nr>Acr EXTERNAL
UKAr REVIEW DRAFT
DO NOT QUOTE OR CITE MAY 1978
CARCINOGEN ASSESSMENT GROUP'S
ASSESSMENT OF CARCINOGENIC RISK
FROM POPULATION EXPOSURE
TO CADMIUM IN THE AMBIENT AIR
NOTICE
This document is a preliminary draft. It has not been
formally released by EPA and should not at this stage be
construed to represent Agency policy. It is being
circulated for comment on its technical accuracy and
policy implications.
DO NOT QUOTE OR CITE
LIBRARY SERVICES RTF NC
CENTAL PROTECTION AGENCY
Research and Development
TECHNICAL DOCUMENT COLLECTION shington, D.C. 20460
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The Carcinogen Assessment Group's DO NOT QUOTE OR Cl'T
Assessment of Carcinogenic Risk from Population
Exposure to Cadmium in the Ambient Air.
This document is being released by EPA for external review
MAY 1 9 19/8
oy E^^lbert, M.D,
Chai rman
Elizabeth L. Anderson, Ph.D.
Charles Brown, Ph. D. (NCI Liason)
Richard N. Hil 1 , Ph.D, M.D.
Charles B. Hiremath, Ph.D.
Robert E. McGaughy, Ph.D.
Lakshmi C. Mishra, Ph.D.
Ruth Pertel, Ph.D.
Wade T. Richardson,J.D.
Dharm Singh, Ph. D.
Todd Thorslund, Sc. D.
STAFF_ASSI^STA]JTS
Irene Schapiro
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CONTENTS
I. SUMMARY AND CONCLUSIONS 1
II. INTRODUCTION 4
III. METABOLISM 4
IV. MUTAGENICITY AND OTHER RELAVENT TESTS 6
V. TOXIC EFFECTS 9
VI CARCINOGENICITY ' 9
A. Human Studies 9
1. OccupationalExposure 9
a) Potts Study (1965) . 9
b) Kipling and Water-house Study (1967) 12
c) Lemen,et al. Study (1976) 13
d) McMichael, et al. Study (1976) 15
e) Summary of Occupational Epidemiology 18
Reports
B. Chronic Animal Studies 21
1. Injection Studies 21
2. Oral Studies 21
a) Schroeder, et al. Prat Study (1965) 21
b) Levy and Clack Rat Study (1975) 21
c) Levy, et al. Mouse Study (1975) 25
3. Summary of Animal Experiments 26
VII. RISK ASSESSMENT 27
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DRAFT
I. SUMMARY AND CONCLUSIONS DO NOT QUOTE OR CITE
Cadmium compounds have been shown to produce adverse
effect in experimental animals, and studies in man link
cadmium exposures with several clinical disease states.
Body concentrations of cadmium increase with age, at least
up to middle age, due to the poor renal excretion of the
compound; thus, each source of exposure to cadmium adds an
increment to the body burden.
Injection of cadmium in experimental animals results in
*
the development of malignant tumors (sarcomas) at the site
of injection. In addition, following subcutaneous injection
of soluble cadmium salts, a significant increase in tumors
at a distant site, namely interstital cell tumors of the
testis, was found in treated rats and mice.
Orally administered cadmium has not produced a
;ignificant increase in tumors in experimental animals, but
the three available studies have deficiencies which preclude
accepting them as negative studies.
Cadmium salts increase the frequency of point and
chromosomal mutations. They induce jji vitro mammalian
cellular transformation and enhance transformation of
virus-infected mammalian cells. The outcome of these tests
is known to be highly correlated with oncogenicity.
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Occupational epidemiology studies at three independent
locations with known exposure to cadmium have reported
associations between cadmium exposure and excess rates of
prostate cancer. At an alkaline battery plant a
proportionate mortality study reported a high frequency of
prostatic cancer amongst deaths in workers exposed to
cadmium for at least 10 years. Another study at the same
plant involving a follow up of the population of workers who
were exposed at least one year to cadmium showed a
statistically significant increase in the incidence of
prostatic cancer. At a cadmium smelter a retrospective
cohort study of workers exposed to cadmium for at least two
years reported a significant increase in cancer deaths,
mainly due to respiratory cancer. A statistically signifi-
cant excess prostate cancer was found only in workers ex
poseed for more than 20 years. In a survey of four rubber
producing plants the authors found that one of the four job
catergories that was associated with workers dying of
prostrate cancer-involved exposure to cadmium and other
metal oxides.
When all of this information is considered together
it is possible that cadmium is a human carcinogen, although
the evidence is not decisive.
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A very crude quantitative assessment of population
risks of prostrate cancer due to cadmium in the ambient air
can be done on the basis of the prostate cancer data on
alkaline battery and smelter workers together with EPA
estimates of ambient concentrations and number of people
exposed. The conclusion is that a, lifetime exposure to
atomospheric cadmium from any of the individual sources
results in a lifetime risk of less than 2 x 10'5 and the
total number of prostate cancer deaths,in the United States
population exposed to ambient airborne cadmium is less than
about 5 deaths per year. Since the daily cadmium retention
from ambient air is only about 1/20 of the retention from
food and about 1/3 of the intake from smoking a half-pack of
cigarettes per day, this report deals with a relatively
small part of the total problem of cadmium contamination
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ION
Environmental exposure to cadmium occurs by several
routes. It is estimated that the exposure to an individual
in food is about 50 ug per day; water, 2 ug per day; and
air, less than 1 ug per day. The major sources of cadmium
in the ambient air are non-ferrous metal smelters, iron and
steel mills and municipal incinerators. In addition sources
of cadmium exposure are wide ranging. For example it is
present in cigarettes at relatively high levels and is used
as a pesticide, largely on turf grasses.
