1979 

National Cancer Institute 

CARCINOGENESIS 

Technical Report Series 

NO. 151 

BIOASSAY OF 

LEAD DIMETHYLDITHIOCARBAMATE 

FOR POSSIBLE CARCINOGENICITY 

CAS No. 19010-66-3 

NCI-CG-TR-151 

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

Public Health Service 

National Institutes of Health 

BIOASSAY OF
 

LEAD DIMETHYLDITHIOCARBAMATE
 

FOR POSSIBLE CARCINOGENICITY
 

Carcinogenssis Testing Program
 

Division of Cancer Cause and Prevention
 

National Cancer Institute
 

National Institutes of Health
 

Bethesda, Maryland 20205
 

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

Public Health Service
 

National Institutes of Health
 

NIH Publication No. 79-1707
 

BIOASSAY OF
 

LEAD DIMETHYLDITHIOCARBAMATE
 

FOR POSSIBLE CARCINOGENICITY
 

Careinogenesis 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
 

lead dimethyldithiocarbamate conducted for the Carcinogenesis
 

Testing Program, Division of Cancer Cause and Prevention,
 

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

Bethesda, Maryland. This is one of a series of experiments
 

designed to determine whether selected chemicals have the
 

capacity to produce cancer in animals. 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 lead dimethyldithiocarbamate was
 

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

Frederick, Maryland, operated for NCI (2) by Litton Bionetics,
 

Inc.
 

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

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

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

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

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

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

iii
 
computer services. Drs. Ulland, Gordon, and R. L. Schueler
 

determined the doses to be administered. Histopathologic
 

evaluations for rats were performed by Dr. J. F. Hardisty (3),
 

and the histopathologic evaluations for mice were performed by
 

Dr. C. E. Gilmore (3). The diagnoses included in this report
 

represent the interpretations of Drs. Hardisty and Gilmore.
 

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

Mason Research Institute (4). Statistical analyses were
 

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

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

The chemicals used in this bioassay were analyzed at Frederick
 

Cancer Research Center by Dr. W. Zielinsky (1). The chemical
 

analyses were reviewed and approved by Dr. Lijinsky (1).
 

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

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

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

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

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

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

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

assisted by Ms. Y. E. Presley. 

The following scientists at NCI were responsible for evaluating
 

the bioassay experiment, interpreting the results, and reporting
 

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

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

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

Milman, Dr. Thomas W. Orme, Dr. Sherman F. Stinson, Dr. Jerrold
 

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

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

Maryland.
 

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

Prevention, National Cancer Institute, National Institutes of
 

Health, Bethesda, Maryland.
 

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

Herndon, Virginia.
 

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

Rockville, Maryland.
 

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

Maryland.
 

(6)	 Mathematical Statistics and Applied Mathematics Section,
 

Biometry Branch, Field Studies and Statistics, Division of
 

Cancer Cause and Prevention, National Cancer Institute,
 

National Institutes of Health, Bethesda, Maryland.
 

V
 

SUMMARY
 

A bioassay of technical-grade lead dimethyldithiocarbamate for
 

possible carcinogenicity was conducted by administering the test
 

chemical in feed to F344 (Fischer) rats and B6C3F1 mice.
 

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

administered lead dimethyldithiocarbamate at one of two doses,
 

either 25 or 50 ppm, for 104 or 105 weeks. Matched controls
 

consisted of 20 untreated rats and 20 untreated mice of each sex.
 

All surviving animals were killed at the end of the period of
 

administration of the test chemical.
 

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

slightly lower than those of the corresponding controls; mean body
 

weights of the dosed female rats and male mice were essentially the
 

same as those of the corresponding controls. Survival rates in both
 

species were unaffected by administration of the test chemical. The
 

lack of toxicity in both species suggests that a maximum tolerated
 

dose level may not have been used. Therefore, the studies may not
 

have been conducted using maximum sensitivity for the assessment of
 

the possible carcinogenicity of lead dimethyldithiocarbamate.
 

No tumors occurred in the rats or mice of either sex at incidences
 

that were significantly higher in the dosed groups than in the
 

control groups.
 

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

dimethyldithiocarbamate was not carcinogenic for F344 rats or B6C3F1
 

mice of either sex.
 

TABLE OF CONTENTS
 

I. Introduction 1
 

II. Materials and Methods 3
 

A. Chemical 3
 

B. Dietary Preparation 3
 

C. Animals 4
 

D. Animal Maintenance 5
 

E. Subchronic Studies 7
 

F. Chronic Studies 10
 

G. Clinical and Pathologic Examinations. 12
 

H. Data Recording and Statistical Analyses 13
 

III. Results - Rats 19
 

A. Body Weights and Clinical Signs (Rats) 19
 

B. Survival (Rats) 19
 

C. Pathology (Rats) 22
 

D. Statistical Analyses of Results (Rats) 23
 

IV. Results - Mice 25
 

A. Body Weights and Clinical Signs (Mice) 25
 

B. Survival (Mice) 25
 

C. Pathology (Mice) 28
 

D. Statistical Analyses of Results (Mice) 29
 

V. Discussion. 31
 

VI. Bibliography 33
 

APPENDIXES
 

Appendix A Summary of the Incidence of Neoplasms in Rats
 

Administered Lead Dimethyldithiocarbamate
 

in the Diet 35
 

Table Al Summary of the Incidence of Neoplasms in Male
 

Rats Administered Lead Dimethyldithiocarbamate
 

in the Diet 37
 

ix
 
Table A2 Summary of the Incidence of Neoplasms in Female 

Rats Administered Lead Dimethyldithiocarbamate 

in the Diet 41 

Appendix B Summary of the Incidence of Neoplasms in Mice 

Administered Lead Dimethyldithiocarbamate in 

the Diet 45 

Table Bl Summary of the Incidence of Neoplasms in Male 

Mice Administered Lead Dimethyldithiocarbamate 

in the Diet 47 

Table B2 Summary of the Incidence of Neoplasms in Female 

Mice Administered Lead Dimethyldithiocarbamate 

in the Diet 51 

Appendix C Summary of the Incidence of Nonneoplastic 

Lesions in Rats Administered Lead 

Dimethyldithiocarbamate in the Diet 55 

Table Cl Summary of the Incidence of Nonneoplastic 

Lesions in Male Rats Administered Lead 

Dimethyldithiocarbamate in the Diet.. 57 

Table C2 Summary of the Incidence of Nonneoplastic 

Lesions in Female Rats Administered Lead 

Dimethyldithiocarbamate in the Diet..... 61 

Appendix D Summary of the Incidence of Nonneoplastic 

Lesions in Mice Administered Lead 

Dimethyldithiocarbamate in the Diet 65 

Table Dl Summary of the Incidence of Nonneoplastic 

Lesions in Male Mice Administered Lead 

Dimethyldithiocarbamate in the Diet 67 

Table D2 Summary of the Incidence of Nonneoplastic 

Lesions in Female Mice Administered Lead 

Dimethyldithiocarbamate in the Diet 70 

Appendix E Analyses of the Incidence of Primary Tumors 

in Rats Administered Lead Dimethyldithiocarbamate 

in the Diet 75 
Page 

Table El Analyses of the Incidence of Primary 

Tumors in Male Rats Administered Lead 

Dimethyldithiocarbamate in the Diet 77 

Table E2 Analyses of the Incidence of Primary 

Tumors in Female Rats Administered Lead 

Dimethyldithiocarbamate in the Diet 82 

Appendix F Analyses of the Incidence of Primary 

Tumors in Mice Administered Lead 

Dimethyldithiocarbamate in the Diet 87 

Table Fl Analyses of the Incidence of Primary 

Tumors in Male Mice Administered Lead 

Dimethyldithiocarbamate in the Diet 89 

Table F2 Analyses of the Incidence of Primary 

Tumors in Female Mice Administered Lead 

Dimethyldithiocarbamate in the Diet. 93 

TABLE 

Table 1 Lead Dimethyldithiocarbamate Chronic Feeding 

Studies in Rats and Mice 11 

FIGURES 

Figure 1 Growth Curves for Rats Administered Lead 

Dimethyldithiocarbamate in the Diet 20 

Figure 2 Survival Curves for Rats Administered Lead 

Dimethyldithiocarbamate in the Diet 21 

Figure 3 Growth Curves for Mice Administered Lead 

Dimethyldithiocarbamate in the Diet 26 

Figure 4 Survival Curves for Mice Administered Lead 

Dimethyldithiocarbamate in the Diet 27 

xi
 

I. INTRODUCTION 

Lead dimethyldithjocarbamate 

The lead salt of bis(dimethyldithiocarbamic) acid (CAS 

19010-66-3; NCI C02891) is used commercially as a rubber 

accelerator in applications involving natural rubber, and 

styrene-butadiene, isobutylene-isoprene, isoprene, and butadiene 

rubber (Del Gatto, 1968). Dithiocarbamate accelerators are known 

as ultra accelerators due to their speed of reaction. They are 

used primarily in latexes and rubber cements (Rogers, 1974; 

Shaver, 1965). 

Production figures on lead dimethyldithiocarbamate are not 

reported (USITC, 1977); this may indicate that production levels 

do not exceed 1,000 pounds or $1,000 of sales. 

Lead dimethyldithiocarbamate was selected by the Careinogenesis 

Testing Program as a result of the preliminary investigations by 

Innes et al. (1969), which gave inconclusive results. 

II. MATERIALS AND METHODS
 

A. Chemical
 

Ledate (lead dimethyIdithiocarbamate; C..HT/,N-S, Pb) was
 

o \.i i Aobtained as technical-grade, nonformulated material from R. T. 

Vanderbilt Co. This material is a fine, gray-white powder, which 

has been used as a rubber accelerator. On the basis of lead 

analysis by atomic absorption spectrometry (experimental: 45.2%; 

theoretical: 46.3%), the material was 98% pure ledate. 

Elemental analysis was consistent with the molecular formula for 

this material (experimental: 16.6% carbon, 2.8% hydrogen, 6.6% 

nitrogen; theoretical: 16.1% carbon, 2.7% hydrogen, 6.3% 

nitrogen). Atomic absorption analysis also showed traces of 

copper; while neutron activation analysis showed trace metal 

levels of 240 ppm iron, 34 ppm antimony, less than 10 ppm 

arsenic, and less than 5 ppm chromium, silver, scandium, 

rubidium, and lanthanum, as well as 3% sodium. 

B. Dietary Preparation
 

Test diets containing lead dimethyIdithiocarbamate were prepared
 
every 1 to 1-1/2 weeks in 6- to 12-kg batches at appropriate
 

doses. A known weight of the chemical was first mixed with an
 

/s\
 

equal weight of the autoclaved Wayne Sterilizable Lab Blox
 

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

pestle.
 

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

and final mixing was performed with the remaining quantity of
 

feed for a minimum of 15 minutes in a Patterson-Kelly twin-shell
 

blender. The diets were routinely stored at 5 C until used.
 

C. Animals
 

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

through contracts of the Division of Cancer Treatment, NCI from
 

the NCI Frederick Cancer Research Center animal farm as
 

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

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

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

weight basis for a given species and sex. For use in the chronic
 

study, male rats were required to weigh 90 to 105 g, averaging at
 

least 100 g; female rats, 80 to 95 g, averaging at least 90 g;
 

male mice, 18 to 22 g, averaging at least 19.5 g; and female
 
mice, 17 to 21 g, averaging at least 18.5 g. Individual animals
 

were identified by ear punch.
 

D. Animal Maintenance
 

The animals were housed in polycarbonate cages (Lab Products,
 

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

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

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

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

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

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

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

Sterilizable Lab Meal containing 4% fat, provided £d libitum in
 

suspended stainless steel hoppers and replenished at least three
 

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

libitum from sipper tubes attached to glass water bottles (Lab
 

Products, Inc.) suspended through the tops of the cages.
 

The contaminated bedding was disposed of through an enclosed
 

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

fed periodically into an incinerator. The cages were sanitized
 

twice per week and the feed hoppers twice per month at 82 to
 
88 c in a tunnel-type cagewasher (industrial Washing Corp.,
 

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

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

(Oxford Chemicals, Atlanta, Ga.).
 

The water bottles were sanitized at 82 to 88 C in a tunnel-type
 

bottle washer (Consolidated Equipment Supply Co., Mercersburg,
 

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

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

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

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

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

time.
 

