National Cancer Institute 

CARCINOGENESIS 

Technical Report Series 

No. 152 

1979 

BIOASSAY OF 

ETHYL TELLURAC 

FOR POSSIBLE CARCINOGENICITY 

CAS No. 20941-65-5 AND 30145-38-1 

NCI-CG-TR-152 

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

Public Health Service 

National Institutes of Health 

BIOASSAY OF
 

ETHYL TELLURAC
 

FOR POSSIBLE CARCINOGENICITY
 

Carcinogenesis Testing Program
 

Division of Cancer Cause and Prevention
 

Natibnal Cancer Institute
 

National Institutes of Health
 

Bethesda, Maryland 20205
 

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

Public Health Service
 

National Institutes of Health
 

NIH Publication No. 79-1708
 

BIOASSAY OF
 

ETHYL TELLURAC
 

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
 

ethyl tellurac conducted for the Carcinogenesis Testing Program,
 

Division of Cancer Cause and Prevention, National Cancer
 

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

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

determine whether selected chemicals have the capacity to produce
 

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

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

does not necessarily mean that the test chemical is not a
 

carcinogen, inasmuch as the experiments are conducted under a
 

limited set of circumstances. A positive result demonstrates
 

that the test chemical is carcinogenic for animals under the
 

conditions of the test and indicates that exposure to the
 

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

the risk to man from chemicals that are carcinogenic in animals
 

requires a wider analysis.
 

CONTRIBUTORS; This bioassay of ethyl tellurac was conducted by
 

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

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

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

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

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

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

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

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

computer services. Necropsies were performed by Drs. B. Ulland,
 

R. Schueler, R. Ball, and R. Cardy. Histopathologic evaluations
 

were performed by Drs. J. F. Hardisty (3) and C. E. Gilmore (3),
 

and the diagnoses included in this report represent their
 

interpretation.
 

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

Mason Research Institute (4). The statistical analyses were
 

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

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

The chemicals used in this bioassay were analyzed at FCRC (1) by
 

Dr. W. Zielinsky. The chemical narrative and analyses were
 

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

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

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

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

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

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

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

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

assisted by Ms. Y. E. Presley. 

The following scientists at NCI were responsible for evaluating
 

the bioassay, interpreting the results, and reporting the
 

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

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

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

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

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

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

Maryland.
 

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

Prevention, National Cancer Institute, National Institutes of
 

Health, Bethesda, Maryland.
 

(3) Experimental Pathology Laboratories, Inc., P.O. Box 474,
 

Herndon, Virginia.
 

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

Rockville, Maryland.
 

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

Maryland.
 

(6) Mathematical Statistics and Applied Mathematics Section,
 

Biometry Branch, Field Studies and Statistics, Division of
 

Cancer Cause and Prevention, National Cancer Institute,
 

National Institutes of Health, Bethesda, Maryland.
 

IV
 
SUMMARY
 

A bioassay of technical-grade ethyl tellurac for possible carcinogenicity was conducted by administering the preparation in feed to
 

F344 rats and B6C3F1 mice.
 

Groups of 50 rats of each sex were administered ethyl tellurac at
 

one of two doses, either 300 or 600 ppm for the males and either 150
 

or 300 ppm for the females, for 105 weeks. Matched controls consisted of 20 untreated rats of each sex. All surviving rats were
 

killed at 105 weeks.
 

Groups of 50 mice of each sex were administered ethyl tellurac at
 

one of two doses, initially either 2,500 or 5,000 ppm. Due to signs
 

of toxicity in the dosed animals, these doses were reduced to 500
 

and 2,000 ppm, respectively, starting at week 41 for the males and
 

at week 38 for the females. The reduced doses were maintained for
 

66 weeks for the males; for the females, the reduced doses were
 

raised after 3 weeks to 2,000 and 5,000 ppm, respectively, and
 

maintained at these levels for 66 weeks. The time-weighted average
 

doses for the males were either 1,255 or 3,132 ppm; for the females,
 

either 2,132 or 4,915 ppm. Matched controls consisted of 20
 

untreated mice of each sex. All surviving mice were killed at 106
 

weeks.
 

Mean body weights of the dosed groups of rats or mice were lower
 

than those of corresponding controls throughout most or all of the
 

bioassay. No other clinical signs in the rats or mice were clearly
 

related to administration of the test chemical. Survival of the
 

rats and the mice was not affected by the chemical, and sufficient
 

numbers of all groups were at risk for the development of late-


appearing tumors.
 

In the male rats, mesotheliomas occurred at incidences that were
 

dose related (P = 0.012); in direct comparisons, the incidences of
 

the tumors in the individual dosed groups were not significantly
 

higher than that in the control group (controls 0/20, low-dose 2/49,
 

high-dose 8/50). However, the historical-control data at this
 

laboratory indicate an incidence of 12/416 (2.9%) in male F344 rats
 

compared with 8/50 (16%) in the male high-dose group in this study.
 

In the female rats, no tumors occurred at incidences that were
 

related to administration of the test chemical.
 

In both male and female mice, adenomas of the lacrimal (harderian)
 

gland of the eye occurred in the dosed groups, but not in the
 

corresponding controls (males: controls 0/17, low-dose 16/46,
 
high-dose 10/49; females: controls 0/20, low-dose 6/50, high-dose
 

5/49). The incidences in the dosed groups were not high enough to
 

show statistically significant dose-related trends. However, in
 

direct comparisons of dosed and control groups of male mice, the
 

incidence was statistically significant in the low-dose males (P =
 

0.003). In female mice, direct comparisons of dosed and control
 

groups indicated that the incidence of this tumor was not
 

statistically significant.
 

It is concluded that under the conditions of this bioassay, ethyl
 

tellurac was not carcinogenic for F344 rats or B6C3F1 mice of either
 

sex. The incidence of mesotheliomas in dosed male rats and the
 

incidence of adenomas of the lacrimal (harderian) gland of the eye
 

in dosed mice of either sex provided evidence which was suggestive
 

but under the conditions of the bioassay insufficient to establish
 

the carcinogenicity of ethyl tellurac in these animals.
 

Vi
 
TABLE OF CONTENTS
 

Page
 

I. Introduction 1
 

II. Materials and Methods 3
 

A. Chemical 3
 

B. Dietary Preparation 4
 

C. Animals 4
 

D. Animal Maintenance 5
 

E. Subchronic Studies 7
 

F. Chronic Studies 8
 

G. Clinical and Pathologic Examinations 11
 

H. Data Recording and Statistical Analyses 12
 

III. Results - Rats 19
 

A. Body Weights and Clinical Signs (Rats) 19
 

B. Survival (Rats) 19
 

C. Pathology (Rats) 22
 

D. Statistical Analyses of Results (Rats) 24
 

IV. Results -Mice 27
 

A. Body Weights and Clinical Signs (Mice) 27
 

B. Survival (Mice) 27
 

C. Pathology (Mice) 30
 

D. Statistical Analyses of Results (Mice) 32
 

V. Discussion 35
 

VI. Bibliography 39
 

APPENDIXES
 

Appendix A Summary of the Incidence of Neoplasms in Rats
 

Administered Ethyl Tellurac in the Diet 41
 

Table Al Summary of the Incidence of Neoplasms in Male
 

Rats Administered Ethyl Tellurac in the Diet... 43
 

Table A2 Summary of the Incidence of Neoplasms in Female
 

Rats Administered Ethyl Tellurac in the Diet... 47
 

vii
 
Appendix B Summary of the Incidence of Neoplasms in Mice 

Administered Ethyl Tellurac in the Diet 51 

Table Bl Summary of the Incidence of Neoplasms in Male 

Mice Administered Ethyl Tellurac in the Diet .. 53 

Table B2 Summary of the Incidence of Neoplasms in Female 

Mice Administered Ethyl Tellurac in the Diet .. 57 

Appendix C Summary of the Incidence of Nonneoplastic 

Lesions in Rats Administered Ethyl Tellurac 

in the Diet 61 

Table Cl Summary of the Incidence of Nonneoplastic 

Lesions in Male Rats Administered Ethyl 

Tellurac in the Diet 63 

Table C2 Summary of the Incidence of Nonneoplastic 

Lesions in Female Rats Administered 

Ethyl Tellurac in the Diet 69 

Appendix D Summary of the Incidence of Nonneoplastic 

Lesions in Mice Administered Ethyl Tellurac 

in the Diet 75 

Table Dl Summary of the Incidence of Nonneoplastic 

Lesions in Male Mice Administered 

Ethyl Tellurac in the Diet 77 

Table D2 Summary of the Incidence of Nonneoplastic 

Lesions in Female Mice Administered 

Ethyl Tellurac in the Diet 80 

Appendix E Analyses of the Incidence of Primary Tumors in 

Rats Administered Ethyl Tellurac 

83 

Table El Analyses of the Incidence of Primary Tumors in 

Male Rats Administered Ethyl Tellurac 

in the Diet 85 

Table E2 Analyses of the Incidence of Primary Tumors in 

Female Rats Administered Ethyl Tellurac 

in the Diet 93 

viii
 
Page 

Appendix F Analyses of the Incidence of Primary Tumors in 

Mice Administered Ethyl Tellurac in 

the Diet 97 

Table Fl Analyses of the Incidence of Primary Tumors in 

Male Mice Administered Ethyl Tellurac in 

the Diet 99 

Table F2 Analyses of the Incidence of Primary Tumors in 

Female Mice Administered Ethyl Tellurac in 

the Diet 104 

TABLES 

Table 1 Ethyl Tellurac Chronic Feeding Studies in 

Rats 9 

Table 2 Ethyl Tellurac Chronic Feeding Studies 

in Mice 10 

FIGURES 

Figure 1 Growth Curves for Rats Administered 

Ethyl Tellurac in the Diet 20 

Figure 2 Survival Curves for Rats Administered 

Ethyl Tellurac in the Diet 21 

Figure 3 Growth Curves for Mice Administered 

Ethyl Tellurac in the Diet 28 

Figure 4 Survival Curves for Mice Administered 

Ethyl Tellurac in the Diet 29 

ix
 

I. INTRODUCTION
 

Ethyl tellurac (CAS 20941-65-5 and
 

30145-38-1; NCI C02857) is the 

common name for tellurium diethyl­ CH3CH2 sII 

Te"1 

dithiocarbamate. It is used in CH3CH2 

X 

rubber processing where it
 

functions to accelerate the rate
 

Ethyl tellurac 

of vulcanization or formation of
 

sulfur bridges between rubber
 

polymers that produces modulus or rigidity in the finished product
 

(LeBras, 1957).
 

Ethyl tellurac belongs to a class of rubber accelerators that are
 

extremely fast-acting and have been termed "ultra-accelerators"
 

(Harris and Trivette, 1964). In addition to shortening the
 

curing time, the ultra-accelerators are active at low temperatures and can be used, for example, in rubber cements (Shaver,
 

1965). While the mechanism by which ethyl tellurac catalyzes
 

vulcanization is not completely understood, it seems probable
 

that tellurium, a group VI relative of sulfur, replaces it in the
 

crosslink so that the linkage now resembles S-Te-S, instead of
 

S-S-S (Ambelang, 1964). Tellurium is more capable of absorbing
 
the thermal energy generated by vulcanization, and prevents these
 

linkages from undergoing reversion, or breakdown, which normally
 

occurs if curing proceeds too far (Dunkel et al., 1959).
 

Natural rubber, styrene-butadiene-rubber, nitrile and butyl
 

rubber (Del Gatto, 1968) and ethylene-propylene-diene rubber are
 

compounded with ethyl tellurac in a ratio of 1 to 2 parts
 

accelerator per 100 parts rubber (Winspear, 1958). Some thiazole
 

accelerators are used in conjunction with ethyl tellurac (Del
 

Gatto, 1968).
 

Production data are not reported for ethyl tellurac alone,
 

although the class of which it is a member, the dithiocarbamates,
 

accounted for 15% of the acyclic rubber-processing chemicals that
 

were sold in 1976 (United States International Trade Commission,
 

1977).
 

Ethyl tellurac was tested by Innes et al. (1969) in a large-scale
 

screen of industrial compounds for carcinogenic activity. Since
 

the results of this preliminary bioassay in mice suggested but
 

did not clearly associate the incidence of lung tumors with
 

administration of the test chemical, ethyl tellurac was selected
 

for further testing in the Carcinogenesis Testing Program.
 
II. MATERIALS AND METHODS
 

A. Chemical
 

Ethyl tellurac (tellurium diethyldithiocarbamate; C H.-N.SgTe)
 

was obtained as technical-grade, nonformulated material from R.
 

T. Vanderbilt Co. The material is a fine, dark-yellow powder.
 

Atomic absorption spectrometric analysis showed the presence of
 

18.3% tellurium in the test material (manufacturer's
 

specification: 17.5 to 19.5% tellurium). This value was slightly
 

higher than the theoretical level of tellurium in ethyl tellurac
 

(17.7%). The high purity of the test material was validated by
 

elemental analysis (experimental: 32.7% carbon, 5.7% hydrogen,
 

7.7% nitrogen; theoretical: 33.3% carbon, 5.6% hydrogen, 7.8%
 

nitrogen). Thin-layer chromatography of the test material on
 

silylated silica showed only a single spot, with no impurities.
 

The material had a melting point of 115 C (literature: 108 to
 

118 C) and an infrared spectrum consistent with the chemical
 

structure for ethyl tellurac. Mass spectral analysis showed the
 

absence of a molecular ion, and a base peak at 60 m/e. Atomic
 

absorption analysis also showed the presence of 0.004% selenium,
 

0.03% lead, 0.05% zinc, and 0.02% sodium.
 
B. Dietary Preparation
 

Appropriate mixtures of dosed feed were prepared fresh every 1 to
 

1-1/2 weeks in 6 to 12-kg batches. A known weight of the chemical
 

®
 

was first mixed with an equal weight of autoclaved Wayne
 

Sterilizable Lab Meal with 4% fat (Allied Mills, Inc., Chicago,
 

111.), using a mortar and pestle. The mixing was continued with
 

second and third additions of feed, and final mixing was performed
 

with the remaining quantity of feed for a minimum of 15 minutes in a
 

Patterson-Kelly twin-shell blender. The diets were routinely stored
 

at 5 C until used.
 