III. METABOLISM
This section is based on literature reviews by Friberg
et al . , (1971) and the International Agency for Research on
Cancer (1976).
The two primary routes of cadmium absorption in man are
the respiratory and gastrointestinal tract. The extent of
absorption varies with the route of exposre.
In acute and chronic inhalation studies of mice, dogs
and rabbits about 10 to 40% of the inhaled dose was
absorbed. Salts tested were cadmium chloride, oxide,
sulfide and cadmium iron dust. It is possible that
absorption differs with the form of cadmium; however, these
studies were not adequate to determine this.
There is markedly less absorption from oral dosing of
cadmium salts than by inhalation. The average absorption by
mice, rats and goats was only a few percent of the dose
(range: 0.5 to 8%). Compounds tested were cadmium chloride
and cadmium nitrate. Dietary factors have also been shown
to influence absorption.
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Low,. calcium and low iron diets have increased cadmium absorption in mice
and rats. Vitamin D has been reported to increase intestinal absorption
in chickens.
Skog and Wahlberg (1964) studied the absorption of cadmium chloride
from the guinea pig skin. Absorption was determined by "disappearance
measurements" using a scintillator to measure radioactive skin deposits.
Six molar concentrations ranging from 0.005 to 4.87 were tested. Dermal
absorption of cadmium was very low. It increased with increasing molar
concentrations to a maximum at 0.235 M when the mean absorption was 1.8%/
5 hours. At other concentrations mean absorption values were less than
1.0%/5 hours.
Cadmium steadily accumulates in the body with normal exposure/ reaching
a peak level at age 50. The background level of a newborn baby is about lug
total; the body burden of a 50-year-old American man is about 30 mg. Fri-
berg estimates that daily cadmium intake from food in the United States is
in the upper portion of the 20 to 50 ug range and calculates that cadmium reten-
tion would have to be 3 to 8% to account for the 30 mg accumulation. This
does not account for intake from sources other than food and assures a
linear accumulation with negligible excretion.
In both animal and human studies, very small amounts of cadmium were
excreted in the urine. In humans, urinary levels have been less than 5 ug/
day; generally excretion is 1 to 2 ug/day. Smckers excrete more cadmium than
nonsmokers; cigarettes contribute to smokers increase in cadmium body burden
and excretion as compared with nonsmckers. Excretion also increases in persons
with renal tubular dysfunction, a condition which can be produced by prolonged
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cadrnium exposure. Cac3mium has a long biological half-life. In
humans it is estimated to be 10 to'30 years,- and in other species it
usually has been found to be at least 200 days.
About one third of the total body burden of cadmium in man is in the
kidneys; together the kidneys and liver store about 50% of the burden.
Renal concentrations of cadmium have generally been 5 to 100% higher in
smokers than nonsmokers.
Cadmium has also been found in significant amounts in the pancreas.
After a single intravenous injection of 109 Cd-dloride, mice were found
to accumulate cadmium in bone marrow, periostium, tastes and hypophysis.
The latter two sites are of interest in light of the tumors observed in
Cd-injected animals.
The metabolism of cadmium is closely associated with zinc metabolism.
Added zinc can protect animals from some cadmium-induced toxic effects.
Metallothionein, a low molecular weight cadmium and zinc-binding protein,
is believed to transport cadmium. Some evidence suggest that low cadmium
exposures are nontoxic because the metal is bound to the protein. When all
metal.lothionein sites are bound to cadmium, any additional cadmium is free
to produce toxic effects.
IV. MEJTAGENICITY AND Qi'H£R pPTTVaNT TESTS
Three secondary as well as several primary sources were consulted in
the preparation of this section. The secondary sources were Sanchu, 1977;
Pertel, 1977 and FDA, 1977; all primary references are cited in those
three sources.
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Oroanism
Reported
Mutageni-
citv
Garments
Authors
(+)
1. Point Mutations
Sacchrcmyces
Drosophila
Chinese hamster cells
in culture
2. Chromosome Mutations
a. Maimalian cells,
in vitro
Human leukocytes (+)
Chinese hanster (+)
line
Human leukocytes
& fibroblast line (-)
Mairnials, in vivo
Sheep leukocytes (+)
Mouse oocytes (+)
Human leukocytes
b.
Sex linked lethals;
low power of test
Numerical not struc-
tural aberrations
Itai-itai patients
Itai-itai patients
and Cd workers
Workers exrosed to Cd
& Pb"
Workers exposed to Cd,
Pb and Zn
Takahashi, 1975
Friberg et al.,
1974
8-azaguanine resist- Costa, 1976
ance
Shirashi et al.,
1972
Rohr & Bauchinger,
1976
Paton & Allison,
1972
Doyle et al., 1974
Shimada et al., 1976
Shirashi & Yosida,
1972
Eui et al., 1975
Deknudt & Leonard,
1975
Bauchinger et al.,
1976
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DOtuJTOliC'Ej:
Oraanisra
Dominant
lethal
Reported
Mutsgeni-
citv
(-)
(-)
Ccimtents
Mouse
Mouse
Authors
Epstein et al. ,
1972
Gilliavcd s
Other Tests
B. subtilis
S. cerevisiae
Syrian hanster
cells
Reported
Effect
for Cl but N03 salt
in "rec" assay
for mitotic segregation
for alteration in DMA
sedimentation in CsCl2
gradients
for unscheduled DMA
synthesis
for _in vitro trans-
formation
Leonard, 1975
Nishioka, 1975
Takahashi, 1972
Costa, 1976
Costa, 1976
Costa, 1976
for enhancement of SA7 Costa, 1976
viral transformation,
in vitro
v, x
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V. TOXIC EFFECTS
Chronic occupational exposure to excessive cadmium in the air
produces emphysema after an exposure period of-about 20 years. Kidney
malfunction also occurs in these workers, manifested by glucosuria,
proteinuria, excess cadmium excretion, and increased incidence cf
renal stones. In rats, many studies have shown that cadmium affects
the testis, causing vascular degeneration and, testicular atrophy.
