National Cancer Institute 

CARCINOGENESIS 

Technical Report Series 

No. 12 

1979 

BIOASSAY OF 

ENDRIN 

FOR POSSIBLE CARCINOGENICITY 

CAS No. 72-20-8 

NCI-CG-TR-12 

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

Public Health Service 

National Institutes of Health 

BIOASSAY OF
 

ENDRIN
 

FOR POSSIBLE CARCINOGENICITY
 

Carcinogenesis Testing Program
 

Division of Cancer Cause and Prevention
 

National Cancer Institute
 

National Institutes of Health
 

Bethesda, Maryland 20014
 

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

Public Health Service
 

National Institutes of Health
 

DHEW Publication No. (NIH) 79-812
 
i i

 
BIOASSAY OF
 

ENDRIN
 

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
 

endrin conducted for the Carcinogenesis Testing Program, Division
 

of Cancer Cause and Prevention, National Cancer Institute (NCl),
 

National Institutes of Health, Bethesda, Maryland. This is one
 

of a series of experiments designed to determine whether selected
 

environmental chemicals have the capacity to produce cancer in
 

animals. Negative results, in which the test animals do not have
 

a greater incidence of cancer than control animals, do not
 

necessarily mean that the test chemical is not a carcinogen,
 

inasmuch as the experiments are conducted under a limited set of
 

circumstances. Positive results demonstrate that the test
 

chemical is carcinogenic for animals under the conditions of the
 

test and indicate that exposure to the chemical is a potential
 

risk to man. The actual determination of the risk to man from
 

chemicals found to be carcinogenic in animals requires a wider
 

analysis.
 

CONTRIBUTORS; This bioassay of endrin was conducted by Gulf
 

South Research Institute, New Iberia, Louisiana, initially under
 

direct contract to NCI and currently under a subcontract to
 

Tracor Jitco, Inc., Rockville, Maryland, prime contractor for the
 

NCI Carcinogenesis Testing Program.
 

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

(1,2) and R. R. Bates (1,3); the doses were selected by Drs. T·
 

E. Shellenberger (4,5), J. Η. Weisburger, and R. R. Bates.
 

Chemical administration and observation of animals were
 

supervised by Drs. T. E. Shellenberger and H. P. Burchfield (4),
 

with the technical assistance of Ms. D. H. Monceaux (4) and
 

Mr. D. Broussard (4). Histopathology was performed by Drs. E.
 

Bernal (4) and B. Buratto (4) at Gulf South Research Institute,
 

and the diagnoses included in this report represent the
 

interpretation of these pathologists.
 

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

Mason Research Institute (6). Statistical analyses were
 

performed by Dr. J. R. Joiner(7) and Ms. P. L. Yong (7) using
 

methods selected for the bioassay program by Dr. J. J. Gart (8).
 

Chemicals used in this bioassay were analyzed under the direction
 

of Dr. H. P. Burchfield, and the results of the analyses were
 

reviewed by Dr. S. S. Olin (7).
 

This report was prepared at Tracor Jitco (7) under the direction
 

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

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

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

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

and Mr. W. D. Reichardt, bioscience writers; Dr. E. W. Gunberg,
 

technical editor, assisted by Ms. Y. E. Presley and Ms. P. J.
 

Graboske.
 

The following scientists at NCI were responsible for evaluating
 

the bioassay experiment, interpreting the results, and reporting
 

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

J. Fielding Douglas, Dr. Dawn G. Goodman (9), Dr. Richard A.
 

Griesemer, Dr. Harry A. Milman, Dr. Thomas W. Orme, Dr. Robert
 

A. Squire (10), Dr. Jerrold M. Ward, and Dr. Carrie E. Whitmire.
 

(1) Carcinogenesis Testing Program, Divison of Cancer Cause and
 

Prevention, National Cancer Institute, National Institutes of
 

Health, Bethesda, Maryland.
 

(2) Now with the Naylor Dana Institute for Disease Prevention,
 

American Health Foundation, Hammond House Road, Valhalla, New
 

York.
 

(3) Now with the National Institute of Environmental Health
 

Sciences, P.O. Box 12233 Research Triangle Park, North
 

Carolina.
 

(4) Gulf South Research Institute, Atchafalaya Basin
 

Laboratories, P. 0. Box 1177, New Iberia, Louisiana.
 

(5) Now with the National Center for Toxicological Research,
 

Jefferson, Arkansas.
 

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

Rockville, Maryland.
 

iv
 
(7) Tracor Jitco., Inc., 1776 East Jefferson Street, Rockville,
 Maryland.
 

(8) Mathematical Statistics and Applied Mathematics Section,
 

Field Studies and Statistics Branch, Division of Cancer Cause
 

and Prevention, National Cancer Institute, National
 

Institutes of Health, Bethesda, Maryland.
 

(9) Now with Clement Associates, Inc., 1010 Wisconsin Avenue,
 N. W., Suite 660, Washington, D. C.
 

(10) Now with the Division of Comparative Medicine, Johns Hopkins
 

university, School of Medicine, Traylor Building, Baltimore,
 

Maryland.
 
v i

 
SUMMARY
 

A bioassay of technical-grade endrin for possible carcinogenicity
 

was conducted by administering the test chemical in feed to
 

Osborne-Mendel rats and B6C3F1 mice. Groups of 50 rats of each
 

sex were administered one of two doses of endrin for 80 weeks,
 

then observed for 31 or 34 weeks. The doses used for the male
 

rats were 2.5 or 5 ppm. The initial doses of 5 or 10 ppm used
 

for the females were not well tolerated and were reduced during
 

the study. The time-weighted average doses used for the females
 

were 3 or 6 ppm. Matched controls consisted of groups of 10 rats
 

of each sex; pooled controls, used for statistical evaluation,
 

consisted of the matched-control groups combined with 40
 

untreated male and 40 untreated female rats from similar
 

bioassays of other test chemicals. All surviving rats were
 

killed at 110 to 114 weeks.
 

Groups of 50 mice of each sex were administered endrin at one of
 

two doses for 80 weeks, then observed for 10 or 11 weeks. Initial
 

doses of 2.5 or 5 ppm used for the males were not well tolerated
 

and were reduced during the study. The time-weighted average
 

doses used for the males were 1.6 or 3.2 ppm; the doses used for
 

the females were 2.5 or 5 ppm. Matched controls consisted of
 

groups of 10 mice of each sex; pooled controls, used for
 

statistical evaluation, consisted of the matched-control groups
 

combined with 50 untreated male and 50 untreated female mice from
 

similar bioassays of other test chemicals. All surviving mice
 

were killed at 90 or 91 weeks.
 

The clinical signs observed in both rats and mice indicated that
 

the doses of endrin used were near the maximum tolerated doses.
 

In mice these signs included hyperexcitability, a manifestation
 

of toxicity of the organochlorine pesticides. However, mean body
 

weights of the rats and mice were not affected by administration
 

of endrin.
 

Although the survival of the high-dose male mice at the end of
 

the study was markedly lower than that of the controls, the
 

survivals of the low- and high-dose female mice and male and
 

female rats were unaffected by the endrin. The survival of the
 

low-dose male mice could not be evaluated, due to the accidental
 

administration of excessive quantities of endrin to this group
 

during week 66. However, a substantial portion of all groups of
 

rats and mice survived to an age at which tumors could be
 

expected to occur.
 

vii
 
In rats, the combination of adenomas and carcinomas of the
 

adrenal occurred at the following incidences — males: pooled
 

controls 2/44, matched controls 2/9, low-dose 4/46, high-dose
 

8/44; females: pooled controls 4/46, matched controls 3/9,
 

low-dose 16/49, high-dose 7/47. These incidences did not show
 

consistent statistical significance. Furthermore, the incidences
 

of the tumors in the matched controls of either sex were higher
 

than those of the corresponding pooled controls, and the
 

incidences in the matched controls equaled or exceeded those in
 

any of the respective dosed groups. Thus, these tumors cannot be
 

clearly related to administration of the test chemical.
 

In mice, no tumors occurred in dosed groups at incidences that
 

were significantly higher than those in pooled or matched
 

controls.
 

It is concluded that under the conditions of this bioassay,
 

endrin was not carcinogenic for Osborne-Mendel rats or for B6C3F1
 

mice.
 

viii
 
TABLE OF CONTENTS
 

Page
 

I· Introduction 1
 

II. Materials and Methods 3
 

A· Chemical · 3
 

B. Dietary Preparation 3
 

C. Animals 5
 

D. Animal Maintenance 5
 

E. Subchronic Studies 7
 

F. Chronic Studies 8
 

G. Clinical and Pathologic Examinations ·· 11
 

H. Data Recording and Statistical Analyses 13
 

III. Results - Rats 19
 

A. Body Weights and Clinical Signs (Rats) 19
 

B. Survival (Rats) 21
 

C. Pathology (Rats) 23
 

D. Statistical Analyses of Results (Rats) 24
 

IV. Results - Mice 27
 

A. Body Weights and Clinical Signs (Mice) 27
 

B. Survival (Mice) 29
 

C. Pathology (Mice) 31
 

D. Statistical Analyses of Results (Mice) 32
 

V· Discussion ···· 35
 

VI. Bibliography 41
 

APPENDIXES
 

Appendix A Summary of the Incidence of Neoplasms in
 

Rats Fed Endrin in the Diet 45
 

Table Al Summary of the Incidence of Neoplasms in
 

Male Rats Fed Endr in in the Diet 47
 

Table A2 Summary of the Incidence of Neoplasms in
 

Female Rats Fed Endr in in the Diet 51
 

ix
 
Appendix Β Summary of the Incidence of Neoplasms in 

Mice Fed Endrin in the Diet 55 

Table Bl Summary of the Incidence of Neoplasms in 

Male Mice Fed Endrin in the Diet 57 

Table B2 Summary of the Incidence of Neoplasms in 

Female Mice Fed Endrin in the Diet 60 

Appendix C Summary of the Incidence of Nonneoplastic 

Lesions in Rats Fed Endrin in the Diet 63 

Table Cl Summary of the Incidence of Nonneoplastic 

Lesions in Male Rats Fed Endrin in the Diet··· 65 

Table C2 Summary of the Incidence of Nonneoplastic 

Lesions in Female Rats Fed Endrin in the Diet. 69 

Appendix D Summary of the Incidence of Nonneoplastic 

Lesions in Mice Fed Endrin in the Diet 73 

Table Dl Summary of the Incidence of Nonneoplastic 

Lesions in Male Mice Fed Endrin in the Diet... 75 

Table D2 Summary of the Incidence of Nonneoplastic 

Lesions in Female Mice Fed Endrin in the Diet. 77 

Appendix Ε Analyses of the Incidence of Primary Tumors 

in Rats Fed Endrin in the Diet 81 

Table El Analyses of the Incidence of Primary Tumors 

in Male Rats Fed Endrin in the Diet 83 

Table E2 Analyses of the Incidence of Primary Tumors 

in Female Rats Fed Endrin in the Diet 89 

Appendix F Analyses of the Incidence of Primary Tumors 

in Mice Fed Endrin in the Diet 97 

Table Fl Analyses of the Incidence of Primary Tumors 

in Male Mice Fed Endrin in the Diet 99 

Table F2 Analyses of the Incidence of Primary Tumors 

in Female Mice Fed Endrin in the Diet 102 

Appendix G Analysis of Formulated Diets for 

Concentrations of Endrin 105 

χ 
TABLES 

Table 1 Endrin Chronic Feeding Studies 

in Rats 9 

Table 2 Endrin Chronic Feeding Studies 

in Mice 10 

FIGURES 

Figure 1

Figure 2

 Growth Curves for Rats Fed 

Endrin in the Diet

 Survival Curves for Rats Fed 

Endrin in the Diet

 <. 20 

 22 

Figure 3 Growth Curves for Mice Fed 

Endrin in the Diet 28 

Figure 4 Survival Curves for Mice Fed 

Endrin in the Diet 30 

xi
 
x i i

 
I. INTRODUCTION
 

Endrin (CAS 72-20-8; NCI C00157)
 

is an organochlorine pesticide
 

having a structure characteristic
 

CI
 

of the cyclodiene group, which
 

includes aldrin (CAS 309-00-2),
 

dieldrin (CAS 60-57-1), chlordane
 

(CAS 57-74-9), heptachlor (CAS
 

76-44-8), and endosulfan (CAS 115-29-7)· It is the most acutely
 

toxic compound in the cyclodiene group (Brooks, 1974 and 1975)
 

but is less persistent in the environment than DDT or dieldrin
 

(Hayes, 1975). As an insecticide, it is currently used for small
 

grains, sugarcane, and cotton; as an avicide, for forest seed and
 

perch applications; and as a rodenticide, for forest seed and
 

orchard soil applications (EPA Compendium, 1971, 1972; Brooks,
 

1974).
 

Evidence for carcinogenicity of certain cyclodiene pesticides
 

other than endrin, such as aldrin, dieldrin, and heptachlor
 

(Secretary's Commission on Pesticides, 1969; Federal Register,
 

1974) suggested that carcinogenicity might be a property common
 

to all pesticides of this general structure. Endrin was there­
fore selected for study in the Carcinogenesis Testing Program
 

because its chemical structure is similar to that of these known
 

cyclodiene carcinogens. Also, the extensive use of endrin
 

(Agricultural Research Service, 1967, 1968, 1970; EPA, 1971) and
 

its persistence (Brooks, 1974; Hayes, 1975) suggested there was a
 

potential for long-term human exposure to residues of the
 

insecticide, especially in foods.
 