C. Animals
 

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

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

NCI Frederick Cancer Research Center animal farm (Frederick, Md.).
 

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

then were assigned four rats to a cage and five mice to a cage on a
 

weight basis for each cage of animals of a given species and sex.
 

Male rats used in the chronic study weighed 90 to 105 g; the female
 

rats, 80 to 95 g; the male mice, 18 to 22 g; and the female mice, 17
 

to 21 g. Individual animals were identified by ear punch.
 
D. Animal Maintenance
 

The animals were housed in polycarbonate cages (Lab Products Inc.,
 

Garfield, N. J.), 19 x 10-1/2 x 8 inches for the rats and 11-1/2 x
 

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

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

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

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

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

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

Sterilizable Lab Meal, provided ad libitum in suspended stainless
 

steel hoppers and replenished as required, at least three times per
 

week. Water, acidified to pH 2.5, was supplied ad libitum from
 

glass bottles. Sipper tubes (Lab Products, Inc.) suspended through
 

the tops of the cages.
 

The contaminated bedding was disposed of through an enclosed vacuum
 

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

periodically into an incinerator. The cages were sanitized at 82 to
 

88 C in a tunnel-type cagewasher (Industrial Washing Machine
 

Corp., Mataway, N. J.) twice per week, using the detergents,
 

Clout (Pharmacal Research Laboratories, Greenwich, Conn.) or
 

Oxford D'Chlor (Oxford Chemicals, Atlanta, Ga.). The feed hoppers
 

were sanitized twice per month in the same equipment. The glass
 
bottles and sipper tubes were sanitized at 82 to 88 C in a
 

tunnel-type bottle washer (Consolidated Equipment Supply Co.,
 

Mercersburg, Pa.) three times per week, using a Calgen Commercial
 

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

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

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

detergent, and the filter paper was changed at the same time.
 

The air in the animal rooms was maintained at 22 to 24 C and 45 to
 

55% relative humidity. Fresh air was passed through a filter of 65%
 

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

through a "Z"-type roughing filter of 30% efficiency and a bag
 

system of 90 to 95% efficiency at the exhaust (American Air Filters,
 

Louisville, Ky.; Mine Safety Appliances, Pittsburgh, Pa.) and was
 

not recirculated. Room air was changed 15 times per hour. The air
 

pressure was maintained negative to a clean hallway and positive to
 

a return hallway. Fluorescent lighting was provided automatically
 

on a 12-hour-per-day cycle.
 

Rats administered ethyl tellurac and their corresponding controls
 

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

following chemicals:
 

(CAS 97-77-8) ethyl tuads
 

(CAS 19010-66-3) lead dimethyldithiocarbamate
 
Mice administered ethyl tellurac and their corresponding controls
 

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

following chemicals:
 

(CAS 103-33-3) azobenzene
 

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

(CAS 298-00-0) methyl parathion
 

(CAS 85-44-9) phthalic anhydride
 

(CAS 51-03-6) piperonyl butoxide
 

(CAS 88-06-2) 2,4,6-trichlorophenol
 

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

E. Subchronic Studies
 

Subchronic feeding studies were conducted to estimate the maximum
 

tolerated doses (MTD's) of ethyl tellurac, on the basis of which
 

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

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

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

fed diets containing ethyl tellurac at one of several doses, and
 

groups of five controls of each species and sex were administered
 

basal diet only for 7 weeks, rollowed by 1 week of additional
 

observation. Each animal was weighed twice per week. At the end
 

of the subchronic studies, all animals were killed using C0«
 

and necropsied.
 
Based on these studies, the low and high doses for chronic
 

studies using male rats were set at 300 and 600 ppm; for female
 

rats, at 150 and 300 ppm. For chronic studies using mice, the
 

low and high doses were set at 2,500 and 5,000 ppm for both males
 

and females.
 

F. Chronic Studies
 

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

feeding studies are shown in tables 1 and 2.
 

Due to excessive depression of weight in both dosed male and
 

dosed female mice, the doses were reduced starting at week 41 for
 

the males and at week 38 for the females. For the males, the
 

lowered doses were retained for the remainder of the
 

administration of the chemical; for the females, they were
 

increased after 3 weeks, as indicated.
 
Table 1. Ethyl Tellurac Chronic Feeding Studies in Rats
 

Ethyl
 

Sex and Initial Tellurac Time on
 

Test No. of in Diet (b) Study
 

Group Animals (a) (ppm) (weeks)
 

Male
 

Mat ched-Contro 1 20 0 105
 

Low-Dose 50 300 105
 

High -Dose 50 600 105
 

Female
 

Matched-yControl •20 0 105
 

Low-Dose 50 150 105
 

High-Dose 50 300 105
 

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

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

week.
 
Table 2. Ethyl Tellurac Chronic Feeding Studies in Mice
 

Sex and
 

Test
 

Group
 

Male
 

Matched-Control
 

Low-Dose
 

High-Dose
 

Female
 

Matched-Control


Low-Dose


High-Dose
 

Initial
 

No. of
 

Animals (a)
 

20
 

50
 

50
 

 20
 

 50
 

50
 

Ethyl
 

Tellurac
 

in Diet (b)
 

(ppm)
 

0
 

2,500
 

500
 

5,000
 

2,000
 

0
 

2,500
 

500
 

2,000
 

5,000
 

2,000
 

5,000
 

Time on
 

Study
 

(weeks)
 

106
 

40
 

66
 

40
 

66
 

106
 

37
 

3
 

66
 

37
 

3
 

66
 

Time-Weighted
 

Average Dose (c)
 

(ppm)
 

1,255
 

3,132
 

2,132
 

4,915
 

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

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

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

E(no. of weeks receiving each dose)
 

10
 
G. Clinical and Pathologic Examinations
 

All animals were observed twice daily. Observations for sick,
 

tumor-bearing, and moribund animals were recorded daily.
 

Clinical examination and palpation for masses were performed each
 

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

Moribund animals and those that survived to the end of the
 

bioassay were killed using CO and necropsied.
 

The pathologic evaluation consisted of gross and microscopic
 

examination of major tissues, major organs, and all gross
 

lesions. The tissues were preserved in 10% formalin, embedded in
 

paraffin, sectioned, and stained with hematoxylin and eosin. The
 

following tissues were examined microscopically: skin, lungs and
 

bronchi, trachea, bone marrow (femur), spleen, lymph nodes
 

(mesenteric and submandibular), thymus, heart, salivary glands
 

(parotid, sublingual, and submaxillary), liver, pancreas,
 

esophagus, stomach (glandular and nonglandular), small and large
 

intestine, kidney, urinary bladder, pituitary, adrenal, thyroid,
 

parathyroid, testis, ptostate, mammary gland, uterus, ovary,
 

brain (cerebrum and cerebellum), and all tissue masses.
 

Peripheral blood smears also were made for all animals, whenever
 

possible.
 

11
 
Necropsies were also performed on all animals found dead, unless
 

precluded in whole or in part by autolysis or cannibalization.
 

Thus, the number of animals from which particular organs or
 

tissues were examined microscopically varies and does not
 

necessarily represent the number of animals that were placed on
 

study in each group.
 

H. Data Recording and Statistical Analyses
 

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

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

descriptive information on the chemicals, animals, experimental
 

design, clinical observations, survival, body weight, and
 

individual pathologic results, as recommended by the
 

International Union Against Cancer (Berenblum, 1969). Data
 

tables were generated for verification of data transcription and
 

for statistical review.
 

These data were analysed using the appropriate statistical
 

techniques described in this section. Those analyses of the
 

experimental results that bear on the possibility of carcinogenicity are discussed in the statistical narrative section.
 

12
 
Probabilities of survival were estimated by the product-limit
 

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

report in the form of graphs. Animals were statistically
 

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

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

causes were not statistically censored. Statistical analyses for
 

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

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

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

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

except the departure from linearity test, which is only reported
 

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

The incidence of neoplastic or nonneoplastic lesions has been
 

given 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
 

t
 

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

denominators consist of the numbers of animals necropsied.
 

13
 
The purpose of the statistical analyses of tumor incidence is to
 

determine whether animals receiving the test chemical developed a
 

significantly higher proportion of tumors than did the control
 

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

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

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

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

compared simultaneously with those for a control group, a
 

correction to ensure an overall significance level of 0.05 may be
 

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

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

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

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

where the Fisher exact P values are shown.
 

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

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

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

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


tailed 0.05 level of significance. Unless otherwise noted, the
 

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

from linear trend.
 
A time-adjusted analysis was applied when numerous early deaths
 

resulted from causes that were not associated with the formation
 

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

first tumor was observed were excluded by basing the statistical
 

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

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

such an early tumor was found, comparisons were based exclusively
 

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

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

obtained, the standard procedures for analyses of the incidence
 

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

followed.
 

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

incidence of tumors. Curves of the proportions surviving without
 

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

The week during which an animal died naturally or was sacrificed
 

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

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.
 

15
 
Significant departures from linearity (P less than 0.05, two-


tailed test) were also noted.
 

The approximate 95 percent confidence interval for the relative
 

risk of each dosed group compared with its control was calculated
 

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

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

binomial probability of the incidence of a specific type of tumor
 

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

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

group. The hypothesis of equality between the true proportion of
 

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

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

of unity represent the condition of a larger proportion in the
 

dosed group than in the control.
 

The lower and upper limits of the confidence interval of the
 

relative risk have been included in the tables of statistical
 

analyses. The interpretation of the limits is that in
 

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
 

16
 
significant result (P less than 0.025 one-tailed test when the
 

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

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

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

limit indicates the absence of a significant result while the
 

upper limit indicates that there is a theoretical possibility of
 

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

detected under the conditions of this test.
 

17
 
18

 
III. RESULTS - RATS
 

A. Body Weights and Clinical Signs (Rats)
 

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

than those of corresponding matched controls throughout the
 

bioassay (figure 1). In the males, the depression in weight was
 

slightly greater in the high-dose group than in the low-dose
 

group; in the females, the weights of the low- and high-dose
 

groups were essentially the same. No other clinical signs were
 

observed that were clearly related to administration of the test
 

chemical.
 

B. Survival (Rats)
 

The Kaplan and Meier curves estimating the probabilities of
 

survival for male and female rats administered ethyl tellurac in
 

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

the matched controls, are shown in figure 2. In each sex, the
 

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

not significant.
 

19
 
TIME ON STUDY (WEEKS) 

Figure 1. Growth Curves for Rats Administered Ethyl Tellurac in the Diet 

20 
TIME ON STUDY (WEEKS) 

Figure 2. Survival Curves for Rats Administered Ethyl Tellurac in the Diet 

21 
In male rats, 26/50 (52%) of the high-dose group, 27/50 (54%) of
 

the low-dose group, and 12/20 (60%) of the control group lived to
 

the end of the bioassay. In females, 43/50 (86%) of the
 

high-dose group, 38/52 (76%) of the low-dose group, and 15/20
 

(75%) of the control group lived to the end of the bioassay.
 

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

development of late-appearing tumors.
 

C. Pathology (Rats)
 

Histopathologic findings on neoplasms in rats are summarized in
 

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

are summarized in Appendix C, tables Cl and C2.
 

With the exception of the mesotheliomas observed in the dosed
 

male rats and the high incidence of malignant lymphoma in all
 

groups, the neoplasms that were observed had similar incidences
 

in control and dosed groups. The nature and incidence of these
 

neoplasms are consistent with the occurrence of similar neoplasms
 

in aged F344 rats.
 

Malignant mesotheliomas were present in 2/49 of the low-dose male
 

22
 
rats and 8/50 of the high-dose male rats. These neoplasms were
 

nodular growths arising from the serous membranes linking the
 

peritoneal cavity and scrotum. Microscopically, they were
 

characterized as papillary projections consisting of a fibrous
 

core covered by large, atypical, mesothelial cells.
 

There was a high incidence of tumors of the hematopoietic system
 

in both control and dosed rats as shown in the following
 

tabulation:
 

Males Females 

Low High Low High 

Control Dose Dose Control Dose Dose 

Numb er of 

Animals 

Necropsied 20 49 50 20 50 50 

Malignant
 

Lymphoma 7 (35%) 27 (55%) 24 (48%) 4 (20%) 14 (28%) 15 (30%)
 

Erythrocytic
 

Leukemia 1 (2%)
 

The most frequent hematopoietic neoplasms encountered were malignant lymphomas. Most of these neoplasms were composed of undifferentiated lymphoreticular cells and involved several organs;
 

spleen and liver were the organs most frequently involved,
 

followed by the lung, lymph nodes, and thymus. Malignant
 

lymphomas (also called mononuclear-cell or monocytic leukemia)
 

frequently occur as in aging F344 rats; there appears to be
 

little difference between the low- and high-dose groups in the
 

incidences of the malignant lymphomas in this bioassay.
 

23
 
Several inflammatory, degenerative, and proliferative lesions
 

commonly seen in aged F344 rats occurred with approximately equal
 

frequency in dosed and control animals.
 

Based on the histopathologic examination, an increase in the
 

number of malignant mesotheliomas in male F344 rats may be
 

associated with the administration of ethyl tellurac under the
 

conditions of this bioassay.
 

D. Statistical Analyses of Results (Rats)
 

Tables El and E2 in Appendix E contain the statistical analyses
 

of the incidences of those primary tumors that occurred in at
 

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

in one or more than one group.
 

Four mesotheliomas of the body cavities were observed in the male
 

high-dose group, but none in the low-dose group or the controls.
 

The result of the Cochran-Armitage test for positive dose-related
 

trend is significant (P = 0.041), but those of the Fisher exact
 

test are not significant. The results of the statistical tests
 

on the incidence of mesothelioma of the tunica vaginalis are not
 

significant. When mesotheliomas of all sites are considered
 

24
 
together, the result of the Cochran-Armitage test is significant
 

(P = 0.012) but those of the Fisher exact test remain not
 

significant. The historical-control data at this laboratory
 

indicate an incidence of 12/416 (2.9%) in male F344 rats,
 

compared with 8/50 (16%) in the male high-dose groups of this
 

study.
 

In females, the result of the Cochran-Armitage test for the
 

incidence of adenomas of the pituitary is not significant. An
 

indicated departure from linear trend is observed, because the
 

incidence in the low-dose group is greater than that in the
 

high-dose group. The Fisher exact test shows that the incidence
 

in the low-dose group is significantly higher (P = 0.012) than
 

that in the control group, but this significance is not confirmed
 

by the incidence in the high-dose group.
 