In addition it causes hypertension and kidney damage in experimental
animals. Itai-itai disease, due to chronic ingestion of cadmium-con-
taminated rice, was characterized by multiple bone fractures mainly in
multiparous post mencpausal women (Friberg, 1971).
VI. CAEONOGENICLTY
A. Human Studies
The epidemiology studies reviewed here include four studies of
workers occupationally exposed to cadmium, two of them with overlapping
samples. Two additional studies analyze cancer mortality in relation to
metals in drinking water.
1. occupational Exposure
a. Potts Study (1965)
This article reports the health status of current and past
employees of a British alkaline battery factory who were exposed to cadmium
oxide dust for at least 10 years. The plant had been in operation since
1920, and in 1946 it was moved to a nev location in the sane town. Before
1950, when an extensive exhaust ventilation system was installed, cacmiun
concentrations of 236 mg/m3 and 0.6 to 2.8 mg/m3^ were
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in two separate areas of the plant. Between 1950 and 1956 the levels
were less than 0.5 rag/in^ in most parts of the factory but seme regions
were well above this. After 1956, when further improvements were made,
most areas had levels below 0.1 rog/ra3, and the operating policy sir.ce
then has been to take special action when the level exceeds 0.5 mg/nr.
The health survey covered workers employed by the plant since 1920.
In 70 employees working over 10 years, 44% had protein in their urine.
The protein had the same characteristics as that observed in workers at
another factory who were exposed to cadmium funes. Kidney function tests
were not done routinely but four case reports of workers with proteinuria
revealed no kidney damage.
Potts reports that "careful search" showed a total of 74 men had been
exposed to cadmium for more than 10 years, and eight of those workers had
died. He leaves the ijnpression that he succeeded in determining the vital
status of all 74 men without indicating the source of his mortality figures
or cause-specific death data. Of the eight deaths he reports, five were
from cancer and three of these were cancer of the prostate. The data from
Potts paper are summarized below.
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11
Mortality Data for Cadmium Workers Exposed for More Than Ten Years
Year
of Death
1960
1960
1961
1962
1962
1963
1964
1964
Aae
65
75
65
63
78
53
65
59
Length of
Cadmium
Exoosure
(Years)
31
14
37
34
18
35
38
24
Cause of Death
Auricular Fibrillation
Carcinoma of Prostate
Carcinoma of Prostate
Bronchitis and Atheroma
Bronchitis
Carcinoma of Bronchus
Carcinoma of Prostate
Carcinoma tosis
All of these people were exposed to the high cadmium concentrations
that existed before 1950; two of the prostate cases were thus exposed
for at least 24 years and the third for at least 4 years. The exact
time of the start of exposure was not stated' and the cadmium concentra-
tions in the earlier period are known only in 1949, when the decision
was made to improve conditions at the new plant. No report was made of
workers exposed less than 10 years.
While Pott's cancer mortality findings are striking, it is impossible
to make a meaningful comparison of rates with the general population since
the age structure of the exposed population is not reported.
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b. Kipling and Waterhouse Study (1967)
In a letter to the editor of Lancet, Kipling and Waterhouse
report on a survey of 248 British workers occupationally exposed to
cadmium oxide. This work was conducted on the same population
as Potts' study, however/ Kipling and Waterhouse examined incidence of
prostate cancer and included workers with at least one year of exposure
to cadmium.
The rate of cancer for all sites as well as for cancer of the prostate,
bronchus, bladder, and testes was determined, using an analysis based on total
time-to-tumor/ and compared with the expected rate for "such a group of men of
known age". No other description of the control group was provided. The results
are shown in the table below. There were 4 cases of prostate cancer compared to
the expected number of 0.58, a significant increase at the .003 level. Three of
these cases are the same as Pott's prostate mortality cases, according to a
personal communication frcm Kipling reported in IABC (1976). There was no report
of the &ge distribution of the cancer cases or the level or duration of exposure
to cadmium.
Cancer Incidence In 248 Workers Exposed To Cadmium Oxide
For More Than 1 Year
Site of Cancer
All sites —
Bronchus —
Bladder —
Prostate —
Testis —
No. of
Excected
— 13.13
— 4.40
— ' 0.51
— 0.58
— 0.11
cases
Observed
12
5
1
4
0
Probability
of occurrence
.0.660
0.449
0.398
0.003
0.898
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C. Lenten et al., Study (1976)
These investigators did a retrospective cohort study of
workers at a cadmium smelter at which cadmium metal powder, cadmium
oxide and cadmium sulf ide were present. The smelter has been producing
cadmium since 1925. Cadmium concentrations were measured on two occasions.