II. MATERIALS AND METHODS
 

A· Chemical
 

Technical-grade endrin was purchased from Shell Chemical Company,
 

Agriculture Division, San Ramon, California, for use in this
 

study. Endrin is made by epoxidation of isodrin, the Diels-Alder
 

adduct of cyclopentadiene and 1,2,3,4,7,7-hexachloronorbornadiene. The product was 97% pure by the manufacturer^ assay.
 

Analyses by Gulf South Research Institute confirmed the identity
 

of the chemical and were consistent with the stated purity.
 

Elemental analyses (C, H, CI) were satisfactory for
 

Cj^HgClgO, the molecular formula of endrin. Gas-liquid and
 

thin-layer chromatography showed minor impurities under a variety
 

of chromatographic conditions. No attempt was made to identify
 

the impurities. Infrared, nuclear magnetic resonance, and mass 

spectra were as expected for endrin. The chemical was stored at 

4°C in the original container. 

B. Dietary Preparation
 

All diets containing endrin were formulated using Wayne® Lab
 

3 
Blox animal meal (Allied Mills, Inc., Chicago, 111·) to which was
 

added the required amount of endrin for each dietary concentration· The test chemical was first dissolved in a small amount of
 

acetone (Mallinckrodt, Inc., St. Louis, Mo.), which was then
 

added to the feed· Corn oil (LouAna , Opelousas Refinery Co.,
 

Opelousas, La.) was also added to the feed, primarily as a dust
 

suppressant, and the diets were mixed mechanically to assure
 

homogeneity of the mixtures and evaporation of the acetone. Final
 

diet89 including those for the control groups of animals,
 

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

diet were stored at room temperature until used, but no longer
 

than 1 week.
 

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

diets, the concentration of endrin was determined in different
 

batches of formulated diets during the chronic study. The
 

results are summarized in Appendix G. At each dietary
 

concentration, the mean of the analytical concentrations for the
 

checked samples was within 3.2% of the theoretical concentration,
 

and the coefficient of variation was never more than 3.6%.
 

4
 
C. Animals
 

Rats and mice of each sex, obtained through contracts of the
 

Division of Cancer Treatment, National Cancer Institute, were
 

used in these bioassays. The rats were of the Osborne-Mendel
 

strain obtained from Battelle Memorial Institute, Columbus, Ohio,
 

and the mice were B6C3F1 hybrids obtained from Charles River
 

Breeding Laboratories, Inc., Wilmington, Massachusetts. On
 

arrival at the laboratory, all animals were quarantined (rats for
 

8 days, mice for 14 days) and then assigned to control or dosed
 

groups.
 

D · Animal Maintenance
 

All animals were housed in rooms in which the temperature ranged
 

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

air entering each room was filtered (Air Maze Incom International,
 

Cleveland, Ohio), and room air was changed 10 to 12 times per
 

hour. Fluorescent lighting provided illumination 10 hours per
 

day. Food and water were provided a<1 libitum. Fresh feed was
 

provided daily, and excess remaining feed was discarded.
 

The rats were housed individually in hanging galvanized steel
 

5 
 2 

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

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

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

Mouse cages were covered with polyester filter bonnets (Lab
 

Products, Inc.). The rat racks and cages were sanitized every


weeks· The mouse cages were sanitized each week. These cages
 

and. racks were washed in an industrial washer at 82 C with
 

Acclaim® detergent (Economics Laboratory, Inc., St. Paul,
 

Minn.) and then rinsed. Absorbent Kimpak cage liners
 

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

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

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

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

per week for females. Filter bonnets were sanitized each week. 

Feed jars and water bottles were changed and sanitized three 

times per week. Sipper tubes and stoppers were sanitized two
 

time3 per week.
 

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

stoppers were washed in a Vulcan Autosan washer (Louisville, Ky·)·
 

Cage racks for each species were rotated to a new position in the
 

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

different row within the same column of a rack. Rats receiving
 

6 
endrin, along with their matched controls, were housed in a room
 

by themselves. Mice were maintained in a room housing mice from
 

the following studies:
 

Feed Studies
 

(CAS 133-90-4) chloramben
 

(CAS 1897-45-6) chlorothalonil
 

(CAS 1918-02-1) picloram
 

E. Subchronic Studies
 

Subchronic feeding studies were conducted to estimate the maximum
 

tolerated doses of endrin, on the basis of which two
 

concentrations (hereinafter referred to as "low11 and "high"
 

doses) were determined for administration in the chronic studies.
 

In the subchronic studies, endrin was added to the animal feed in
 

twofold increasing concentrations, ranging from 2.5 to 80 ppm for
 

rats and from 2.5 to 20 ppm for mice. The chemical was provided
 

in feed to dosed groups of five male and five female animals of
 

each species for 6 weeks, followed by observation for 2 weeks.
 

Untreated-control groups consisted of five animals of each
 

species and sex.
 

In rats, at 10 ppm there were no deaths, and mean weight gains of
 

both males and females were comparable to those of corresponding
 

7 
controls. At 20 ppm one animal of each sex died, but weights of
 

the survivors were not significantly affected. The low and high
 

doses for the chronic studies using rats were set at 7.5 and 15
 

ppm.
 

In mice, three males and four females in the groups at 10 ppm
 

died during the study. At 5 ppm no animals died, and mean weight
 

gains were comparable to those of controls. The low and high
 

doses for the chronic studies using mice were set at 2.5 and 5
 

ppm.
 

F. Chronic Studies
 

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

feeding studies are shown in tables 1 and 2. Due to high
 

mortality in the rats at the doses set by the subchronic study,
 

the studies with rats were terminated and restarted using lower
 

doses of 2.5 or 5 ppm for males and 5 or 10 ppm for females.
 

Because of subsequent toxic effects, the doses for the female
 

rats and the male mice were reduced during the course of the
 

studies.
 

Since the numbers of animals in the matched-control groups were
 

8 
Table 1. Endrin Chronic Feeding Studies in Rats
 

Sex and 

Test 

Group 

Initial 

No. of 

Animals(i i)

Endrin 

in Diet(b) 

 (ppm) 

Time on Study 

Dosed Observed(c) 

(weeks) (weeks ) 

Time-Weighted 

Average Dose(d) 

(ppm) 

Male 

Matched-Control 10 0 110 

Low-Dose 50 2.5 

0 

80 

31 

2.5 

High-Dose 50 5 

0 

80 

34 

5 

Female 

Matched-Control 10 0 110 

Low-Dose 50 5 

2.5 

0 

9 

71 

31 

3 

High-Dose 50 10 

5 

0 

9 

71 

34 

6 

(a) All animals were 5 weeks old when placed on study.
 

(b) Initially, concentrations of 15 and 7.5 ppm of endrin were fed to
 

rats of each sex; these doses were too toxic, however, and the rat
 

study was terminated and restarted as shown in the table.
 

(c) When diets containing endrin were discontinued, dosed rats were
 

fed control diets (2% corn oil added) until termination; matchedcontrol rats received control diets throughout the study.
 

(d) Time-weighted average dose = Σ(dose in ppm x no. weeks at that dose)
 

Σ(no. of weeks receiving each dose)
 

9
 
Table 2. Endrin Chronic Feeding Studies in Mice
 

Sex and 

Test 

Group A

Initial 

No. of 

nimals(a) 

Endrin 

in Diet(b) 

(ppm) 

Time 

Dosed 

(weeks) 

on Study 

Obs erved 

(weeks) 

Time-Weighted 

Average Dose(c) 

(ppm) 

Male 

Matched-Control 10 0 90 

Low-Dose 50 2.5 

1.2 

0 

25 

55 

10 

1.6 

High-Dose 50 5 

5(d) 

2.5 

0 

15 

10 

55 

11 

3.2 

Female 

Matched-Control 10 0 90 

Low-Dose 50 2.5 

0 

80 

10 

2.5 

High-Dose 50 5 

0 

80 

11 

5 

(a)	 All animals were 5 weeks old when placed on study.
 

(b)	 When diets containing endrin were discontinued, dosed mice were
 

fed control diets (2% corn oil added) until termination; matchedcontrol mice received control diets throughout the study.
 

(c)	 Time-weighted average dose = Z(dose in ppm χ no. weeks at that dose)
 

Z(no. of weeks receiving each dose)
 

(d)	 The diets shown and control diets were fed on alternate weeks.
 

10
 
small, pooled-control groups also were used for statistical
 

evaluation. In rats, matched controls from the current bioassay
 

on endrin were combined with matched controls from studies
 

performed on captan (CAS 133-06-2), malathion (CAS 121-75-5),
 

phosphamidon (CAS 13171-21-6), photodieldrin (CAS 13366-73-9),
 

and tetrachlorvinphos (CAS 961-11-5). In mice, matched controls
 

from endrin were combined with those from captan, chloramben,
 

chlorothalonil, photodieldrin, and picloram. The pooled
 

controls for statistical tests consisted of 50 rats and 60 mice
 

of each sex. In both species, these controls were started no
 

more than 3 months apart from the endrin controls. The studies
 

on chemicals other than endrin were also conducted at Gulf South
 

Research Institute and were diagnosed by the same pathologists.
 

The matched-control groups for the different test chemicals were
 

of the same strain and from the same supplier.
 

G. Clinical and Pathologic Examinations
 

All animals were observed twice daily for signs of toxicity,
 

weighed every 2 weeks for the first 12 weeks, and monthly
 

thereafter, and palpated for masses at each weighing. Sick,
 

tumor-bearing, and moribund animals were observed daily.
 

11
 
Moribund animals and animals that survived to the end of the
 

bioassay were killed using ether and necropsied. Necropsies were
 

also performed on all animals found dead, unless precluded by
 

autolysis or severe cannibalization.
 

The pathologic evaluation consisted of gross and microscopic
 

examination of major tissues, major organs, and all gross
 

lesions. The different tissues were preserved in 10% buffered
 

formalin, embedded in paraffin, sectioned, and stained with
 

hematoxylin and eosin. Special staining techniques were utilized
 

when indicated for more definitive diagnosis. The following
 

tissues were examined microscopically: skin, lungs and bronchi,
 

trachea, bone and bone marrow, spleen, lymph nodes, heart,
 

salivary gland, liver, gallbladder (mice), pancreas, stomach,
 

small intestine, large intestine, kidney, urinary bladder,
 

pituitary, adrenal, thyroid, parathyroid, mammary gland, prostate
 

or uterus, testis or ovary, and brain. Occasionally, additional
 

tissues were also examined microscopically.
 

A few tissues from some animals were not examined, particularly
 

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

been in advanced states of cannibalization or autolysis. Thus,
 

the number of animals from which particular organs or tissues
 

were examined microscopically varies, and does not necessarily
 

12
 
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 analyzed using the appropriate statistical
 

techniques described in this section. Those analyses of the
 

experimental results that bear on the possibility of
 

carcinogenicity are discussed in the statistical narrative
 

sections.
 

Probabilities of survival were estimated by the product-limit
 

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

13
 
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 Ρ values have been reported for all tests
 

except the departure from linearity test, which is only reported
 

when its two-tailed Ρ value is less than 0·05.
 

The incidence of neoplastic or nonneoplastic lesions has been
 

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

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

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

the denominators included only those animals for which that site
 

was examined histologically. However, when macroscopic
 

examination was required to detect lesions prior to histologic
 

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

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

denominators consist of the numbers of animals necropsied.
 

The purpose of the statistical analyses of tumor incidence is to
 

determine whether animals receiving the test chemical developed a
 

14
 
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
 

 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 Ρ 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 onetailed 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
 

15
 
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. 

Significant departures from linearity (P less than 0.05, 

two-tailed test) were also noted. 

16
 
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 pt /pt where pt is the true
 

binomial probability of the incidence of a specific type of tumor
 

in a dosed group of animals and pc 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 dos.ed group and the proportion in a control
 

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

of unity represent the condition of a larger proportion in the
 

dosed group than in the control.
 

The lower and upper limits of the confidence interval of the
 

relative risk have been included in the tables of statistical
 

analyses. The interpretation of the limits is that in
 

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

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

control group would be within the interval calculated from the
 

experiment. When the lower limit of the confidence interval is
 

greater than one, it can be inferred that a statistically
 

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

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

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

17
 
than unity, bu.t 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. 

18
 
III. RESULTS - RATS
 

A. Body Weights and Clinical Signs (Rats)
 

The mean body weights of the dosed male and female rats were
 

similar to those of corresponding controls (figure 1).
 

Fluctuation in the growth curve may be due to mortality; as the
 

size of a group diminishes, the mean body weight may be subject
 

to variation. The high-dose female rats lost weight at week 9,
 

and the doses for the low- and high-dose females were lowered at
 

that time, after which the weight was recovered.
 

During the first 16 weeks of the bioassay, clinical signs
 

including alopecia (primarily in facial areas), diarrhea, and
 

epistaxis were observed in a few animals in both the high- and
 

low-dose groups. At week 8, several animals in both the dosed
 

and control groups developed ocular infections that were
 

diagnosed as viral conjunctivitis. For the remainder of the
 

first year of the bioassay, the dosed animals were generally
 

comparable to the controls in appearance and behavior.
 