In male rats, the results of the Cochran-Armitage test and Fisher
 

exact test for the incidence of lymphoma are not significant.
 

When the life-table method is applied, the result of the Tarone
 

test is also not significant. The historical records of this
 

laboratory show an incidence of lymphoma and leukemia of 91/416
 

(22%) among untreated F344 male rats compared with 24/50 (48%) in
 

the high-dose groups of male rats in this study.
 

25
 
Significant results in the negative direction are observed in the
 

incidence of cortical adenomas or carcinomas of the adrenal and
 

the incidence of islet-cell adenomas in male rats, in which the
 

incidences in the control group exceed those in the dosed groups.
 

In summary, the occurrence of mesotheliomas in male rats may be
 

associated with the administration of ethyl tellurac.
 

26
 
IV. RESULTS - MICE
 

A. Body Weights and Clinical Signs (Mice)
 

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

lower than those of corresponding matched controls throughout 

most of the bioassay (figure 3). The depression in weight was 

slightly greater in the high-dose groups than in the low-dose 

groups. Tissue masses were observed in dosed females at higher 

incidences than in corresponding controls, but no other clinical 

signs in either the males or females were related to 

administration of the test chemical. 

B. Survival (Mice) 

The Kaplan and Meier curves estimating the probabilities of 

survival for male and female mice administered ethyl tellurac in 

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

the matched controls, are shown in figure 4. In each sex, the 

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

not significant. 

27 
TIME ON STUDY (WEEKS) 

Figure 3. Growth Curves for Mice Administered Ethyl Tellurac in the Diet 

28 
TIME ON STUDY (WEEKS) 

Figure 4. Survival Curves for Mice Administered Ethyl Tellurac in the Diet 

29 
In male mice, 36/50 (72%) of the high-dose group, 37/50 (74%) of
 

the low-dose group, and 16/20 (80%) of the control group lived to
 

the end of the bioassay. In females, 37/50 (74%) of the
 

high-dose group, 34/50 (68%) of the low-dose group, and 14/20
 

(70%) of the control group lived to the end of the bioassay.
 

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

development of late-appearing tumors.
 

C. Pathology (Mice)
 

Histopathologic findings on neoplasms in mice are summarized in
 

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

are summarized in Appendix D, tables Dl and D2.
 

The majority of neoplasms observed in dosed mice were observed in
 

incidences similar to those of the controls except for tumors of
 

the lacrimal (harderian) gland in male and female mice, tumors of
 

the lung in male mice, and tumors of the liver in female mice.
 

Adenomas of the lacrimal (harderian) gland were noted grossly as
 

masses adjacent to the eyes; the glands were not examined
 

microscopically unless such a mass was observed grossly. None
 

30
 
were found in the control mice but several were present in dosed
 

animals (males: low-dose 16/46 or 35%, high-dose 10/49 or 20%;
 

females: low-dose 6/50 or 12%, high-dose 5/49 or 10%). The
 

adenomas of the lacrimal gland consisted of clearly defined areas
 

of proliferating epithelial cells arranged in fronds supported by
 

thin fibrous trabeculae and without evidence of invasion.
 

Hepatocellular carcinomas were observed more frequently in dosed
 

females than in female controls.
 

Controls Low Dose High Dose
 

Male 8/17 (47%) 15/46 (33%) 16/49 (33%)
 

Female 1/19 (5%) 7/49 (14%) 10/48 (21%)
 

Metastases of the tumor to lung and/or lymph nodes occurred in one
 

control male and in two males in the dosed groups.
 

Alveolar/bronchiolar adenomas or carcinomas were observed in
 

increased incidences in dosed male mice (controls 0/17, low-dose
 

16/46, high-dose 11/46). The carcinomas were distinguished from
 

the adenomas by their hyperchromatic staining, increased number of
 

mitoses, and solid growth.
 

In addition to the neoplastic lesions, degenerative, proliferative,
 

31
 
and inflammatory lesions occurred that were similar in number and
 

kind to those naturally occurring lesions found in aged B6C3F1 mice.
 

Based on the histopathologic examinations, an increased incidence
 

of adenoma of the lacrimal (harderian) gland in both male and
 

female B6C3F1 mice, and neoplasms of the lung in male mice and of
 

the liver in female mice may be associated with the administration
 

of ethyl tellurac under the conditions of this bioassay.
 

D. Statistical Analyses of Results (Mice)
 

Tables Fl and F2 in Appendix F contain the statistical analyses of
 

the incidences of those primary tumors that occurred in at least
 

two animals 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 Fisher exact test applied to the
 

incidence of animals with alveolar/bronchiolar adenomas or carcinomas are significant (P = 0.003 and P = 0.022, for the low-dose and
 

high-dose, respectively). The result of the Cochran-Armitage test
 

is not significant, but a departure from linear trend is indicated,
 

because the incidence in the low-dose is higher than that in the
 

high-dose group. The incidence in the control group (0/17) may,
 

32
 
however, have been unusually low, since the incidence of these
 

tumors in historical controls at this laboratory is 78/422 (18%).
 

Thus, the occurrence of the alveolar/bronchiolar carcinomas or
 

adenomas in the dosed male mice cannot clearly be related to
 

administration of the test chemical.
 

The result of the Cochran-Armitage test for the incidence of
 

adenomas of the lacrimal (harderian) gland of the eye in male mice
 

is not significant. An indicated departure from linear trend is
 

observed, because the incidence in the low-dose group is greater
 

than that in the high-dose group. The Fisher exact comparisons of
 

the incidences in the low- and high-dose groups with that of the
 

control group show P values of 0.003 and 0.039, respectively. The
 

latter is above the 0.025 level for significance when the
 

Bonferroni inequality criterion is used for multiple comparison.
 

The historical-control data at this laboratory, however, indicate
 

an incidence of 10/422 (2.4%) in male B6C3F1 mice, compared with
 

10/49 (20%) in the high-dose male group in this study.
 

In females, the incidence of adenomas of the lacrimal (harderian)
 

gland is 0/20 in the control group, 6/50 (12%) in the low-dose
 

group, and 5/49 (10%) in the high-dose group. The results of the
 

Cochran-Armitage test and of the Fisher exact test are not
 

significant. The historical-control data at this laboratory
 

33
 
indicate an incidence of 2/440 (0.5%) in female B6C3F1 mice. Using
 

this rate of tumors as a parameter (Fears et al., 1977) and
 

assuming a binomial distribution, the probability level of the
 

occurrence of 5 or more such tumors out of a possible 49 animals is
 

less than 0.001.
 

In summary, the incidence of adenoma of the lacrimal (harderian)
 

gland of the eye in mice of each sex is associated with the
 

administration of ethyl tellurac.
 

34
 
V. DISCUSSION
 

Mean body weights of both rats and mice administered
 

technical-grade ethyl tellurac were lower than those of controls
 

under the conditions of the bioassay, and the depressions were
 

greater in the mice than in the rats. No other clinical signs
 

were observed that clearly were related to administration of the
 

test chemical. Survivals of the rats and mice were unaffected by
 

the ethyl tellurac and were 76% or greater in all groups at week
 

90 of the bioassay; thus, sufficient numbers of dosed and control
 

rats and mice of each sex were at risk for the development of
 

late-appearing tumors.
 

In the male rats, mesotheliomas were observed on the peritoneal
 

surfaces of multiple abdominal organs and on the tunica
 

vaginalis. These tumors occurred at incidences that were dose
 

related (P - 0.012); in direct comparisons, the incidences of the
 

tumors in the individual dosed groups were not significantly
 

higher than that in the control group (controls 0/20, low-dose
 

2/49, high-dose 8/50). However, the historical-control data at
 

this laboratory indicate an incidence of 12/416 (2.9%) in male
 

F344 rats compared with 8/50 (16%) in the male high-dose groups
 

of this study.
 

35
 
No tumors occurred in female rats that could clearly be
 

associated with administration of the test chemical.
 

In the male mice, alveolar/bronchiolar carcinomas or adenomas
 

occurred in the dosed groups, but not in the control group
 

(controls 0/17; low-dose 16/46, or 35%; high-dose 11/46, or
 

25%). In direct comparisons of dosed and control groups, the
 

incidences were statistically significant in both the low-dose
 

(P = 0.003) and the high-dose (P = 0.022) groups. The incidence
 

in the control group may, however, have been unusually low, since
 

the incidence of these tumors in historical-control male mice at
 

this laboratory is 78/422 (18%). Thus, the occurrence of the
 

alveolar/bronchiolar carcinomas or adenomas in the dosed male
 

mice cannot be clearly related to administration of the test
 

chemical.
 

In both the male and female mice, adenomas of the lacrimal
 

(harderian) gland of the eye occurred in the dosed groups, but
 

not in the corresponding controls (males: controls 0/17,
 

low-dose 16/46, high-dose 10/49; females: controls 0/20,
 

low-dose 6/50, high-dose 5/49). The incidences in the dosed
 

groups were not high enough to show statistically significant
 

dose-related trends. However, in direct comparisons of dosed and
 

control groups of male mice the incidence was statistically
 

36
 
significant in the low-dose males (P = 0.003) and the historical-


control data at this laboratory indicate an incidence of 10/422
 

(2.4%) in male B6C3F1 mice, compared with 16/46 (35%) in the
 

low-dose and 10/49 (20%) in the high-dose male groups in this
 

study. In female mice, direct comparisons of dosed and control
 

groups indicated that the incidences of adenomas of the lacrimal
 

(harderian) gland were not statistically significant.
 

In other tests for tumorigenicity, it was reported that when the
 

chemical was administered at 46.4 mg/kg by stomach tube for 4 weeks,
 

then in the diet at 149 ppm for 18 months, to each of two different
 

strains of hybrid mice (C57BL/6 X C3H/Anf and C57BL/6 X AKR), an
 

elevated incidence of lung tumors in 7/36 dosed animals as compared
 

with 12/172 in controls (P = 0.02) was observed in the second strain
 

(innes et al., 1969). The data were considered as inconclusive.
 

It is concluded that under the conditions of this bioassay, ethyl
 

tellurac was not carcinogenic for F344 rats or B6C3F1 mice of either
 

sex. The incidence of mesotheliomas in dosed male rats and the
 

incidence of adenomas of the lacrimal (harderian) gland of the eye
 

in dosed mice of either sex provided evidence which was suggestive
 

but under the conditions of the bioassay insufficient to establish
 

the carcinogenicity of ethyl tellurac in these animals.
 

37
 

VI. BIBLIOGRAPHY
 

Ambelang, J. C., Curatives for general-purpose elastomers. In:
 

Vulcanization of Elastomers - Principles and Practice of
 

Vulcanization o£ Commercial Rubbers, Alliger, G. and Sjothun, I.
 

J., eds., Reinhold Publishing Corp., New York, 1964, pp. 139-140.
 

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 o_f_ Carcinogenicity £f the Cancer Research Commission of_
 

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

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

Soc. B34;187-220, 1972.
 

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

1970, pp. 48-52.
 

Del Gatto, J. V., Accelerators. In: Rubber World; Materials
 

and Compounding Ingredients for Rubber, Bill Publications, New
 

York, 1968, p. 52.
 

Dunkel, W. L., Neu, R. F., and Zapp, R. L., Butyl rubber. In:
 

Introduction _to Rubber Technology, Morton, M., ed., Reinhold
 

Publishing Corp., New York, 1959, pp. 321-322.
 

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

false-negative rates for carcinogenicity. Cancer Res. 

3^:1941-1945, 1977. 

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

significance tests, confidence limits and adjustments for
 

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

Harris, J. 0. and Trivette, C. D., Jr., Acceleration of
 

vulcanization. In: Vulcanization o_f_ Elastomers - Principles and
 

Practice of Vulcanization of Commercial Rubbers, Alliger, G. and
 

Sjothun, I. J., eds., Reinhold Publishing Corp., New York, 1964,
 

p. 185.
 

Innes, J. R. M., Ulland, B. M., Valerio, M. G., Petrucelli, L.,
 

39
 
Fishbein, L., Hart, E. R., Pallotta, A. J., Bates, R. R., Falk,
 

H. L., Gart, J. J., Klein, M., Mitchell, I., and Peters, J.,
 

Bioassay of pesticides and industrial chemicals for tumorigenicity in mice: a preliminary note. .J^ Natl Cancer Inst. 42(6);
 

1101-1106, 1969.
 

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

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

1958. ~
 

Le Bras, J., Vulcanization. In: Rubber - Fundamentals of Its
 

Science and Technology, Chemical Publishing Co., Inc., New York,
 

1957, pp7T64-171. 

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.
 

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.
 

Shaver, F. W., Rubber chemicals. In: Kirk-Orhmer Encyclopedia
 

£f Chemical Technology, Vol. 17, Standen, A., ed., Interscience
 

Publishers, New York, 1965, pp. 509-518.
 

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

Biometrika 62_:679-682, 1975.
 

United States International Trade Commission, Rubber-processing
 

chemicals. In: Synthetic Organic Chemicals - United States
 

Production and Sales, 1976, USITC Publication 833, United States
 

International Trade Commission, Washington, D.C., 1977, pp. 191
 

and 193.
 

Winspear, G. G., ed., Dithiocarbamate accelerators. The
 

Vanderbilt Rubber Handbook, R. T. Vanderbilt Co., Inc., New York,
 

1958, p. 180.
 