The air in the animal rooms was regulated automatically at a
 

temperature of 22 to 24 C and a relative humidity of 45 to
 

55%. Fresh air was passed through a filter of 65% efficiency and
 

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

"Z"-type roughing filter of 30% efficiency and a bag system of 90
 

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

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

not recirculated,. The rate of movement allowed 15 changes of
 

room air per hour. The air pressure was maintained negative to a
 
clean hallway and positive to a return hallway. Fluorescent
 

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

Both the control and dosed rats were housed in the same room as
 

rats on feeding studies of the following chemicals:
 

(CAS 20941-65-5) ethyl tellurac
 

(CAS 97-77-8) tetraethylthiuram disulfide
 

Both the control and dosed mice were housed in the same room as
 

mice on feeding studies of the following chemicals:
 

(CAS 156-62-7) calcium cyanamide
 

(CAS 999-81-5) (2-chloroethyl) trimethylammonium chloride (CCC)
 

(CAS 95-80-7) 2,4 diaminotoluene
 

(CAS 088-96-0) phthalamide
 

(CAS 120-62-7) piperonyl sulfoxide
 

(CAS 086-30-6) N-nitrosodiphenylamine
 

(CAS 137-17-7) 2,4,5-trimethylaniline 

E. Subchronic Studies
 

Subchronic feeding studies were conducted to estimate the maximum
 

tolerated doses (MTD's) of lead dimethyldithiocarbamate, on the
 

basis of which two concentrations (hereinafter referred to as
 

"low" and "high" doses) were selected for administration in the
 

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

of each sex were administered feed containing lead dimethyldithiocarbamate at one of several doses. Groups of five control
 
animals of each species and sex were administered basal diet
 

only. The period of administration of the test chemical was 7
 

weeks, followed by 1 week of additional observation.
 

At the end of the subchronic studies, all animals were killed
 

using C0? inhalation and necropsied. The lowest dose at which
 

relevant histopathologic findings were observed in male rats was
 

62 ppm. The principal changes due to the administration of lead
 

dimethyldithiocarbamate in groups dosed at 500 and 250 ppm were
 

in the kidneys. Moderate (500 ppm) or slight-to-moderate (250
 

ppm) diffuse hypertrophy of the proximal convoluted tubular
 

epithelium was associated with nuclear swelling. Many enlarged
 

nuclei contained smooth, eosinophilic inclusion bodies of varying
 

sizes. Occasional nuclei contained two to four small round
 

inclusions which were acid-fast when stained by Kinyon's method.
 

Similar inclusions were observed in the group at 125 ppm;
 

however, in the group at 62 ppm, both the number and size of the
 

intranuclear inclusions were greatly diminished and were not seen
 

in groups at lower doses. Rare mitotic figures were observed in
 

the tubular epithelium and mild degenerative changes were
 

sometimes seen. These lesions were considered to be consistent
 

with lead nephropathy.
 

Less prominent, dose-related changes were present in the blood
 
and hematopoietic tissues. There was evidence of mild anemia in
 

the groups dosed at 500 and 250 ppm as shown by slight
 

anisocytosis, poikilocytosis, and polychromatophilia in their
 

blood smears. Slight anisocytosis was found in the group dosed
 

at 125 ppm. Very slight to slight increased splenic
 

extramedullary hematopoiesis occurred in one male and two female
 

rats in the group dosed at 500 ppm and in three male and two
 

female rats in the group dosed at 250 ppm. A slight increase in
 

cellularity of femoral bone marrow was detected in the group
 

dosed at 500 ppm and a very slight increase was noted in the
 

group dosed at 250 ppm.
 

It was concluded that the renal lesions, mild anemia, and lead
 

nephropathy were induced by administration of 250 and 500 ppm
 

lead dimethyIdithiocarbamate to rats during the subchronic
 

studies. Similar signs of anemia were slightly detectable in
 

rats given 125 ppm lead dimethyIdithiocarbamate; however, lead
 

nephropathy was similar to that observed in the higher dosed
 

groups. Lead nephropathy was minimal at 62 ppm. It was
 

concluded that administration of 62 ppm or more of lead
 

dimethyldithiocarbamate would result in lead nephropathy.
 

In both male and female mice, the 125 and 250 ppm were the lowest
 

doses at which histopathologic findings were observed. A very
 
small number of tiny, rounded intranuclear inclusions and rare
 

mitotic figures of the renal tubular epithelium were observed in
 

both males and females. Similar changes were not observed in
 

mice at lower doses. Vacuolar degeneration in the proximal
 

convoluted tubular epithelium of the kidney, which was considered
 

to be lipid accumulation, was found in the male mice. These
 

changes were slight to moderate in the group at 250 ppm, slight
 

in the groups at 62 and 125 ppm, and in only trace amounts in the
 

control group. These changes were considered to be dose
 

related. Very slight to slight hydronephrosis, which was not
 

considered to be dose related was observed in control and dosed
 

male mice. It was concluded that lead nephropathy did not occur
 

in mice given 62 ppm or less lead dimethyldithiocarbamate.
 

Based on the histopathologic data, the low and high doses for
 

rats and mice were set at 25 and 50 ppm for the chronic studies.
 

F. Chronic Studies
 

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

feeding studies are shown in table 1.
 

10
 
Table 1. Lead Dimethyldithiocarbamate Chronic Feeding Studies
 

in Rats and Mice
 

Lead Dimethyldi-


Sex and Initial thiocarbamate Time on 

Test No. of in Diet (b) Study 

Group Animals (a) (ppm) (weeks) 

RATS 

Males 

Matched-Control 20 0 104 

Low-Dose 50 25 104 

High-Dose 50 50 104 

Females 

Matched-Control 20 0 104 

Low-Dose 50 25 104 

High-Dose 50 50 104 

MICE 

Males 

Matched-Control 20 0 105 

Low-Dose 50 25 105 

High-Dose 50 50 105 

Females 

Matched-Control 20 0 105 

Low-Dose 50 25 105 

High-Dose 50 50 105 

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

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

11
 
G. Clinical and Pathologic Examinations
 

All animals were checked twice daily for deaths. Observations
 

for sick, tumor-bearing, and moribund animals were recorded
 

daily. Clinical examination and palpation for masses were
 

performed each month, and the animals were weighed at least once
 

per month. Moribund animals and animals that survived to the end
 

of the bioassay were killed using CCL 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 observed
 

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

embedded in paraffin, sectioned, and stained with hematoxylin and
 

eosin. The following tissues were examined microscopically:
 

skin, lungs and bronchi, trachea, bone marrow (femur), spleen,
 

lymph nodes (mesenteric and submandibular), thymus, heart,
 

salivary glands (parotid, sublingual, and submaxillary), liver,
 

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

and large intestine, kidney, urinary bladder, pituitary, adrenal,
 

thyroid, parathyroid, pancreatic islets, testis, prostate,
 

mammary gland, uterus, ovary, brain (cerebrum and cerebellum),
 

12
 
and all tissue masses. Peripheral blood smears also were made
 

for all animals, whenever possible.
 

A few tissues from some animals were not examined, particularly
 

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

been in advanced states of cannibalization or autolysis. Thus,
 

the number of animals from which particular organs or tissues
 

were examined microscopically varies, and does not necessarily
 

represent the number of animals that were placed on study in each
 

group.
 

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.
 

13
 
These data were analyzed using the appropriate statistical
 

techniques described in this section. Those analyses of the
 

experimental results that bear on the possibility of
 

carcinogenicity are discussed in the statistical narrative
 

section.
 

Probabilities of survival were estimated by the product-limit
 

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

report in the form of graphs. Animals were statistically
 

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

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

causes were not statistically censored. Statistical analyses for
 

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

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

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

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

except the departure from linearity test, which is only reported
 

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

The incidence of neoplastic or nonneoplastic lesions has been
 

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

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

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

the denominators included only those animals for which that site
 

14
 
was examined histologically. However, when macroscopic
 

examination was required to detect lesions prior to histologic
 

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

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

denominators consist of the numbers of animals necropsied.
 

The purpose of the statistical analyses of tumor incidence is to
 

determine whether animals receiving the test chemical developed a
 

significantly higher proportion of tumors than did the control
 

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

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

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

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

compared simultaneously with those for a control group, a
 

correction to ensure an overall significance level of 0.05 may be
 

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

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

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

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

where the Fisher exact P values are shown.
 

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

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

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

15
 
of the dose-response curve is different from zero at the one-


tailed 0.05 level of significance. Unless otherwise noted, the
 

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

from linear trend.
 

A time-adjusted analysis was applied when numerous early deaths
 

resulted from causes that were not associated with the formation
 

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

first tumor was observed were excluded by basing the statistical
 

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

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

such an early tumor was found, comparisons were based exclusively
 

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

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

obtained, the standard procedures for analyses of the incidence
 

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

followed.
 

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

incidence of tumors. Curves of the proportions surviving without
 

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

The week during which an animal died naturally or was sacrificed
 

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

16
 
methods of comparing these curves were used for two groups;
 

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

groups. The statistical tests for the incidence of tumors which
 

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

noted, in the direction of a positive dose relationship.
 

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


tailed test) were also noted.
 

The approximate 95 percent confidence interval for the relative
 

risk of each dosed group compared with its control was calculated
 

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

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

binomial probability of the incidence of a specific type of tumor
 

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

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

group. The hypothesis of equality between the true proportion of
 

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

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

of unity represent the condition of a larger proportion in the
 

dosed group than in the control.
 

The lower and upper limits of the confidence interval of the
 

relative risk have been included in the tables of statistical
 

analyses. The interpretation of the limits is that in
 

17
 
approximately 95% of a large number of identical experiments, the
 

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

control group would be within the interval calculated from the
 

experiment. When the lower limit of the confidence interval is
 

greater than one, it can be inferred that a statistically
 

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

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

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

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

limit indicates the absence of a significant result while the
 

upper limit indicates that there is a theoretical possibility of
 

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

detected under the conditions of this test.
 

18
 
III. RESULTS - RATS
 

A. Body Weights and Clinical Signs (Rats)
 

Mean body weights of the high-dose male rats were slightly lower
 

than those of the corresponding controls beginning with week 30;
 

the depression in the amount of body weight gained increased in
 

the males during the last 20 weeks of the bioassay and in the
 

females during the last 10 weeks (figure 1). Other clinical
 

signs, such as corneal opacity, tissue masses, and wasting were
 

observed in dosed and control groups of the rats.
 

B. Survival (Rats)
 

The Kaplan and Meier curves estimating the probabilities of
 

survival for male and female rats administered lead
 

dimethyldithiocarbamate in the diet at the doses of this
 

bioassay, together with those of the matched controls, are shown
 

in figure 2. The results of the Tarone tests indicated no
 

significant dose-related trend in mortality in either sex.
 

19
 
500 

111 

g go 

@ 5 A A

D 

25 ii 

g 0 

8 A 

O 

g 

> 

Q 

O 

GO 

e MALE RATS 

D MATCHED CONTROL 

O LOW DOSE 

A HIGH DOSE 

40 SO 60 70 

TIME ON STUDY (WEEKS) 

o 8 § 

O A A X 300­ U 

Q

O H m 

FEMALE RATS 

D MATCHED CONTROL 

O LOW DOSE 

A HIGH DOSE 

70 

TIME ON STUDY (WEEKS) 

Figure 1. Growth Curves for Rats Administered Lead Dimethyldithiocarbamate in the Diet 

20 
1 UU — — — — — — — I j=-g , -=..=..1B. • is „.- -JL 

090 ­

080 ­

070 • 

> 

OC 060 ­ 3

o) 

0

 050 ­

1­

§ 040 ­

m 

O 

a: 

°- 030 ­

020 ­

, 010­

0

090­

080­

070­ _J 

> 

> 

3 

CO 

° 050­

b 

§040­

m 

o 

DC 

°- 030 ­

020­

010-1 

M"X":0,

6

 itt'A ^ 

O-2Z 

X1 

i 

_

^ ~t i 

-i -r 

MALE RATS 

O MATCHED CONTROL 

O LOW DOSE 

Li HIGH DOSE 

 15 30 45 60 75 90 105 12 

TIME ON STUDY (WEEKS) 

.-.-&.-..-..-..-. ~~r> ^-T^ | 

A-.-­

A" I'f^.^ -^H-V. A

""4"A""felS 

1 fti

=1 

-r —i • 

f

i 

, \­

—i 

FEMALE RATS 

D MATCHED CONTROL 

O LOW DOSE 

L

\ HIGH DOSE 

78 

TIME ON STUDY (WEEKS) 

Figure 2. Survival Curves for Rats Administered Lead Dimethyldithiocarbamate in the Diet 

21 
In male rats, 35/50 (70%) of the high-dose group, 35/50 (70%) of
 

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

the end of the bioassay. In females, 39/50 (78%) of the high-


dose group, 40/50 (80%) of the low-dose group, and 16/20 (80%) of
 

the control group lived to the end of the bioassay.
 

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

development of late-appearing tumors.
 