In 1947 the average concentration of cadmium fumes ranged from 0.04 to
6.59 mg/nr and of cadmium dust was 17.23 mg/m , with most plant operations
below 1.5 mg/nr. In 1973, another measureirent shewed average air concentra-
tions ranging below 1 mg/nr on an 8-hour tome-weighted average basis, with
excursions up to 24 mg/nr during infrequent operations. The authors reported
that in 1973 a respirator program was in use at the plant which reduced
exposures by a factor of about 10. No information was given about how long
before 1973 the respirator program had been in operation or whether the
respirators were routinely used by workers in all sections of the plant.
In two sections of the plant concentrations of 75 to 90 ug/nr were measured
in 1973. The arsenic air concentrations were generally less than accut 1/1CO
of the cadmium levels. The ratios of zinc and arsenic to cadmium in the ores
which are processed are about 1/10 and 1/200, respectively, and the authors
concluded that exposure to metals other than cadmium were insignificant.
The study included 292 white male workers who worked at the plant
between 1940 and 1969 and who were employed for at least two years. The
vital status of these workers was determined as of 1974, and it was found
that 92 had diedr 180 were still alive and 20 were not accounted for; the
latter were assumed to be alive in the analysis of the data. Person-years
at risk of dying were coipuued and observed cancer rates were ccnpared to age-
adjusted rates for the total U.S. white male population.
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A significant increase in cancer mortality among the exposed
group was observed; most of this excessive risk was accounted for by
neoplasms of the respiratory system which was significant at the .05
level. Of the 12 malignant respiratory disease cases, the cell type
of eight was known. Three of these eight were squamous cell carcinomas,
the type most conroonly associated with cigarette smoking. No smoking
histories for the groups were included. An association between respira-
tory cancer and cadmium has not been observed in other studies. In one
dog study, the cause of death for cadmium-exposed animals was non-necplastic
respiratory problems (personal communication, Dr. Richard Lemen, 8/10/77).
Because of previous reports of increased prostate cancer in workers
exposed to cadmium, the prostate cancer mortality of the cohort was also
studied. The results are given in the table below:
Prostate
Case
1
2
3
4
Cancer
Age
71
77
79
64
Deaths Amorc
More Than 2
ExDosure
4
13
18
17
Cadmium Smelter
Years Exposure
Latencv
32
25 *''
31
26
Workers with
Date of Death
2/26/72
3/19/68
12/10/60
4/3/51
The four deaths from prostate cancer were not significantly higher
than the 1.15 expected to occur in the full cohort. However, an increased
risk was found (4 cases compared to 0.88 expected) at the .05 level among
workers with a 20 year latency period since initial cadadum exposure.
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d. McMlchael et al. (1976) DO NOT QUOT; CR
These investigators identified cohorts of active and
retired workers, aged 40 to 84, at four rubber-producing
plants and followed their mortality experience for 10 years.
The mortality experience was determined from group life
insurance records and confirmed with internal companny
records. In the case of one cohort, a random sample of
apparent survivors was checked against Internal Revenue
t
Service records to verify that they were still alive.
It is important to note that rubber workers are
potentially exposed to numerous organic and inorganic
chemicals, some of them known or suspected carcinogens.
While cadmium is present in these factories, mortality rates
and cause-specific deaths in this study, which is not
controlled for type of exposure, can not be attributed to
cadmium alone.
A total of 18,903 male workers from the four facctories
were included. About 1% of this group — active workers who
switched jobs during the course of the study-- was lost to
follow-up. Death certificates were obtained from 98% of the
remaining cohort members who had died.
For the entire group 18,903 men, 98% had worked at the
plant for at least 10 years. The study did not include
former workers who had transferred to another place of
employment or had died as of the date the cohort was
identified. As a result, the sample could have selected
for the stronger workers who survived and could have
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excluded some who might have died due to occupational
exposure. While such a study might show an excess mortality
in the worker population, the effects of the work
environment could be underestimated or overlooked.
The mortality data for the workers was compared to
mortality figures for the 1968 U.S. male population. The
analysis was made using standardized Mortality Ratios (SMR),
controlling for race and using age categories of 40-64,
65-84, and 40-84. A SMR of 100 indicates no difference
between the study group and the standard populaton. An SMR
greater than 100 indicates an excess of deaths in the test
group. However, since worker populations are generally
healthier than the general population, in a non-hazardous
work environment the SMR is expected to be slightly less
than 100.
The total number of deaths from all causes was 5,106,
with 1,014 due to cancer. The SMR for deaths from all
causes for the full cohort was 94, it was relatively higher
in the older group than in the younger workers. The SMR for
all cancer sites showed similar trends, with a value of 100
for all ages and companies combined, 104 for the older group
and 92 for the younger group. When specific sites were
examined, SMR's for all companies combined were considerably
higher than 100 for stomach (148), rectum (116), prostate
(119), all leukemias (130), lymphatic leukemia (15), and
lymphosarcoma and Hodgkin's disease (129). No striking
excesses were seen in the combined-company SMR's
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for cancers of the rectum, pancreas, respiratory system,
bladder , and brai n.
These figures reflect exposure to a variety of
substances in the workplace. In an attempt to correlate
cancer sites with specific job exposures, an exploratory
study was made of the job classifications of workers with
stomach, prostate and bladder cancer and lymphosarcoma and
Hodgkin's disease. The work histories of men dying from
each of these causes was compared to an age-stratified
random sample of 23% of the full cohort (n=1476) to see
whether differences existed in the porportion of men who had
worked for at least two years in any job category.