40
 
APPENDIX A
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

RATS ADMINISTERED ETHYL TELLURAC IN THE DIET
 

41
 

TABLE A1. 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE RATS 

ADMINISTERED ETHYL TELLURAC IN THE DIET 

CONTROL LOW DOSE HIGH DOSE
 

ANIMALS INITIALLY IN STUDY
 

ANIMALS MISSING
 

ANIMALS NECROPSIED
 

ANIMALS EXAMINED HISTOPATHOL03ICALLY
 

INTEGUMENTARY SYSTEM
 

*SKIN
 

SQUAMOUS CELL CARCINOMA
 

SEBACEOUS ADENOMA
 

*SUBCUT TISSUE
 

SQUAMOUS CELL CARCINOMA
 

FIBEOMA
 

LIPOMA
 

OSTEOSARCOMA
 

RESPIRATORY SYSTEM
 

#LUNG
 

HEPATOCELLULAR CARCINOMA, METAST
 

ALVEOLAR/BRONCHIOLAR ADENOMA
 

ALVEOLAR/BRONCHIOLAR CARCINOMA
 

FOLLICULAR-CELL CARCINOMA, METAS
 

OSTEOSARCOMA, METASTATIC
 

HEMATOPOIETIC SYSTEM
 

*MULTIPL£ ORGANS
 

MALIGNAN T LYMPHOMA, NOS
 

MALIG. LYMPHOMA, UNDIFFER-TYPE
 

#SPLEEN
 

MALIG. LYMPHOMA, UNDIFF3R-TYPE
 

CIRCULATORY SYSTEM
 

HONE
 

20 50 50 

1 

20 49 50 

20 49 50 

(20) (U9) (50) 

1 (5*) 1 (2*) 

1 (2%) 

(20) (49) (50) 

2 (4X) 

1 (5*) 3 (61) 3 (6*) 

1 (2») 

1 (5*) 

(20) (49) (48) 

1 (5*) 

1 (2X| 2 («*) 

1 (2*) 

1 (2S) 

1 (5X) 

(20) (49) (50) 

1 (2S) 4 (8») 

6 (3CX) 26 (53X) 20 (40%) 

(19) (49| (48) 

1 (5%) 

* NUMBER OF ANIMAL S WITH TISSUE EXAMINE D MICROSCOPICALLY
 « NUM3SR OF ANIMAL S NECROPSIED
 

43
 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE 

DIGESTIVE SYSTEM
 

*LIVSR (19) (49)
 

NEOPLASTIC NODULE 1 (2*)
 

HEPATOCELLULAR CARCINOMA 1 (5%) 1 (2*)
 

•STOMACH	 (18) (49|
 

FIBROSARCOMA 1 (6X)
 

*SHALL INTESTINE (17) (49)
 

LEIOMYOSARCOMA 1 (2»)
 

»COLON (17) (49)
 

ADENOMATOUS POLYP, NOS 1 (2*)
 

LEIOMYOSARCOMA 1 (2*)
 

URINAR Y SYST3M
 

•KIDNEY	 (20) (49|
 

HEPATOCELLULAR CARCINOMA, METAST 1 (2*)
 

•KIDNEY/CORTEX	 (20) (49)
 

ADENOMA, NOS
 

ENDOCRINE SYSTEM
 

•PITUITARY	 (19) (45)
 

ADENOMA, NOS 7 (37X) 9 (23X)
 

•ADRENAL	 (20) (48)
 

CORTICAL ADENOMA 2 (10*)
 

CORTICAL CARCINOMA 1 (5X)
 

PHEOCHROMOCYTOMA 1 (5*) 1 (2X)
 

•THYROID	 (20) (49)
 

FOLLICULAR-CELL ADENOMA 1 (2*)
 

FOLLICULAR-CELL CARCINOMA 3 (5X)
 

C-CELL ADENOMA 4 (8»)
 

C-CELL CARCINOMA 1 (5*)
 

•PANCREATIC ISLETS (16) (48)


ISLET -CJLL ADENOMA __3_1J!9*L ^.liii
 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

HIGH DOSE 

(47)
 

(47)
 

(47)
 

(46)
 

(48)
 

(48)
 

1 (2X)
 

(45)
 

7 (16X)
 

(48)
 

3 (6%)
 

(47)
 

1 (2X)
 

2 (4X)
 

1 (2X)
 

(48)
 

i_I2»L_
 

44
 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

ISLET-CELL CARCINOMA


REPRODUCTIVE SYSTEM
 

*MAMMA8Y GLAND


ADENOCABCINOMA, NOS


FIBROSARCOMA


FIBROADENOMA


ITESTIS


INTERSTITIAL-CELL TUMOR


NERVOUS SYSTEM
 

#BEAIN/BENINGES


MENINGIOMA


fBRAIN


ASTFOCYTOMA


SPECIAL SENSE ORGANS
 

*ZYMBAL'S GLAND


SQUAMOUS CELL CARCINOMA


MUSCULOSKELETAL SYSTEM
 

*SKELETAL MUSCLE


SARCOMA, NOS


BODY CAVITIES
 

*BODY CAVITIES


MESOTHELIOMA, NOS


*TUNICA VAGINALIS


MESOTHELIOMA, NOS


ALL OTHER SYSTEMS
 

NONE
 

# NUMBE R OF ANIMAL S WITH TISSUE

* NUMBE R OF ANIMAL S NECROPSIED 

CONTROL LOW DOSE HIGH DOSE 

1 (2*) 

 (20) (49) (50) 

1 (5X) 

1 (2X) 

2 (4*) 

 (20) (43) (49) 

 16 (80X) 40 (83*) 43 (88S) 

 (20) (49) (48) 

1 (2%) 

 (20) (49) (48) 

1 (5X) 1 (2X) 

 (20) (49) (50) 

1 (5X) 1 (2X) 

 (20) (49) (50) 

1 (2X) 

 (20) (49) (50) 

4 (8X) 

 (20) (49) (50) 

2 («X) 4 (8%) 

 EXAMINE D MICROSCOPICALY 

45 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

ANIMAL DISPOSITION SUMMARY
 

ANIMALS INITIALLY IN STUDY


NATURAL DEATHS


MORIBUND SACRIFICE


SCHEDULED SACRIFICE
 

ACCIDENTALLY KILLED
 

TERMINAL SACRIFICE


ANIMAL MISSING


8 INCLUDES AOTOLYZED ANIMALS
 

TUMOR SUMMAR Y
 

TOTAL ANIMALS WITH PRIMARY TUMORS*


TOTAL PRIMARY TUMORS


TOTAL ANIMALS WITH BENIGN TUMORS


TOTAL BENIGN TUMORS


TOTAL ANIMALS WITH MALIGNAN T TUMORS


TOTAL MALIGNAN T TUHOHS


TOTAL ANIMALS WITH SECONDARY TUMORS*


TOTAL SECONDARY TUMORS


TOTAL ANIMALS WITH TUMORS UNCERTAIN­ BENIGN OR MALIGNANT


TOTAL UNCERTAIN TUMORS


TOTAL ANIMALS HITH TUMORS UNCERTAIN­ PRIMARY OR METASTATIC
 

TOTAL UNCERTAIN TUMOBS
 

CONTROL

 20


 8


 12


 20


 46


 19


 30


 13


 16


 2


 2


 LOW DOSE HIGH DOSE 

 5D 50 

 17 21 

5 3 

 27 26 

1 

US 47 

 104 104 

 43 44 

 64 63 

 32 28 

 37 33 

2 

2 

3 8 

3 8 

* PRIMARY TUMOHS: ALL TUMORS EXCEPT SECONDARY TUMOR S
 

# SECONDARY TUMORS: METASTATIC TUMORS OR TUMORS INVASIVE INTO AN ADJACENT OR3AN
 

46
 
TABLE A2. 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS 

ADMINISTERED ETHYL TELLURAC IN THE DIET 

CONTROL LOW DOSE HIGH DOSE 

ANIMALS INITIALLY IN STUDY 20 50 50
 

ANIMALS NECROPSIED 20 50 50
 

ANIMALS EXAMINED HISTOP ATHOLOGICALLY 20 50 50
 

INTEGUMENTARY SYSTEM
 

*SKIN (20) (50) (50)
 

SQUAMOUS CELL CARCINOMA 1 (2*)
 

KERATOACANTHOMA 1 (2%)
 

FIBROSARCOMA 2 (<U)
 

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

LIPOSARCOMA 1 (2*)
 

RESPIRATORY SYSTEM
 

ILUNG (20) 0*9) (50)
 

SQUAMOUS CELL CARCINOMA, METASTA 1 (5%)
 

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

CORTICAL CARCINOMA. METASTATIC 1 (2*)
 

C-CELL CARCINOMA, METASTATIC 1 (2*)
 

HEMATOPOIETIC SYSTEM 

*MDLTIPLE ORGANS

MALIGNANT LYMPHOMA, NOS 

MALIG. LYMPHOMA, UNDIFFEH-T YPE

ERYTHROCYTIC LEUKEMIA 

 (20) 

H (20%) 

(50) 

2 (»X) 

12 (24*) 

1 (2*) 

(50) 

2

13

 (HI.) 

(26%) 

*SUBCUT TISSUE

MALIG. LYMPHOMA, HISTIOCYTIC TYPE 

 (20) (50) (50) 

1 (2*) 

CIRCULATORY SYSTEM
 

_NONE_ __ _
 

* NUMBER OF ANIMALS HITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

47
 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE 

DIGESTIVE SYSTEM
 

•LIVER	 (20) (49)
 

NEOPLASTIC NODULE
 

CORTICAL CARCINOMA, METASTATIC 1 (21)
 

•LARGE INTESTINE (20) (49|
 

ADENOMATOUS POLYP, NOS
 

LEIOMYOSARCOMA 1 (5X)
 

URINARY SYSTEM
 

•URINARY BLADDER (19) (<*6)
 

TRANSITIONAL-CELL CARCINOMA 1 (2X)
 

ENDOCRINE SYSTEM
 

•PITUITARY	 (20) (47)
 

ADENOMA, NOS 2 (10%) 19 (U3X)
 

•ADRENAL	 (19) (49)
 

CORTICAL ADENOMA
 

CORTICAL CARCINOMA 1 (2X)
 

PHEOCHROMOCYTOMA 1 (5%) 1 (2X)
 

•THYROID	 (20) (48)
 

FOLLICULAR-CELL ADENOMA 2 (4X)
 

FOLLICULAR-CELL CARCINOMA 1 (2J)
 

C-CELL ADENOMA 3 (15%) 3 (6X)
 

C-CELL CARCINOMA 1 (2%)
 

•PANCREATIC	 ISLETS (20) (48)
 

ISLET-CELL ADENOMA 1 (5*) 1 (2X)
 

REPRODUCTIVE SYSTEM
 

*MAMMARY GLAND (20) (50)
 

ADENOCARCINOMA, NOS
 

PAPILLARY CYSTADENOCARCINOMA.NOS 1 (2X)
 

FIBROMA
 

FIBROAjDOOMA 3. J15J1 8.J16S1
 

* NUMBER Of ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBE R OF ANIMAL S NECROPSIED 

HIGH DOSE 

(50)
 

1 (2X)
 

(50)
 

1 (2%)
 

(49)
 

(49)
 

9 (18%)
 

(50)
 

1 (2X)
 

2 (4*)
 

(48)
 

7 (15%)
 

(50)
 

(50)
 

1 (2%)
 

1 (2S)
 

1 (2%)
 

9 ^ 1 8§1_
 

48 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

tOTERUS

ENDOHETRIAL STROMAL POLYP

ENDOMETRIAL STROMAL SARCOMA

*OVARY

PAPILLARY CYSTADENOCARCINONA.NOS

 (20)

 4 (20%)

 (20)

 (48(

 3 (6X)

 (47)

 (49) 

7 (14*) 

1 (2%) 

 (49) 

1 (2») 

NERVOUS SYSTEM 

NONE 

SPECIAL SENSE ORGANS 

*ZYMBAL'S GLAND

SQUAMOUS CELL CARCINOMA

 (20)

 1 (5X) 

 (50) (50) 

MUSCULOSKELETAL SYSTEM 

*BONE

OSTEOSARCOMA

 (20) (50) (50) 

1 (2%) 

BODY CAVITIES 

NON E 

ALL OTHER SYSTEMS 

NONE 

ANIMAL DISPOSITION SUMMARY 

ANIMAL S INITIALL Y IN STUDY

NATURA L DEATHS

MORIBUN D SACRIFICE

SCHEDULE D SACRIFICE 

ACCIDENTALL Y KILLED 

TERMINA L SACRIFICE

ANIMA L MISSING 

 20

 3

 2 

 15

 50

 10

2 

 38

 50 

3 

4 

 43 

I_iNCUJDES_AUTOLYZED_ANIMALS 

# NUMBE R

* NUMBE R

 OF

 OF

 ANIMAL S

 ANIMAL S

 WIT H TISSUE

 NECROPSIED 

 EXAMINE D MICROSCOPICALL Y 

49 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE
 

TUMOR SUMMARY
 

TOTAL ANIMALS WITH PRIMARY TUMORS* 15 40 39
 

TOTAL PRIMARY TUMORS 22 6D 64
 

TOTAL ANIMALS WITH BENIGN TUMORS 12 27 30
 

TOTAL BENIGN TUMORS 16 33 40
 

TOTAL ANIMALS HITH MALIGNANT TUMORS 6 20 22
 

TOTAL MALIGNANT TUMORS 6 22 23
 

TOTAL ANIMALS WITH SECONDARY TUMORS* 1 2
 

TOTAL SECONDARY TUMORS 1 3
 

TOTAL ANIMALS WITH TUMORS UNCERTAIN­ BENIGN OR MALIGNANT 1
 

TOTAL UNCERTAIN TUMORS 1
 

TOTAL ANIMALS WITH TUMORS UNCERTAINPRIMARY OR METASTATIC
 

TOTAL UNCERTAIN TUMOBS
 

* PRIMARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 * SECONDARY TUMORS: METASTATIC TUMORS OR TUMORS INVASIVE INTO AN ADJACENT OR3AN
 

50
 
APPENDIX B
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

MICE ADMINISTERED ETHYL TELLURAC IN THE DIET
 

51
 

TABLE B1.