Clinical signs were noted with increasing frequency in both the
 

high- and low-dose groups early in the second year of the study.
 

19
 
TIME ON STUDY (WEEKS) 

Figure 1· Growth Curves for Rats Fed Endrin in the Diet
 

20
 
In addition to the signs previously described, rough hair coats,
 

dermatitis, tachypnea, pale mucous membranes, hematuria, and
 

discolored urine also were observed. During the latter half of
 

the second year, the dosed and control groups began to exhibit
 

similar signs, and by the end of week 110, clinical observations
 

were essentially the same in both groups.
 

B. Survival (Rats)
 

The Kaplan and Meier curves estimating the probabilities of
 

survival for male and female rats receiving endrin at the doses
 

used in this bioassay, together with those of the controls, are
 

shown in figure 2. The results of the Tarone test for
 

dose-related trend in mortality are not statistically significant
 

for either sex.
 

At week 110, 33/50 (66%) of the high-dose males, 30/50 (60%) of
 

the low-dose males, and 8/10 (80%) of the control males were
 

still alive. In females, 42/50 (84%) of the high-dose group,
 

38/50 (76%) of the low-dose group, and 7/10 (70%) of the control
 

group were alive at week 110. Sufficient numbers of rats of each
 

sex were at risk for the development of late-appearing tumors.
 

21
 
TIME ON STUDY (WEEKS) 

Figure 2. Survival Curves for Rats Fed Endrin in the Diet
 

22
 
C. Pathology (Rats)
 

Histopathologic findings on neoplasms in rats are summarized in
 

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

are summarized in Appendix C, tables Cl and C2.
 

A variety of tumors occurred with a low frequency in control and
 

dosed rats. These tumors are not uncommon in this strain of rat,
 

and have been observed in the bioassay program independent of any
 

administration of test chemicals.
 

In addition to the neoplastic lesions, degenerative,
 

proliferative, and inflammatory pathologic changes were observed
 

in dosed and control rats, mostly with approximately equal
 

frequency. In a few instances, some lesions affected rats of the
 

dosed groups, but not those of the controls. These included
 

follicular-cell hyperplasia of the thyroid, and cysts and
 

angiectasis of the pituitary gland. The lesions observed in this
 

study are not uncommon in aged Osborne-Mendel rats, and they have
 

been known to occur spontaneously in this and other laboratories.
 

Based on the histopathologic examination, there was no evidence
 

for the carcinogenicity of endrin in Osborne-Mendel rats under
 

the conditions of this bioassay.
 

23
 
D. Statistical Analyses of Results (Rats)
 

Tables El and E2 in Appendix Ε 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 each sex, there are no significant statistical test results
 

when the incidences in the dosed groups are compared with those
 

in the matched controls.
 

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

incidence of adenomas of the pituitary is significant (P = 0.015)
 

using the pooled controls, and the results of the Fisher exact
 

test show that the incidence in the high-dose group is
 

significantly higher (P = 0.016) than that in the pooled
 

controls. When the incidence of female rats with either
 

adenomas, carcinomas, adenocarcinomas, or chromophobe adenomas of
 

the pituitary is analyzed, there is no significant result. It
 

should be noted that there are only three carcinomas reported;
 

all other pituitary tumors were adenomas.
 

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

combined incidence of adenomas and carcinomas of the adrenal,
 

24
 
using the pooled controls, is significant (P = 0.028). The
 

result of the Fisher exact comparison between the incidence in
 

the high-dose group and that in the pooled controls indicates a P
 

value of 0.045, which is above the 0.025 level required for 

significance when the Bonferroni inequality criterion is used for 

multiple comparison. In females, although the result of the 

Cochran-Armitage test is not significant, an indicated departure
 

from linear trend (P = 0.003) is observed when the pooled-control
 

group is used, because the incidence in the low-dose group is
 

greater than that in the high-dose group. The results of the
 

Fisher exact test show that the incidence in the low-dose group
 

is significantly higher (P = 0.004) than that in the pooled
 

controls; however, a significant result is not observed in the
 

incidence in the high-dose group. In both males and females, the
 

incidences observed in the matched controls are higher than those
 

reported in the pooled controls, and these incidences in the
 

matched-control groups equal or exceed those observed in any of
 

the respective dosed groups.
 

In male rats, the incidence of hemangiomas of all sites is
 

significantly higher in the low-dose group (P = 0.024) than in
 

the pooled controls, but a significant result is not indicated by
 

the incidence in the high-dose group. The result of the Cochran-


Armitage test for the incidences of this tumor is not significant.
 

25
 
In male rats, islet-cell carcinomas of the pancreas are observed
 

exclusively in the high-dose group (3/47, or 6%), and the result
 

of the Cochran-Armitage test shows a probability level of 0.039
 

using the pooled controls; however, the results of the Fisher
 

exact test are not significant.
 

Significant results in the negative direction are observed in the
 

incidence of chromophobe adenomas of the pituitary in male rats,
 

using the pooled controls. A significant trend in the negative
 

direction is also observed in the combined incidence of adrenal
 

tumors in female rats when the matched-control group is used.
 

In summary, the statistical evidence does not indicate an 

association between the incidence of any tumors with the 

administration of the test chemical in either male or female 

Osborne-Mendel rats.
 

26
 
IV. RESULTS - MICE
 

A. Body Weights and Clinical Signs (Mice)
 

The mean body weights of the dosed male and female mice were
 

similar to those of corresponding controls (figure 3).
 

Fluctuation in the growth curve may be due to mortality; as the
 

size of a group diminishes, the mean body weight may be subject
 

to variation.
 

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

generally comparable to the controls in appearance and behavior.
 

At week 24, all of the high-dose male group appeared hyperexcitable, and doses for the males were lowered at that time. This
 

condition persisted in the majority of this group until termination of the study. In the latter half of the first year,
 

clinical signs including alopecia (generalized and localized),
 

abdominal distention, and rough hair coats became apparent.
 

During the second year of the study, the above clinical signs
 

were noted with increasing frequency in all dosed groups. At
 

week 66, administration of excessive quantities of endrin to the
 

low-dose male group occurred, and the majority of these animals
 

27
 
TIME ON STUDY (WEEKS)
 

Figure 3. Growth Curves for Mice Fed Endrin in the Diet
 

28
 
appeared hyperexcitable. This condition persisted until termination of the study. There was also fighting among the majority
 

of the males, which resulted in fight wounds and rough hair coats·
 

B. Survival (Mice)
 

The Kaplan and Meier curves estimating the probabilities of
 

survival for male and female mice receiving endrin at the doses
 

used in this bioassay, together with those of the controls, are
 

shown in figure 4. In male mice, the result of the Tarone test
 

for dose-related trend in mortality is not significant· In
 

females, the result of the Tarone test is significant (P s
 

0.045). An indicated departure (P = 0.003) from linear trend is
 

observed in male mice, because of the earlier mortality of the
 

low-dose group as compared with that of the high-dose group.
 

An error in preparation of the diet resulted in excess dosing of
 

all the low-dose male mice, and 17 of this group died during week
 

66 and three more in week 67. However, in males, 32/50 (64%) of
 

the high-dose group, 23/50 (46%) of the low-dose group, and all
 

10 of the controls survived to the end of the study. In females,
 

39/50 (78%) of the high-dose group, 45/50 (90%) of the low-dose
 

29
 
TIME ON STUDY (WEEKS)
 

Figure 4. Survival Curves for Mice Fed Endrin in the Diet
 

30
 
group, and 9/10 (90%) of the controls were still alive at week
 

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

development of 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.
 

There was great variation in the types of neoplastic and
 

nonneoplastic lesions in the mice. The lesions observed are not
 

uncommon in aged B6C3F1 mice.
 

The most frequent neoplastic lesions occurred in the liver and
 

comprised hepatocellular carcinomas and neoplastic nodules. They
 

were observed in 1/10 (10%) control males, 3/38 (8%) low-dose
 

males, 10/45 (22%) high-dose males; 2/10 (20%) control females,
 

3/50 (6%) low-dose females, and 1/47 (2%) high-dose females. The
 

incidences were similar to those observed in other control B6C3F1
 

mice in this laboratory and were not considered to be related to
 

administration of the test chemical.
 

31
 
Based on the histopathologic examination, there was no evidence
 

for the carcinogenicity of endrin in B6C3F1 mice under the
 

conditions of this bioassay.
 

D· Statistical Analyses of Results (Mice)
 

Tables Fl and F2 in Apendix 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 each sex, the results of the Cochran-Armitage test for
 

positive dose-related trend and those of the Fisher exact test in
 

the positive direction are not significant.
 

Significant results in the negative direction are observed in the
 

incidences of hepatocellular carcinomas in each sex. In male
 

mice, the Fisher exact test shows that the incidence of
 

hepatocellular carcinomas in the pooled-control group is
 

significantly (P = 0.009) higher than that in the low-dose group,
 

which may be accounted for by the poorer survival of the low-dose
 

group. This significance in the negative direction is not
 

observed when the incidence of the tumors in the low-dose males
 

32
 
is compared with that in the matched-control group, nor is it
 

observed when the incidence of neoplastic nodules or
 

hepatocellular carcinomas in the low-dose male mice is compared
 

with the incidences of these combined tumors in the pooled or
 

matched controls.
 

In female mice, a significant trend in the negative direction is
 

observed in the incidence of hepatocellular carcinomas (P =
 

0.011) and in the combined incidence of hepatocellular carcinomas
 

and neoplastic nodules (P = 0.047) using the matched-control
 

group. This significance in the negative direction may be due to
 

the poorer survival of the high-dose group. The Fisher exact
 

comparison of the incidences of hepatocellular carcinomas in the
 

matched-control and high-dose groups indicates a P value of 0.028
 

in the negative direction. This Ρ value is above the 0.025 level
 

required for significance when the Bonferroni inequality
 

criterion is used for multiple comparison. The result of the
 

Fisher exact test on the incidence of hepatocellular carcinomas
 

or neoplastic nodules also is not significant. No significant
 

result is observed when the pooled-control group is used for
 

analysis of incidences of hepatocellular carcinomas or of
 

combined hepatocellular carcinomas and neoplastic nodules in the
 

female mice.
 

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

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

indicating the absence of significant positive results. It
 

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

the incidence of hepatocellular carcinomas in high-dose female
 

mice, using the matched controls, and in the low-dose male mice,
 

using the pooled controls) has an upper limit greater than one,
 

indicating the theoretical possibility of the induction of tumors
 

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

this test.
 

Time-adjusted analyses, eliminating animals that died before week
 

52 on study, were performed on the incidences of tumors shown in
 

tables Fl and F2. No significant positive results were observed.
 

34
 
V. DISCUSSION
 

Endrin is a member of an organochlorine group of pesticides which
 

can be classed as neurotoxins. Hyperexcitability, a manifestation of toxicity that is characteristic of these chemicals, was
 

observed in male mice given the low or high dose of endrin. A
 

variety of clinical signs, usually associated with aging, were
 

observed in the dosed animals prior to their appearance in
 

corresponding controls. In rats, these signs included alopecia,
 

diarrhea, epistaxis, tachypnea, pale mucous membranes, hematuria,
 

rough hair coats, and dermatitis; in mice, they included
 

alopecia, abdominal distention, and rough hair coats. The mean
 

body weights of the rats and mice were not affected by endrin.
 

The chronic study in rats was restarted at lower doses when the
 

rats receiving doses of 7.5 or 15 ppm endrin in feed showed
 

unacceptable rates of survival; at the new doses of 2.5 to 10 ppm
 

the survival rates of the rats were improved and were not
 

significantly affected by administration of the test chemical.
 

In mice, the original doses selected, i.e., 2.5 and 5 ppm endrin,
 

were used for females throughout the bioassay, but were lowered
 

for males after week 25 on study. The survival rates were
 

unaffected in the low- and high-dose female mice but decreased in
 

35
 
the high-dose male mice. The survival rate of the low-dose male
 

mice could not be evaluated, since a large proportion of this
 

group died following an accidental overdose. However, 64% of the
 

high-dose male mice survived to the end of the study, so that
 

adequate numbers of animals were at risk for the development of
 

late-appearing tumors. With the exception of the low-dose male
 

mice, a substantial proportion of all groups of rats and mice
 

survived to an age at which tumors could be expected to appear.
 

In rats, the combination of adenomas and carcinomas of the
 

adrenal occurred at the following incidences — males: pooled
 

controls 2/44, matched controls 2/9, low-dose 4/46, high-dose
 

8/44; females: pooled controls 4/46, matched controls 3/9,
 

lw-dose 16/49, high-dose 7/47. These incidences did not show
 

consistent statistical significance. Furthermore, the incidences
 

of the tumors in the matched controls of either sex were higher
 

than those of the corresponding pooled controls, and the 

incidences in the matched controls equaled or exceeded those in 

any of the respective dosed groups. Thus, these tumors cannot be 

clearly related to administration of the test chemical. 

In male rats, hemangiomas and islet-cell carcinomas occurred in
 

small numbers of animals and had inconsistent statistical
 

36
 
significance; thus, they cannot be clearly related to
 

administration of the test chemical.
 

In mice, no tumors occurred in dosed groups at incidences that
 

were significantly higher than those in pooled or matched
 

controls.
 