C. Pathology (Rats)
 

Histopathologic findings on neoplasms in rats are summarized in
 

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

are summarized in Appendix C, tables Cl and C2.
 

A variety of neoplasms commonly seen in aged F344 rats occurred
 

with approximately equal frequency in dosed and control rats.
 

The low incidence, distribution, and nature of these neoplasms
 

are similar, however, to spontaneously occurring neoplasms in
 

aged F344 rats.
 

22
 
Several inflammatory, degenerative, and proliferative lesions
 

commonly seen in aged F344 rats occurred with approximately equal
 

frequency in dosed and control animals. Among the groups
 

receiving lead dimethyldithiocarbamate, only one animal was
 

reported to have renal pelvic epithelial hyperplasia, and no lead
 

inclusions were reported.
 

Based on the histopathologic examination, administration of lead
 

dimethyldithiocarbamate at the doses used in this bioassay did
 

not induce either neoplastic or nonneoplastic lesions in F344
 

rats of either sex under conditions of this bioassay.
 

D. Statistical Analyses of Results (Rats)
 

Tables El and E2 in Appendix E contain the statistical analyses
 

of the incidences of those primary tumors that occurred in at
 

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

in one or more than one group.
 

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

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

test comparing the incidences of tumors in the dosed groups with
 

those in corresponding control groups are not significant in
 

either sex.
 

23
 
In each of the 95% confidence intervals for relative risk, shown
 

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

absence of significant positive results. It should also be noted
 

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

indicating the theoretical possibility of the induction of tumors
 

by lead dimethyldithiocarbamate, which could not be detected
 

under the conditions of this test.
 

24
 
IV. RESULTS - MICE
 

A. Body Weights and Clinical Signs (Mice)
 

Mean body weights of the dosed male mice were essentially the
 

same as those of corresponding controls throughout the bioassay;
 

however, the mean body weights of the dosed females were slightly
 

lower than those of the corresponding controls after week 20
 

(figure 3). Other clinical signs, such as corneal opacity and 

tissue masses, were observed in dosed and control groups of the 

mice. 

B. Survival (Mice)
 

The Kaplan and Meier curves estimating the probabilities of
 

survival for male and female mice administered lead
 

dimethyldithiocarbomate in the diet at the doses of this
 

bioassay, together with those of the matched controls, are shown
 

in figure 4. The results of the Tarone tests indicate no
 

significant dose-related trend in mortality in either sex.
 

25
 
60 

a ae a g 

D g g o

 a a 

MALE MICE 

D MATCHED CONTROL 

O LOW DOSE 

A HIGH DOSE 

40 50 60 70 

TIME ON STUDY (WEEKS) 

D°

 D 

o o S ° c °° °o 

n a " X 0 o 

g O a o 

FEMALE MICE 

D MATCHED CONTROL 

O LOW. DOSE 

A HIGH DOSE 

TIME ON STUDY (WEEKS) 

Figure 3. Growth Curves for Mice Administered Lead Dimethyldithiocarbamate in the Diet 

26 
__ __ __ 

A"" "*""o-, ll ] 

O--! ft"­ 090- O -. tt 

080­

URVIVAL

O C 

s s 

<n 

o 

H 

j 

CO nan ­

m 

O 

DC 

MALE MICE 

020- D MATCHED CONTROL 

O LOW DOSE 

010­ L\ HIGH DOSE 

. 

46 60 75 

TIME ON STUDY (WEEKS) 

0- A

 A""^ ---a-­ *\ 

^ ^H A, 

°0 

3 

> 

> 

1C 060­

D to 

u. 

O nRn 

1­

J 

m 

O 

oc 

0. 030­

FEMALE MICE 

020- D MATCHED CONTROL 1 , 

O LOW DOSE 

010- L\ HIGH DOSE — 

TIME ON STUDY (WEEKS) 

Figure 4. Survival Curves for Mice Administered Lead Oimethyldithiocarbamate in the Diet 

27 
In male mice, 43/50 (86%) of the high-dose group, 43/50 (86%) of
 

the low-dose group, and 19/20 (95%) of the control group lived to
 

the end of the bioassay. In females, 42/50 (84%) of the
 

high-dose group, 38/50 (76%) of the low-dose group, and 15/20
 

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

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

development of late-appearing tumors.
 

C. Pathology (Mice)
 

Histopathologic findings on neoplasms in mice are summarized in
 

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

are summarized in Appendix D, tables Dl and D2.
 

A variety of neoplasms commonly seen in aged B6C3F1 mice occurred
 

with approximately equal frequency in dosed and control mice
 

Other proliferative or neoplastic lesions were of single
 

occurrence or low incidence, with no obvious differences in
 

incidences in dosed and control groups of the mice.
 

In addition to the proliferative lesions, there were occasional
 

28
 
inflammatory and degenerative lesions commonly seen in aged
 

B6C3F1 mice which occurred with approximately equal frequency in
 

dosed and control animals. Intranuclear inclusion bodies
 

characteristic of lead toxicity were not reported.
 

Based on the histopathologic examination, there was no evidence
 

that the administration of lead dimethyldithiocarbamate exerted
 

any influence on the incidence of proliferative or other lesions
 

in B6C3F1 mice under the conditions of this bioassay.
 

D. Statistical Analyses of Results (Mice)
 

Tables Fl and F2 in Appendix F contain the statistical analyses
 

of the incidences of those primary tumors that occurred in at
 

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

in one or more than one group.
 

The result of the Cochran-Armitage test for dose-related trend in
 

the incidences of tumors and the results of the Fisher exact test
 

comparing the incidences of tumors in the dosed groups with those
 

in corresponding control groups are not significant in either sex.
 

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

29
 
in the tables, the value of one is included; this indicates the
 

absence of significant positive results. It should also be noted
 

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

indicating the theoretical possibility of the induction of tumors
 

by lead dimethyldithiocarbamate, which could not be detected
 

under the conditions of this test.
 

30
 
V. DISCUSSION
 

Mean body weights of the high-dose male rats and the dosed female
 

mice were slightly lower than those of the corresponding
 

controls; mean body weights of the dosed female rats and male
 

mice were essentially the same as those of the corresponding
 

controls. Other clinical signs, such as corneal opacity and
 

tissue masses, were observed in both dosed and control groups of
 

rats and mice. Survival rates of both species were unaffected by
 

administration of the test chemical.
 

The results of the subchronic studies indicated that higher doses
 

could have caused toxicity due to the lead in the test chemical.
 

In the rats, doses of 250 or 500 ppm of the test chemical
 

administered for only 7 weeks caused diffuse hypertrophy of the
 

proximal convoluted tubular epithelium, and the hypertrophy was
 

associated with enlarged nuclei containing eosinophilic inclusion
 

bodies. The occurrence of the nuclear inclusion bodies was
 

observed at doses as low as 62 and 125 ppm. The lesions of the
 

kidney were considered to be consistent with lead nephropathy.
 

In the mice, evidence of lead nephropathy was observed at doses
 

above 62 ppm but not at 62 ppm or below.
 

31
 
No tumors occurred in the rats or mice of either sex at incidences
 

that were significantly higher in the dosed groups than in the
 

control groups.
 

In the chronic study the essential absence of toxic signs in the
 

dosed rats and mice at 25 and 50 ppm under the conditions of the
 

bioassay as well as the lack of mortality and weight depression
 

suggests that both species may have been able to tolerate higher
 

doses. Therefore, the studies may not have been conducted using
 

maximum sensitivity for the assessment of the possible carcinogenicity of the test compound. Moreover, in previous tests for
 

tumorigenicity with two different hybrid mice (C57BL/6 x 63H/Anf and
 

C57BL/6 x AKR) (NTIS, 1968; Innes et al., 1969), it was reported
 

that when higher doses of the test chemical were administered, i.e.,
 

46.4 mg/kg body weight by stomach tube for 3 weeks, followed by 130
 

ppm in the diet for 18 months, an elevated incidence of reticulum-


cell sarcoma (P less than 0.01) was observed in the first indicated
 

hybrid mice.
 

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

dimethyldithiocarbamate was not carcinogenic for F344 rats or B6C3F1
 

mice of either sex.
 

32
 
VI. BIBLIOGRAPHY
 

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

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

Berenblum, I., ed«, Carcinogenicity Testing; A Report £f the
 

Panel on Careinog€inici ty of_ the Cancer Research Commission of the
 

UICjC, Vol. 2^. International Union Against Cancer, Geneva, 1969.
 

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

Soc. B 34:187-220, 1972.
 

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

1970, pp. 48-52.
 

Del Gatto, J. V., Accelerators. In: Materials and Compounding
 

Ingredients for Rubber, Bill Publication, Inc., New York, 1968,
 

p. 41.
 

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.
 

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

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

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

Bioassay of pesticides and industrial chemicals for 

tumorigenicity in mice: a preliminary note. J. Natl Cancer 

Inst. 42:1101-1114, 1969. 

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

incomplete observations. J_. Am. Statist. Assoc. _53:457-481, 1958.
 

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

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

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

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


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

National Technical Information Service, Evaluation o_f
 

Carcinogenic, Tereitogenic, and Mutagenic Activities o_f Selected
 

Pesticides and Industrial Chemicals, Vol. _!_, National Technical
 

Information Service, Washington, D.C., 1968, p. 64.
 

33
 
Rogers, T. H., Jr., Rubber, natural. In: Chemical and Process
 

Technology Encyclopedia, Considine, D. M., ed., McGraw-Hill Book
 

Co., New York, 1974, pp. 984-987.
 

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

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

induced by different numbers of administrations of benzo(a)
 

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

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

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

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

Tarone, R. E., Tests for

Biometrika 62:679-682, 1975. 

 trend in life table analysis. 

United States International Trade Commission, Synthetic Organic 

Chemicals - United States Production and Sales, 1976, USITC
 

Publication 833, United States International Trade Commission,
 

Washington, D.C., 1977.
 

34
 
APPENDIX A
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN RATS
 

ADMINISTERED LEAD DIMETHYLDITHIOCARBAMATE IN THE DIET
 

35
 

TABLE A1. 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE RATS ADMINISTERED 

LEAD DIMETHYLDITHIOCARBAMATE IN THE DIET 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

ANIHAL S INITIALLY IN STUDY 20 50 50 

ANIHALS NECROPSIED 20 50 50 

ANIMALS EXAMINE D HISTOPATHOLOGICALLY 20 50 50 

INTEGUMENTAR Y SYSTEM 

*SKIN (20) (50) (50)

 

KERATOACANTHOMA 1 (2%)

 

*SOBCUT TISSUE (20) (50) (50) 

UNDIFFERENTIA7ED CARCINOMA 1 (5X) 

ADENOCARCINOMA, NOS 1 (2X) 

SARCOMA , NOS 1 (2%)

 

FIBROM A 1 (2%) 2 (<•«)

 

FIBROSARCOM A 1 (2%) 2 (455)

 

LIPOM A 1 (5%) 1 (21)

 

RSSPIRATOR Y SYSTEM 

#LUS3 (20) (50) (50) 

ALVEOLAR/BRONCHIOLA P ADENOM A 2 (10%) 5 (1055) 5 (10%) 

C-CELL CARCINOMA , METASTATIC 1 (2S) 

HEMATOPOIETIC SYSTEM 

*MULTIPLE ORGAN S (20) (50) (50) 

MALIGNAN T LYMPHOMA , NOS 2 (10%) 6 (12«) 7 (14%) 

tULIG.LYMPHOMA, UNDIFFER-TYPE 6 (30X) 9 (18%) 5 (10%) 

MAST-CELL LEUKEMI A 1 (2X) 

ISPLEEN (19) (50) (50) 

FIBROM A 1 (255) 

CIRCULATOR Y SYSTEM 

NONE 

# NUMBE R OF ANIMAL S WITH TISSUE EXAMINE D MICROSCOPICALLY 

* NUMBE R OF ANIMAL S NECROPSIED 

37 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

DIGESTIVE SYSTEM 

»LIVER 

HEPATOCELLULA R CARCINOM A 

#LARG E INTESTINE 

ADENOMATOU S POLYP, NOS 

URINAR Y SYSTEM 

• KIDNEY/PELVI S 

TRANSITIONAL-CEL L CARCINOM A 

ENDOCRINE SYSTEM 

#PITaiTAP Y 

ADENOMA , NOS 

tADRSNA L 

CORTICAL ADENOM A 

PHEOCHROMOCYTOM A 

• THYROI D 

FOLLICULAR-CELL CARCINOM A 

C-CELL ADENOM A 

C-CELL CARCINOMA 

• PANCPEATIC ISLETS 

ISLET-CELL ADENOM A

 

REPRODUCTIV E SYSTEM 

*MAM«AP Y GLAN D 

FIBRO ADENOM A 

• PROSTATE 

ADENOCARCINOMA , NO S 

tTESTIS 

INTERSTITIAL-CELL TUMOR 

* NU«3E R 0 ? ANIMAL S KIT H TISSUE

* NUMBE R OF ANIMAL S NECPOPSIED 

38 

MATCHED 

CONTROL LOW DOSE 

(20) (50) 

(20) (33) 

(20) (50) 

(20) (49) 

7 (35?) 16 (33%) 

(20) (50) 

2 (4«) 

3 (15%) 11 (22R) 

(20) (49) 

1 (5X) 

1 (5%) 3 (6%) 

2 (H%) 

(18) (50) 

1 (6%) 3 (6%) 

(20) (50) 

1 (2X) 

(16) (49) 

1 (27.) 