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE MICE 

ADMINISTERED ETHYL TELLURAC IN THE DIET 

HIGH DOSE
 

50
 

49
 

49
 

(49)
 

(46)
 

2 («*)
 

11 (24%)
 

(49) 

1 (2%) 

(46) 

1 (2%) 

3 (7%) 

(43) 

(46)
 

(49)
 

(49)
 

ANIMALS INITIALLY IN STUDY
 

ANIMALS MISSING
 

ANIMALS NECROPSIED
 

ANIMALS EXAMINED HISTOPATHOLOGICALLY
 

INTEGUMENTARY SYSTEM
 

*SUBCUT TISSUE
 

FIBROSARCOMA
 

HEMANGIOMA
 

RESPIRATORY SYSTEM
 

ILUNG
 

HEPATOCELLULAR CARCINOMA, METAST
 

ALVEOLAR/BRONCHIOLAR ADENOMA
 

ALVEOLAR/BRONCHIOLAR CARCINOMA
 

HEMATOPOIETIC SYSTEM
 

*MULTIPLE ORGANS
 

MALIGNANT LYMPHOMA, NOS
 

tSPLEEN
 

HEMANGIOSARCOMA
 

MALIGNANT LYMPHOMA, NOS
 

#MESENTERIC L. NODE
 

HEPATOCELLULAR CARCINOMA, METAST
 

MALIGNANT LYMPHOMA, NOS
 

MALIG. LYMPHOMA, HISTIOCYTIC TYPE
 

#PANCREAS
 

MALIGNANT LYMPHOMA, NOS
 

#SMALL INTESTINE
 

MALIGNANT LYMPHOMA, NOS
 

*MESENTERY
 

CONTROL
 

20
 

17
 

17
 

(17)
 

(17)
 

1 (6*)
 

(17)
 

1 (655)
 

(14)
 

1 (7X)
 

(17)
 

1 (6)5)
 

(17)
 

(17)
 

(17)
 

LOW DOSE
 

50
 

2
 

46
 

46
 

(46)
 

1 (21)
 

1 (2S)
 

(46)
 

2 (US)
 

2 (4X)
 

14 (30)1)
 

(46)
 

1 (2X)
 

(44)
 

(43)
 

1 (2S)
 

1 (2%)
 

(46|
 

1 (2X)
 

(46)
 

1 (2%)
 

(46)
 

» NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

53
 
TABLE B1. MALE MICE: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE
 

CIPCULATOBY SYSTEM
 

tHEART (17) (it 6|
 

HEMANGIOSARCOMA 1 (2X)
 

DIGESTIVE SYSTEM
 

#LIVER (17) (46)
 

HEPATOCELLULAR CARCINOMA 8 (47%) 15 (33*)
 

HEMANGIOSARCOMA
 

tPANCREAS (17) (U6(
 

HEMANGIOMA
 

*ESOPHAGUS (17) (46)
 

SQUAMOUS CELL CARCINOMA 1 (2X)
 

#SHALL INTESTINE (17) (<*6|
 

ADENOCARCINOMA, NOS <t (9»)
 

URINAR Y SYSTEM
 

•KIDNEY	 (17) (46»
 

CORTICAL CARCINOMA, METASTATIC
 

ENDOCRINE SYSTEM
 

f ADRENAL (17) (t5)
 

CORTICAL ADENOMA 1 (2X)
 

CORTICAL CARCINOMA
 

•THYROID	 (17) (45)
 

ADENOCARCINOMA, NOS
 

FOLLICULAR-CELL ADENOMA 1 (2*)
 

tPANCREATIC ISLETS (17) (46)
 

ISLET-CELL CARCINOMA
 

REPRODUCTIVE SYSTEM
 

•PROSTATE	 (16) (4 it)
 

CARCINOMAXNOS
 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

HIGH DOSE
 

(U6)
 

(49)
 

16	 (33*)
 

1 (2%)
 

(46)
 

1 (2X)
 

(tt5)
 

(49)
 

(U9)
 

1 (2%)
 

(47)
 

1 (2*)
 

1 (2*)
 

(Hit)
 

1 (2S)
 

(46)
 

1 (2X)
 

(48)
 

1-lllL54
 
TABLE 61. MALE MICE: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

NERVOU S SYSTEM 

NONE 

SPECIAL SENSE ORGAN S 

* EYE/LACRIMAL GLAND (17) (46) (1*9) 

ADENOMA , NOS 16 (35*) 10 (20%) _..,-.— _.___..,,__..— ,.,__•*.-.___ — -.———-._ _«._\_ — _-.____-. — — -._ — -._-._ —____ — — _ — — — —— —__ — — — — — — -.— — — —— 

MDSCULOSKELETAL SYSTEM 

NONE 

BODY CAVITIES 

NON E 

A LL OTHER SYSTEMS 

*MULTIPLE ORGAN S (17) (46) (19) 

HEMANGIOSARCOM A 1 (2X) 

ANIMA L DISPOSITION SUMMAR Y 

ANIMAL S INITIALLY IN STUDY 20 50 50 

NATURA L DEATH3 4 11 14 

MORIBUN D SACRIFICE 

SCHEDULED SACRIFICE 

ACCIDENTALLY KILLE D 

TERMINA L SACRIFICE 16 37 36 

ANIMA L MISSING 2 

l_IN£LUDES_AUTgLYZED_ANIMALS 

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

* NUMBE R OF ANIMAL S NECROPSIED 

55 
TABLE 81. MALE MICE: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

TUMO R SUMMAR Y 

TOTAL ANIMAL S WITH PRIMAR Y TUMOfiS* 10 39 35 

TOTAL PRIMAR Y TUMORS 10 63 50 

TOTAL ANIMAL S WITH BENIG N TUMORS 18 12 

TOTAL BENIGN TUMOBS 21 12 

TOTAL ANIMAL S WITH MALIGNAN T TUMORS 10 30 33 

TOTAL MALIGNAN T TUMORS 10 U2 38 

TOTAL ANIMAL S WITH SECONDAR Y TUMORSt 1 2 3 

TOTAL SECONDAR Y TUMORS 2 2 3 

TOTAL ANIMAL S WITH TUMORS UNCERTAIN ­

BENIG N OR MALIGNAN T 

TOTAL UNCERTAI N TUMORS 

TOTAL ANIMAL S WITH TUMORS UNCERTAIN ­

PRIMAR Y OR METASTATIC 

TOTAL UNCERTAIN TUMORS 

* PRIMARY TUMORS: ALL TUMORS EXCEPT SECONDAEY TUMOBS
 

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

56
 
TABLE B2. 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE MICE 

ADMINISTERED ETHYL TELLURAC IN THE DIET 

CONTROL LOW DOSE HIGH DOSE 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUM3EP OF ANIMALS NECROPSIED
 

57
 
TABLE B2. FEMALE MICE: NEOPLASMS (CONTINUED) 

HIGH DOSE
 

(48)
 

1 (2%)
 

(45)
 

(48)
 

1 (2*)
 

(48)
 

(48)
 

1 (2*)
 

10 (21S)
 

(48)
 

2 (<•*)
 

(46)
 

4 (9«)
 

(44)
 

1 (2»)
 

(46)
 

(43)
 

2_ISS1_
 

OLIVER
 

MALIGNANT LYMPHOMA, NOS
 

#SMALL INTESTINE
 

MALIGNANT LYMPHOMA, NOS
 

tKIDNEY
 

MALIGNANT LYMPHOMA, NOS
 

CIRCULATORY SYSTEM
 

tHEAHT
 

HEMANGIOSARCOMA
 

DIGESTIVE SYSTEM
 

#LIVER
 

CARCINOMA, NOS, METASTATIC
 

HEPATOCELLULAR CARCINOMA
 

HEMANGIOSARCOMA
 

URINARY SYSTEM
 

tKIDNEY
 

TUBULAR-CELL ADENOCARCINOMA
 

ENDOCRINE SYSTEM
 

#ADRENAL
 

CORTICAL ADENOMA
 

*THYROID
 

FOLLICULAR-CELL ADENOMA
 

REPRODUCTIVE SYSTEM
 

#UTERUS
 

LEIOMYOSARCOMA
 

#OVARY
 

GRANULOSA-CELL TUMOR
 

CONTROL
 

(19)
 

(19)
 

(19)
 

(19)
 

(19)
 

1 (5%)
 

(19)
 

(19)
 

(18)
 

(19)
 

(19)
 

LOW DOSE
 

C»9)
 

(48)
 

1 (2X)
 

(49)
 

1 (2*)
 

(49)
 

1 (2X)
 

(49)
 

7 (14S)
 

1 (2X)
 

(U 9)
 

1 (2X)
 

(46)
 

3 (7X)
 

(46)
 

(48)
 

1 (2X)
 

(46)
 

1-I2JL
 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

58
 
TABLE B2. FEMALE MICE: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

NERVOU S SYSTEM 

NONE 

SPECIAL SENSE ORGAN S 

*£YE/LACRIMAL GLAN D

ADENOMA , NOS

 (20) (50)

 6 (12X )

 (49) 

5 (10S) 

MUSCULOSKELETAL SYSTEM 

*PUBIS

OSTEOSARCOMA

 (20)

 1 (5X) 

 (50) (49) 

BODY CAVITIES 

*ABDOHINAL CAVITY

NEOPLASM, NOS

 (20) (50)

 1 (24) 

 (49) 

*PERITONEUM

MESOTHELIOMA, NOS

 (20) (50|

 1 (2*) 

 (49) 

*ABDOMINAL VISCERA

NEUROFIBROSARCOMA, METASTATIC

 (20) (50) (49) 

1 (2%) 

ALL CTHEE SYSTEMS 

THORAX 

ALVEOLAR/BRONCHIOLAR CA, METASTA 1 

ANIMAL DISPOSITION SUMMARY 

ANIMALS INITIALLY IN STUDY

NATURAL DEATHS

MORIBUND SACRIFICE 

SCHEDULED SACRIFICE 

ACCIDENTALLY KILLED 

TERMINAL SACRIFICE

ANIMAL MISSING

 20

 6

 14

 50

 16

 34

 50 

 12 

 37 

1 

a,lNCLUDES_AUTQL12EC_ANigALS 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED

* NUMBER OF ANIMALS NECROPSIED 

 MICROSCOPICALLY 

59
 
TABLE B2. FEMALE MICE: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE
 

TUMOR SUMMARY
 

TOTAL ANIMALS WITH PRIMARY TUMORS* 8 36 35
 

TOTAL PRIMARY TUMOFS 9 53 51
 

TOTAL ANIMALS WITH BENIGN TUMORS 1 1U 17
 

TOTAL BENIGN TUMORS 1 17 19
 

TOTAL ANIMALS WITH MALIGNANT TUMORS 7 28 22
 

TOTAL MALIGNANT TUMORS 8 33 30
 

TOTAL ANIMALS WITH SECONDARY TUMORSt 1 3
 

TOTAL SECONDARY TUMORS 1 3
 

TOTAL ANIMALS WITH TUMORS UNCERTAIN­ BENIGN OR MALIGNANT 3 2
 

TOTAL UNCERTAIN TUMORS 3 2
 

TOTAL ANIMALS WITH TUMORS UNCERTAIN­ PRIMARY OR METASTATIC
 

TOTAL UNCERTAIN TUHORS
 

* PRIMARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 

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

60
 
APPENDIX C
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS
 

IN RATS ADMINISTERED ETHYL TELLURAC IN THE DIET
 

61
 

TABLE C1. 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE RATS 

ADMINISTERED ETHYL TELLURAC IN THE DIET

 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

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

CONTROL LOW DOSE HIGH DOSE
 

tHESENTERIC L. NODE (20) (i»9) C*8)
 

LYMPHANGIECTASIS 1 (5%)
 

NECROSIS, FOCAL 1 (2X)
 

HYPERPLASIA, LYMPHOID 1 (2X)
 

fRENAL LYMPH NODE (20) C*9) (48)
 

HEMOSIDEROSIS 1 (2»)
 

CIRCULATOBY SYSTEM
 

tHEART (19) (49) (48)
 

ENDOCARDITIS, BACTERIAL 1 (2X)
 

PERIARTERITIS' 1 (2%)
 

ENDOCARDIOSIS 1 (2K)
 

IHEART/ATRIUM (19) (49) (48)
 

THROMBOSIS, NOS 2 ((»«) 4 (8%)
 

•MYOCARDIUM	 (19) (49) (48)
 

INFLAMBATION, FOCAL 1 (5»)
 

FIBROSIS 2 (11%) 1 (2X)
 

FIBROSIS, FOCAL 1 (2»)
 

*PULMONARY ARTERY (20) (49) (50)
 

MEDIAL CALCIFICATION 1 (5*)
 

'MESENTERIC ARTERY (20) (49) (50)
 

ARTERIOSCLEROSIS, NOS 1 (2X) 1 (2%)
 

*PORTAl VEIN (20) (49) (50)
 

THROMBOSIS, NOS 1 (2S)
 

DIGESTIVE SYSTEH
 

tLIVER (19) (49) (47)
 

HEBORRHAGIC CYST 1 (2*)
 

INFLAMMATION, SUPPURATIVE 1 (2X)
 

FIBROSIS 2 (41)
 

NECROSIS, FOCAL 9 (13X) 3 (6X)
 

HETAMORPHOSIS FATTY 1 <5») 1 (2X) 1 (2*)
 

__ fl££AT2£I10M£GAL CYTOPLASMIC VACUOLIZATIO Y N 5 (10»)
 2 {«)
 

2_J11SL 3.16X1.
 

f BOMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 * NUMBER OF ANIMALS NECROPSIED
 

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

CONTROL LOW DOSE HIGH DOSE
 

HYPERPLASIA, FOCAL 2 (11%) 3 (6X)
 

ANGIECTASIS 1 (2X)
 

HENATOPOIESIS 2 (4*)
 

NODULAR REGENERATION 1 (2*)
 

tPORTAL TRACT (19) (49) (47)
 

FIBROSIS 1 (2*)
 

tLIVER/CENTBILOBULAR (19) (49) (47)
 

NECROSIS, NOS 4 (9»)
 

NECROSIS, DIFFUSE 1 (2X)
 

CYTOPLASMIC VACUOLIZATION 3 (6») 4 (9%)
 

#LIVER/PERIPORTAL (19) (49) (47)
 

FIBROSIS 2 (4*) 3 (6«)
 

CYTOPLASMIC VACUOLIZATION 2 (4X)
 

•LIVER/HEPATOCYTES	 (19) (49) (47)
 

NECROSIS, FOCAL 1 (2X) 4 (9*)
 

CYTOPLASMIC VACUOLIZATION 1 (2*)
 

*BILE DUCT (20) (49| (50)
 

INFLAMMATION, CHRONIC 1 (2*)
 

HYPERPLASIA, NOS 14 (70S) 39 (SOU) 33 (66%)
 

#PANCREATIC ACINUS (16) (48) (48)
 

ATROPHY, NOS 2 (13S) 1 (2*) 3 (6»)
 

ATROPHY, FOCAL 3 (19S) 15 (3U) 4 (8%)
 

#STOMACH (18) (49| (47)
 

ULCER, NOS 1 (6X) 1 (2*)
 

ULCER, ACUTE 1 (6%) 1 (2»)
 

INFLAMMATION, ACUTE FOCAL 1 (2X)
 

tSHALL INTESTINE (17) (49| (47)
 

CYST, NOS 1 (2t)
 

tLARGE INTESTINE (17) (49) (46)
 

NEMATODIASIS 3 (6*)
 

URINARY SYSTEM	 .
 

