

1.128
 

0.467
 

3.241
 

61 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice
 

Administered Fenthion in the Diet (a)
 

(continued)
 

Topography: Morphology 

Matched 

Control 

Low 

Dose 

High 

Dose 

Liver: Hepatocellular Carcinoma or 

Adenoma (b) 6/25 (24) 17/49 (35) 17/48 (35) 

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

Relative Risk (f) 

Lower Limit 

Upper Limit 

1.446 

0.639 

3.980 

1.476 

0.653 

4.055 

Weeks to First Observed Tumor 82 84 61 

(a) Dosed groups received 10 or 20 ppm.
 

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

observed tumor is based on time at death with tumor.
 

(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 (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 groiiT~
 
Table F2. Analyses of the Incidence of Primary Tumors in Female Mice
 

Administered Fenthion in the Diet (a)
 

Topography: Morphology


Lung: Alveolar/Bronchiolar


Adenoma or Carcinoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


vo
 

Hematopoietic System: Lymphoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched
 

 Control
 

k
 

 3/24 (13)
 

 N.S.
 

 103
 

 6/24 (25)
 

 N.S.
 

103
 

Low
 

Dose
 

3/46 (7)
 

N.S.
 

0.522
 

0.076
 

3.662
 

104
 

12/47 (26)
 

N.S.
 

1.021
 

0.416
 

2.964
 

84
 

High
 

Dose
 

3/50 (6)
 

N.S.
 

0.480
 

0.070
 

3.380
 

104
 

13/50 (26)
 

N.S.
 

1.040
 

0.433
 

2.989
 

96 
Table F2. Analyses of the Incidence of Primary Tumors in Female Mice
 

Administered Fenthion in the Diet (a)
 

(continued)
 

Topography: Morphology


Liver: Hepatocellular Carcinoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


Liver: Hepatocellular Carcinoma or
 

Adenoma (b)


P Values (c,d)


Relative Risk (f )
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched Low High 

 Control Dose Dose 

 2/24 (8) 4/47 (9) 1/50 (2) 

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

1.021 0.240 

0.161 0.004 

10.779 4.429 

 103 104 96 

 2/24 (8) 4/47 (9) 2/50 (4) 

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

1.021 0.480 

0.161 0.037 

10.779 6.350 

103 104 96 
Table F2. Analyses of the Incidence of Primary Tumors in Female Mice
 

Administered Fenthion in the Diet (a)
 

(continued)
 

Matched Low
 

Topography: Morphology Control Dose
 

Pituitary: Adenoma, NOS, Acidophil
 

Adenoma, or Chromophobe Adenoma (b) 0/21 (0) 3/37 (8)
 

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

Relative Risk (f) Infinite
 

Lower Limit 0.354
 

Upper Limit Infinite
 

Weeks to First Observed Tumor 100
 VO
 

Thyroid: Papillary Adenoma (b) 3/21 (14) 0/42 (0)
 

P Values (c,d) P = 0.009 (N) P = 0.033 (N)
 

Departure from Linear Trend (e) P = 0.036
 

Relative Risk (f) 0.000
 

Lower Limit 0.000
 

Upper Limit 0.821
 

Weeks to First Observed Tumor 104
 

High
 

Dose
 

4/42 (10)
 

N.S.
 

Infinite
 

0.481
 

Infinite
 

103
 

0/40 (0)
 

P = 0.037 (N)
 

0.000
 

0.000
 

0.861
 
Table F2. Analyses of the Incidence of Primary Tumors in Female Mice
 

Administered Fenthion in the Diet (a)
 

(continued)
 

(a) Dosed groups received 10 or 20 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 (N) indicates a lower incidence in a dosed group than in the control group.
 

OT	 (e) Th probabilit e y 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.
 
APPENDIX G
 

ANALYSIS OF FORMULATED DIETS FOR
 

CONCENTRATIONS OF FENTHION
 

99
 
100

 
APPENDIX G
 

Analysis of Formulated Diets for
 

Concentrations of Fenthion
 

A 10-g sample from a formulated diet was shaken with 250 ml
 

benzene for 3 hours. Sample aliquots of the extract were
 

analyzed by gas chromatography using a flame photometric detector
 

in the phosphorus mode.
 

Spiked samples were worked up simultaneously and the recoveries
 

used to correct ^the recoveries from the dosed feed samples for
 

losses due to the method.
 

Theoretical No. of Sample Coefficient of Range (ppm) 

Concentration Samples Analytical Variation (%) 

(ppm) Mean (ppm) 

10 11 10.09 5.37 9.37-11.1! 

20 11 19.98 6.74 18.3-21.5 

101
 

Review of the Bioassay of Fenthion* for Carcinogenicity
 

by the Data Evaluation/Risk Assessment Subgroup
 

of the Clearinghouse on Environmental Carcinogens
 

October 25, 1978
 

The Clearinghouse on Environmental Carcinogens was established in
 

May, 1976, in compliance with DHEW Committee Regulations and the Provisions of the Federal Advisory Committee Act. The purpose of the
 

Clearinghouse is to advise the Director of the National Cancer Institute
 

(NCI) on its bioassay program to identify and to evaluate chemical
 

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

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

organized labor, public interest groups, 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 Fenthion for carcinogenicity.
 

The primary reviewer for the report on the bioassay of Fenthion
 

said that the compound was not carcinogenic in either sex of treated
 

rats or female mice, under the conditions of test. An increased
 

incidence of sarcomas of the skin in treated male mice suggested that
 

Fenthion was sarcomagenic in this sex and strain. The primary reviewer
 

pointed out an increased but statistically insignificant incidence of
 

leukemia and endometrial polyps in treated female rats.
 

The secondary reviewer of the bioassay of Fenthion recommended
 

that the conclusion regarding the male mice be changed to read that the
 

findings indicated the need for further study of Fenthion, and that the
 

reference to the compound's carcinogenicity be deleted. He further
 

suggested that the report contain literature references about the
 

effects of fighting on subcutaneous sarcoma production in mice. The
 

secondary reviewer concluded that Fenthion was not carcinogenic, under
 

the conditions of test, and he recommended that the compound be retested
 

by subcutaneous injection into an appropriate species.
 

A Program staff pathologist noted the increased incidence of
 

rhabdomyosarcomas observed among treated male mice. He said that
 

this was a relatively rare tumor in historical control animals.
 

103
 
There was no objection to a recommendation that the report be
 

accepted as written.
 

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
 

(Michael B. Shimkin, University of California at San Diego, submitted
 

a written review)
 

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.
 

1> U . S GOVERNMEN T PRINTIN G OFFICE : 1978-281-217/333 2
 

104
 

DHEW Publication No. (NIH) 79-1353