(20) (49) 

16 J80!S1_ 40_J82*1 

 EXAMINE D MICROSCOPICALLY 

HIGH DOSE 

(50) 

1 (2%) 

(43) 

1 (2*) 

(50) 

1 (21) 

(49) 

9 (18%) 

(50) 

1 (2)5) 

8 (16% ) 

(50) 

1 (2X ) 

6 (12*) 

1 (2«) 

(47) 

2 («*) 

(50) 

(50) 

(50) 

37 J74°5J. 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

— — — T — —— —. _ —_. __

MATCHED 

CONTROL

 _.. —

 LOW DOSE

 -.__ ___ _

 HIGH DOSE 

—_ _. 

NERVOUS SYSTEM 

tBRAIN/MENINGES

ADENOCARCINOMA, NOS, MSTASTATIC

HENINGIOHA

 (20) (50) (50) 

1 (2X) 

1 (2%) 

#BRAIN

GLIOBA, NOS

 (20) (50)

 1 (2%)

 (50) 

1 (2%) 

SPECIAL SENSE ORGANS 

NONE 

MUSCULCSKELETAL SYSTEM 

NONE 

BODY CAVITIES 

*TUNICA VAGINALIS

FIBROMA

BESOTHELIOMA, NOS

 (20)

 1 (5%)

 (50)

 1 (2%) 

2 (435) 

 (50) 

ALL OTHER SYSTEHS 

*MULTIPLE ORGANS

SARCOMA, NOS

MESOTHELIOMA, SOS

 (20) (53)

 1 (2%) 

 (50) 

1 (2%) 

ANIMAL DISPOSITION SUMMARY 

ANIMALS INITIALLY IN STUDY

NATURAL DEATHS

MORIBUND SACRIFICE

SCHEDULED SACRIFICE 

ACCIDENTALLY KILLED 

TERHINAL SACRIFICE

ANIMAL MISSING 

 20

 3

 1

 16

 50

 9

 6

 35

 50 

 13 

2 

 35 

8 INCLUDES APTOLYZED AMIHALS 

t NUMBER

* NUMBER

 OF" ANIMALS

 OF ANIMAL S

 WITH TISSUE

 NECROPSIED 

 EXAMINED MICROSCOPICALLY 

39 
TABLE A1. MALE RATS: NEOPLASMS (CONTINUED) 

MATCHED
 

CONTROL LOW DOSE HIGH DOSE
 

TUMOP SUMMAR Y 

TOTAL ANIMALS WITH PRIMARY

TOTAL PPIMAPY TUMORS 

 TUMORS* 19 

42 

49 

108 

47 

96 

TOTAL ANIMAL S WITH BENISN TUMORS 

TOTAL BENIGN TUMORS 

18 

31 

49 

an 

44 

74 

TOTAL ANIMALS WITH MALI3NANT TIJKORS 

TOTAL MALIGNANT TUKCRS 

9 

10 

21 

21 

18 

22 

TOTAL ANIMALS WITH SECONDARY TUMORS* 

TOTAL SECONDARY TUMORS 

1 

1 

1 

1 

TOTAL ANIMALS WITH TUMORS UNCERTAINBENIGN OR MALIGNANT 

TOTAL UNCERTAIN TUMORS 

1 

1 

3 

3 

TOTAL ANIMALS WITH TUMOSS UNCERTAIMPPINARY OR METASTATIC 

TOTAL UNCSFTAIN TUMORS 

* PRIMARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 

* SECONDARY TUMORS: METASTATIC TUMORS 08 TUMORS INVASIVE INTO AN ADJACENT OH3AN
 

40
 
TABLE A2.

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE RATS ADMINISTERED 

LEAD DIMETHYLDITHIOCARBAMATE IN THE DIET 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

ANIMAL S INITIALL Y IN STUDY 20 50 50 

ANIMAL S NBCROPSIED 20 50 50 

ANIMAL S EXAMINE D HISTOPATHOLOGICALLY 20 53 50 

INTEGUMENTAR Y SYSTEM 

*SKIN (20) (50) (50)
 

SQUAMOUS CELL CARCINOMA 1 (2%)
 

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

SARCOMA , NOS 1 (2X ) 

LIPOM A 1 (535) 1 (2X ) 1 (2fc ) 

R2SPIRAT03 Y SYSTEM 

fLURS (20) (53) (53)
 

ALVEOLAR/ERONCHIOLAB ADENOMA 1 (5%) 4 (&%} 3 (67.)
 

PHEOCHPOMOCYTOMA, KETASTATIC 1 (5«)
 

HEMATOPOIETIC SYSTEM
 

*MULTIPLE OPGANS (20) (53) (53)
 

MALIGNAN T LYMPHOMA , NOS 1 (5%) 1 (2% ) 5 (10?.) 

MALIG.LYMPHONA , UNDIF F EP-TYPE 7 (KU) 5 (10% ) 

CIPCULATOR Y SYSTEM 

NO!*? 

DIGESTIV E SYSTEM 

#LIVE ? (20) (50) (50) 

NEOPLASTIC NODUL E 1 (5%) 1 (27,) 

___ _ HE?AIP.CELLULAP_CAPCINOM A ____________________________ _ 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUK3SR OF ANIMALS NECPCPSIED
 

41 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE 

'J3INAP Y SYSTE M 

#U?INAR Y BLADDE R (20) («9 ) 

TRANSITIONAL-CEL L CARCINOM A 1 (5%) 

LEIOMYOSARCOM A 1 (27,) 

ENDOCRIN E SYSTEM 

#PITUITA F Y (19) (5D ) 

ADENOKA , NO S 4 (2n> 13 (261) 

tADFSNA L (20) (50) 

CORTICA L ADENOM A 1 (5%) 

PHEOCHROMOCYTOM A 1 (2%) 

PHEOCHROMOCYTOMA , MALIGNAN T 1 (5%) 

tTHYROI D (20) (50) 

C-CELL ADENOM A U (3%) 

C-CELL CAPCINOM A 1 (2%) 

fPANCFEATIC ISLETS (20) (50) 

ISLET-CELL ADENOM A 1 (2% ) 

REPRODUCTIV E SYSTE M 

*MAMMAR Y GLAN D (20) (50) 

ADENOCAPCINOMA , NOS 2 (4%) 

FIBROADENOM A 6 (30%) 8 (1675) 

*Ci:rOPAL GLAN D (20) (50)

 

ADENOMA , NO S 

*VAGIN A (20) (50) 

ANGIOSAHCOK A 1 (2%) 

fOTEPU S (20) (50) 

ENDOMETPIA L STROMA L POLYP U (20*) 7 (14% ) 

fOVAR Y (20 ) (50) 

GPANULOSA-CEL L TUMO R 1 (5%) 1 (2% ) 

NERVOU S SYSTEM 

#BPAI N (23) (50) 

GLIOMA, NOS 

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

* NUMBE R OF ANIMAL S NSCROPSIED 

HIGH 

(49) 

(48 ) 

17 

(SO ) 

1 

(48) 

4 

1 

(49 ) 

1 

(50) 

6 

(50) 

2 

(50) 

(49) 

5 

(50) 

(49) 

1 

DOSE 

(35*) 

(2?,) 

(3/i) 

(>1>) 

(24 ) 

(12< ) 

(4t) 

(10% ) 

(2*1 

42 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

SPECIAL SENSE OPGANS 

NOUS 

NJSCULOSK2LETAL SYSTEM 

NONE 

30DY CAVITIES 

NONE 

A LL OTHT;P

NON E 

 SYSTEMS 

ANIMA L DISPOSITION SUMMAR Y 

ANIMAL S INITIALL Y IN STUDY

NATURA L DEATHS)

MORIBUN D SACRIFICE

SCHEDULE D SACRIFICE 

ACCIDENTALL Y KILLED 

TERMINA L SACRIFICE

ANIMA L MISSING 

 20

 4

 16

 50

 6

 U

 40

 50 

 13 

1 

 39 

3^INCLUDES, AUTOLYZED_ANIHA_LS _ 

f NUMBE R OF ANIMAL S WIT H TISSUE

* NUMBE R OF ANIMAL S NECROPSIED 

 EXAMINE D MICROSCOPICALLY 

43 
TABLE A2. FEMALE RATS: NEOPLASMS (CONTINUED) 

MATCHED
 

CONTROL LOW DOSE HIGH DOSE
 

TUKOR SUMMARY
 

TOTAL ANIMALS WITH PRIMARY TUMOPS* 15 33 36
 

TOTAL PRIMARY TUMORS 22 55 5!*
 

TOTAL ANIMALS WITH BENIGN TUMORS 12 29 26
 

TOTAL BSNIGN TUMORS 17 39 UO
 

TOTAL ANIMALS WITH 1ALIGNANT TUHORS 3 1U 13
 

TOTAL MALIGNANT TUMORS 3 15 13
 

TOTAL ANIMALS KITH SECONDARY TUMORS* 1
 

TOTAL SECONDAPY TUMOBS 1
 

TOTAL ANIMALS WITH TUMORS UNCERTAIN­ BENIGN OR MALIGNANT 2 1 1
 

TOTAL UNCERTAIN TUMORS 2 1 1
 

TOTAL ANIMAL S WITH TUMORS UNCERTAIN ­

PRIMAR Y OR MHTASTATIC 

TOTAL UNCERTAIN TUMORS 

* PRIMAR Y TUMORS : ALL TUMORS EXCEPT SECONDARY TUMORS 

# SECONDAR Y TUMORS : METASTATIC TUMORS OR TUMORS INVASIV E INTO AN ADJACENT OR3<V N 

44 
APPENDIX B
 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MICE
 

ADIMINISTEREO LEAD DIMETHYLDITHIOCARBAMATE IN THE DIET
 

45
 

TABLE B1. 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN MALE MICE ADMINISTERED 

LEAD DIMETHYLDITHIOCARBAMATE IN THE DIET 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

ANIMAL S INITIALLY IN STUDY 20 50 50 

ANIRALS KISSING 1 1 

ANIHAL S NECHOPSIED 20 49 49 

ANIMALS EXAMINED HISTOPATHOLOGICALLY 20 49 49 

INTEGUMENTAR Y SYSTEM 

NONE 

RESPIRATOR Y SYSTEM 

ILUNG - (20) (48) (49) 

CARCINOMA , NOS, METASTATIC 1 (2%) 

HEPATOCELLOLAR CARCINOMA , METAST 1 (2«) 

ALVEOLAR/BRONCHIOLAR ADENOHA 4 (20*) 4 (8%) 3 (6%)
 

ALVEOLAR/BP.ONCHIOLAR CARCINOMA 5 (25%) 10 (21%) 12 (24X)
 

HEMANGIOSARCOHA 1
 

HEMATOPOIETIC SYSTEM
 

*MOLTIPLE ORGANS (20) (49) (49) 

MALIGNANT LYMPHOMA, NOS 1 (5X) 1 (2%) 2 (4%) 

*BLOOD (20) (49) (49) 

LEOKEMIA.NOS 1 (2%) 

fBONE HARROW (20) (48) (49)

 

CARCINOMA , NOS, METASTATIC 1 (2*)

 

HEMANGIOSARCOMA 1 (5%) 

tSPLEEN (20) (47) (47) 

HEMANGIOM A 3 (6%) 1 (2%) 

HEHAHGIOSARCOMA 1 (5X) 2 (<»*) 1 (21 ) 

MALIGNAN T LY8PHOMA, NOS 1 (2S) 

tHESENTERIC L. NODE (20) (48) (47) 

MALIGNANT LYMPHOMA, NOS 1 (2%) 

fLIVSR (20) (49) (49)

 

HALIG.LYHPHOHA. HI5TIOCYTIC TYPE 1L.J2KJ

 

t NUMBER OF ANIMALS BITH TISSOE EX1BINED HICBOSCOPICALLY 

* NUMBER OF ANIMALS NECPOPSIED 

47 
TABLE B1. MALE MICE: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

#SMALL INTESTINE (20) (48)