#KIDNEY (20) (49) (48)
 

HYDRONEPHROSIS l_i2IL 1_I2,SL_
 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

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

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

66
 
TABLE C1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

HYPERPLASIA, NOS 3 (6X) 4 (8%) 

*PREPUTIAL GLAND

ABSCESS, NOS

 (20)

 1 (5X)

 (49)

 1 (2») 

 (50) 

tPROSTATE

CAST, NOS

INFLAMMATION, SUPPURATIVE

INFLAHHATION, ACOTE SUPPURATIVE

INFLAMMATION, CHRONIC

 (17)

 7 (41*)

 (48)

 1 (2*) 

5 (10X)

 3 (6*)

 (47) 

2 (4X) 

2 (4X) 

1 (2%) 

• TESTIS

INFARCT, NOS

ATROPHY, NOS

ASPERMATOGENESIS

HYPERPLASIA, INTERSTITIAL CELL

 (20)

 1 (5X) 

1 (5X)

 1 (5S)

 (48)

 3 (6J)

 1 (2*) 

1 (2i)

 (49) 

1 (2X) 

2 (UH) 

•TESTIS/TUBULE

ATROPHY, DISUSE

 (20) (48)

 1 (2*) 

 (49) 

*EPIDIDYMIS

RETENTION OF CONTENT

STEATITIS

 (20) (49)

 1 (2%) 

 (50) 

1 (2X) 

NERVOUS SYSTEM 

IBRAIN

MINERALIZATION

EPIDERMAL INCLUSION CYST

HEMORRHAGE

GLIOSIS

INFARCT, NOS

 (20) (49)

 4 (8X)

 1 (2X) 

1 (2J) 

 (48) 

2 (4X) 

1 (2X) 

3 (6X) 

SPECIAL SENSE ORGANS 

NONE 

MUSCULOSKELETAL SYSTEM 

NONE 

BODY CAVITIES 

• MESENTERY

STEATITIS

 (20)

 1

 (49) (50) 

(2% 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

67
 
TABLE H1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

PERIARTERITIS

*TUNICA VAGINALI S

STEATITIS

 (20)

 1 (5%)

 (<*9)

 2 (H%) 

 (50) 

1 (2*) 

ALL OTHER SYSTEMS 

*MULTIPLE ORGANS

AMYLOIDOSIS

HYPERPLASIA, LYMPHOID

 (20) (U9)

 2 («X) 

 (50) 

1 (2%) 

SPECIAL MORPHOLOGY SUMMAR Y 

ANIMA L MISSING/HO NECROPSY

AUTO/NECROPSY/HISTO PERF

t NUMBER OF ANIMAL S WITH TISSUE * NDMBER OF ANIMALS NECROPSIED  EXAMINE D MICROSCOPICALLY 

1 

1 

68 
TABLE C2.

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE RATS 

ADMINISTERED ETHYL TELLURAC IN THE DIET

 

HIGH DOSE
 

50
 

50
 

50
 

(50)
 

(50)
 

1 (2%)
 

1 (2%)
 

5 (10*)
 

(50)
 

1 (2X)
 

(50)
 

(50)
 

(50)
 

1 (2%)
 

6	 (12X)
 

(50)
 

1_12&L_
 

ANIMALS INITIALLY IN STUDY
 

ANIMALS NECROPSIED
 

ANIMALS EXAMINED HISTOP ATHOLOGICALLY
 

INTEGDHENTARY SYSTEM
 

NONE
 

RESPIRATORY SYSTEM
 

•LUNG/ BRONCHOS
 

INFLAMMATION, ACUTE SOPPURATIVE
 

ILUNG
 

INFLAMMATION, INTERSTITIAL
 

INFLAMMATION, CHRONIC
 

HYPERPLASIA, ALVEOLAR EPITHELIUM
 

HYPERPLASIA, LYMPHOID
 

•ALVEOLAR	 EPITHELIUM
 

FOAM-CELL
 

HEMATOPOIETIC SYSTEM
 

* BLOOD
 

LEUKOCYTOSIS, NOS
 

#BONE MARROW
 

FIBROSIS
 

tSPLEEN
 

HEMOSIDEROSIS
 

HYPERPLASIA, LYMPHOID
 

HEMATOPOIESIS
 

•MANDIBULAR	 L. NODE
 

_LYMPHANGIECTASIS
 

CONTROL
 

20
 

20
 

20
 

(20)
 

(20)
 

1 (5%)
 

(20)
 

(20)
 

1 (5%)
 

(20)
 

(20)
 

5 (25*)
 

3	 (15%)
 

(20)
 

LOW DOSE
 

50
 

50
 

50
 

(49)
 

1 (2X)
 

(49)
 

3	 (6S)
 

(49)
 

3 (6*)
 

(50)
 

(49)
 

2 (4X)
 

(49)
 

3 (6X)
 

1 (2X)
 

9 (18S)
 

(49)
 

#	 NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

*	 NUMBER OF ANIMALS NECROPSIED
 

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

INFLAMMATION, ACUTE/CHRONIC
 

CIRCULATORY SYSTEM
 

•MYOCARDIUM
 

INFLAMMATION, CHRONIC FOCAL
 

#CARDIAC VALVE
 

INFLAMMATION, CHRONIC
 

DIGESTIVE SYSTEM
 

#LIVER
 

HEMORRHAGE
 

GRANULOMA, NOS
 

CHOLANGIOFIBROSIS
 

NECROSIS, FOCAL
 

METAMORPHOSIS FATTY
 

HEPATOCYTOMEGALY
 

HYPERPLASIA, FOCAL
 

HEBATOPOIESIS
 

REGENERATIVE NODULE
 

#LIVER/CENTRILOBULAR
 

CYTOPLASMIC VACUOLIZATION
 

fLIVKR/PEBIPORTAL
 

FIBROSIS
 

*BILE DOCT
 

INFLAMMATION, NOS
 

INFLAMMATION, FOCAL
 

INFLAMMATION, CHRONIC
 

INFLAMMATION, CHRONIC FOCAL
 

HYPERPLASIA, NOS
 

•PANCREAS
 

PERIARTERITIS
 

NECROSIS, FAT
 

•PANCREATIC ACINUS
 

ATROPHY, NOS
 

ATROPni* FOCAL
 

I NUMBER OF ANIMALS HITH TISSUE

* NUMBER OF ANIMALS NECROPSIED 

CONTROL LOW DOSE 

(20) (50» 

1 (5X) 1 (2X) 

(20) (50) 

(20)	 (49)
 

1 (2*)
 

1 (2X)
 

1 <2X)
 

1 (5X) 2 (4*)
 

2 (10X) 8 (16X)
 

10 (SOX) 23 (47*)
 

1 (5X)
 

1 (2X)
 

(20)	 (49|
 

4 (8«)
 

(20)	 (49)
 

1 (2*)
 

(20)	 (50)
 

6 (12*)
 

3 (15%) 10 (20*)
 

(20)	 (48)
 

1	 (5X)
 

1 (2*)
 

(20)	 (48J
 

1 (2*)
 

!_i5§l._ _2 -P5X.L
 

 EXAHINE D MICROSCQPIC&LL Y 

HIGH DOSE 

1 (2X)
 

(50)
 

3 (6*)
 

(50)
 

1 (2X)
 

(50)
 

1 (2X)
 

2 (4X)
 

10 (20X)
 

35 (70%)
 

(50)
 

2 (4X)
 

(50)
 

(50)
 

4 (8S)
 

1 (2X)
 

16 (32X)
 

1 (2*)
 

10 (20X)
 

(50)
 

(50)
 

1 (2*)
 

10 I20X.1.
 

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

CONTROL LOW DOSE
 

•STOMACH	 (20) (49)
 

CYST, NOS 1 (2*)
 

ILAEGE INTESTINE (20) (49)
 

NEHATODIASIS
 

HYPERPLASIA, LYMPHOID 1 (5X) 1 (2*)
 

OEINAKY SYSTEM 

f KIDNEY 

HYDRONEPHROSIS 

PYELONEPHRITIS, ACUTE 

INFLAMMATION, CHRONIC 

NEPHROSIS, CHOLEMIC 

(20) 

5 (25X) 

(49) 

1 (2X) 

1 (2«) 

12 (24X) 

1 (2X) 

#KIDNEY/TUBULE 

HINEPALIZATION 

PIGMENTATION, NOS 

REGENERATION, NOS 

(20) 

1

1

 (5*) 

 (5%) 

(49) 

1 (2J) 

#URINARY BLADDER 

INFLAMMATION, NOS 

(19) (46| 

1 (2X) 

ENDOCRINE SYSTEM
 

#PITUITARY (20) (47)
 

CYST, NOS 1 (5*) 5 (11*)
 

ANGIECTASIS 2 (10%) 1 (2*)
 

f ADRENAL (19) (49)
 

LIPOIDOSIS
 

#ADRENAL CORTEX (19) (49)
 

ATROPHY, DIFFUSE 1 (2X)
 

HYPERPLASIA, NODULAR 1 (5*)
 

HYPERPLASIA, NOS
 

HYPERPLASIA, FOCAL 2 (4X)
 

HYPERPLASIA, DIFFUSE
 

•ADRENAL	 MEDULLA (19) (49)
 

ANGIECTASIS 1 (5%)
 

tTHYROID (20) (48)
 

GRANULOMA.j_NOS
 

t NUMBER OF ANIMALS BITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

HIGH DOSE
 

(50)
 

(50)
 

1 (2X)
 

2 (4X)
 

(50)
 

11 (22X)
 

(50)
 

2 (4»)
 

(49)
 

(49}
 

4 (8«)
 

2 (4X)
 

(50)
 

2 (4X)
 

(50)
 

1 (2«)
 

1 (2X)
 

1 (2S)
 

(50)
 

(48)
 

1_J2I1_
 

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

 

CONTROL LOW DOSE HIGH DOSE 

HYPERPLASIA, C-CELL 8 (40%) 10 (2U) 31 (65%) 

REPRODUCTIVE SYSTEM 

*MAMMAR Y GLAN D (20) (50) (50) 

GftLACTOCSLE 1 (2X) 1 (2») 

HYPERPLASIA , NOS 2 (10%) 

# UTERUS/ENDOMETRIUM (20) (48) (49) 

CYST, NOS 1 (5??) 1 (2X) 1 (2X> 

HYPERPLASIA, CYSTIC 3 (6X) 1 (2X) 

*OVARY/PAROVARIA N (20) C*8) (49) 

HEMATOMA , NOS 1 (2X) 

«OVAR Y (20) («7) (49) 

CYSTIC FOLLICLES 1 (5X) 5 (11X) 2 (<»X) 

NERVOU S SYSTEH 

#BRAIN/MENINGES (20) (50) (50)

 

THROMBOSIS, NOS . 1 (5%)

 

#BRAI N (20) (50) (50) 

MINERALIZATIO N 1 (2«) 

HYDROCEPHALUS, NOS 1 (5S) 

HEMORRHAG E 1 (5X) 2 (<•*) 2 (4X) 

SPECIAL SENSE ORGAN S 

*EYE (20) (50) (50)

 

CATARACT 1 (2«)

 

•EYE/CRYSTALLINE LENS (20) (50) (50) 

CATARACT 1 (5X) 1 (2») 2 (4X) 

MUSCULOSKELETAL SYSTEM 

NON E 

BODY CAVITIES 

*HESENTERY (20) (50) (50) 

STEATITIS 1 (551)

 

« NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

72 
TABLE C2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE
 

GRANULATION, TISSUE 1 (2%)
 

PERIARTERITIS 2 (UX)
 

ALL OTHER SYSTEHS
 

OHENTUB
 

STEATIfIS 1
 

SPECIAL MORPHOLOGY SUHHARY
 

HO LESION REPORTED 1
 

AUTO/NECROPSY/HISTO PERF 1
 

t NUMBER OF ANIHALS WITH TISSUE EXAMINED MICROSCOPICALLY
 * NUMBER OF ANIHALS NECROPSIED
 

73 

APPENDIX D
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS
 

IN MICE ADMINISTERED ETHYL TELLURAC IN THE DIET
 

75
 

TABLE D1.

 h 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE MICE 

ADMINISTERED ETHYL TELLURAC IN THE DIET 

CONTROL LOW DOSE HIGH DOSE
 

ANIMALS INITIALLY IN STUDY 20 50 50
 

ANIMALS MISSING 2
 ANIMALS NECROPSIED 17 46 49
 

ANIMALS EXAMINED HISTOPATHOLOGICALLY 17 46 49
 

INTEGUMENTARY SYSTEM
 

*SKIN (17) (46) (49)
 

CYST, NOS 1 (2*)
 

*SUBCOT TISSUE (17) (46| (49)
 

ABSCESS, NOS 2 (4X)
 

RESPIRATORY SYSTEM
 

*TRACHEA (17) (46) (45)
 

HEMATOPOIESIS 1 (2X)
 

*LUNG (17) (46) (46)
 

HEMORRHAGE 2 (4X)
 

INFLAMMATION, NOS 1 (2%)
 

PIGMENTATION, NOS 1 (2X)
 

HEMATOPOIETIC SYSTEM
 

IBONE MARROW (17) (46) (49)
 

HYPOPLASIA, HEMATOPOIETIC 1 (2*)
 

tSPLEEN (14) (44) (46)
 

HYPERPLASIA, LYMPHOID 1 (2X)
 

HEMATOPOIESIS 3 (21%) 7 (16X) 10 (22X)
 

CIRCULATORY SYSTEH
 

NONE
 

DIGESTIVE SYSTEH
 

#LIVER (17) (46) (49)
 

INFLAMMATION, FOCAL J.J2S1
 

* NUMBER OF AHIHALS WITH TISSUE EXAMINED MICROSCOPICALLY
 * NDMBEB OF ANIMALS NECROPSIED
 

77
 
TABLE 01. MALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

HIGH DOSE
 

1 (2X)
 