There was no convincing evidence to show that the ingestion of
 

endrin under the conditions of this bioassay induced any of the
 

different types of tumors which were observed in the dosed male
 

or female rats or mice. Tumors of the liver, which can be
 

induced in mice by other organochlorine pesticides such as
 

dieldrin, DDT, and benzene hexachloride (Hayes, 1975), appeared
 

in the mice administered endrin, but not in proportions
 

significantly higher than those in the controls.
 

When compared with dieldrin and other organochlorine insecticides, endrin is relatively nonpersistent in mammalian tissues
 

(IARC Monograph, 1974; Brooks, 1975). The chemical is
 

oxidatively metabolized in the liver, secreted in the bile, and
 

excreted primarily in the feces and only slightly in the urine
 

(Baldwin et al., 1970; Hutson et al., 1975). It is eliminated
 

largely as the metabolite anti-12-hydroxyendrin, and its toxic
 

form appears to be 12-ketoendrin. As the principal metabolite
 

37
 
found in the brain of dosed animals (Bedford et al., 1975),
 

12-ketoendrin may be responsible for the hyperexcitability
 

observed in the dosed male mice of the present study·
 

In two previous studies, incidences of tumors in animals
 

administered endrin in the diet were reported to be no different
 

than those in controls; these tests involved Osborne-Mendel rats
 

given 2 to 12 ppm for their lifetimes (Deichmann et al., 1970)
 

and Carworth rats given 1 to 100 ppm for 2 years (Treon et al.,
 

1955). In the latter study, the average ratios of the weights of
 

livers to body weights in male rats receiving 5 or 25 ppm were
 

significantly greater than those of the controls; furthermore,
 

survivals of male or female rats that received 50 or 100 ppm were
 

low, and hepatic degenerative changes were noted only in animals
 

that survived these high doses. In a third study, carcinomas and
 

sarcomas were reported to occur in Osborne-Mendel rats
 

administered endrin in the diet at 0.1 to 25 ppm for 2 years
 

(Reuber, 1978). The incidence was higher in animals administered
 

0.1 or 1.0 ppm than in control animals or in animals administered
 

the higher doses· The commonest lesions observed were carcinomas
 

of the mammary gland in the females and hyperplasia of the liver
 

in both the males and the females. Statistical evidence for
 

occurrence of tumors in the rats at 0.1 or 1.0 ppm compared with
 

38
 
controls was based on cumulative totals of tumors of all types
 

and at all sites.
 

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

was not carcinogenic for Osborne-Mendel rats or for B6C3F1 mice.
 

39
 
40

 
VI. BIBLIOGRAPHY
 

Agricultural Research Service, Cancellation of registration of
 

endrin products bearing directions for use on certain crops. PR
 

Notice 67-4, August, 1967.
 

Agricultural Research Service, Cancellation of registration of
 

certain products bearing directions for use on food in the 

absence of finite tolerances or exemptions. PR Notice 68-6, 

February, 1968. 

Agricultural Research Service, Proposed cancellation of
 

registration of certain products bearing directions for use on
 

food in the absence of finite tolerances or exemptions. PR
 

Notice 70-4, February, 1970.
 

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

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

Baldwin, M. K., Robinson, J·, and Parke, D. V., Metabolism of
 

endrin in the rat. J. Agric. Food Chem. 18(6):1117-1123, 1970.
 

Bedford, C. T·, Hutson, D. H., and Natoff, I. L·, The acute
 

toxicity of endrin and its metabolites to rats. Toxicol. Appl.
 Pharmacol. 33;115-121, 1975.
 

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

Panel on Carcinogenicity of the Cancer Research Commission of
 

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

Brooks, G.T., Chlorinated Insecticides, Technology and
 

Application, Vol. I., Chemical Rubber Company, Cleveland, 1974.
 

Brooks, G· T., Chlorinated Insecticides, Biological and
 

Environmental Aspects, Vol. II., Chemical Rubber Company,
 

Cleveland, 1975.
 

Cox, D. R., Analysis of Binary Data, Methuen & Co., Ltd., London,
 1970, pp. 48-52.
 

Cox, D. R., Regression models and life tables. J. R. Statist.
 Soc. Β 34;187-220, 1972.
 

41
 
Deichmann, W. Β., MacDonald, W. E., Blum, E., Bevilacqua, M.,
 Radomski, J., Keplinger, M., and Balkus, M., Tumorigenicity of
 

aldrin, dieldrin and endrin in the albino rat. Indust. Med.
 39:37-45, 1970.
 

Environmental Protection Agency, Cancellation of registration of
 

certain products bearing directions for use on food in the
 

absence of finite tolerances or exemptions. PR Notice 71-3,
 March, 1971.
 

Environmental Protection Agency, EPA Compendium of Registered
 

Pesticides, U.S. Government Printing Office, Washington, D.C.,
 Vol. 3, 1971.
 

Environmental Protection Agency, EPA Compendium of Registered
 

Pesticides, U.S. Government Printing Office, Washington, D.C.,
 Vol. 4, 1972.
 

Federal Register, Environmental Protection Agency, Notice of
 

intention to suspend and findings as to imminent hazard, U.S.
 Government Printing Office, Washington, D.C., 39(203):
 

37246-37272, 1974.
 

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.
 

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

Wilkins, Baltimore, 1975.
 

Hutson, D. H., Detoxication and reactivation of endrin in the
 

rat. Xenobiotica 5(11):697-714, 1975.
 

International Agency for Research on Cancer, IARC Monographs on
 

the Evaluation of Carcinogenic Risk of Chemicals to Man, Some
 

Organochlorine Pesticides, Vol. 5., World Health Organization,
 

Geneva, 1974, pp. 157-171.
 

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

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

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

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

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

42
 
Miller, R. G., Jr., Simultaneous Statistical Inference,
 McGraw-Hill Book Co., New York, 1966, pp. 6-10.
 

Reuber, M. D., Carcinomas, sarcomas and other lesions in Osborne-


Mendel rats ingesting endrin. Expl Cell Biol. 46;129-145, 1978.
 

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

Kaufiinan, 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.
 

Secretary's Commission on Pesticides and Their Relationship to
 

Environmental Health, U. S. Dept. of Health, Education and
 

Welfare, Report of the Secretary's Commission on Pesticides and
 

Their Relationship to Environmental Health, U. S. Government
 

Printing Office, Washington, D.C., 1969.
 

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

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

Treon, J. F., Cleveland, F. P., and Cappel, J., Toxicity of
 

endrin for laboratory animals. J. Agric. Food Chem. 3: 842-848,
 

1955.
 

43
 
44

 
APPENDIX A
 

SUMMARY OF THE INCIDENCE OF NEOPLASM» IN
 

RATS FED ENDRIN IN THE DIET
 

45
 
46

 
TABLE ΑΙ.
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE RATS
 

FED ENDRIN IN THE DIET
 

CONTROL LOW DOSE HIGH DOSE 

ANIMALS INITIALLY IN STUDY 10 50 50 

ANIMALS NECROPSIED 10 46 47 

ANIMALS EXAMINED HISTOPATHOLOGICALLY 10 46 47 

INTEGUHENTARY SYSTEM 

•SUBCUT TISSUE 

FIBROMA 

FIBROUS HISTIOCYTOMA,

LIPOMA 

 MALIGNANT 

(10) (46) 

1 (2%) 

1 (2%) 

1 (2%) 

|47 ) 

1 (2%) 

1 (2X) 

RESPIRATORY SYSTEM 

#LUNG (10) (45) (47) 

ALVEOLAR/BRONCHIOLAR CARCINOMA 1 (2X) 

FIBROSARCOMA# METASTATIC 1 (2%) 

HEMATOPOIETIC SYSTEM 

•MULTIPLE	 ORGANS (10) (46) (47) 

GRANULOCYTIC LEUKEMIA 1 (2%) 

#SPLEEN	 (10) (46) (45) 

HEMANGIOMA 4 (9%) 2 (4%) 

CIRCULATORY SYSTEM 

NONE 

DIGESTIVE SYSTEM 

#PARATID GLAND (10) (44) (47) 

HEMANGIOMA 1 (2%) 

#STOMACH (10) (44) (46) 

PAPILLOMA. NOS 1 (10%) 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

47
 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

«COLON (4) (16) (21)

 

ADENOMATOUS POLYP, NOS 1 (25%)

 

URINARY SYSTEM 

•KIDNEY (10) (46) (47) 

TUBULAR-CELL ADENOCARCINOMA 1 (2%) 

MIXED TUMOR, MALIGNANT 1 (2%) 

HAMARTOMA 1 (2%) 2 (4%) 

«URINARY BLADDER (8) (42) (41) 

PAPILLOMATOSIS 1 (2%) 

ENDOCRINE SYSTEM 

«PITUITARY (10) (43) (41) 

ADENOMA, NOS 4 (40%) 8 (19%) 12 (29%) 

CHROMOPHOBE ADENOMA 6 (14%) 1 (2%) 

«ADRENAL (9) (46) (44) 

CARCINOMA,NOS 2 (4%) 

ADENOMA, NOS 2 (22*) 2 (4%) 8 (18%) 

«THYROID (9) (42) (4 3) 

FOLLICULAR-CELL ADENOMA 3 (7%) 

FOLLICULAR-CELL CARCINOMA 1 (11%) 1 (2%) 

C-CELL ADENOMA 1 (2%) 2 (5%) 

«PANCREATIC ISLETS (10) (45) (47) 

ISLET-CELL ADENOMA 1 (2%) 1 (2%) 

ISLET-CELL CARCINOMA 3 (6%) 

REPRODUCTIVE SYSTEH 

NONE 

NERVOUS SYSTEM 

«BRAIN (10) (44) (47)

 

MENINGIOMA 1 (2%)

 

SPECIAL SENSE ORGANS 

NONE 

« NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

t This is considered to be a benign form of the malignant mixed tumor
 

of the kidney and consists of lipocytes, tubular structures, and
 

fibroblasts in varying proportions.
 

48
 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED)

 

HIGH DOSE
 

(47)
 

(47)
 

(47)
 

1 (2%)
 

(47)
 

1 (2%)
 

(47)
 

2 (4%)
 

50
 

10
 

16
 

24
 

MUSCULOSKELETAL SYSTEM
 

•SKELETAL MUSCLE
 

HEMANGIOMA
 

•MUSCLE OF NECK
 

FIBROSARCOMA
 

•MUSCLE HIP/THIGH
 

FIBROUS HISTIOCYTOMA, MALIGNANT
 

BODY CAVITIES
 

•BODY CAVITIES
 

MESOTHELIOMA, MALIGNANT
 

ALL OTHER SYSTEMS
 

•MULTIPLE ORGANS
 

FIBROUS HISTIOCYTOMA, MALIGNANT
 

ANIMAL DISPOSITION SUMMARY
 

ANIMALS INITIALLY IN STUDY
 

NATURAL DEATHd
 

MORIBUND SACRIFICE
 

SCHEDULED SACRIFICE
 

ACCIDENTALLY KILLED
 

TERMINAL SACRIFICE
 

ANIMAL HISSING
 

3 INCLUDES AUTOLYZED ANIMALS
 

CONTROL LOW DOSE 

(10) (46) 

1 (2%) 

(10) (46) 

1 (2X) 

(10) (46) 

(10) (46) 

(10) (46) 

10 50 

2 9 

2 15 

6 26 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

• NUMBER OF ANIMALS NECROPSIED 

49 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED)
 

CONTROL LOW DOSE
 

TUMOR SUMMARY
 

TOTAL ANIMALS WITH PRIMARY TUMORS* 5 25
 

TOTAL PRIMARY TUMORS 9 36
 

TOTAL ANIMALS WITH BENIGN TUMORS 5 21
 

TOTAL BENIGN TUMORS β 29
 

TOTAL ANIMALS WITH MALIGNANT TUMORS 1 6
 

TOTAL MALIGNANT TUMORS 1 7
 

TOTAL ANIMALS WITH SECONDARY TUMORS* 1
 

TOTAL SECONDARY TUMORS 1
 

TOTAL ANIMALS WITH TUMORS UNCERTAIN-


BENIGN OR MALIGNANT
 

TOTAL UNCERTAIN TUMORS
 

TOTAL ANIMALS WITH TUMORS UNCERTAIN-
 PRIMARY OR METASTATIC
 

TOTAL UNCERTAIN TUMORS
 

•PRIMARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS 

* SECONDARY TUMORS: METASTATIC TUHORS OR TUMORS IN7ASIVE INTO

50
 

HIGH DOSE
 

27
 

42
 

23
 

31
 

9
 

11
 

 AN ADJACENT ORGAN 
TABLE A2. 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS 

ENDRIN IN THE DIET 

CONTROL LOW DOSE HIGH DOSE 

ANIMALS INITIALLY IN STUDY 10 50 50 

ANIMALS NECROPSIED 10 49 50 

ANIMALS EXAMINED HISTOPATHOLOGICALLY 10 49 50 

INTEGUMENTARY SYSTEM 

•SUBCUT	 TISSUE (10) (49) (50)
 

FIBROSARCOMA 1 (2%)
 

FIBROUS HISTIOCYTOMA, MALIGNANT 1 (2%)
 

RESPIRATORY SYSTEM 

#LUNG (10) (49) (50)
 

ALVEOLAR/BRONCHIOLAR CARCINQMA 1 (10%)
 

FIBROUS HISTIOCYTOMA, METASTATIC 1 (10%)
 