 

MAJ.I3NANT LYHPHOMA, NOS 1 (5X) 3 (6%)

 

tTHYMU S (17) (43) (43) 

HEMANGIOM A 1 12%) 

CIRCULATORY SYSTEM
 

NONE
 

DIGESTIVE SYSTEH
 

#LIVER (20) (49) (49)
 

CARCINOHA, NOS, METASTATIC
 

ADENOCARCINOMA, NOS, HETASTATIC 1 (2X)
 

HEPATOCELLULAR ADENOMA 1 (5X) 1 (2X) 1 (2<)
 

HEPATOCELLOLAP CABCINOHA 3 (1556) 10 (20X) 6 (12X)
 

#PANCREAS (20) C»8) (45)
 

CARCINOMA,NOS 2
 

#SMALL INTESTINE (20) (47) (48)
 

ADENOCASCINOMA, NOS 1 (2%) 1 (2%)
 

URINARY SYSTEM
 

NONE
 

ENDOCRINE SYSTEM
 

fPAMCREATIC ISLETS (20) (48) (45) 

ISLET-CEIL ADENOMA 1 (2%) 

REPRODUCTIV E SYSTEM 

NERVOU S SYSTEM 

#BPAIN (20) (49) (49) 

# NUMBE R OF ANIMAL S HITH TISSUE EXAMINE D HICBOSCOPICALLY 

* NUMBE R OF ANIMAL S NECROPSIED 

48 
_ _ _ __ _ _____ _ ___________ _ _ ___ _ ____ _

TABLE B1. MALE MICE: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

SPECIAL SENSE ORGANS
 

*EYE/LACRIMAL GLAND (20) (49) (49)
 

ADENOMA. NOS 1 (5%)
 

HUSCULOSKELETAL SYSTEM
 

NONE
 

BODY CAVITIES 

*MESENTEPY (20) (49) (49) 

­ LIPOM — ____« A 1 . _—__._ — — . — M___„.__ _•_.. __~, «___«__•»«.—.__—.«•»__.•> (2%) ' 

ALL OTHER SYSTEMS
 

*MULTIPLE ORGANS (20) (49) (49)
 

SARCOMA, NOS 1 (2X)
 

ANIMA L DISPOSITION SOnRARY 

ANIMALS INITIALLY IN STUDY 20 50 50 

NATURA L DEATHd 1 6 6 

MORIBUN D SACRIFICE 

SCHEDULED SACRIFICE 

ACCIDENTALLY KILLED 

TERMINA L SACRIFICE 19 43 43 

ANIMAL MISSING 1 1 

a-IHCLUPES AUTOLYZED ANIHALS
 

t NOHBER OF ANIHALS WITH TISSUE EXAHINED BICROSCOPICALLI 

* NUMBE R OF ANIMALS NECROPSIED 

49 
TABLE B1. MALE MICE: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

TUMOR SUMMAR Y 

TOTAL ANIHAL S WITH PRIMAR Y

TOTAL PRIMAR Y TUMORS 

 TUMORS* 12 

18 

32 

39 

28 

35 

TOTAL ANIMAL S WIT H BENIGN

TOTAL BENIGN TUMORS 

 TUMORS 6 

6 

7 

8 

8 

8 

TOTAL ANIMALS WITH MALIGNAN T

TOTAL MALIGNANT TUMORS 

 TUMORS 9 

12 

27 

31 

23 

27 

TOTAL ANIMALS BITH SECONDARY TUMOPSf

TOTAL SECONDARY TOMOBS

 3 

5 

TOTAL ANIHALS WITH TUMORS UNCERTAIN­ BENIGN OR MALIGNANT 

TOTAL UNCERTAIN TUMORS 

TOTAL ANIMALS WITH TUMORS

PRIMARY OR HETASTATIC 

 UNCERTAINTOTAL UNCERTAIN TUMORS
 

* PRIHARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 

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

50
 
TABLE B2.

 

SUMMARY OF THE INCIDENCE OF NEOPLASMS IN FEMALE MICE ADMINISTERED 

LEAD DIMETHYLDITHIOCARBAMATE IN THE DIET 

ANIMAL S INITIALLY IN STUDY

ANIMAL S NECROPSIE D

ANIMAL S EXAMINE D HISTOPATHOLOGICALL Y

INTEGUMENTAR Y SYSTEM 

*SKIN

FIBROSAHCOM A

HEMANGIOSARCOM A

*SU3CUT TISSUE

HEMANGIOM A

RESPIRATOR Y SYSTEM 

CARCINOMA , NOS, METASTATIC

ALVEOLAR/BRONCHIOLA R ADSNOM A

ALVEOLAR/RRONCHIOLAR CARCINOMA

HEHATOPOIETIC SYSTEM 

'MULTIPL E ORGAN S

MALIGNAN T LYMPHOMA , NOS

MALIG.LYMPHOMA , HISTIOCYTIC TYPE 

MAST-CELL TUMO R

*SPLEEN

HEMANGIOM A 

H2MANGIOSARCOM A 

MALIGNAN T LYMPHOMA , NO S 

#KESENTERI C L. NODE

MALIGNAN T LYMPHOMA , NO S 

MALIG.LYMPHOMA , HISTIOCYTIC TYPE 

tSMALL INTESTINE


MALIGNANT LY HPHOMAJ__NQS
 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

 20 50 50 

 20 50 50 

 20 50 50 

 (20) (50) (50) 

1 (5%) 

1 (2% ) 

 (20) (50) (50) 

1 (535) 

(20) (50) (50) 

1 (5«) 

2 (1 0%) 1 (2%) 2 (4^ ) 

1 (5JS) 3 (6%) 3 (6X) 

 (20) (50) (50) 

2 (10%) 11 (22%) 2 (4",) 

1 (2%) 

1 (5%) 

 (20) (50) (50) 

2 («*) 

1 (23) 

1 (25) 

 (20) (47) (49) 

2 (4?) 

1 (2%) 

 (19) (50) (50) 

* NUMBER OF ANIMALS KITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECEOPSIED
 

51
 
TABLE B2. FEMALE MICE: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

CIRCULATOR Y SYSTEM 

NONE 

DIGESTIVE SYSTEM 

tLIVER

HEPATOCELLULAR ADENOMA

HEPATOCELLULAR CARCINOMA

 (20) (50)

 1 (2%) 

 (50) 

1 (2*) 

URINARY SYSTEM 

NONE 

ENDOCRINE SYSTEM 

IPITUITARY

ADENOMA. NOS

 (20)

 1 (5%) 

 (41) (43) 

tADRENAL

CORTICAL ADENOMA

PHEOCHROMOCYTOMA

 (20) (48)

 1 (2%) 

 (50) 

1 (2S) 

#THYROI D

FOLLICULAR-CELL ADENOM A

 (20)

 1 (5%)

 (46) (49) 

2 (4% ) 

REPRODUCTIV E SYSTEM 

*MAMMAE Y GLAND

CARCINOMA,NO S

ADENOMA , NOS

CYSTftDENOMA , NOS

 (20)

 1 (5%) 

 (50) (50) 

2 (415) 

1 (2!5) 

#UTERUS

ENDOMETRIAL STROMA1 POLYP

HEMANGIOM A

HEMANGIOSARCOM A

 (20) (49)

 1 (2%) 

 (50) 

1

 1 

 (2«) 

NERVOUS SYSTEM 

NONE ; 

* NUMBE R

* NUMBER

 OF ANIMAL S WITH TISSDE

 OF ANIHALS NECROPSIED 

 EXAMINED MICROSCOPICALLY 

52 
TABLE B2. FEMALE MICE: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

SPECIAL SENSE ORGANS 

NONE 

MUSCULOSKELETAL SYSTEM 

NONE 

BODY CAVITIES 

*ABDOMINAL CAVITY

NEUROFIBROSARCOMA

 (20) (50)

 1 (235) 

 (50) 

ALL OTHER SYSTEMS 

NOME 

ANIMAL DISPOSITION SUMMARY 

ANIMALS INITIALLY IN STUDY

NATURAL DEATHS

MORIBUND SACRIFICE

SCHEDULED SACRIFICE 

ACCIDENTALLY KILLED 

TERMINAL SACRIFICE

ANIMAL MISSING 

 20

 3

 2

 15

 50

 11

 1 

 38

 50 

8 

 U2 

3 INCLUDES AUTQLYZED ANI_HALS 

t NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY 

* NUMBER OF ANIMALS NECROPSIED 

53
 
TABLE B2. FEMALE MICE: NEOPLASMS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

TUMO R SUMMAR Y 

TOTAL ANIMAL S WIT H PRIMAR Y

TOTAL PRIMAR Y TUMORS 

 TUMOR3* 9 

11 

18 

22 

18 

2H 

TOTAL ANIMAL S WIT H BENIGN

TOTAL BENIG N TUMORS 

 TUMORS 14 

5 

3 

3 

10 

12 

TOTAL ANIMAL S WIT H MALIGNAN T

TOTAL MALIGNAN T TUMORS 

 TUMORS 5 

5 

17 

19 

1 ) 

12 

TOTAL ANIMALS WITH SECONDARY TUMORS* 

TOTAL SECONDARY TUMORS 1 

TOTAL ANIMALS WITH TUMORS UNCERTillNBENIGN OR MALIGNANT

TOTAL UNCERTAIN TUMORS

 1 

1 

TOTAL ANIMALS WITH TUBOHS UNCERTAINPRIMARY OF MSTASTATIC 

TOTAL UNCERTAIN TUMORS
 

* PRI1ARY TUMORS: ALL TUMORS EXCEPT SECONDARY TUMORS
 

# SECONDARY TUMORS: METASTATIC TUMORS OR TUMOPS INVASIVE INTO AN ADJACENT OU3AS
 

54
 
APPENDIX C
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN RATS
 

ADMINISTERED LEAD DIMETHYLDITHIOCARBAMATE IN THE DIET
 

55
 

TABLE C1. 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE RATS ADMINISTERED 

LEAD DIMETHYLDITHIOCARBAMATE IN THE DIET 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

ANIMAL S INITIALLY IN STUDY 20 50 50 

ANIMAL S NECROPSIE D 20 50 50 

ANIMAL S EXAMINE D HI STOPATHOL03ICALL Y 20 50 50 

INTEGUMENTAR Y SYSTEM 

*SKIN (20) (50) (50) 

EPIDERMA L INCLUSION CYST 1 (2%)

 

RESPIRATOR Y SYSTEM 

#LUNG (20) (50) (53) 

BRONCHOPNEUMONIA , NOS 1 (2%) 

HYPERPLASIA , ALVEOLA R EPITHELIU M 3 (6%) 2 (4*) 

HEMATOPOIETIC SYSTEM 

JSPLEEN (19) (50) (53) 

HYPERPLASTI C NODULE 1 (2X) 

HYP^RPLASIA , RETICULU M CELL 1 (21) 

HYPERPLASIA . LYMPHOI D 1 (2S) 

HEMATOPOISSI S 1 (2?) 

*MANDIBOLA R L. NCDE (20) (50) (50) 

LYMPHANGIECTASI S 1 (5%) 

HYPERPLASIil , LYMPHOI D 1 (2%) 

SMESSNTERIC L., NODI (20) (50) (50)

 

LYMPHANGIECTASI S 1 (5%) 2 (4?)