Four jobs, compounding and mixing, cement mixing,
janitoring»and trucking, were assocciated with prostate
cancer. The compounding and mixing association is of
interest because these workers are exposed to cadmium oxides
and other metal oxides that are used as vulcanization
accelerators. The exposure levels are not reported. While
this is of interest as a basis for future investigations, it
is clearly insufficient as a basis for associating cadmium
with prostate cancer since the worker's exposure to other
substances and the extent of cadmium exposure have not been
a n ay 1 s e d.
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e. Summary of Occupational Ep_j_denji'o1 ogy Reports
Four occupational epidemiology studies have been
reviewed. In all of them an association between prostate
cancer and cadmium is suggested. In one study (Kipling &
Waterhouse, 1967) an excess number of cases of prostate
cancer occurred in exposed workers. Another study on the
same population shows a high death rate from prostate cancer
(Potts, 1965). Excess mortality from prostate cancer among
workers whose initial cadmium exposure had been at least 20
years before the study was observea in a third paper (Lemen
et al . , 1976). Although it was not a controlled study, a
fourth report (McMichael et al., 1976) suggested a possible
correlation between excess prostate cancer mortality and
possible exposure to cadmium.
All of these studies involved small numbers which makes
the estimation of risk difficult. However, because of the
consistency of the findings, together they raise a serious
question as to a possibility of a relationship between
cadmium and prostate cancer.
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f. Non-occupational Epidgniology Stariies
Correlations between cancer mortality and cadmium in drinking water
have been studied by Berg and Burbank (1972) and by Zyka (1973). In Berg
and Burbank1s study, the drinking water concentrations of eight metals,
including cadmium, were determined in 15 water basins of the United States.
Death rates for 34 types of cancer were also determined for the regions
corresponding to the sane water basins. The water basins were then ranked
with respect to each metal and each cancer site, and rank correlation
coefficients were calculated.
For cadimum 10 positive (statistically significant) correlations were
observed. No correlation was noted for testicular cancer, which might be
expected from animal experiments. The authors did not report looking for
prostate cancer correlations. Positive associations were observed for
intestinal cancer and "smokers cancer" of the mouth, esophagus, larynx, lung,
and bladder. The authors were unable to separate the effects of tobacco
from possible effects of cadmium in the "smokers cancer". Cigarettes contain
cadmium, and smokers have excess body burdens of cadmium; this could account
for the correlation. Other studies cited by the authors have found no cor-
relation between cadmium levels and intestinal cancer.
The authors note that, depending how cadmium is measured, rank orders
of cadmium levels can be vastly different from one another. Berg and Burbaak
report that their results "are based on less than perfect analytical results
and sampling." In light of this study's limitations, no conclusions can be
drawn about cadmium's relationship to cancer mortality. It does suggest areas
for further investigation.
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DRAh
DOM,"QUOit ORCilL
Zyka (1973) chemically analyzed current and past drinking watsr
sources in districts of the city of Kutna Hora, near Prague, Czecholslovakia
and correlated metal concentrations with cancer mortality rates. Considerable
disparity existed in cancer mortality rates among the several districts
of the city, and Zyka reported that the source of drinking water was the only
environmental factor that varied.
He found that the water from the Havirna mine, the water source for the
area with the highest cancer mortality/ had high levels of Cd, Zn, As, Cu, Al,
Pe and Se. In contrast, in the districts with the lowest cancer mortality,
the only drinking water contaminants found were NO^ and low levels of Pbf Zn,
As and Eg.
There was apparently no attempt to control for other factors possibly
associated with the variation in mortality rates (e.g. age structure of
the population), and the effect of cadmium independent of other trace metals
was not identified. High concentrations in drinking water of several of the
trace metals found in the Eavirna water have been associated with cancer
in previous studies. Cie effect of this study is to suggest a possible
relationship between high concentrations of trace metals in drinking water
and excess cancer mortality without specifically implicating cadmium.
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B. Chronic Anrnal Studies
1. Injection Studies
In 14 chronic studies on rats reviewed by a working group for the Inter-
national Agency for Research on Cancer {IMC) (1976), malignant tumors at the
injection site wer reported in 10. Tumors followed administration of soluble
cadmium salts (chloride and sulfate), insoluble salts (sulfide and oxide) and
finely divided cadmium metal. Rats receiving 'injections at four sites
(0.04 or 0.08 rag/site) developed local tuners in .areas originating frcra mese-
nchymal mesoderm (subcutaneous, intramuscular, subperiostial) but not from
those originating frcin ectodenaal (intracutaneous), endodermal (liver, ventral
prostate, salivary gland) or epithelial mescdenn (kidney) (Gunn et al., 1967).
In several studies, subcutaneous injection of soluble cadmium salts has
resulted in the development of interstitial cell tuners of the testis in rats
and mice (IAEC, 1976). Injection of cadmium produces degeneration of semini-
ferous tubules followed by proliferation of interstitial cells and f ir^aUy
tumor?. A sumrary of the findings is given on the next page.
2. Oral Studies
a. Schroeder et al. (1965) Rat study"
In a laboratory designed for lew trace-metal aninal experiments
Long-Evans rats were fed a lew-metal diet supplemented with 5 pan of
cadmium, lead, or chromium (III) as acetate salts in drinking water.
This treatment was continued frcm weaning until death of the animals.
Initially there were 69 males and 58 females; but high early mortality
(before 3 months) occurred in treated animals; and the groups were replen-
ished before 3 months so that each group had more than 52 animals. Further
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TESnOJLAR INTERSTITIAL m*- TUMORS IN ANIMALS
GIVEN CADMIUM BY SOBOJTMffiOGS INJECTION
Strain
Cd C12 a/
Dose(inaAa)
Tumor Bearira Animals Observation
Treated
Control Time{mo.)