HEMATOPOIETIC SYSTEM 

«SPLEEN (9) (48) (50) 

FIBROMA 1 (2%) 

CIRCULATORY SYSTEM 

NONE 

DIGESTIVE SYSTEM 

•SALIVARY	 GLAND (9) (49) (49) 

SARCOMA, NOS 1 (2%) 

#LIVER (10) (49) (50) 

NEOPLASTIC NODULE 1 (2%) 1 (2%) 

FIBROUS HISTIOCYTOMA, METASTATIC 1 (10%) 

•BILE	 DUCT (10) (49) (50)
 

BU E DUCT ΑΓ2ΕΝΟΜ& ..
 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

• NUMBER OF ANIMALS NECROPSIED 

51
 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED)

 

CONTROL LOW DOSE HIGH DOSE 

URINARY SYSTEM 

«KIDNEY (10) (19) (49) 

HAMARTOMA 1 (10%) 3 (6%) 2 («*} 

ENDOCRINE SYSTEM 

# PITUITARY (7) (47) 

CARCINOMA,NOS 

ADENOMA, NOS 2 (29%) 

2

11

 (4%) 

 (23%) 13 (29 X) 

ADENOCARCINOMA, NOS 

CHROMOPHOBE ADENOMA 

1

9

 (2%) 

 (19%) 7 (16X) 

«ADRENAL (9) (49) (47) 

CARCINOMA,NOS 

ADENOMA, NOS 

1

2

 (11%) 

 (22%) ' 

7

9

 (14%) 

 (18%) 

3

1

 (6X) 

 (9%) 

PHEOCHROMOCYTOMA 1 <2X) 

«THYROID (8) (46) (49) 

FOLLICULAR-CELL

C-CELL ADENOMA 

 ADENOMA 1

4

 (2%) 

 (9%) 

1

3

 <2X) 

 (6X) 

«PANCREATIC ISLETS (10) (47) (50) 

ISLET-CELL ADENOMA 1 (2X) 

REPRODUCTIVE SYSTEM 

•MAMMARY GLAND (10) (49) (50) 

ADSNOMA, NOS 1 (2%) 2 <4X)

 

ADENOCARCINOMA, NOS 1 (2%)

 

FIBROMA 3 (6%)

 

FIBROADENOMA 1 (10%) 3 (6%) 2 (4X)

 

«UTERUS (*) (48) (4 5) 

ADENOCARCINOMA, NOS 1 (2%) 

PAPILLARY ADENOMA 1 (2%) 

LEIOMYOSARCOMA 1 (13%) 

ENDOMETRIAL STROMAL POLYP 1 (13%) 5 (10%) 2 (4*) 

«OVARY (107 (47) (47) 

FIBROMA 1 (2X) 

NERVOUS SYSTEM 

« NUMBER OF ANIMALS WITH TISSUE EXAMINED HICROSCOPICALLY 

• NUMBER OF ANIMALS NECROPSIED 

t This is considered to be a benign form of the malignant mixed tumor
 

of the kidney and consists of lipocytes, tubular structures, and
 

fibroblasts in varying proportions.
 

52
 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED)
 

CONTROL LOW DOSE HIGH DOSE ι 

SPECIAL SENSE ORGANS 

NONE 

MUSCULOSKELETAL SYSTEM 

•SKELETAL MUSCLE 

FIBROUS HISTIOCYTOMA, MALIGNANT 

(10) 

1 (10%) 

(4 9) (50) 

BODY CAVITIES 

NONE 

ALL OTHER SYSTEMS 

•MULTIPLE ORGANS 

FIBROUS HISTIOCYTOMA, MALIGNANT 

(10) 

1 (10%) 

(49) (50) 

ANIMAL DISPOSITION SUMMARY 

ANIMALS INITIALLY IN STUDY 

NATURAL DEATH* 

MORIBUND SACRIFICE 

SCHEDULED SACRIFICE 

ACCIDENTALLY KILLED 

TERMINAL SACRIFICE 

ANIMAL MISSING 

10 

2 

3 

5 

50 

1 

12 

37 

50 

4 

6 

40 

9 INCLUDES AUTOLYZED ANIMALS 

* NUMBER

• NUMBER

 OF

 OF

 ANIMALS

 ANIMALS

 WITH TISSUE

 NECROPSIED 

 EXAMINED MICROSCOPICALLY 

53
 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED)

 

CONTROL LOW DOSE HIGH DOSE 

TUMOR SUMMARY 

TOTAL ANIMALS WITH PRIMARY TUMORS* 8 37 33 

TOTAL PRIMARY TUMORS 12 66 45 

TOTAL ANIMALS WITH BENIGN TUMORS 6 34 31 

TOTAL BENIGN TUMORS 7 51 40 

TOTAL ANIMALS WITH MALIGNANT TUMORS 5 13 4

 

TOTAL MALIGNANT TUMORS 5 14 4

 

TOTAL ANIMALS WITH SECONDARY TUMORS* 1

 

TOTAL SECONDARY TUMORS 2

 

TOTAL ANIMALS WITH TUMORS UNCERTAINBENIGN OR MALIGNANT 1 1 

TOTAL UNCERTAIN TUMORS 1 1 

TOTAL ANIMALS WITH TUMORS UNCERTAIN-

PRIMARY OR METASTATIC 

TOTAL UNCERTAIN TUMORS 

* PRIMARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 

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

54
 
APPENDIX B
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN
 

MICE FED ENDRIN IN THE DIET
 

55
 
56

 
TABLE B1. 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE 

MICE FED ENDRIN IN THE DIET

 

CONTROL LOW DOSE HIGH DOSE 

ANIMALS INITIALLY IN STODY 10 50 50 

ANIMALS NECROPSIED 10 4 2 49 

ANIMALS EXAMINED HISTOPATHOLOGICALLY 10 42 49 

INTEGUMENTARY SYSTEM 

NONE 

RESPIRATORY SYSTEM 

«LUNG (10) (40) (44) 

ALVEOLAR/BRONCHIOLAR ADENOMA 1 (3%) 5 (11%) 

HEMATOPOIETIC SYSTEM 

NONE 

CIRCULATORY SYSTEM 

NONE 

DIGESTIVE SYSTEM 

tLIVER (10) (38) (45) 

NEOPLASTIC NODULE 2 (5%) 3 (7*) 

HEPATOCELLULAR CARCINOMA 1 (10%) 1 (3%) 7 (16%) 

HEMANGIOMA 1 (2%) 

«STOMACH (10) (30) (44) 

ADENOMATOUS POLYP, NOS 1 (2%) 

URINARY SYSTEM 

NONE 

ENDOCRINE SYSTEM 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

• NUMBER OF ANIMALS NECROPSIED 

57 
TABLE B1. MALE MICE: NEOPLASMS (CONTINUED)

 

CONTROL LOW DOSE HIGH DOSE 

REPRODUCTIVE SYSTEM 

NONE 

NERVOUS SYSTEM 

NONE 

SPECIAL SENSE ORGANS 

NONE 

MUSCULOSKELETAL SYSTEM 

NONE 

BODY CAVITIES 

NONE 

ALL OTHER SYSTEMS 

NONE 

ANIMAL DISPOSITION SUMMARY 

ANIMALS INITIALLY IN STUDY 10 50 50 

NATURAL DEATHS 22 10 

MORIBUND SACRIFICE 5 8 

SCHEDULED SACRIFICE 

ACCIDENTALLY KILLED 

TERMINAL SACRIFICE 10 23 32 

ANIMAL MISSING 

d INCLUDES AUTOLYZED ANIMALS 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

• NUMBER OF ANIMALS NECROPSIED 

58 
TABLE B1. MALE MICE: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE
 

TUMOR SUMMARY
 

TOTAL ANIMALS WITH PRIMARY TUMORS* 1 3 1H
 

TOTAL PRIMARY TUMORS 1 4 17
 

TOTAL ANIMALS WITH BENIGN TUMORS 1 6
 

TOTAL BENIGN TUMORS 1 7
 

TOTAL ANIMALS WITH MALIGNANT TUMORS 1 1 7
 

TOTAL MALIGNANT TUMORS 1 1 7
 

TOTAL ANIMALS WITH SECONDARY TUMORS*
 

TOTAL SECONDARY TUMORS
 

TOTAL ANIMALS WITH TUMORS UNCERTAIN-
 BENIGN OR MALIGNANT 2 3
 

TOTAL UNCERTAIN TUMORS 2 3
 

TOTAL ANIMALS WITH TUMORS UNCERTAIN-


PRIMARY OR METASTATIC
 

TOTAL UNCERTAIN TUMORS
 

* PRIMARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 

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

59
 
TABLE B2. 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE 

MICE FED ENDRIN IN THE DIET 

CONTROL LOW DOSE HIGH DOSE 

ANIMALS INITIALLY IN STUDY

ANIMALS NECROPSIED

ANIflALS EXAMINED HISTOPATHOLOGICALLY

 10

 10

 10

 50

 5 0

 50

 50 

 48 

 4 8 

INTEGUMENTARY SYSTEM 

NONE 

PESPIRATORY SYSTEM 

#LUNG

ALVEOLAR/BRONCHIOLAR ADENOMA

ALVEOLAP/BRONCHIOLAR CARCINOMA

 (10) (49)

 1 (2%)

 1 (2%) 

 (48) 

 1 (2%) 

HEMATOPOIETIC SYSTEM 

•MULTIPLE ORGANS

MALIG.LYMPHOMA,

MALIG.LYMPHOMA,

 LYMPHOCYTIC TYPE

 HISTIOCYTIC TYPE

 (10) (50)

 1 (2%)

 (48) 

 1 (2%) 

 1 (2%) 

CIRCULATORY SYSTEM 

NONE 

DIGESTIVE SYSTEM 

#LIVER

NEOPLASTIC NODULE

HEPATOCELLULAR CARCINOMA

 (10)

 2 (20%)

 (50)

 2 (4%)

 1 (2%) 

 (47) 

 1 (2%) 

URINARY SYSTEM 

NONE 

ENDOCRINE SYSTEM 

___NQNE 

# NUMBER

• NUMBER

 OF

 OF

 ANIMALS

 ANIMALS

 WITH TISSUE

 NECROPSIED 

 EXAMINED MICROSCOPICALLY 

60 
9

TABLE B2. FEMALE MICE: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE 

REPRODUCTIVE SYSTEM 

tUTERUS (10) (48) 

SARCOMA, NOS 

#OVARY ( 9) (45) 

CYSTADENOMA, NOS 

NERVOUS SYSTEM 

•CHOROID	 PLEXUS (10) (50) 

EPENDYMOMA 

SPECIAL SENSE ORGANS 

NONE 

MUSCULOSKELETAL SYSTEM 

•SKELETAL	 MUSCLE (10) (50) 

SARCOMA, NOS 

BODY CAVITIES
 

NONE
 

ALL OTHER SYSTEMS 

NONE 

ANIMAL DISPOSITION SUMMARY 

ANIMALS INITIALLY IN STUDY 10 50 

NATURAL DEATHS 2 

MORIBUND SACRIFICE 1 4 

SCHEDULED SACRIFICE 

ACCIDENTALLY KILLBD 

TERMINAL SACRIFICE 9 44 

ANIMAL MISSING 

 INCLUDES AUTOLYZBD ANIMALS 

• HOHBEH OF ANIHALS BIT TISSOE EXAHIHED HICROSCOPICALLT 

* WJHBER OF ANIMALS MECROPSIBD 

HIGH DOSE 

(43) 

1 (2%) 

(46) 

1 (2%) 

(48) 

1 (2%) 

(48) 

1 (2%) 

50
 

3
 

11
 

36 

61
 
TABLE B2. FEMALE MICE: NEOPLASMS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE
 

TUMOR SUMMARY
 

TOTAL ANIMALS WITH PRIMARY TUMORS* 2 5 8
 

TOTAL PRIMARY TUMCRS 2 6 8
 

TOTAL ANIMALS WITH BENIGN TUMORS 1 2
 

TOTAL BENIGN TUMORS 1 2
 

TOTAL ANIMALS WITH MALIGNANT TUMORS 2 3 5
 

TOTAL MALIGNANT TUMORS 2 3 5
 

TOTAL ANIMALS WITH SECONDARY TUMORS#
 

TOTAL SECONDARY TUMORS
 

TOTAL ANIMALS WITH TUMORS UNCERTAIN-
 BENIGN OR MALIGNANT 2 1
 

TOTAL UNCERTAIN TUMORS 2 1
 

TOTAL ANIMALS WITH TUMORS UNCERTAIN-
 PRIMARY OR METASTATIC
 

TOTAL UNCERTAIN TUBORS
 

* PRIMARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 

# SECONDARY TUMORS: METASTATIC TUMORS OR TUTORS IMVASIVE INTO AN ADJACENT ORGAN
 

62
 
APPENDIX C
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN RATS FED ENDRIN IN THE DIET
 

63
 
64

 
TABLE CI. 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS 

IN MALE RATS FED ENDRIN IN THE DIET 

HIGH DOSE 

50 

47 

47 

(47) 

1 {2%) 

(47) 

(47) 

(45) 

1 {2%) 

(47) 

(47) 

(47) 

(47) 