 

CIRCULATOR Y SYSTEM 

#MYOCARDIU M (20) (50) (50) 

FIBPOSIS 2 (10%) 12 (2H%) 5 (103) 

DIGESTIV E SYSTF M 

*LIV5P (20) (50) (53)

 

METAMORPHOSI S FATTY 1 J5XJ. 1 (2%)

 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECPOPSIED
 

57
 
TABLE C1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

CYTOPLASHIC VACUOLIZ ATIOH 

FOCAL C5LLULAP CHANGE 

HEPATOCYTOSEGALY 

AHGIECTASIS 

tBIL3 DCCT 

HYPEPPLASIA, NOS 

•PANCREATIC ACINOS 

ATROPHY, NOS 

•ST01ACH 

INFLAMMATION, NOS 

ULCER, NOS 

U5INARY SYSTEM 

•KIDNEY 

HYDRONEPHROSIS 

PYELONEPHRITIS, NOS 

INFLAMMATION, CHRONIC 

•KIDNEY/CORTEX 

CYST, NOS 

•KIDNEY/PELVIS 

HYPERPLASIA, EPITHELIAL 

•URINARY BLADDER 

CAST, NOS 

HYPERPLASIA, EPITHELIAL 

ENDOCPINE SYSTEM 

•PITUITARY 

CYST, NOS 

ANGIECTASIS 

•ADRENAL CORTEX 

CYST, NOS 

LIPOIDOSIS 

HYPEBPLASIA, NOS 

•ADRENAL HEDOLLA 

HYPERPLASIA, HOS 

MATCHED 

CONTROL 

(20)

3 (15X) 

(18) 

(20) 

1 (5X) 

(20) 

17 (85X) 

(20) 

(20) 

(17) 

(20) 

(20)

1 (5X) 

1 (5X) 

(20) 

LOW DOSE 

2 (4%) 

(50)

10 (20*) 

(50) 

B (165) 

(50)

5 (10X) 

(5J) 

1 (2X) 

42 (84%) 

(50) 

(50) 

1 (2X) 

(49) 

3 (6X) 

1 (2X) 

(49) 

2 (4X) 

(50) 

1 (2X) 

1 (2X) 

(50) 

3 (6X1 

HIGH DOSE 

1 (2%) 

8 (16fc) 

2 (4%) 

1 (2%) 

(50) 

13 (26") 

(47) 

4 (9%) 

(50) 

1 (2%) 

1 (2*) 

(53) 

1 (2%) 

44 (83%) 

(50) 

1 (2<) 

(50) 

(48) 

1 (21) 

(49) 

3 (6X) 

1 (2S) 

(50) 

1 (2X) 

5 (13X) 

(50) 

3 J6%1 

t NUHBER OF ANIHALS WITH TISSUE EXAMINED HICFOSCOPICALLY
 

* NOHBER OF ANIHALS NECPOPSIED
 

58
 
TABLE C1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

•THYROID (20) (49) (50) 

FOLLICULAR CYST, NOS 2 (4%) 

INFLAKHATION, CHRONIC FOCAL 1 (2%) 

HYP5RPLASIA, C-CELL 3 (15%) 2 (4S) 12 (24%) 

HYPERPLASIA, FOLLICULAH-CELL 1 (2%) 

REPRODUCTIVE SYSTEH 

•PROSTATE (16) (49) (50) 

INFLAHHATION, ACUTE 3 (19%) 8 (16X) 3 (65) 

fTESTIS (20) (49) (50) 

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

ASPERHATO GENESIS 2 (4%) 

*EP!DIDYHIS (20) (50) (50)

 

IN?LAHMATION, ACUTE 1 (2X)

 

NERVOUS SYSTEH 

tBRAIN (23) (50) (50) 

HEMOPFHAG H 1 (5%) 1 (2*) 1 (2",) 

SPECIAL SENSE OPGANS 

*EYF (20) (50) (50) 

HFHORRHAG E 1 (21) 

INFLAMMATION . NOS 1 (2=5) 

flUSCULOSKELETAL SYSTEH 

NONE 

BODY CAVITIES 

*SESENTSPY (20) (50) (50) 

PEPIAPTEBITIS 1 (2%) 2 (4*) 

ALL CTKFP SYSTEMS 

*«ULTI?LF. ORGAN S (23) (53) P» 

* SUS3EH OF ANIMALS BITK TISSUE EXAMINED SIC8OSCOPICALLY
 

* »;U«3ER OF ANIHALS NECPOPSIED
 

59
 
TABLE C1. MALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

ADIPOSE TISSUE 

STEATITIS 

SPECIAL MORPHOLOGY SUMMARY 

NO LESION REPORTED
 

* NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECPOPSIED
 

60
 
TABLE C2. 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE RATS ADMINISTERED 

LEAD DIMETHYLDITHIOCARBAMATE IN THE DIET 

MATCHED 

CONTROL LOW DOSE 

ANIMALS INITIALLY IN STUDY 20 50 

ANIHAL S NECROPSIED 20 50 

ANIHAL S EXAMINE D HISTOPATHOIOGICALLY 2 0 50 

INTEGUMENTARY SYSTEM
 

NONE
 

RESPIRATORY SYSTEM
 

*LUN3 (20) (50)
 

PNEUMONIA, ASPIRATION 1 (5»)
 

INFLAMMATION, ACUTE SUPPURATIVE 1 (2%)
 

INFLAMMATION, CHRONIC 2 (4X)
 

HYPERPLASIA, ALVEOLAR EPITHELIUM 1 (2%)
 

HEMATOPOIETIC SYSTEM
 

#SPLEEN (20) (50)
 

HEMOSIDEROSIS 2 (4«)
 

HYPSRPLASIA. LYMPHOID 1 (2%)
 

HEMATOPOIESIS 1 (2%)
 

tSPLENIC CAPSULE (20) (50)
 

GRANULATION, TISSUE 1 (2%)
 

#MANDIBULAR L. NODE (20) (50)
 

LYSPHANGIECTASIS 1 (2%)
 

CIRCULATORY SYSTEM
 

fHEART (20) (50)
 

FIBROSIS 1 (2%)
 

PEPIAFTEPITIS 1 (5%)
 

((MYOCARDIUM (20) (50) _
 

. INFLAMMATION, FOCAL ._ 1 1521
 

# NUMBER OP ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 * NUMBER OF ANIMALS NECROPSIED
 

61
 

HIGH DOSE 

50
 

50
 

50
 

(50)
 

(50)
 

3 (635)
 

2 (4)5)
 

1 (2«)
 

(50)
 

(50)
 

(50)
 

(50)
 
TABLE C2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE 

FIB^OSIS 1 (2% ) 

#ENDOCARDIU M 

HYPEPPLASIA , NOS 

(20) (50) 

DIGESTIVE SYSTEM 

tLIVEP (20) (50) 

NECROSIS , NOS 3 (6% ) 

NECROSIS, FOCAL 1 (5%) 

METAMORPHOSI S FATTY 1 (2%) 

FOCAL CELLULA P CHANGE 7 (35%) 21 (42%) 

#HEPATIC CAPSDLE (20) (50) 

FIBPOSIS, FOCAL 1 (5%) 

*LIVER/CENTRILOBULA P (20 ) (50) 

DEGENEPATION , NO S 1 (5%) 1 (2% ) 

#BII.E DUCT (20) (50) 

INFLAMMATION , NO S 1 (5%) 1 (2%) 

HYPERPLASIA , NOS 6 (12%) 

IPANCREA S (20) (50) 

FIBROSIS, FOCAL 1 (2%) 

• PANCREATIC ACINU S (20) (50) 

ATROPHY, NOS 9 (1855) 

#STOMAC H (20) (<*9) 

INFLAMMATION , NO S 

IPEY5RS PATCH (20) (50) 

HYPERPLASIA , LYMPHOID 1 12%) 

tSMAL L INTEST./SEROSA (20) (50) 

GRANULATION , TISSUE 1 (2X) 

tLAPG E INTESTINE (12) (45) 

NEMATODIASIS 1 (8*) 1 (2%) 

URINAR Y SYSTEM 

#KIDNE Y (20) (50) 

MINERALIZATIO N 1 (2*1 

t NUMBER OF ANIHALS WITH TISSUE EXAMINED MICEOSCOPICALLY
 

* NUKBER OF ANIHALS NECROPSIED
 

HIGH DOSE 

2 (4? ) 

(50) 

1 (2X ) 

(50) 

1 (23) 

4 (8JJ) 

(50) 

(50) 

2 (47.) 

(50) 

2 (4X) 

(49) 

(49) 

7 (14%) 

(50) 

1 (2< ) 

(48) 

1 (2R) 

(48) 

(45) 

(50) 

62
 
TABLE C2. FEMALE RATS: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE 

HYDRONEPHROSI S 

INFLAMMATION , CHRONIC 

PYELONEPHRITIS , CHRONIC 

CALCIFICATION, NOS 

11 (55%) 

1 

24 

1 

(2%) 

(48%) 

(2%) 

tKIDNEY/PELVI S 

NECROSIS, NOS 

(20) (50) 

1 (2% ) 

tUPINAR Y BLADDER 

INFLAMMATION , NOS 

(20) (49) 

1 (2% ) 

ENDOCRIN E SYSTEM 

#PITUITARY (19) (50) 

CYST, NOS 1 (5%) 5 (10%) 

ANGIECTASI S 4 (21%) 4 (8%) 

JADPENA L (20) (50) 

ANGIECTASIS 1 (5%) 

#ADPENA L CORTEX (20) (50) 

LTPOIDOSIS 1 (2%) 

HYPERPLASIA , NOS 3 (15*) 9 (18%) 

#ADFENA L MEDULLA (20) (50) 

HYPEPPLASIA , NOS 2 (4% ) 

tTHYROI D (20) (50) 

FOLLICULA P CYST, SOS 

HYPEP.PLASIA , C-CELL I D (50*) 12 (24%) 

REPRODUCTIV E SYSTEM 

*MAMMAR Y GLAN D (20) (53 ) 

DILATATION/DUCTS 4 (20%) 3 (6%) 

fUTF.E'JS (20) (50) 

D2CIDU A 1 (2% ) 

#UTERUS/ENDO«ETRIU M (20 ) (50) 

CYST, NOS 1 (555) 2 (4% ) 

#OVA5 Y (20) (50) 

CYST, NOS 1 .15X1 2 Jtil 

t NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NU13KR OF ANIMALS NSCFOPSIED
 

HIGH 

16 

2 

(50) 

(49 ) 

(43) 

3 

4 

(50) 

(53) 

1 

10 

(50) 

(48) 

3 

4 

(50 ) 

3 

(49) 

(49 ) 

1 

(50) 

DOSE 

(32% ) 

(4*) 

(6? ) 

(3«) 

(2% ) 

(20% ) 

(65?) 

(3X) 

(6X ) 

(2%) 

63
 
TABLE C2. FEMALE RATS: NONNEOPLASTIC

FOLIIC'JLAH CYST. NOS

CORPUS LUTEU M CYST

NERVOU S SYSTEM 

tBRAI N

H310PRHAG1?

SPECIAL SENSE ORGANS
 

*EYE


CATARACT .


MUSCULOSKELETAL SYSTEM
 

NONE
 

BODY CAVITIES
 

*MESENTERY


PERIARTERITIS


ALL OTHER SYSTEMS
 

*MULTIPLE ORGANS


PEBIARTERITIS


SPECIAL MORPHOLOGY SUMMARY
 

NO LFSION REPORTED


 LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

1 (2)4 ) 

1 (2%) 

 (25) (5D ) (49) 

1 (2% ) 

 (20)	 (50) (50)
 

1 (5*) 1 (2%)
 

 (20)	 (50) (50)
 

1 (5X) 1 (255)
 

 (20)	 (50) (50)
 

1 (2X)
 

1	 1 4
 

t	 NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

*	 NUMBER OF ANIMALS NECROPSIED
 

64
 
APPENDIX D
 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MICE
 

ADMINISTERED LEAD DIMETHYLDITHIOCARBAMATE IN THE DIET
 

65
 

TABLE 01. 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN MALE MICE ADMINISTERED 

LEAD DIMETHYLDITHIOCARBAMATE IN THE DIET 

MATCHED
 

CONTROL LOW DOSE HIGH DOSE
 

ANIBALS INITIALLY IN STUDY 20 50 50
 

ANIMALS BISSINS 1 1
 

ANIHALS NECROPSIED 20 49 49
 

ANIMALS EXAMINED HISTOPATHOLOGICALLY 29 49 49
 

INTEGUMENTARY SYSTEM
 

*SKIN (20) (49) (49)
 

ABSCESS, NOS 1 (255)
 

*SU3CUT TISSUE (20) (49) (49)
 

ABSCESS, NOS 1
 

RESPIRATORY SYSTEM
 

SLUN G (20) (48) (49) 

HEHORPHAG E 2 (495) 

ALVEOLA R KACROPHAGE S 1 (2%) 

HEMATOPOIETIC SYSTEM 

#SPIEE N (20) (47) (47) 

HEBORRHAGIC CYST 1 (5X) 

NECROSIS, FOCAL 1 (2%) 

KYPFPPLASIA, LYMPHOID 1 (5%) 6 (13X) 1 (2*) 

HEMATOPOIESIS 1 (5X) 

SBESENTEPIC 1. NODE (20) (48) (47) 

CYST, NOS 1 (2?) 