References
Mouse
Charles River 5.5
Rat
20/26
Gunn et al., 1963C
Wistar
Albino CB
Wistar
Wistar
Fischer 344
5.5
0. Sing/rat
5.5
3.7 to 5.5
5.5
17/25
10/18
10/25
13/13
16/20
0/20^/ 11
0/16^ 20
23
11
0/10^' 12
Gunn et al. , 1963f/
Roe et al. , 1964f/
Knorre, 1971
Lucis et al. ,1972
Reddy et al. , 1973
a/ Single S.C. injection except Roe et al., who used 10 weekly injections
" of CdSO^
b/ Difference significant at p<.001.
c/ Reviewed by IARC (1976); original pacers not received in tins to be reviewed
by CAG.
-------
-23-
nortality occurred because of a pneumonia epidemic during weeks 107 to 117,
reducing the effective size of the groups to 42 males and 44 females in
controls and 50 niales and 46 females .in treated groups. In the cadmium
group there was significantly higher mortality as compared with controls
during the first 33 months of observation. (Animals survived up to 42
months).
The major gross causes of death were pneumonia and tumors. Hypertension
contributed to the progressive mortality of males, especially since treated
animals had enlarged hearts and thickened left ventricles, and the authors
had previously reported hypertension in rats. Of the animals which were
autopsied, gross tumors were the cause of death in 13/48 treated males compared
to 9/35 control males. For females the corresponding observations were 15/36
in treated versus 15/35 in controls. The differences are not statistically
significant. No microscopic examination of the tumors was reported. All but
one animal with tumors died after 86 weeks. Sixteen of 20 cadmium-fed rats
examined (80%) had cirrhosis of the liver as did 13 of 21 control rats (62%).
The high frequency of cirrhosis in controls is unusual and makes one wonder
what accounted for this finding. Other adverse effects of the cadmium treat-
ment include arteriolarsclerosis in the kidney and enlarged hearts. Cadmium
accumulated in livers and kidneys of young rats, but not in animals older
than 2 years.
b. Lew and Clack (1975) Rat Study
These investigators administered cadmium sulfate in distilled water
to male specific pathogen-free CB hooded rats. Doses of 0.35, 0.18, and
0.087 mgAg/week in distilled water were administerd%by stcmach tube for
2 years. Initially there were 30 animals in each treated group and 90
-------
-24
animals in the control group. All sick and moribund animals as well as
those surviving for the 2-year period were examined grossly. Microscope
preparations were made of all tissues of ten high-dose and ten control
animals randomly selected from the 'animals killed at termination of the
experiment. In addition, sections of all testes and any abnormal tissue
or organ were examined. Hie survival at 100 weeks for controls, low, medium,
and high dose groups were 67%, 53%, 67%, and 57%, respectively, with some
early deaths from mechanical injury during passage of the stomach tube.
The incidence of interstitial-cell testicular tumors was 75% in
controls; in the treated rat it was not significantly different. Careful
observation of prostate glands shewed no gross abnormalities, but foci of
slight hyperplasia, inflammation and descuamation of epithelial cells were
observed in high-dose and control groups. These changes were not interpreted
as metaplastic or pre-neoplastic. Tumors of other organs were observed as
follows (number of tumors observed/number of animals in the initial group):
controls, 10/90; low dose, 4/30; nredium dose, 3/30; high dose,. 8/30. All
tumors were benign except one basal-cell skin carcinoma in the high-dose
group and two sarcomas in the control group^
The number of liver adenomas in the four dose groups was: controls, 1;
low dose, 2; medium dose, 0; high dose, 3. The paper did not report which
of the tumors were identified on gross examination and which by random
selection, making it impossible to determine statistical significance.
The Cancer Assessment Group is seeking additional information in this area.
-------
-25-
It is difficult to draw conclusions from this report because: (1) only
10 animals randomly selected from the high dose and control group were
microscopically examined, rather than all aniraals from all dose groups; and
(2) because of the higher mortality in the high-dose group compared to controls,
a correction of the tumor incidence 'data is necessary. This correction
cannot be done without data for the tice when the tumors occur in individual
animals.
c. Levy et al. (1975) Mouse Study
Groups of specific pathogen-free male Swiss mice were given cadmium
sulphate once per week for a period of 18 months. Three treated groups
of 50 animals each were given 1.75, 0.88, and 0.44 mgAg/week by stomach
tube and the control group of 150 animals received distilled water alone.
All sick and moribund animals as well as those surviving for the 18
month period were examined grossly. Tissue sections of 20 animals frcm
the high-dose group and 20 frcm the control group were examined microscopi-
cally. These animals were selected randomly from animals with no gross
lesions that had survived until termination of the experiment. In addition,
sections were examined microscopically from all tissues appearing abnormal
grossly. The fraction of animals surviving at the time of terminal sacrifice
in the control, lew, medium, and high-dose groups were 83%, 94%, 84%, and 84%,
respectively".
No gross abnormalities were observed in prostate, bladder, kidney, or
testis. A small number of animals in each group had over-distension of
seminal vesicles and several showed lesions of the lung and/or liver. Frcm
the microscopic sections examined occasional slight epithelial hyperplasia
or desquamation was seen in the prostate of both hi(gh-dose and control
animals. The testes were either normal or had slight atrophy of isolated
-------
-26-
seminiferous tubules, occur ing with equal frequency in control and high-dose
groups. No treatment-related differences in tumor frequency were observed
for kidney, lung, or liver tumors.