ANIMALS INITIALLY IN STUDY 

ANIMALS NECROPSIED 

ANIMALS EXAMINED HISTOPATHOLOGICALLY 

INTEGUMENTARY SYSTEM 

•SUBCUT TISSUE 

ABSCESS, NOS 

RESPIRATORY SYSTEM 

#LUNG 

HEMORRHAGE 

#LUNG/ALVEOLI 

EMPHYSEMA, NOS 

HEMATOPOIETIC SYSTEM 

•SPLEEN 

HEMOSIDEROSIS 

HYPERPLASIA, RETICULUM CELL 

CIRCULATORY SYSTEM 

#HEART 

FIBROSIS 

NECFOSIS, NOS 

CALCIFICATION, DYSTROPHIC 

#MYOCARDIUM 

INFLAMMATION, INTERSTITIAL 

•ARTERY 

MEDIAL CALCIFICATION 

•AORTA 

_ MEDIAL_CALCIFICATION _ 

CONTROL 

10 

10 

10 

.(10) 

(10) 

(10) 

(10) 

(10) 

(10) 

(10) 

(10) 

LOW DOSE 

50 

46 

46 

(46) 

(45) 

1 (2%) 

(45) 

2 (4%) 

(46) 

1 (2%) 

(45) 

1 (2%) 

1 (2%) 

1 (2%) 

(45) 

1 (2%) 

(46) 

1 (256) 

(46) 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

• NUMBER OF ANIMALS NECROPSISD 

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

 

CONTROL LOW DOSE
 

DIGESTIVE SYSTEM
 

•LIVER	 (10) (46)
 

INFLAMMATION, NOS 1 (2%)
 

CIRRHOSIS, NOS 1 (10%)
 

PARASITISM 1 (2%)
 

DEGENERATION, BALLOONING 1 (2%)
 

METAMORPHOSIS FATTY 1 (10X) 7 (15%)
 

FOCAL CELLULAR CHANGE
 

•BILE DUCT	 (10) (46)
 

DISTENTION 1 (2%)
 

INFLAMMATION, CHRONIC
 

HYPERPLASIA, NOS	 3 (7%)
 

•PANCREAS	 (10) (45)
 

PERIARTERITIS 1 (10%) 2 (4%)
 

• PANCREATIC ACINUS <10) (»5)
 

ATROPHY, NOS 1 (2%)
 

•STOMACH	 (10) (<*4)
 

ULCER, NOS
 

CALCIFICATION, DYSTROPHIC 1 (2%)
 

•GASTRIC MUCOSA	 (10) (44)
 

EROSION
 

CALCIFICATION, DYSTROPHIC 1 (2%)
 

•CECUM	 (4) (16)
 

INFLAMMATION, ACUTE 1 (6%)
 

URINARY SYSTEM
 

•KIDNEY	 (10) (46)
 

PYELONEPHRITIS SUPPURATIVE
 

PYELONGPHRITIS, ACUTE/CHRONIC
 

INFLAMMATION, CHRONIC 4 (4 0%) 23 (50%)
 

•URINARY BLADDER	 (8) (42)
 

INFLAMMATION, NOS 1 (2%)
 

INFLAMMATION ACUTE AND CHRONIC
 

HYPERPLASIA. EPITHELIAL 1 (2%)
 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

• NUMBER OF ANIMALS NECROPSIED
 

HIGH DOSE
 

(47)
 

1 (2%)
 

(47)
 

2 (4%)
 

(47)
 

(47)
 

(46)
 

1 (2%)
 

(46)
 

3 (7%)
 

(21)
 

(47)
 

1 (2%)
 

1 (2%)
 

22 (47%)
 

(41)
 

1 (2%)
 

1 (2%)
 

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

CONTROL LOW DOSE HIGH DOSE 

#U. BLADDER/MOCOSA (8) (42) (41)

 

HYPERPLASIA, PAPILLARY 1 (2%)

 

METAPLASIA, SQUAMOUS 1 (2%) 

ENDOCRINE SYSTEM 

•PITUITARY (10) (43) (41) 

CYST, NOS 5 (12%) 

DEGENERATION, CYSTIC 2 (5%) 

NECROSIS, HEMORRHAGIC 1 (2%) 

HYPERPLASIA, CHROMOPHOBE-CELL 2 (5%) 

#ADRENAL (9) (46) (44) 

DEGENERATION, CYSTIC 1 (2%) 

FOCAL CELLULAR CHANGE 1 (2%) 

•ADRENAL CORTEX (9 ) (46) (44) 

METAMORPHOSIS FATTY 3 (7%) 

•THYROID (9) (42) (43) 

CYSTIC FOLLICLES 1 (11%) 

FOLLICULAR CYST, NOS 1 (2%) 

ATROPHY, NOS 1 (2%) 

HYPERPLASIA, FOLLICULAR-CELL 1 (2%) 5 (12%) 

•PARATHYROID (8) (23) (26)

 

HYPERPLASIA, NOS 2 (9%)

 

REPRODUCTIVE SYSTEM 

•PROSTATE (10) (40) (44) 

INFLAMMATION, NOS 1 (3%) 

INFLAMMATION, ACUTE SUPPURATIVE 1 (2%) 

INFLAMMATION, CHRONIC 1 (3%) 

*SEMINAL VESICLE (10) (46) (47) 

ABSCESS, NOS 1 (2%) 

•TESTIS (10) (42) (45) 

PERIARTERITIS 2 (5%) 

ATROPHY, NOS 8 (19%) 14 (31%) 

NERVOUS STSTEM 

NONE 

• NUMBER OF AMIHALS WITH TISSUE EXAMINED MICROSCOPICALLY 

• NUMBER OF ANIMALS NECROPSIED 

67 
TABLE C1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED)
 

SPECIAL SENSE ORGANS
 

NONE
 

MUSCULOSKELETAL SYSTEM
 

NONE
 

BODY CAVITIES
 

•MESENTERY
 

PERIARTERITIS
 

ALL OTHER SYSTEMS
 

NONE
 

SPECIAL MORPHOLOGY SUMMARY
 

NO LESION REPORTED
 

AUTOLΥSIS/NO NECROPSY
 

# NUMBER OF ANIMALS WITH TISSUE

* NUMBER OF ANIMALS NECROPSIBD 

CONTROL LOW DOSE HIGH DOSE
 

(10)	 (46) (47)
 

1 (2%)
 

3	 4 3
 

4 3
 

 EXAMINED MICROSCOPICALLY 

68
 
TABLE C2.

 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN 

FEMALE RATS FED ENDRIN IN THE DIET 

CONTROL LOW DOSE HIGH DOSE 

ANIMALS INITIALLY IN STUDY 10 5 0 50 

ANIMALS NECROPSIED 10 49 50 

ANIMALS EXAMINED HISTOPATHOLOGICALLY 10 49 50 

INTEGUMENTARY SYSTEM 

•SKIN (10) (49) (50) 

ULCER, NOS 1 (2%) 

RESPIRATORY SYSTEM 

•LUNG/BRONCHUS (10) (49) (50) 

INFLAMMATION, ACUTE/CHRONIC 1 (2%) 

#LUNG (10) (49) (50) 

ATELECTASIS 1 (2%) 

INFLAMMATION, FOCAL 1 (2%) 

HEMATOPOIETIC SYSTEM 

#BONE MARROW (9) (49) (50) 

HYPERPLASIA, HEMATOPOIETIC 1 (11%) 

tSPLEEN (9) (48) (50) 

HEMORRHAGE 2 (4%) 

HEMATOPOIESIS 1 (11%) 

CIRCULATORY SYSTEM 

«MYOCARDIUM (9) (49) (50) 

INFLAMMATION, INTERSTITIAL 1 (2%) 

IENDOCARDIUM (9) (49) (50) 

INFLAMMATION, NOS 1 (2%) 

DIGESTIVE SYSTEM 

•LIVER (10) (49) (50) 

METAMORPHOSIS FATTY 1 2 (4%) 2 (4%) no%) 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

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

 

BASOPHILIC CYTO CHANGE 

CLEAR-CELL CHANGE 

•BILE DUCT 

HYPERPLASIA, NOS 

«STOMACH 

ULCER, NOS 

URINARY SYSTEM 

#KIDNEY 

INFLAMMATION, CHRONIC 

NEPHROSIS, TOXIC 

#U. BLADDER/MUCOSA 

ULCER, NOS 

ENDOCRINE SYSTEM 

•ADRENAL 

NECROSIS, HEMORRHAGIC 

METAMORPHOSIS FATTY 

ANGIECTASIS 

•ADRENAL CORTEX 

METAMORPHOSIS FATTY 

ATROPHY, NOS 

ANGIECTASIS 

•THYROID 

CYSTIC FOLLICLES 

FOLLICULAR CYST, NOS 

HYPERPLASIA, C-CELL

 

REPRODUCTIVE SYSTEM 

•CERVIX UTERI 

HYPERPLASIA, STROMAL 

•UTERUS/ENDOMETRIUM 

HYPERPLASIA, CYSTIC 

# NUMBER OF ANIMALS WITH TISSUE

* NUMBER OF ANIMALS NECROPSIED 

CONTROL LOW DOSE 

2 (4%) 

(10) (49) 

2 (20%) 1 (2%) 

(9) (49) 

1 (2%) 

(10) (49) 

3 (6%) 

1 (2%) 

(8) (47) 

(9) 

1 (2%) 

3 (6%) 

3 (6*) 

(9) (49) 

1 (11%) 

(8) (46) 

1 (2%) 

1 (2%) 

7 (15%) 

(8) (48) 

(8) (48) 

 EXAMINED MICROSCOPICALLY 

70 

HIGH DOSE 

1 (2%) 

3 (6%) 

(50) 

5 (10%) 

(50) 

(49 ) 

5 (10%) 

(43) 

1 (2%) 

(47) 

4 (9%) 

(47) 

2 (4%) 

1 (2X) 

1 (2X) 

(4 9) 

1 (2X) 

9 (18X) 

(45) 

1 (2%) 

(45) 

1 (2%) 
TABLE C2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

CONTROL LOW DOSE HIGH DOSE 

#OVARY 

FOLLICULAR CYST, NOS 

(10) (47) 

1 (2%) 

(4 7) 

NERVOUS

NONE 

 SYSTEM 

SPECIAL

NONE 

 SENSE ORGANS 

MUSCULOSKELETAL

NONE 

 SYSTEM 

BODY CAVITIES 

NONE 

ALL OTHER

NONE 

 SYSTEMS 

SPECIAL MORPHOLOGY SUMMARY 

NO LESION REPORTED 

AUTO/NECROPSY/HISTO PERF 

AUTOLYSIS/NO NECROPSY 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED

• NUMBER OF ANIMALS NECROPSIED 

1 

 MICROSCOPICALLY 

1 

8 

1 

71
 
72

 
APPENDIX D
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC
 

LESIONS IN MICE FED ENDRIN IN THE DIET
 

73
 
74

 
TABLE D1. 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN 

MALE MICE FED ENDRIN IN THE DIET 

CONTROL LOW DOSE HIGH DOSE 

ANIMALS INITIALLY IN STUDY 10 50 50 

ANIMALS NECROPSIED 10 42 49 

ANIMALS EXAMINED HISTOPATHOLOGICALLY 10 42 49 

INTEGUMENTARY SYSTEM 

NONE 

RESPIRATORY SYSTEM 

NONE 

HEMATOPOIETIC SYSTEM 

NONE 

CIRCULATORY SYSTEM 

NONE 

DIGESTIVE SYSTEM 

#LIV2R (10) (38) (45) 

INFLAMMATION, FOCAL 1 (10%) 

NECROSIS, FOCAL 1 (3%) 1 (2%) 

URINARY SYSTEM 

NONE 

ENDOCRINE SYSTEM 

NONE 

REPRODUCTIVE SYSTEM 

NONE 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

75
 
TABLE D^MALE MICE: NONNEOPLASTIC LESIONS (CONTINUED)

 

CONTROL LOW DOSE HIGHDO6E
 

NERVOUS SYSTEM
 

NONE
 

SPECIAL SENSE ORGANS
 

NONE
 

MUSCULOSKELETAL SYSTEM
 

NONE
 

BODY CAVITIES
 

•MESENTERY	 (10) (42)
 

EPIDERMAL INCLUSION CYST 1 (2%)
 

ALL OTHER SYSTEMS
 

NONE
 

SPECIAL MORPHOLOGY SUMMARY
 

NO LESION REPORTED 8 34 32
 

AUTO/NECROPSY/HISTO PERP 4 1
 

AUTOLYSIS/NO NECROPSY 8 1
 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

• NUMBER OF ANIMALS NECF OPS IE D
 

76
 
TABLE 02.
 