4 (8X)
 

1 (2X)
 

(46)
 

(49)
 

2 (4X>
 

(49)
 

(49)
 

(49)
 

(38)
 

1 (3X)
 

(44)
 

1 (2%)
 

(46)
 

1 (2X)
 

(49)
 

(49)
 

NECROSIS, FOCAL
 

HYPERPLASIA, NODULAR
 

ANGIECTASIS
 

HEHATOPOIESIS
 

•PANCREAS
 

CYSTIC DOCTS
 

ATROPHY, NOS
 

* STOMACH
 

INFLAMMATION, FOCAL
 

tSMALL INTESTINE
 

POLYP
 

URINARY SYSTEM
 

•KIDNEY
 

HYDRONEPHROSIS
 

INFLAMMATION, INTERSTITIAL
 

•KIDNEY/CORTEX
 

CYST, NOS
 

ENCOCBINE SYSTEM
 

tPITUITARY
 

CYST, NOS
 

•THYROID
 

CYSTIC FOLLICLES
 

•PANCREATIC ISLETS
 

HYPERPLASIA. NOS
 

REPRODUCTIVE SYSTEM
 

*PREPOTIAL GLAND
 

CYST, NOS
 

*SEMINAL VESICLE
 

CAST, ,NO§_^__^ _r, _„
 

CONTROL
 

1 (6X)
 

(17)
 

(17)
 

(17)
 

(17)
 

1 (6X)
 

(17)
 

(15)
 

(17)
 

(17)
 

2 (12X)
 

(17)
 

1 (6%)
 

(17)
 

LOW DOSE
 

1 (2%)
 

2 (4X)
 

(46)
 

1 (2»)
 

1 (2X)
 

(45)
 

(46)
 

1 (2*)
 

1*6)
 

2 (4X)
 

(46)
 

1 (2X)
 

(39)
 

(45)
 

(46)
 

(46)
 

(46)

i.mi
 

# NUMBER OF ANIMALS WITH TISSOE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

78
 
TABLE D1. MALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

tTESTIS

ATROPHY , NOS

 (16)

 2 (13%)

 (46)

 4 (9X)

 (48) 

2 (4X) 

NERVOU S SYSTEM 

#BRAIN

MINERALIZATION

 (17)

 7 (41%)

 (46)

 22 (USX)

 (46) 

 21 (46X) 

SPECIAL SENSE ORGANS 

NONE 

MUSCULOSKELETAL SYSTEM 

NONE 

BODY CAVITIES 

NONE 

ALL OTHER

NONE 

 SYSTEMS 

SPECIAL MORPHOLOGY SUMMARY 

NO LESION REPORTED 4

ANIMAL MISSING/NO NECROPSY

AUTO/NECROPSY/HISTO PERF

AUTOLYSIS/NO NECROPSY 3

# NUMBER OF ANIMALS HITH TISSDE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

1

 2 

2

 4 

1 

1 

79
 
TABLE D2.

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE MICE 

ADMINISTERED ETHYL TELLURAC IN THE DIET 

CONTROL LOW DOSE
 

ANIMALS INITIALLY IN STUDY 20 50
 

ANIMALS MISSING
 

ANIMALS NECROPSIED 20 50
 

ANIMALS EXAMINED HISTOPATHOLOGICALLY 19 49
 

INTEGUMENTARY SYSTEM
 

NONE
 

RESPIRATORY SYSTEM
 

* LONG/ BRONCHUS (19) (49)
 

HYPERPLASIA, NOS 3 (6X)
 

HYPERPLASIA, EPITHELIAL 1 (2X)
 

ILUNG (19) (49)
 

INFLAMMATION, NOS 1 (2*)
 

INFLAMMATION, FOCAL 1 (2X)
 

HEMATOPOIETIC SYSTEM 

tBONE MARROW (19) (48) 

HYPOPLASIA, HEMATOPOIETIC 1 (2X) 

tSPLEEN (19) (48) 

ANGIECTASIS 1 (5X) 

HYPERPLASIA, LYMPHOID 2 (4X) 

HEMATOPOIESIS 7 (37X) 10 (21X) 

•THYMUS (19) (46) 

HYPERPLASIA, LYMPHOID
 

CIRCULATORY SYSTEM
 

NONE
 

DIGESTIVE SYSTEM
 

#LIVER (19) (49)
 

CYST. NOS „
 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

HIGH DOSE
 

50
 

1
 

49
 

48
 

(48)
 

(48)
 

(46)
 

(48)
 

9 (19S) 

(46) 

1 (2%) 

(48)
 

J-J2&1_
 

80
 
TABLE 02. FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE
 

INFLAMMATION, FOCAL 

NECROSIS, FOCAL 

INFARCT, HEALED 

HYPERPLASIA, NODULAR 

ANGIECTASIS 

T

1

1

 (5*) 

 (5X) 

 (5%) 

2 (OX) 

3 (6*) 

1 (2X) 

fPANCHEAS 

CYSTIC DUCTS 

ATROPHY, NOS 

(19) 

1 (5X) 

(48) 

1 (2X) 

tSTOBACH 

INFLAMMATION, NOS 

INFLAMMATION, FOCAL 

(19) 

1

1

 (5%) 

 (5*) 

(48) 

tSMALL INTESTINE 

POLYP, INFLAMMATORY 

(19) (48) 

URINARY SYSTEM
 

#KIDNEY (19) (49)
 

PERIVASCULAR CUFFING 2 (11*) 2 (4X)
 

#KIDNEY/CORTEX (19) (49)
 

CYST, NOS
 

ENDOCRINE SYSTEM
 

tPITUITARY (16) (43)
 

CYST, NOS 1 (2X)
 

#ADRENAL CORTEX (19) (46)
 

HYPERPLASIA, NODULAR
 

*THYROID (18) (46)
 

CYSTIC FOLLICLES 2 (4*)
 

ATROPHY, NOS
 

REPRODUCTIVE SYSTEM
 

tUTERDS (19) (48)
 

POLYP, INFLAMMATORY 1 (5S)
 

t UTERUS/ENDOMETRIUM _ __ fl_JL42IL (19) (48)
 

CYST, NOS
 8.J1ZS1
 

# NUMBER OF ANIMALS HITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

HIGH DOSE
 

1

4

3

 (2X) 

 (8%) 

 (6X) 

(42) 

1

2

 (2X) 

 (5X) 

(47) 

(45)
 

1 (2X)
 

(48)
 

1 (2*)
 

(48)
 

1 (2%)
 

(38)
 

(46)
 

1 (2X)
 

(44)
 

2 (5X)
 

1 (2X)
 

(46)
 

(46)


2_i2Si
 

81
 
TABLE D2. FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

tOVARY

CYST, NOS

 (19)

 3 (16X)

 (46)

 6 (13X)

 (43) 

 11 (26X) 

NERVOUS SYSTEM 

tBRAIN

MINERALIZATION

HYDROCEPHALUS, NOS

 (19)

 4 (21%)

 (48)

 24 (SOX)

 2 (4X) 

 (48) 

 25 (52X) 

SPECIAL SENSE ORGANS 

NONE 

MUSCULOSKELETAL SYSTEM 

NONE 

BODY CAVITIES 

NONE 

ALL OTHER SYSTEMS 

NONE 

SPECIAL MORPHOLOGY SUHHARY 

NO LESION REPORTED

ANIMAL HISSING/NO NECROPSY

AOTO/NECROPSY/HISTO PERF

AOTO/NECROPSYyNO HISTO 1

t NOHBER OF ANIMALS BITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

1

 1

 1 

1 

1 

1 

82
 
APPENDIX E
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS
 

IN RATS ADMINISTERED ETHYL TELLURAC IN THE DIET
 

83
 

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

Administered Ethyl Tellurac in the Diet (a)
 

Topography: Morphology


Integumentary System: Fibroma of the
 

Subcutaneous Tissue (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


Lung: Alveolar/Bronchiolar
 

Carcinoma or Adenoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


Matched
 

 Control
 

 1/20 (5)
 

 N.S.
 

 105
 

 0/20 (0)
 

 N.S.
 

—
 

Low
 

Dose
 

3/49 (6)
 

N.S.
 

1.224
 

0.108
 

62.958
 

95
 

1/49 (2)
 

N.S.
 

Infinite
 

0.023
 

Infinite
 

105
 

High
 

Dose
 

3/50 (6)
 

N.S.
 

1.200
 

0.106
 

61.724
 

102
 

3/48 (6)
 

N.S.
 

Infinite
 

0.261
 

Infinite
 

105
 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats
 

Administered Ethyl Tellurac in the Diet (a)
 

(continued)
 

Topography: Morphology


Hematopoietic System: Lymphoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 *
 

Pituitary: Adenoma, NOS (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


Matched
 

 Control
 

 7/20 (35)
 

 N.S.
 

 98
 

 7/19 (37)
 

 N.S.
 

 101
 

Low
 

Dose
 

27/49 (55)
 

N.S.
 

1.574
 

0.835
 

3.604
 

82
 

9/45 (20)
 

N.S.
 

0.543
 

0.222
 

1.500
 

95
 

High
 

Dose
 

24/50 (48)
 

N.S.
 

1.371
 

0.713
 

3.217
 

7/45 (16)
 

N.S.
 

0.422
 

0.155
 

1.241
 

101
 

62 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats
 

Administered Ethyl Tellurac in the Diet (a)
 

(continued)
 

Topography: Morphology
 

Adrenal: Cortical
 

Carcinoma or Adenoma (b)
 

P Values (c,d)
 

Departure from Linear Trend (e)
 

Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Adrenal: Pheochromocytoma (b)
 

P Values (c,d)
 

Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched


Control


3/20 (15)


P = 0.005 (N)


P = 0.016
 

75
 

1/20 (5)


N.S.


105


 Low
 

 Dose
 

 0/48 (0)
 

P = 0.023 (N)
 

0.000
 

0.000
 

0.686
 

 1/48 (2)
 

 N.S.
 

0.417
 

0.006
 

32.058
 

 105
 

High
 

Dose
 

0/48 (0)
 

P = 0.023 (N)
 

0.000
 

0.000
 

0.686
 

—
 

3/48 (6)
 

N.S.
 

1.250
 

0.110
 

64.251
 

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

Administered Ethyl Tellurac in the Diet (a)
 

(continued)
 

Topography: Morphology


Thyroid: Follicular-cell
 

Carcinoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


Thyroid: Follicular-cell Carcinoma
 

or Adenoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


Matched
 

 Control
 

 0/20 (0)
 

 N.S.
 

—
 

 0/20 (0)
 

 N.S.
 

—
 

Low
 

Dose
 

3/49 (6)
 

N.S.
 

Infinite
 

0.255
 

Infinite
 

87
 

4/49 (8)
 

N.S.
 

Infinite
 

0.394
 

Infinite
 

87
 

High
 

Dose
 

2/47 (4)
 

N.S.
 

Infinite
 

0.131
 

Infinite
 

105
 

3/47 (6)
 

N.S.
 

Infinite
 

0.266
 

Infinite
 

105
 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats
 

Administered Ethyl Tellurac in the Diet (a)
 

(continued)
 

Topography: Morphology
 

Thyroid: C-cell
 

Carcinoma or Adenoma (b)
 

P Values (c,d)
 

Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Pancreatic Islets: Islet-cell
 

Adenoma (b)
 

P Values (c,d)
 

Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched


Control


1/20 (5)


N.S.


105


3/16 (19)


P = 0.027 (N)


105


 Low
 

 Dose
 

 4/49 (8)
 

 N.S.
 

1.633
 

0.179
 

78.704
 

 105
 

 2/48 (4)
 

 N.S.
 

0.222
 

0.021
 

1.808
 

 105
 

High
 

Dose
 

1/47 (2)
 

N.S.
 

0.426
 

0.006
 

32.720
 

101
 

1/48 (2)
 

P = 0.045 (N)
 

0.111
 

0.002
 

1.296
 

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

Administered Ethyl Tellurac in the Diet (a)
 

(continued) 

Topography: Morphology

Matched 

 Control 

Low 

Dose 

Testis: Interstitial-cell 

Tumor (b) 16/20 (80) 40/48 (83) 

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

Relative Risk (f) 

Lower Limit 

Upper Limit 

1.042 

0.830 

1.432 

Weeks to First Observed Tumor 76 82 

Body Cavities: Mesothelioma, NOS (b) 0/20 (0) 0/49 (0) 

P Values (c,d) P = 0.041 — 

Relative Risk (f) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 

— 

— 

— 

__ 

High
 

Dose
 

43/49 (88)
 

N.S.
 

1.097
 

0.880
 

1.457
 

62
 

4/50 (8)
 

N.S.
 

Infinite
 

0.386
 

Infinite
 

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

Administered Ethyl Tellurac in the Diet (a)
 

(continued)
 

Topography: Morphology


Tunica Vaginalis: Mesothelioma,
 

NOS (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

All Sites: Mesothelioma, NOS (b)


P Values (c,d)


Relative Risk (f)
 

Upper Limit
 

Lower Limit
 

Weeks to First Observed Tumor
 

Matched
 

 Control
 

 0/20 (0)
 

 N.S.
 

 0/20 (0)
 

P = 0.012
 

Low
 

Dose
 

2/49 (4)
 

N.S.
 

Infinite
 

0.125
 

Infinite
 

82
 

2/49 (4)
 

N.S.
 

Infinite
 

0.125
 

Infinite
 

82
 

High
 

Dose
 

4/50 (8)
 

N.S.
 

Infinite
 

0.386
 

Infinite
 

88
 

8/50 (16)
 

N.S.
 

Infinite
 

0.952
 

Infinite
 

88
 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats
 

Administered Ethyl Tellurac in the Diet (a)
 

(continued)
 

(a) Dosed groups received 300 or 600 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.
 