It is difficult to make quantitative conclusions from this experiment
because (1) not all animals were examined histologically and therefore it
is possible that small tumors not noticed in gross examination remain
undetected; (2) the results of the microscopic examination were only quali-
tatively stated. Hcwever, there is no fina reason to reject the authors'
conclusion that this treatment caused no carcinogenic effect.
3. Sunroary of Animal Experiments
Although direct injection of cadmium salts intramuscularly and
subcutaneously usually produces malignant tumors at the injection site
and interstitial-cell tumors in the testes, no carcinogenic effect has
been clearly seen in rats or mics following oral administration. A plausible
explanation for the difference in response is that only about 0.3 to 1% of
the orally-administered cadmium dose is absorbed in chronic studies,
(Fleischer, et al., 1974). The tumors observed in typical injection
experiments are produced by single doses of 4 to 5 mgAg or repeated doses
of 1.7 mg/kg/week. The highest oral dose tested by Levy was 1.75 mg/kg/week
in mice and 0.35 mgAg/week in rats, and the oral dose used by Schroeder
in rats was 2.6 mg/kg/week. If only 1% of this oral dose is absorbed,
the actual exposure of the animals in the oral experiments is only about
1% of the dose administered in the injection experiments. Therefore, the
oral dose might be too snail to produce observable effects. In keeping with
this only in the Schroeder study was there any indication of a treatment
effect as to weight or survival.
-------
-27-
DRAFT
DO NOT QUOTE OR Gill
VII_ RISK ASSESSMENT
Introduction and Summary
It was noted in section IV, part 8, that cadmium is carcinogenic
in experimental animals by subcutaneous injection. In the case of human
exposure to atmospheric cadmium, epidemiological evidence is accumulat-
ing from several small-scale studies which suggests an increase in the
prostate cancer rate where workers were exposed to high levels of
cadmium dust and/or fumes.
Two of these studies, Potts (1965) and Lemen et al. (1976), con-
tain enough exposure information that crude dose-response relationships
can be established between lifetime exposure levels and prostate cancer
death rates. It was estimated that the percentage increase in the pros-
3
tate cancer rate per increase of 1 ygm/m of atmospheric cadmium was
10.1% based on the Potts study and 9.4% based on the Lemen et al. study.
The consistencies of these estimates should be viewed as merely coinci-
dental. Considering the crudeness of the exposure data and the small
sample sizes of the study cohorts, it would not have been surprising to
find a difference of a full order of magnitude, even assuming an identi-
cal effect in the two exposed populations.
Using the Potts rate estimate of 10.1% and a 1978 exposure docu-
ment prepared by Energy and Environmental Analysis, Inc. (EEAI), for EPA,
it was calculated that a population of about 34 x 10 males was exposed
to atmospheric cadmium from point sources in sufficient amounts to
increase their lifetime probability of death due to prostate cancer by
-------
-28-
more than 10 . This total exposure resulted in an estimate of about
5 expected deaths per year, which amounts to approximately .03% of the
total prostate cancer deaths in the United States.
Epidemiological Studies with Pertinent
Exposure Information
Potts (1965)
Potts describes the observed mortality in a cohort of men
exposed, for at least ten years, to cadmium oxide dust in the manufac-
ture of alkaline batteries. Unfortunately, neither the age structure of
the worker population nor the duration of its exposure is given in the
paper. As a result, it is not possible to calculate age-exposure-specific
mortality rates from the supplied information.
However, three deaths due to prostate cancer were noted in the
eight observed deaths in the cohort. If a sample of eight deaths age-
matched to the eight deaths in Potts' cohort were taken from the United
States population, the probability of three or more prostate-cancer-
caused deaths occurring by pure chance in the sample is calculated, based
-4
on 1973 U.S. vital statistics, to be 2.16 x 10 . The derivation of this
result is shown in appendix I. Since this strongly suggests a cadmium-
caused elevation in prostate cancer, we decided to base part of our risk
analysis on the proportional mortality of the deceased workers in Potts'
cohort.
Based on results of efforts at monitoring industrial plant
hygiene dating from 1949 and on worker records, it was possible to make
a crude estimate of the lifetime average exposure to atmospheric cadmium
for each of the deceased. The bases for these estimates are shown in
-------
-29-
table 1 . The marked decrease in the average level of exposure over time
is due primarily to major plant hygiene improvements in 1950 and 1956.
The exposure in the early time period is taken as the geometric mean of
the quoted measured levels.
In table 2 the proportional mortality ratio of prostate cancer
to total deaths on an age-specific basis is shown for Potts' cohort, as
well as U.S. male death rates based on 1973 vital statistics. Under the
following assumptions it is possible to utilize t"he data contained in
table 2 to estimate the increase in the U.S. prostate cancer rate per
change in each ygm of cadmium in the atmosphere.
1. Given the same exposure, x, the age-specific proportional
mortality ratio, p., is the same for Potts' cohort as for the U.S. male
population.
2. The increase in the age-specific U.S. prostate cancer rate
is a. linear function of the exposure x.
From these assumptions it follows that :
otgjd + Bx.)
where a = the U.S. prostate age-specific death rate for the jth
interval
a. = the total U.S. age-specific death rate for the jth age
interval
x. average lifetime exposure for those in the jth age
interval
$ = unknown increase in prostate cancer rate in percent per
3
change of one ugm/m of atmospheric cadmium.
Solving for 3x., we have that
-------
-30-
ex. = __ -.- i =Y.