SUMMARY OF THE INCIDENCE OF NONNOEPLASTIC LESIONS IN
 

FEMALE MICE FED ENDRIN IN THE DIET
 

CONTROL LOW DOSE 

ANIMALS INITIALLY IN STUDY 10 50 

ANIMALS NECROPSIED 10 50 

ANIMALS EXAMINED HISTOPATHOLOGICALLY 10 50 

INTEGUMENTARY SYSTEM 

NONE 

RESPIRATORY SYSTEM 

NΟΝΕ 

HEMATOPOIETIC SYSTEM 

•SPLEEN	 (10) (49) 

CONGESTION, NOS 1 (10%) 

IBFLA ΙΜΑΤΙΟ* , CHRONIC FOCAL 

HYPERPLASIA, RETICULUM CELL 1 (2%) 

HYPERPLASIA, LYHPHOID 1 (10%) 1 (2%) 

•LYMPH	 «ODE (9) (48)
 

HYPERPLASIA, NOS
 

CIRCULATORY SYSTEM 

NOME 

DIGESTIVE SYSTEM 

•LITER	 (10) (50)
 

INFLAMMATION, ACUTE 1 (10*)
 

ABSCESS, «OS
 

•BILE	 DOCT (10) (50) 

INFLABHlrtON VOS 1 (2%) 

• SOMBER OF ANIMALS ΪΙΤ TISSUE EXAMINED MICROSCOPICALLY
 

•	 NUMBER OF ANIMALS «ECROPSISD
 

HIGH DOSE 

50 

48 

48 

(47) 

1	 (2%) 

(42) 

1 (2%) 

(47) 

1 (2%) 

(4 8) 

77
 
TABLE D2. FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED)

 

HIGH DOSE
 

(45)
 

1 (2%)
 

{48)
 

1 (2%)
 

1 (2%)
 

(48)
 

1 (2%)
 

(43)
 

6 (14%)
 

(46)
 

2 (4%)
 

2 (4%)
 

4 (9%)
 

#PANCREAS
 

DILATATION/DUCTS
 

URINARY SYSTEM
 

#KIDNEY
 

HYDRONEPHROSIS
 

DEGENERATION, CYSTIC
 

#KIDNEY/CORTEX
 

ATROPHY, NOS
 

ENDOCRINE SYSTEM
 

NONE
 

REPRODUCTIVE SYSTEM
 

#UTERUS/ENDOMETRIUM
 

HYPERPLASIA, CYSTIC
 

#OVARY
 

CYST, NOS
 

FOLLICULAR CYST, NOS
 

INFLAMMATION, NOS
 

INFLAMMATION, SUPPURATIVE
 

NERVOUS SYSTEM
 

NONE
 

SPECIAL SENSE ORGANS
 

NONE
 

MUSCULOSKELETAL SYSTEM
 

NONE
 

BODY CAVITIES
 

NONE
 

CONTROL
 

(10)
 

(10)
 

(10)
 

(10)
 

3 (30%)
 

(9)
 

1 (11%)
 

LOW DOSE
 

(46)
 

(50)
 

(50)
 

(48)
 

(45)
 

1 (2%)
 

2 (4%)
 

4 (9%)
 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

78
 
TABLE D2. FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

ALL OTHER SYSTEMS
 

•MULTIPLE ORGANS
 

BACTERIAL SEPTICEMIA
 

SPECIAL MORPHOLOGY SUMMARY
 

NO LESION PEFORTED
 

AUTC/NECROPSY/HISTO PERF
 

AUTOLYSIS/NO NECROPSY
 

# NUMBER OF ANIMALS WITH TISSUE


* NUMBER OF ANIMALS NECROPSIED
 

CONTROL
 

(10)
 

3
 

LOW DOSE
 

(50)
 

1 (2%)
 

35
 

1
 

 EXAMINED MICROSCOPICALLY
 

HIGH DOSE
 

(48)
 

25
 

2
 

79
 
80

 
APPENDIX E
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS
 

IN RATS FED ENDRIN IN THE DIET
 

81
 
82

 
Table E1. Analyses of the Incidence of Primary Tumors in Male Rats
 

Fed Endrin in the Diet (a) 

Topography: Morphology 

Pooled 

Control 

Matched 

Control 

Low 

Dose 

All Sites: Hemangioma (b) 0/49 (0) 0/10 (0) 5/46 (11) 

 Values (c,d) N.S. N.S. = 0.024** 

Relative Risk (Pooled Control) 

Lower Limit 

Upper Limit 

(f) Infinite 

1.345 

Infinite 

oo 

u> 

Relative Risk (Matched Control) 

Lower Limit 

Upper Limit 

(f) Infinite 

0.306 

Infinite 

Weeks to First Observed Tumor — — 91 

Pituitary: Adenoma, NOS (b) 6/42 (14) 4/10 (40) 8/43 (19) 

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

Relative Risk (Pooled Control) 

Lower Limit 

Upper Limit 

(f) 1.302 

0.435 

4.171 

Relative Risk (Matched Control) 

Lower Limit 

Upper Limit 

(f) 0.465 

0.176 

1.826 

Weeks to First Observed Tumor 91 87 

High
 

Dose
 

3/47 (6)
 

N.S.
 

Infinite
 

0.628
 

Infinite
 

Infinite
 

0.142
 

Infinite
 

114
 

12/41 (29)
 

N.S.
 

2.049
 

0.792
 

6.005
 

0.732
 

0.315
 

2.660
 

58 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats
 

Fed Endrin in the Diet (a)
 

(continued)
 

84
 

Topography: Morphology
 

Pituitary: Chromophobe
 

Adenoma (b)
 

 Values (c,d)
 

Departure from Linear Trend (e)
 

Relative Risk (Pooled Control) (f)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control) (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Pituitary: Chromophobe Adenoma
 

or Adenoma, NOS (b)
 

 Values (c,d)
 

Relative Risk (Pooled Control) (f)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control) (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Pooled
 

Control
 

10/42 (24)
 

 - 0.004 (Ν)
 

—
 

15/42 (36)
 

N.S.
 

—
 

Matched
 

Control
 

0/10 (0)
 

N.S.
 

 = 0.037
 

—
 

4/10 (40)
 

N.S.
 

91
 

Low
 

Dose
 

6/43 (14)
 

N.S.


0.586
 

0.192
 

1.612
 

Infinite
 

0.416
 

Infinite
 

111
 

14/43 (33)
 

N.S.
 

0.912
 

0.470
 

1.761
 

0.814
 

0.362
 

2.899
 

87
 

High
 

Dose
 

1/41 (2)
 

Ρ = 0.004** (N)
 

0.102
 

0.002
 

0.669
 

Infinite
 

0.014
 

Infinite
 

93
 

13/41 (32)
 

N.S.
 

0.888
 

0.448
 

1.736
 

0.793
 

0.347
 

2.844
 

58
 
85
 

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

Fed Endrin in the Diet (a)
 

(continued)
 

Topography: Morphology 

Pooled 

Control 

Hatched 

Control 

Low 

Dose 

High 

Dose 

Adrenal: Adenoma, NOS (b) 2/44 (5) 2/9 (22) 2/46 (4) 8/44 (18) 

 Values (c,d) « 0.020 N.S. N.S. - 0.045** 

Departure from Linear Trend (e) - 0.038 

Relative Risk (Pooled Control) 

Lower Limit 

Upper Limit 

(f) 0.957 

0.072 

12.702 

4.000 

0.858 

36.904 

Relative Risk (Matched Control) 

Lower Limit 

Upper Limit 

(f) 0.196 

0.018 

2.519 

0.818 

0.219 

7.302 

Weeks to First Observed Tumor — 110 95 108 

Adrenal: Adenoma or 

Carcinoma, NOS (b) 2/44 (5) 2/9 (22) 4/46 (9) 8/44 (18) 

 Values (c,d) ­ 0.028 N.S. N.S. - 0.045** 

Relative Risk (Pooled Control) 

Lower Limit 

Upper Limit 

(f) 1.913 

0.290 

20.310 

4.000 

0.858 

36.904 

Relative Risk (Matched Control) 

Lower Limit 

Upper Limit 

(f) 0.391 

0.073 

4.022 

0.818 

0.219 

7.302 

Weeks to First Observed Tumor 110 95 108 
Table El· Analyses of the Incidence of Primary Tumors in Male Rats
 

Fed Endrin in the Diet (a)
 

(continued)
 

Topography: Morphology
 

Thyroid: Follicular-cell
 

Adenoma or Carcinoma (b)
 

 Values (c,d)
 

Relative Risk (Pooled Control) (f)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control) (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Thyroid: C-cell Adenoma (b)
 

 Values (c,d)
 

Relative Risk (Pooled Control) (f)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control) (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Pooled
 

Control
 

2/46 (4)
 

N.S.
 

—
 

1/46 (2)
 

N.S.
 

—
 

Matched
 

Control
 

1/9 (11).
 

N.S.
 

110
 

0/9 (0)
 

N.S.
 

Low
 

Dose
 

3/42 (7)
 

N.S.
 

1.643
 

0.198
 

18.855
 

0.643
 

0.064
 

32.958
 

95
 

1/42 (2)
 

N.S.
 

1.095
 

0.014
 

83.964
 

Infinite
 

0.013
 

Infinite
 

111
 

High
 

Dose
 

1/43 (2)
 

N.S.
 

0.535
 

0.009
 

9.888
 

0.209
 

0.003
 

16.081
 

100
 

2/43 (5)
 

N.S.
 

2.140
 

0.116
 

123.245
 

Infinite
 

0.069
 

Infinite
 

112
 

86
 
Table El· Analyses of the Incidence of Primary Tumors in Male Rats
 

(continued) 

Topography: Morphology 

Fed Endrin in the Diet (a) 

Pooled 

Control 

Matched 

Control 

Low 

Dose 

Pancreatic Islets:

Carcinoma (b) 

 Islet-cell 

0/46 (0) 0/10 (0) 0/45 (0) 

 Values (c,d) * 0.039 N.S. — 

Relative Risk (Pooled Control) (f) 

Lower Limit 

Upper Limit 

~ 

— 

oo 

Relative Risk (Matched Control) (f) 

Lower Limit 

Upper Limit 

__ 

— 

— 

Weeks to First Observed Tumor — — 

Pancreatic Islets: Islet-cell 

Adenoma or Carcinoma (b) 1/46 (2) 0/10 (0) 1/45 (2) 

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

Relative Risk (Pooled Control) (f) 

Lower Limit 

Upper Limit 

1.022 

0.013 

78.492 

Relative Risk (Matched Control) (f) 

Lower Limit 

Upper Limit 

Infinite 

0.013 

Infinite 

Weeks to First Observed Tumor 111 

High
 

Dose
 

3/47 (6)
 

N.S.
 

Infinite
 

0.590
 

Infinite
 

Infinite
 

0.142
 

Infinite
 

100
 

4/47 (9)
 

N.S.
 

3.915
 

0.407
 

188.455
 

Infinite
 

0.220
 

Infinite
 

100
 
88
 

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

Fed Endrin in the Diet (a)
 

(continued)
 

(a) Dosed groups received time-weighted average doses of 2.5 or 5 ppm.
 

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

(c) Beneath the incidence of tumors in a control group is the probability level for the Cochran-
 Armitage test when Ρ 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 (*) or with the pooled­ control group (**) when Ρ less than 0.05 for either control group; otherwise, not significant
 

(N.S.) is indicated.
 

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

group.
 

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

comparison.
 

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

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

Fed Endrin in the Diet (a)
 

Topography: Morphology
 

Kidney: Hamartoma (b)
 

 Values (c,d)
 

Relative Risk (Pooled Control) (f)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control) (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Pituitary: Adenoma, NOS (b)
 

 Values (c,d)
 

Relative Risk (Pooled Control) (f)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control) (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Pooled
 

Control
 

1/47 (2)
 

N.S.
 

«...
 

4/44 (9)
 

 - 0.015
 

—
 

Matched
 

Control
 

1/10 (10)
 

N.S.
 

110
 

2/7 (29)
 

N.S.
 

110
 

Low
 

Dose
 

3/49 (6)
 

N.S.
 

2.878
 

0.241
 

147.907
 

0.612
 

0.059
 

31.507
 

111
 

11/47 (23)
 

N.S.
 

2.574
 

0.833
 

10.320
 

0.819
 

0.264
 

6.928
 

83
 

High
 

Dose
 

2/49 (4)
 

N.S.
 

1.918
 

0.103
 

110.851
 

0.408
 

0.025
 

23.619
 

114
 

13/45 (29)
 

 « 0.016**
 

3.178
 

1.078
 

12.369
 

1.011
 

0.338
 

8.364
 

89
 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Fed Endrin in the Diet (a)
 

(continued)
 

Topography: Morphology
 

Pituitary: Adenoma or
 

Carcinoma, NOS (b)
 

 Values (c,d)
 

Relative Risk (Pooled Control) (f)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control) (f)
 

Lower Limit
 

Upper Limit
 

VO
 

ο
 Weeks to First Observed Tumor
 

Pituitary: Chromophobe
 

Adenoma (B)
 

 Values (c,d)
 

Relative Risk (Pooled Control) (f)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control) (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 —
 

Pooled
 

Control
 

7/44 (16)
 

N.S.
 

—
 

6/44 (14)
 

N.S.
 

—
 

Low
 

Dose
 

12/47 (26)
 

N.S.
 

1.605
 

0.645
 

4.376
 

0.894
 

0.294
 

7.479
 

83
 

9/47 (19)
 

N.S.
 

1.404
 

0.489
 

4.414
 

Infinite
 

0.464
 

Infinite
 

89
 

High
 

Dose
 

13/45 (29)
 

N.S.
 

1.816
 

0.749
 

4.858
 

1.011
 

0.338
 

8.364
 

89
 

7/45 (16)
 

N.S.
 

1.141
 

0.357
 

3.789
 

Infinite
 

0.358
 

Infinite
 

99
 

Matched
 

Control
 

2/7 (29)
 

N.S.
 