INFLAMMATION, GHANULOBATOUS 1 (5X) 

HYPSRPLASIA, LYMPHOID 1 (2%) 1 (2*) 

fTHYIUS (17) (43) (43) 

ATROPHY, NOS 1 (6X) 

HYPERPLASIA, LYMPHOID 1 (2*) 1 (2S) 

CIRCULATOR Y SYSTEM 

IHEART (20) (48) (49) 

__ PSSIARTE1ITI.S 

t NUMBE R OF ANIBALS WITH TISSUE EXARIHED MICROSCOPICALLY 

* NUMBER OF ANIMAL S NECROPSIED 

67 
TABLE 01. MALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

• MYOCARDIU M (20) C*8) (49)

 

INFLAMMATION , FOCAL 1 (5%) 

DIGESTIVE SYSTEM 

•LIVER (20) (<49) (49) 

LYMPHOCYTIC INFLAMMATORY INFILTR 1 (5%) 

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

CYTOPLASMIC VACUOLIZATION 2 (10%) 2 (4*) 

BASOPHILIC CYTO CHANGE 2 (4%) 

•LIVER/HEPATOCYTES	 (20) (49) (49)

 

CYTOPLASMIC VACUOLIZATION 1 (2%)

 

•STOMACH	 (20) (49) (49)

 

INFLAMMATION , FOCAL 1 (2%)

 

• SMALL INTESTINE (20) (47) (48) 

POLYPOID HYPERPLASIA	 1 (2%)
 

URINARY SYSTEM
 

•KIDNEY	 (20) (49) (49)
 

HYDRONEPHPOSIS 1 (2%)
 

LYMPHOCYTIC INFLAMMATORY INFILTR 1 (5«) 1 (2%) 2 (4^)
 

INFLAMMATION, CHRONIC 1 (2%)
 

ENDOCRINE SYSTEM
 

• PITUITAPY (19) (45) (45)
 

CYST, NOS 1 (55?) 1 (2%)
 

•THYROID	 (19) (48) (49)
 

CYSTIC FOLLICLES 1 (2*)
 

FOLLICULAR CYST, NOS 1 (555) J M)
 

•PANCREATIC	 ISLETS (20) (48) (45)
 

HYPEHPLASIA, NOS 1 (2"'.)
 

REPRODUCTIVE SYSTEM
 

*MAMMARY GLAND (20) (49) (49)
 

HY PE.R PL ASI AA_ CYSTIC
 

# NUHBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECROPSIED
 

68 
TABLE D1. MALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

#TESTIS

ATROPHY. DOS

 (20) (48)

 2 (4%) 

 (49) 

NERVOU S SYSTEM 

#BRAI N

MINERALIZATIO N

 (23)

 7 (35%)

 (49)

 20 (41% )

 (U9 ) 

 17 

SPECIAL

NONE 

 SENSE ORGAN S 

JiUSCULOSKELETAL SYSTEH 

*LUMBA R VERTEBR A

SPONDYLOLISTHESIS

 (20) (49)

 1 (2% ) 

 (49) 

BODY CAVITIES 

NONE 

ALL OTHER

NONE 

 SYSTEMS 

SPECIAL MORPHOLOG Y SUMMAR Y 

N O LESION REPORTED

ANIMA L MISSING/NO NECROPSY

f NUMBER OF ANIMAL S HITH TISSUE

* NUMBER OF ANIMALS NECHOPSIED 

5 

 EXAMINED MICROSCOPICALLY 

5 

1

8 

1 

69 
__ 

TABLE D2. 

SUMMARY OF THE INCIDENCE OF NONNEOPLASTIC LESIONS IN FEMALE MICE ADMINISTERED 

LEAD DIMETHYLDITHIOCARBAMATE IN THE DIET 

ANIMALS INITIALLY IN STUDY
 

ANIMALS 'NECROPSIED
 

ANIMALS EXAMINED HI STO PATHOLOGICALLY
 

INTEGUMENTARY SYSTEM
 

NONE
 

RESPIRATORY SYSTEM
 

#LUN3
 

LYMPHOCYTIC INFLAMMATORY INFILTR
 

HEMATOPOIETIC SYSTEM
 

*BLOOD
 

LEUKOPENIA, NOS
 

tSPLEEN
 

ECTOPIA
 

HYPEPPLASIA, LYMPHOID
 

HEMATOPOIESIS
 

tMANDIBULAR L. NODE
 

HYPEPPLASIA, LYMPHOID
 

IMESENTEPIC L. NODE
 

INFLAMMATION, GRANULOMATOUS
 

HYPERPLASIA, LYMPHCID
 

#THY1US
 

LIPOIDOSIS
 

HYPEPPLASIA, LYKPHOID
 

CIPCULATOPY SYSTEM 

IMYOCAPDI'J M 

INFLAMMATION*. FOCAL
 

MATCHED 

CONTROL 

——~ ——— — 

LOW DOSE 

20 

20 

20 

50 

50 

50 

(20) 

3 (15%) 

(50) 

2 (456) 

(20) (50) 

(20) 

2 (1DS) 

7 (35%) 

(20) 

(20) 

1 (5%) 

(50) 

1 (2%) 

1 (258) 

1 (2*) 

(HI) 

1 (2%) 

(HI) 

(19) 

1 (5<8) 

(HH) 

1 (256) 

(20) (50) 

# NUMBEP OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUM3SP OF ANIMALS NECPOPSIED
 

70 

HIGH DOSE
 

50
 

50
 

50
 

(50)
 

H (3%)
 

(50)
 

1 (2?)
 

(50)
 

4 (8X)
 

1 (238)
 

(49)
 

1 (2*)
 

(U9)
 

1 (2*)
 

(U7)
 

(5"))
 
TABLE D2. FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE 

DIGESTIVE SYSTEM 

#SALIVAR Y GLAN D (18) (46) 

LYKPHOCYTI C INFLAMMATOR Y INFILTR 1 (6%) 

#LIVSR (20) (50) 

INFLAMMATION , NOS 

LYMPHOCYTI C INFLAMMATOR Y INFILTR 

1 (5%) 

3 (6%) 

NECROSIS, FOCAL 1 (5%) 

CYTOPLASMI C V ACUOLIZATIO N 1 (2% ) 

HEPATOCYTOMEGAL Y 

HYPEPPLASIA , FOCAL 

ANGIECTASI S 1 (53S) 

tLIYER/HEPATOCYTE S (20) (50) 

CYTOPLASMIC VACUOLI Z ATION 2 (4%) 

tBILE DUCT (20) (50) 

INFLAMMATION , NC S 1 (5%) 

# PA NC R EA S (20) (45) 

CYST, NOS 

CYSTIC DUCTS 1 (5% ) 

INFLAMMATION , GR ANULOMATOO S 1 (556) 

ISTOMAC H (20) (50) 

CYST, NOS 1 (2% ) 

INFLAMMATION , FCCAL 1 (555) 1 (2%) 

#SMAL L INTESTIN E (19) (50) 

POLYPOI D HYPEPPLASI A 1 (2% ) 

#LAB^ E INTESTIN E (19) (149) 

PEPIARTERITI S 1 (5"&) 

HYPERPLASIA , LYMPHOI D 

URINAR Y SYSTEM 

#KIDNE Y (20) (53) 

HYDRONEPHFOS I S 

HEMOFPHAG E 

LYMPHOCYTI C INFLAMMATOR Y INFILTR 1 (5S) 4 (8%) 

PERIARTEEITI S 1_J5351 _. 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 * NUMBER OF ANIMALS NECPOPSIED
 

HIGH DOSE 

(48) 

(50) 

3 (6X ) 

1 (256) 

1 (2?) 

2 (4U ) 

(50) 

1 (2*) 

(50) 

(49) 

1 (2t) 

(50) 

1 (2X ) 

(50) 

(50) 

1 (2%) 

(50 ) 

2 (4S) 

1 (2*) 

6 (12% ) 

71
 
TABLE 02. FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

INFAPCT, NOS
 

AMYLOIDOSIS
 

tURTNARY BLADDER
 

LYMPHOCYTIC INFLAMMATORY INFILTR
 

PERIAFTEHITIS
 

ENDOC3I5J3 SYSTEM
 

tADREN AL
 

CYST, NOS
 

#ADPENAL CORTEX
 

HYP3RPLASIA, NOS
 

STHYROID
 

F01LICULAP CYST, NOS
 

PEPRODUCTIVE SYSTEM
 

#UTER(JS/ENDOHETPI'JM
 

CYST. NOS
 

#OVARY
 

CYST, NOS
 

NEPVCUS SYSTEM
 

•BRAIN
 

MINERALIZATION
 

PERIAETSRITIS
 

SPECIAL SENSE ORGANS
 

NONE
 

MUSCULOSKELETAL SYSTEM
 

NONE
 

MATCHED
 

CONTROL
 

(17)
 

1 (6*)
 

(20)
 

(20)
 

1 (5X)
 

(20)
 

1 (5«)
 

(20)
 

11 (55X)
 

(19)
 

7 (37X)
 

(20)
 

8 (40%)
 

1 (5X)
 

LOW DOSE
 

1 (2%)
 

1 (2%)
 

(47)
 

(48)
 

(48)
 

(46)
 

4 (9%)
 

(49)
 

23 (47%)
 

(47)
 

9 (19*)
 

(47)
 

18 (38%)
 

HIGH
 

(48)
 

2
 

(53)
 

1
 

(50)
 

(49)
 

4
 

(50)
 

22
 

(49)
 

10
 

(50)
 

18
 

DOSE
 

(4<)
 

(2X)
 

(3*)
 

(44«)
 

(20*)
 

(36%)
 

# NUMBER OF ANIMALS WITH TISSUE EXAMINED MICROSCOPICALLY
 

* NUMBER OF ANIMALS NECEOPSIED
 

72
 
TABLE 02. FEMALE MICE: NONNEOPLASTIC LESIONS (CONTINUED) 

MATCHED 

CONTROL LOW DOSE HIGH DOSE 

BODY CAVITIES 

*PL2URA

INFLAMMATION , FOCAL

*MESENTEE Y

LYMPHOCYTIC INFLAMMATOR Y INFILTR

INFLAMMATION , FOCAL GRANULOMATO U

 (21)

 1

 (20)

 1

 (58)

 (5S) 

 (51)

 1 (2%) 

 (50)

 1 (2%) 

 (50) 

 (50) 

A LL OTHER SYSTEMS 

NONE 

SPECIAL MORPHOLOG Y SUMMAR Y 

NO LESION REPORTE D

A'JTO/NECPOPSY/HISTO PERF

# NUMBE R OF ANI1AI.S WITH TISSUE

* NUMBE R OF ANIMAL S N3CROPSISD 

 EXAMINE D MICROSCOPICALLY 

6

 1

 « 

1 

73 

APPENDIX E
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS IN RATS
 

ADMINISTERED LEAD DIMETHYLDITHIOCARBAMATE IN THE DIET
 

75
 

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

Administered Lead Dimethyldithiocarbamate in the Diet (a) 

Matched Low High 

Topography: Morphology Control Dose Dose 

Lung: Alveolar/Bronchiolar 

Adenoma(b) 2/20 (10) 5/50 (10) 5/50 (10) 

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

Relative Risk (f) 1.000 1.000 

Lower Limit 0.184 0.184 

Upper Limit 10.007 10.007 

Weeks to First Observed Tumor 104 104 104 

Hematopoietic System: 

Lymphomas (b) 8/20 (40) 15/50 (30) 12/50 (24) 

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

Relative Risk (f) 0.750 0.600 

Lower Limit 0.373 0.280 

Upper Limit 1.765 1.471 

Weeks to First Observed Tumor 77 87 89 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats
 

Administered Lead Dimethyldithiocarbamate in the Diet (a)
 

(continued)
 

Matched Low
 

Topography: Morphology Control Dose
 

Hematopoietic System:
 

Lymphomas or Leukemias (b) 8/20 (40) 15/50 (30)
 

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

Relative Risk (f) 0.750
 

Lower Limit 0.373
 

Upper Limit 1.765
 

Weeks to First Observed Tumor 77 87
 

-J Pituitary: Adenomas, NOS (b) 7/20 (35) 16/49 (33)
 00
 

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

Relative Risk (f) 0.933
 

Lower Limit 0.448
 

Upper Limit 2.331
 

Weeks to First Observed Tumor 104 89
 

High
 

Dose
 

13/50 (26)
 

N.S.
 

0.650
 

0.311
 

1.570
 

89
 

9/49 (18)
 

N.S.
 