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

Administered Ethyl Tellurac in the Diet (a) 

Matched Low High
 

Topography: Morphology Control Dose Dose
 

Lung: Alveolar/Bronchiolar Adenoma (b) 2/20 (10) 0/49 (0) 3/50 (6)
 

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

Departure from Linear Trend (e) P = 0.040
 

Relative Risk (f) 0.000 0.600
 

Lower Limit 0.000 0.076
 

Upper Limit 1.372 6.860
 

Weeks to First Observed Tumor 105 98
 —
 

VQ 

u> Hematopoietic System: Lymphoma 

or Leukemia (b) 4/20 (20) 15/50 (30) 16/50 (32) 

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

Relative Risk (f) 1.500 1.600
 

Lower Limit 0.566 0.613
 

Upper Limit 5.627 5.950
 

Weeks to First Observed Tumor 97 47 74
 
__ 

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

Administered Ethyl Tellurac in the Diet (a)
 

(continued) 

Topography: Morphology

Matched 

 Control 

Low 

Dose 

Pituitary: Adenoma, NOS (b) 2/20 (10) 19/47 (40) 

P Values (c,d) N.S. P = 0.012 

Departure from Linear Trend (e) P = 0.003 

Relative Risk (f) 

Lower Limit 

Upper Limit 

4.043 

1.134 

33.427 

Weeks to First Observed Tumor 99 81 

Thyroid: Follicular-cell 

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

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

Departure from Linear Trend (e) P = 0.044 

Relative Risk (f) 

Lower Limit 

Upper Limit 

Infinite 

0.261 

Infinite 

Weeks to First Observed Tumor — 105 

High
 

Dose
 

9/49 (18)
 

N.S.
 

1.837
 

0.434
 

16.572
 

0/48 (0)
 

—
 

—
 

91 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Administered Ethyl Tellurac in the Diet (a)
 

(continued) 

Topography: Morphology

Matched 

 Control 

Thyroid: C-cell 

Carcinoma or Adenoma (b) 3/20 (15) 

P Values (c,d) N.S. 

Relative Risk (f) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 105 

Ul 

Mammary Gland:

P Values (c,d)

 Fibroadenoma (b) 3/20 (15) 

 N.S. 

Relative Risk (f) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 80 

Low
 

Dose
 

4/48 (8)
 

N.S.
 

0.556
 

0.106
 

3.546
 

105
 

8/50 (16)
 

N.S.
 

1.067
 

0.295
 

5.813
 

92
 

High
 

Dose
 

7/48 (15)
 

N.S.
 

0.972
 

0.255
 

5.422
 

105
 

9/50 (18)
 

N.S.
 

1.200
 

0.346
 

6.408
 

104
 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Administered Ethyl Tellurac in the Diet (a)
 

(continued)
 

Topography; Morphology 

Matched 

Control 

Low 

Dose 

High 

Dose 

Uterus: Endometrial Stromal 

Polyp (b) 4/20 (20) 3/48 (6) 7/49 (14) 

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

Relative Risk (f) 

Lower Limit 

Upper Limit 

0.313 

0.051 

1.708 

0.714 

0.211 

3.052 

Weeks to First Observed Tumor 80 105 105 

(a) Dosed groups received 150 or 300 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.
 
APPENDIX F
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS
 

IN MICE ADMINISTERED ETHYL TELLURAC IN THE DIET
 

97
 

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

Administered Ethyl Tellurac in the Diet (a)
 

Topography: Morphology

Matched 

 Control 

Low 

Dose 

High 

Dose 

Lung: Alveolar/Bronchiolar 

Carcinoma (b) 0/17 (0) 14/46 (30) 11/46 (24) 

P Values (c,d) N.S. P = 0.006 P = 0.022 

Departure from Linear Trend (e) P = 0.021 

Relative Risk (f) 

Lower Limit 

Upper Limit 

Infinite 

1.703 

Infinite 

Infinite 

1.296 

Infinite 

Weeks to First Observed Tumor 87 82 

Lung: Alveolar/Bronchiolar 

Carcinoma or Adenoma (b) 0/17 (0) 16/46 (35) 11/46 (24) 

P Values (c,d) N.S. P = 0.003 P = 0.022 

Departure from Linear Trend (e) P = 0.007 

Relative Risk (f) 

Lower Limit 

Upper Limit 

Infinite 

1.976 

Infinite 

Infinite 

1.296 

Infinite 

Weeks to First Observed Tumor 87 82 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice
 

Administered Ethyl Tellurac in the Diet (a)
 

(continued)
 

Topography: Morphology


Hematopoietic System: Lymphoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


All Sites: Hemangiosarcoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


Matched
 

 Control
 

 1/17 (6)
 

 N.S.
 

 86
 

 1/17 (6)
 

 N.S.
 

 106
 

Low
 

Dose
 

6/46 (13)
 

N.S.
 

2.217
 

0.306
 

99.570
 

91
 

1/46 (4)
 

N.S.
 

0.370
 

0.005
 

28.408
 

106
 

High
 

Dose
 

4/49 (8)
 

N.S.
 

1.388
 

0.154
 

66.919
 

91
 

3/49 (6)
 

N.S.
 

1.041
 

0.093
 

53.527
 

85
 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice
 

Administered Ethyl Tellurac in the Diet (a)
 

(continued)
 

Topography: Morphology


All Sites: Hemangiosarcoma


or Hemangioma (b)
 

P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


liver: Hepatocellular Carcinoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


Matched
 

 Control
 

 1/17 (6)
 

 N.S.
 

 106
 

 8/17 (47)
 

 N.S.
 

 106
 

Low
 

Dose
 

2/46 (4)
 

N.S.
 

0.739
 

0.042
 

42.678
 

106
 

15/46 (33)
 

N.S.
 

0.693
 

0.362
 

1.592
 

96
 

High
 

Dose
 

4/49 (8)
 

N.S.
 

1.388
 

0.154
 

66.919
 

85
 

16/49 (33)
 

N.S.
 

0.694
 

0.367
 

1.585
 

81
 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice
 

Administered Ethyl Tellurac in the Diet (a)
 

(continued)
 

Topography: Morphology


Small Intestine: Adenocarcinoma,
 

NOS (b)


P Values (c,d)


Departure from Linear Trend (e)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Eye/Lacrimal Gland: Adenoma, NOS (b)


P Values (c,d)


Departure from Linear Trend (e)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched
 

 Control
 

 0/17 (0)
 

 N.S.
 

 P = 0.029
 

 0/17 (0)
 

 N.S.
 

 P = 0.004
 

Low
 

Dose
 

4/46 (9)
 

N.S.
 

Infinite
 

0.361
 

Infinite
 

106
 

16/46 (35)
 

P = 0.003
 

Infinite
 

1.976
 

Infinite
 

106
 

High
 

Dose
 

0/49 (0)
 

—
 

—
 

—
 

—
 

—
 

10/49 (20)
 

P = 0.039
 

Infinite
 

1.089
 

Infinite
 

106
 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice
 

Administered Ethyl Tellurac in the Diet (a)
 

(continued)
 

(a) Dosed groups received time-weighted average doses of 1,255 or 3,132 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.
 
__ 

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

Administered Ethyl Tellurac in the Diet (a)
 

Topography: Morphology


Integumentary System: Fibrosarcoma
 

of the Subcutaneous Tissue (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


Lung: Alveolar/Bronchiolar
 

Carcinoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


Matched
 

 Control
 

 0/20 (0)
 

 N.S.
 

—
 

 2/19 (11)
 

 N.S.
 

 106
 

Low
 

Dose
 

3/50 (6)
 

N.S.
 

Infinite
 

0.250
 

Infinite
 

101
 

5/49 (10)
 

N.S.
 

0.969
 

0.180
 

9.685
 

101
 

High
 

Dose
 

0/49 (0)
 

—
 

—
 

—
 

—
 

6/48 (13)
 

N.S.
 

1.188
 

0.242
 

11.426
 

97 
Table F2. Analyses of the Incidence of Primary Tumors in Female Mice
 

Administered Ethyl Tellurac in the Diet (a)
 

(continued)
 

Topography: Morphology


Lung: Alveolar/Bronchiolar Carcinoma
 

or Adenoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


Hematopoietic System: Lymphoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


Matched
 

 Control
 

 3/19 (16)
 

 N.S.
 

 106
 

 4/20 (20)
 

 N.S.
 

 83
 

Low
 

Dose
 

9/49 (18)
 

N.S.
 

1.163
 

0.338
 

6.195
 

95
 

11/50 (22)
 

N.S.
 

1.100
 

0.384
 

4.321
 

82
 

High
 

Dose
 

12/48 (25)
 

N.S.
 

1.583
 

0.502
 

8.066
 

97
 

9/49 (18)
 

N.S.
 

0.918
 

0.300
 

3.730
 

75 
Table F2. Analyses of the Incidence of Primary Tumors in Female Mice
 

Administered Ethyl Tellurac in the Diet (a)
 

(continued) 

Topography: Morphology

Matched 

 Control 

All Sites: Hemangioma (b) 0/20 (0) 

P Values (c,d) N.S. 

Relative Risk (f) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor — 

All Sites: Hemangiosarcoma (b) 0/20 (0) 

P Values (c,d) N.S. 

Relative Risk (f) 

Lower Limit 

Upper Limit 

Weeks to First Observed Tumor 

Low 

Dose 

1/50 (2) 

N.S. 

Infinite 

0.022 

Infinite 

100 

4/50 (8) 

N.S. 

Infinite 

0.386 

Infinite 

103 

High 

Dose 

3/49 (6) 

N.S. 

Infinite 

0.255 

Infinite 

94 

1/49 (2) 

N.S. 

Infinite 

0.023 

Infinite 

93 
Table F2. Analyses of the Incidence of Primary Tumors in Female Mice
 

Administered Ethyl Tellurac in the Diet (a)
 

(continued)
 

Topography: Morphology


All Sites: Hemangioma or
 

Hemangiosarcoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


Liver: Hepatocellular Carcinoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


Matched
 

 Control
 

 0/20 (0)
 

 N.S.
 

—
 

 1/19 (5)
 

 N.S.
 

 106
 

Low
 

Dose
 

5/50 (10)
 

N.S.
 

Infinite
 

0.525
 

Infinite
 

100
 

7/49 (14)
 

N.S.
 

2.714
 

0.393
 

119.544
 

86
 

High
 

Dose
 

4/49 (8)
 

N.S.
 

Infinite
 

0.394
 

Infinite
 

93
 

10/48 (21)
 

N.S.
 

3.958
 

0.639
 

167.483
 

62 
Table F2. Analyses of the Incidence of Primary Tumors in Female Mice
 

Administered Ethyl Tellurac in the Diet (a)
 

(continued) 

Topography: Morphology

Matched 

 Control 

Low 

Dose 

High 

Dose 

Adrenal: Cortical Adenoma (b) 0/19 (0) 3/46 (7) 4/46 (9) 

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

Relative Risk (f) 

Lower Limit 

Upper Limit 

Infinite 

0.259 

Infinite 

Infinite 

0.400 

Infinite 

Weeks to First Observed Tumor 106 97 

Ovary: Granulosa-cell Tumor (b) 0/19 (0) 1/46 (2) 2/43 (5) 

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

Relative Risk (f) 

Lower Limit 

Upper Limit 

Infinite 

0.023 

Infinite 

Infinite 

0.136 

Infinite 

Weeks to First Observed Tumor 106 106 
Table F2. Analyses of the Incidence of Primary Tumors in Female Mice
 

Administered Ethyl Tellurac in the Diet (a)
 

(continued)
 

Topography: Morphology

Matched 

 Control 

Low 

Dose 

High 

Dose 

Eye/Lacrimal Gland: Adenoma, NOS (b) 0/20 (0) 6/50 (12) 5/49 (10) 

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

Relative Risk (f) 

Lower Limit 

Upper Limit 

Infinite 

0.667 

Infinite 

Infinite 

0.536 

Infinite 

Weeks to First Observed Tumor — 106 106 

(a) Dosed groups received time-weighted average doses of 2,132 or 4,915 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.
 

Review of the Bioassay of Ethyl Tellurac* for Carcinogenicity
 

by the Data Evaluation/Risk Assessment Subgroup
 

of the Clearinghouse on Environmental Carcinogens
 

December 13, 1978
 

The Clearinghouse on Environmental Carcinogens was established
 

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

Provisions of the Federal Advisory Committee Act. The purpose of
 

the Clearinghouse is to advise the Director of the National Cancer
 

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

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

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

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

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

chemistry, biochemistry, biostatistics, toxicology, pathology, and
 

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

of the Clearinghouse is charged with the responsibility of providing
 

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

studied for carcinogenicity. It is in this context that the below cri­ tique is given on the bioassay of Ethyl Tellurac.
 

The reviewer for the report on the bioassay of Ethyl Tellurac
 

briefly described the experimental design, and said that the statistical
 

analysis required the use of historic controls, because of the small
 

matched control group size. A dose-related increase of mesotheliomas
 

occurred in treated rats, although it was not statistically significant.
 

The reviewer questioned if the finding was sufficient to call it "sug­ gestive of carcinogenicity," as concluded in the report. An increase
 

in the incidence of adenomas of the lacrimal gland was also found in
 

treated mice, which was statistically significant when compared to
 

historic controls. The reviewer opined that the findings were probably
 

not adequate for basing a firm conclusion of carcinogenicity.
 

A discussion ensued in which there was general agreement that
 

the evidence supported a conclusion that an effect was induced by
 

Ethyl Tellurac. However, the effect was not sufficiently strong or
 

of such a nature to conclude that the compound was carcinogenic.
 

One Subgroup member emphasized that the major finding was benign
 

tumors of the lacrimal gland in mice. Since the natural progression
 

of this tumor type is unknown, he argued that it was not possible
 

to draw any conclusion on the carcinogenicity of Ethyl Tellurac.
 He recommended that a revised conclusion not include the term
 

"carcinogenic." It was agreed that the Program staff would revise
 

the language in the report's conclusion so as to reflect the substance
 

of the Subgroup's discussion.
 

Ill
 
Clearinghouse Members Present;
 

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

Joseph Highland, Environmental Defense Fund
 

William Lijinsky, Frederick Cancer Research Center
 

Henry Pitot, University of Wisconsin Medical Center
 

Verne A. Ray, Pfizer Medical Research Laboratory
 

Verald K. Rowe, Dow Chemical USA
 

Michael Shimkin, University of California at San Diego
 

Louise Strong, University of Texas Health Sciences Center
 

Kenneth Wilcox, Michigan State Health Department
 

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

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

Thus, certain comments and criticisms reflected in the review may
 

no longer be appropriate.
 

U.S. GOVERNMENT PRINTING OFFICE: 1979 281-217/3158 1-3 112 


NIH Publication No. 79-1708