110
 

0/7 (0)
 

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

Fed Endrin in the Diet (a)
 

(continued)
 

Topography: Morphology
 

Pituitary: Chromophobe Adenoma,
 

Adenoma, NOS, Carcinoma, NOS, or
 

Adenocarcinoma, NOS (b)
 

 Values (c,d)
 

Relative Risk (Pooled Control) (f)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control) (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Adrenal: Carcinoma, NOS (b)
 

 Values (c,d)
 

Relative Risk (Pooled Control) (f)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control) (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Pooled
 

Control
 

13/44 (30)
 

N.S.
 

—
 

2/46 (4)
 

N.S.
 

—
 

Matched
 

Control
 

2/7 (29)
 

N.S.
 

110
 

1/9 (11)
 

N.S.
 

110
 

Low
 

Dose
 

21/47 (45)
 

N.S.
 

1.512
 

0.833
 

2.843
 

1.564
 

0.565
 

12.338
 

83
 

7/49 (14)
 

N.S.
 

3.286
 

0.668
 

31.129
 

1.286
 

0.211
 

56.687
 

106
 

High
 

Dose
 

20/45 (44)
 

N.S.
 

1.504
 

0.821
 

2.838
 

1.556
 

0.559
 

12.286
 

3/47 (6)
 

N.S.
 

1.468
 

0.176
 

16.917
 

0.574
 

0.057
 

29.541
 

89 

114 
Table Ε2· Analyses of the Incidence of Primary Tumors in Female Rats
 

Fed Endrin in the Diet (a)
 

(continued)
 

Topography: Morphology 

Pooled 

Control 

Matched 

Control 

Low 

Dose 

Adrenal: Adenoma or 

Carcinoma, NOS (b) 4/46 (9) 3/9 (33) 16/49 (33) 

 Values (c,d) N.S. - 0.041 (Ν) Ρ » 0.004** 

Departure from Linear Trend (e) « 0.0&3 

Relative Risk (Pooled Control) 

Lower Limit 

Upper Limit 

(f) 3.755 

1.330 

14.298 

Relative Risk (Matched Control) 

Lower Limit 

Upper Limit 

(f) 0.980 

0.396 

4.617 

Weeks to First Observed Tumor — 110 67 

Thyroid: C-cell Adenoma (b) 1/45 (2) 0/8 (0) 4/46 (9) 

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

Relative Risk (Pooled Control) 

Lower Limit 

Upper Limit 

(f) 3.913 

0.408 

188.275 

Relative Risk (Matched Control) 

Lower Limit 

Upper Limit 

(f) Infinite 

0.186 

Infinite 

Weeks to First Observed Tumor 111 

High
 

Dose
 

7/47 (15)
 

N.S.
 

1.713
 

0.469
 

7.483
 

0.447
 

0.143
 

2.384
 

114
 

3/49 (6)
 

N.S.
 

2.755
 

0.231
 

141.569
 

Infinite
 

0.113
 

Infinite
 

114
 

92
 
__ 

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

93
 

(continued)
 

Topography: Morphology
 

Mammary Gland: Fibroma (b)
 

 Values (c, d)
 

Relative Risk (Pooled Control) (f)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control) (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Mammary Gland: Fibroadenoma (b)
 

 Values (c,d)
 

Relative Risk (Pooled Control) (f)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Mached Control) (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Fed Endrin in the Diet (a)
 

Pooled Matched 

Control Control 

1/48 (2) 0/10 (0) 

N.S. N.S. 

— —
 

6/48 (13) 1/10 (10)
 

N.S. N.S.
 

100
 

Low
 

Dose
 

3/49 (6)
 

N.S.
 

2.939
 

0.246
 

151.057
 

Infinite
 

0.136
 

Infinite
 

70
 

3/49 (6)
 

N.S.
 

0.490
 

0.083
 

2.152
 

0.612
 

0.059
 

31.507
 

106
 

High
 

Dose
 

0/50 (0)
 

N.S.
 

0.000
 

0.000
 

17.913
 

—
 

—
 

—
 

2/50 (4)
 

N.S.
 

0.320
 

0.033
 

1.687
 

0.400
 

0.025
 

23.156
 

109 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Fed Endrin in the Diet (a)
 

(continued)
 

Topography: Morphology 

Pooled 

Control 

Matched 

Control 

Low 

Dose 

High 

Dose 

Uterus: Endometrial Stromal 

Polyp (b) 5/42 (12) 1/8 (13) 5/48 (10) 2/45 (4) 

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

Relative Risk (Pooled Control) (f) 

Lower Limit 

Upper Limit 

0.875 

0.217 

3.551 

0.373 

0.037 

2.142 

Relative Risk (Matched Control) (f) 

Lower Limit 

Upper Limit 

0.833 

0.122 

38.589 

0.356 

0.023 

20.543 

Weeks to First Observed Tumor — 110 67 47 

(a) Dosed groups received time-weighted average doses of 3 or 6 ppm.
 

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

(c) Beneath the incidence of tumors in a control group is the probability level for the Cochran-
 Armitage test when Ρ 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 (*) or with the pooled­ control group (**) when Ρ less than 0.05 for either control group; otherwise, not significant
 

(N.S.) is indicated.
 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Fed Endrin in the Diet (a)
 

(continued)
 

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

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

comparison.
 

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

control group.
 

vo
 
96

 
APPENDIX F
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS
 

IN MICE FED ENDRIN IN THE DIET
 

97
 
98

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

Fed Endrin in the Diet (a)
 

Topography: Morphology
 

Lung: Alveolar/Bronchiolar
 

Adenoma (b)
 

 Values (c,d)
 

Relative Risk (Pooled Control) (f)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control) (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Liver: Neoplastic Nodule (b)
 

 Values (c,d)
 

Relative Risk (Pooled Control) (f)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control) (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Pooled
 

Control
 

4/58 (7)
 

N.S.
 

—
 

1/58 (2)
 

N.S.
 

—
 

Matched
 

Control
 

0/10 (0)
 

N.S.
 

—
 

0/10 (0)
 

N.S.
 

—
 

Low
 

Dose
 

1/40 (3)
 

N.S.
 

0.362
 

0.007
 

3.472
 

Infinite
 

0.015
 

Infinite
 

90
 

2/38 (5)
 

N.S.
 

3.053
 

0.164
 

175.234
 

Infinite
 

0.086
 

Infinite
 

90
 

High
 

Dose
 

5/44 (11)
 

N.S.
 

1.648
 

0.357
 

7.817
 

Infinite
 

0.320
 

Infinite
 

87
 

3/45 (7)
 

N.S.
 

3.867
 

0.323
 

198.299
 

Infinite
 

0.149
 

Infinite
 

91
 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice
 

Fed Endrin in the Diet (a)
 

(continued)
 

Topography: Morphology
 

Liver: Hepatocellular
 

Carcinoma (b)
 

 Values (c,d)
 

Departure from Linear Trend (e)
 

Relative Risk (Pooled Control) (f)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control) (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Liver: Neoplastic Nodule or
 

Hepatocellular Carcinoma (b)
 

 Values (c,d)
 

Relative Risk (Pooled Control) (f)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control) (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 —
 90
 

Low
 

Dose
 

1/38 (3)
 

 - 0.009(N)**
 

0.127
 

0.003
 

0.800
 

0.263
 

0.004
 

20.149
 

90
 

3/38 (8)
 

N.S.
 

0.352
 

0.068
 

1.173
 

0.789
 

0.077
 

40.346
 

90
 

High
 

Dose
 

7/45 (16)
 

N.S.
 

0.752
 

0.272
 

1.887
 

1.556
 

0.249
 

68.402
 

82
 

10/45 (22)
 

N.S.
 

0.991
 

0.427
 

2.204
 

2.222
 

0.397
 

93.874
 

82
 

Pooled
 

Control
 

12/58 (21)
 

N.S.
 

 = 0.020
 

—
 

13/58 (22)
 

N.S.
 

Matched
 

Control
 

1/10 (10)
 

N.S.
 

90
 

1/10 (10)
 

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

Fed Endrin in the Diet (a)
 

(continued)
 

(a) Dosed groups received time-weighted average doses of 1.6 or 3.2 ppm.
 

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

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


Armitage test when Ρ 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 (*) or with the
 

pooled-control group (**) when Ρ less than 0.05 for either control group; otherwise, not
 

significant (N.S.) is indicated.
 

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

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

comparison.
 

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

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

Fed Endrin in the Diet (a)
 

ο
 

Topography: Morphology
 

Liver: Hepatocellular
 

Carcinoma (b)
 

 Values (c,d)
 

Departure from Linear Trend (e)
 

Relative Risk (Pooled Control) (f)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control) (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Liver: Neoplastic Nodule or
 

Hepatocellular Carcinoma (b)
 

 Values (c,d)
 

Relative Risk (Pooled Control) (f)
 

Lower Limit
 

Upper Limit
 

Relative Risk (Matched Control) (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Pooled
 

Control
 

2/59 (3)
 

N.S.
 

—
 

3/59 (5)
 

N.S.
 

Matched
 

Control
 

2/10 (20)
 

 = O.Oll(N)
 

 = 0.029
 

90
 

2/10 (20)
 

 = 0.047 (Ν)
 

90
 

Low
 

Dose
 

1/50 (2)
 

N.S.
 

0.590
 

0.010
 

10.973
 

0.100
 

0.002
 

1.810
 

90
 

3/50 (6)
 

N.S.
 

1.180
 

0.165
 

8.432
 

0.300
 

0.043
 

3.368
 

90
 

High
 

Pose
 

0/47 (0)
 

 - 0.028*(N)
 

0.000
 

0.000
 

4.239
 

0.000
 

0.000
 

0.708
 

—
 

1/47 (2)
 

N.S.
 

0.418
 

0.008
 

4.998
 

0.106
 

0.002
 

1.922
 

91
 
Table F2. Analyses of the Incidence of Primary Tumors in Female Mice
 

Fed Endrin in the Diet (a)
 

(continued)
 

(a) Dosed groups received time-weighted average doses of 2.5 or 5 ppm·
 

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

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


Armitage test when Ρ 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 (*) or with the pooledcontrol group (**) when Ρ less than 0.05 for either control group; otherwise, not significant
 

(N.S.) is indicated.
 

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

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

comparison.
 

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

control group.
 
104

 
APPENDIX G
 

ANALYSIS OF FORMULATED DIETS
 

FOR CONCENTRATIONS OF ENDRIN
 

105
 
106

 
APPENDIX G
 

Analysis of Formulated Diets for
 

Concentrations of Endrin
 

A 100-g sample of the formulated diet was shaken with 125 ml
 

hexane for 16 hours at room temperature· The extract was
 

filtered through Celite with hexane washes and reduced in volume
 

to 10 ml. After appropriate dilutions, the solution was analyzed
 

quantitatively for endrin by gas-liquid chromatography (electron
 

capture detector, 10% DC-200 on Gas Chrom Q)· Recoveries were 

determined from spiked samples, and external standards were used 

for calibrations· 

Theoretical No. of Sample Coefficient of Range (ppm) 

Concentrations Samples Analytical Variation (%) 

in Diet (ppm) Mean (ppm) 

1.25 13 1.29 3.6% 1.18-1.33 

2.50 22 2.53 2.9% 2.40-2.65 

5.00 21 5.04 3.6% 4.75-5.40 

10.00 3 10.0 0.6% 9.90-10.0 

107
 

Review of the Bioassay of Endrin* for Carcinogenicity
 

by the Data Evaluation/Risk Assessment Subgroup of the
 

Clearinghouse on Environmental Carcinogens
 

August 31, 1978
 

The Clearinghouse on Environmental Carcinogens was established in
 

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

Clearinghouse is to advise the Director of the National Cancer Institute
 

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

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

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

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

quasi-public health and research organizations. Members have been
 

selected on the basis of their experience in carcinogenesis or related
 

fields and, collectively, provide expertise in chemistry, biochemistry,
 

biostatistics, toxicology, pathology, and epidemiology. Representatives
 

of various Governmental agencies participate as ad hoc members. The
 

Data Evaluation/Risk Assessment Subgroup of the Clearinghouse is charged
 

with the responsibility of providing a peer review of reports prepared
 

on NCI-sponsored bioassays of chemicals studied for carcinogenicity. It
 

is in this context that the below critique is given on the bioassay of
 

Endrin for carcinogenicity.
 

The primary reviewer said that Endrin was not carcinogenic in rats
 

or mice, under the conditions of test. He added that the negative
 

findings could be a reflection of the high toxicity of Endrin, which
 

permitted the administration of relatively low chronic dosages. The
 

primary reviewer pointed out that an accidental overdose among low dose
 

male mice resulted in the early death of a number of animals in this
 

treatment group. He also indicated that the study was marred by the
 

small number of matched control animals. However, this deficiency was
 

compensated for by the use of pooled controls in the statistical analysis
 

of the study. The primary reviewer said that the study provided little
 

or no information on the potential risk to man of Endrin, particularly
 

since there is no information on how chloro-cyclic alkanes act in humans.
 

The secondary reviewer said that the shortcomings of the study did
 

not invalidate the conclusion that, under the conditions of test, Endrin
 

was not carcinogenic.
 

A motion was as approved unanimously that the report on the bioassay
 

of Endrin be accepted as written.
 

109
 
*	 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: 197 8 28 1 21 7 326 6 

110 

DHEW Publication No. (NIH) 79-812