0.525
 

0.211
 

1.464
 

99
 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats
 

Administered Lead Dimethyldithiocarbamate in the Diet (a)
 

(continued)
 

Topography: Morphology

Matched 

 Control 

Low 

Dose 

High 

Dose 

Adrenal: Pheochromocytoma (b) 3/20 (15) 11/50 (22) 8/50 (16) 

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

Relative Risk (f) 

Lower Limi t 

Upper Limit 

1.467 

0.450 

7.594 

1.067 

0.295 

5.813 

Weeks to First Observed Tumor 104 81 66 

Thyroid: C-Cell Adenoma or
 

Carcinoma (b) 1/20 (5) 5/49 (10) 7/50 (14)
 

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

Relative Risk (f) 2.041 2.800
 

Lower Limit 0.254 0.403
 

Upper Limit 94.440 123.407
 

Weeks to First Observed Tumor 104 95 85
 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats
 

Administered Lead Dimethyldithiocarbamate in the Diet (a)
 

(continued)
 

Matched Low
 

Topography: Morphology Control Dose
 

Pancreatic Islets: Islet-


Cell Adenoma (b) 1/18 (6) 3/50 (6)
 

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

Relative Risk (f) 1.080
 

Lower Limit 0.096
 

Upper Limit 55.565
 

oo
 

o Weeks to First Observed Tumor 104 104
 

Testis: Interstitial-Cell
 

Tumor (b) 16/20 (80) 40/49 (82)
 

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

Relative Risk (f) 1.020
 

Lower Limit 0.813
 

Upper Limit 1.419
 

Weeks to First Observed Tumor 77 80
 

High
 

Dose
 

2/47 (4)
 

N.S.
 

0.766
 

0.043
 

44.252
 

104
 

37/50 (74)
 

N.S.
 

0.925
 

0.732
 

1.334
 

89
 
Table El. Analyses of the Incidence of Primary Tumors in Male Rats
 

Administered Lead Dimethyldithiocarbamate in the Diet (a)
 

(continued)
 

(a) Dosed groups received 25 or 50 ppm.
 

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

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


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

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

the comparison of that dosed group with the matched-control group when P less than 0.05; otherwise, not significant (N.S.) is indicated.
 

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

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

comparison.
 

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

Administered Lead Dimethyldithiocarbamate in the Diet (a)
 

Matched Low
 

Topography: Morphology Control Dose
 

Lung: Alveolar/Bronchiolar
 

Adenoma (b) 1/20 (5) 4/50 (8)
 

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

Relative Risk (f) 1.600
 

Lower Limit 0.175
 

Upper Limit 77.169
 

Weeks	 to First Observed Tumor 104 104
 

00
 to	 Pituitary: Adenoma, NOS (b) 4/19 (21) 13/50 (26)
 

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

Relative Risk (f) 1.235
 

Lower Limit 0.454
 

Upper Limit 4.716
 

Weeks	 to First Observed Tumor 104 81
 

High
 

Dose
 

3/50 (6)
 

N.S.
 

1.200
 

0.106
 

61.724
 

104
 

17/48	 (35)
 

N.S.
 

1.682
 

0.658
 

6.170
 

82 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Administered Lead Dimethyldithiocarbamate in the Diet (a)
 

(continued)
 

Matched Low
 

Topography: Morphology Control Dose
 

Hematopoietic System: All Lymphomas (b) 1/20 (5) 8/50 (16)
 

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

Relative Risk (f) 3.200
 

Lower Limit 0.482
 

Upper Limit 138.771
 

Weeks to First Observed Tumor 99 77
 

oo
 

u>
 Thyroid: C-Cell Adenoma or
 

Carcinoma (b) 0/20 (0) 5/50 (10)
 

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

Relative Risk (f) Infinite
 

Lower Limit 0.525
 

Upper Limit Infinite
 

Weeks to First Observed Tumor 104
 

High
 

Dose
 

10/50 (20)
 

N.S.
 

4.000
 

0.642
 

169.457
 

35
 

5/48 (10)
 

N.S.
 

Infinite
 

0.547
 

Infinite
 

94
 
00 

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

Administered Lead Dimethyldithiocarbamate in the Diet (a)
 

(continued)
 

Matched Low High
 

Topography: Morphology Control Dose Dose
 

Mammary Gland: Fibroadenoma (b) 6/20 (30) 8/50 (16) 6/50 (12)
 

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

Relative Risk (f) 0.533 0.400
 

Lower Limit 0.194 0.126
 

Upper Limit 1.669 1.345
 

Weeks to First Observed Tumor 82 100 104
 

Uterus: Endometrial Stromal
 

Polyp (b) 4/20 (20) 7/50 (14) 5/49 (10)
 

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

Relative Risk (f) 0.700 0.510
 

Lower Limit 0.207 0.126
 

Upper Limit 2.994 2.367
 

Weeks to First Observed Tumor 82 80 104
 
Table E2. Analyses of the Incidence of Primary Tumors in Female Rats
 

Administered Lead Dimethyldithiocarbamate in the Diet (a)
 

(continued)
 

(a) Dosed groups received 25 or 50 ppm.
 

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

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


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

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

the comparison of that dosed group with the matched-control group when P less than 0.05; otherwise, not significant (N.S.) is indicated.
 

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

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

comparison.
 

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

APPENDIX F
 

ANALYSES OF THE INCIDENCE OF PRIMARY TUMORS IN MICE
 

ADMINISTERED LEAD DIMETHYLDITHIOCARBAMATE IN THE DIET
 

87
 

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

Administered Lead Dimethyldithiocarbamate in the Diet (a) 

Topography: Morphology

Matched 

 Control 

Low 

Dose 

High 

Dose 

Lung: Alveolar /Bronchiolar 

Carcinoma (b) 5/20 (25) 10/48 (21) 12/49 (24) 

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

Relative Risk (f) 

Lower Limit 

Upper Limit 

0.833 

0.309 

2.794 

0.980 

0.384 

3.184 

c» 

Weeks to First Observed Tumor 105 86 105 

Lung: Alveolar /Bronchiolar 

Carcinoma or Adenoma (b) 9/20 (45) 14/48 (29) 15/49 (49) 

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

Relative Risk (f) 

Lower Limit 

Upper Limit 

0.648 

0.331 

1.451 

0.680 

0.354 

1.506 

Weeks to First Observed Tumor 105 86 105 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice
 

Administered Lead Dimethyldithiocarbamate in the Diet (a)
 

(continued)
 

Topography: Morphology


Hematopoietic System:
 

Lymphomas or Leukemias (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


VO 

o	 All Sites: Hemangioma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched
 

 Control
 

 2/20 (10)
 

 N.S.
 

 105
 

 0/20 (0)
 

 N.S.
 

Low
 

Dose
 

5/49 (10)
 

N.S.
 

1.020
 

0.188
 

10.204
 

105
 

3/49 (6)
 

N.S.
 

Infinite
 

0.255
 

Infinite
 

105
 

High
 

Dose
 

4/49 (8)
 

N.S.
 

0.816
 

0.131
 

8.603
 

90
 

2/49 (4)
 

N.S.
 

Infinite
 

0.125
 

Infinite
 

105
 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice
 

Administered Lead Dimethyldithiocarbamate in the Diet (a)
 

(continued)
 

Matched Low
 

Topography: Morphology Control Dose
 

All Sites: Hemangioma or
 

Hemangiosarcoma (b) 1/20 (5) 5/49 (10)
 

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

Relative Risk (f) 2.041
 

Lower Limit 0.254
 

Upper Limit 94.440
 

vo Weeks to First Observed Tumor 105 76
 

Liver: Hepatocellular Carcinoma (b) 3/20 (15) 10/49 (20)
 

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

Relative Risk (f) 1.361
 

Lower Limit 0.406
 

Upper Limit 7.138
 

Weeks to First Observed Tumor 105 67
 

High
 

Dose
 

3/49 (6)
 

N.S.
 

1.224
 

0.108
 

62.958
 

100
 

6/49 (12)
 

N.S.
 

0.816
 

0.199
 

4.706
 

55
 
Table Fl. Analyses of the Incidence of Primary Tumors in Male Mice
 

Administered Lead Dimethyldithiocarbamate in the Diet (a)
 

(continued)
 

Matched Low High
 

Topography : Morphology Control Dose Dose
 

Liver: Hepatocellular Carcinoma
 

or Adenoma (b) 4/20 (20) 11/49 (22) 7/49 (14)
 

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

Relative Risk (f) 1.122 0.714
 

Lower Limit 0.392 0.211
 

Upper Limit 4.404 3.052
 

Weeks to First Observed Tumor 105 67 55
 

(a) Dosed groups received 25 or 50 ppm.
 

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

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


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

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

the comparison of that dosed group with the matched-control group when P less than 0.05; otherwise, not significant (N.S.) is indicated.
 

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

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

comparison.
 

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

Administered Lead Dimethyldithiocarbamate in the Diet (a)
 

Topography: Morphology


Lung: Alveolar/Bronchiolar
 

Carcinoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor


Lung: Alveolar/Bronchiolar
 

Carcinoma or Adenoma (b)


P Values (c,d)


Relative Risk (f)
 

Lower Limit
 

Upper Limit
 

Weeks to First Observed Tumor
 

Matched Low High 

 Control Dose Dose 

 1/20 (5) 3/50 (6) 3/50 (6) 

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

1.200 1.200 

0.106 0.106 

61.724 61.724 

 105 99 105 

 3/20 (15) 4/50 (8) 5/50 (10) 

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

0.533 0.667 

0.102 0.147 

3.410 4.014 

105 99 95 
Table F2. Analyses of the Incidence of Primary Tumors in Female Mice
 

Administered Lead Dimethyldithiocarbamate in the Diet (a)
 

(continued)
 

Topography: Morphology

Matched 

 Control 

Low 

Dose 

High 

Dose 

Hematopoietic System: 

Lymphomas (b) 2/20 (10) 13/50 (26) 7/50 (14) 

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

Relative Risk (f) 

Lower Limit 

Upper Limit 

2.600 

0.677 

22.444 

1.400 

0.303 

13.138 

Weeks to First Observed Tumor 94 24 99 

All Sites: Hemangioma (b) 1/20 (5) 0/50 (0) 3/50 (6)
 

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

Relative Risk (f) 0.000 1.200
 

Lower Limit 0.000 0.106
 

Upper Limit 7.475 61.724
 

Weeks to First Observed Tumor 105
 78 
Table F2. Analyses of the Incidence of Primary Tumors in Female Mice
 

Administered Lead Dimethyldithiocarbamate in the Diet (a)
 

(continued)
 

Topography; Morphology 

Matched 

Control 

Low 

Dose 

High 

Dose 

All Sites: Hemangioma or 

Hemangiosarcoma (b) 1/20 (5) 1/50 (2) 4/50 (8) 

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

Relative Risk (f) 

Lower Limit 

Upper Limit 

0.400 

0.005 

30.802 

1.600 

0.175 

77.169 

Weeks to First Observed Tumor 105 105 78 vo
 

(a) Dosed groups received 25 or 50 ppm.
 

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

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


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

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

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

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

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

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

comparison.
 

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

control group.
 

Review of the Bioassay of Lead Dimethyldithiocarbamate* for Carcinogenicity
 

by the Data Evaluation/Risk Assessment Subgroup
 

of the Clearinghouse on Environmental Carcinogens
 

December 13, 1978
 

The Clearinghouse on Environmental Carcinogens was established
 

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

Provisions of the Federal Advisory Committee Act. The purpose of
 

the Clearinghouse is to advise the Director of the National Cancer
 

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

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

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

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

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

chemistry, biochemistry, biostatistics, toxicology, pathology, and
 

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

of the Clearinghouse is charged with the responsibility of providing
 

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

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

The reviewer for the report on the bioassay of Lead Dimethyldithiocarbamate agreed with the conclusion in the report that the compound was
 

not carcinogenic under the conditions of test. After a brief description
 

of the experimental design, he said that there were no highlights worth
 

noting. He opined that maximum tolerated doses (MTD) may not have been
 

tested, since there were no chronic signs of toxicity. Also an earlier
 

study had reported using much higher dose levels. Based on the results
 

of the study, he said that there was no evidence that Lead Dimethyldithiocarbamate posed a carcinogenic hazard to man.
 

One Subgroup member wondered if the compound dissociated such
 

that the lead component itself would be available to induce tumors.
 

A discussion ensued as to whether the treated animals exhibited any
 

of the biological effects usually associated with lead.
 

There was no objection to the reviewer's motion that 1) the
 

report on the bioassay of Lead Dimethyldithiocarbamate be accepted
 

as written and 2) the compound be considered for retest since the
 

MTD may not have been attained in the chronic study.
 

97
 
Clearinghouse Members Present:
 

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

Joseph Highland, Environmental Defense Fund
 

William Lijinsky, Frederick Cancer Research Center
 

Henry Pitot, University of Wisconsin Medical Center
 

Verne A. Ray, Pfizer Medical Research Laboratory
 

Verald K. Rowe, Dow Chemical USA
 

Michael Shimkin, University of California at San Diego
 

Louise Strong, University of Texas Health Sciences Center
 

Kenneth Wilcox, Michigan State Health Department
 

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

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

Thus, certain comments and criticisms reflected in the review may
 

no longer be appropriate.
 

*US. GOVERNMENT PRINTING OFFICE: 1979 281-217/3153 1-3 98 



NIH Publication No. 79-1707