J U - pjAa2j J ]
so that 3 may be estimated given Y., x., a., ct_ . by means of fitting a
least squares linear equation through the origin. If we weight each
point by the value W., which in this case is the number of deaths in
A
the age interval, we have that 3 = .5024 (the data utilized to compute
2
g is shown in table 3). The goodness of fit in a x sense is shown in
table 4, where we note that the variation is reduced to less than half
that observed assuming that age or exposure has no effect on the pros-
tate cancer rates.
At the usual levels of environmental exposures, x, it is gener-
ally the case that a. » 3<*2.x. If x is continuous over time, a very
close approximation to the increase in the lifetime probability of pros-
tate cancer due to a lifetime exposure x is P ~ PnBx, where Pn is the
lifetime probability of prostate cancer in the U.S. population. From
1973 vital statistics we calculate that P_ = .0187, so that our predictor
equation for lifetime probability for low-level atmospheric exposures
is
P ~ .0187 x .1005 = 1.879 x 10~3x,
x '
3
where x is lifetime average exposure in ugm/m .
Lemen et al. (1976)
The mortality observed in a cohort of 292 white males engaged in
the production of cadmium metal and cadmium compounds for at least two
years is discussed in Lemen's paper. These workers were exposed to
cadmium fumes and dust during normal smelter operations.
-------
DRAFT
M NOT QUOTE OR CITt
Ideally the entire exposure pattern for each of the workers, in
conjunction with age-specific expected and observed death rates, would
be utilized for a complete analysis. Unfortunately, the only data
available from the paper regarding exposure durations are for four
individuals who died from prostate cancer. Under the assumption that
this is a random sample from the entire cohort we calculate the lifetime
average exposure as indicated in table 5. The air exposure levels in
each of the time periods is approximated by utilizing information
obtained from industrial hygiene studies conducted in 1947 and 1973.
It was found that the cohort with 20 or more years since first
exposure had 4 observed prostate deaths where only .88 would be
expected. However, two biasing factors exist that tend to make the
expected number larger than its best estimate:
(1) A U.S. white male death rate was used, while it is well
known that factory workers in demanding jobs tend to have death
rates lower than the U.S. average. To correct for this factor, we
note that our observed-to-expected ratio in this cohort for total
nonmalignant neoplasm deaths is f 65/81.8. = .79, which, assuming
the same ratio of general health regarding prostate cancer, would
give a 21% reduction in the .88 expected cases.
(2) A total of 20, or 8% of the cohort, whose vital status was
not known were assumed by Lemen to be alive and were included in the
calculations of the expected deaths. Since they could not con-
tribute to observed deaths, they can be eliminated by assuming they
were of the same age structure as the rest of the cohort. This
would result in a reduction of 8% in the expected number of cases.
-------
-32-
Accounting for these two factors we calculate that an unbiased
estimate of the standard mortality ratio, R, is
R 4/(.88 x .79 x .92) = 6.254 .
Under the assumptions of a linear dose response and equivalence
of part and total lifetime risk, it can be shown that an estimate of
the percentage change in the lifetime probability of contracting a
disease is approximately
(B/a) = (R - l)/x
3
per change in one ygm/m of lifetime exposure, where x is the average
lifetime exposure in ygm/m . In this case
(B/ct) = (6.254 - 1)/56.1 = .0937, or 9.4%.
The predictor equation in this case for the lifetime probability
of prostate cancer is
P ~ .0187 x .Q937x = 1.752 x 10~3x,
X
where x is the lifetime average exposure to atmospheric cadmium in
Vgm/m .
Risk to U.S. Population from Different Sources
Releasing Cadmium into the Atmosphere
The 1978 EEAI document prepared for EPA estimated the human
exposure to cadmium for selected major emission sources. These data
were summarized in table 1 of that document, which listed average
exposures from different emission sources and the number of people
exposed from each source.
-------
33-
In table 6 this data is shown along with the average lifetime
probabilities of prostate cancer by source and the expected number of
cases per year calculated from the equations:
P = 1.879 x 10~6x
x
and
E(D) ~ [1.879 x 10 6 T 70.9]xN = 2.65 x 10 8xN
where, to correspond to the units of exposure"given, x is lifetime aver-
age exposure in ng^/m , and N is the number of males exposed. Based on
1973 vital statistics, males make up 48.7% of the U.S. population.
Assuming that exposure is independent of sex, multiplying EEAI's esti-
mate of total people exposed by .487 gives the number of males exposed.
It is estimated that about 5 cases of prostate cancer would be
caused by atmospheric cadmium each year, with about 87% of that total
due to municipal incinerators. This amounts to approximately .03% of
the total yearly deaths due to prostate cancer, based on 1973 vital
statistics. To place this risk in perspective, a comparison using
EEAI's Sources of Atmospheric Cadmium (p. 16) can be developed: based
on a retention rate of .07 ugm of cadmium per cigarette smoked, the
average risk to a person exposed to cadmium from municipal incinerators
is equivalent to smoking 1 cigarette every other day.
If we had used the estimates derived from Lemen's data rather
than Potts', all the calculated probabilities and expected numbers of
deaths would have been reduced by a factor of only 1.07.
-------
TABLE 1
EXPOSURES OVER TIME AND CALCULATION OF
LIFETIME AVERAGE EXPOSURE TO CADMIUM
Age
.Interval
50-54
55-59
60-64
65-70
75-80
Individual ' s
Age at Death
53
59
63
65
65
65
75
78
Working Years of Exposure to Cadmium
1920-1949
(Average Exposure
Level: 7.4 mg/m3)
21
19
21
20
25
23
14
18
1950-1955
(Average Exposure
Level: .5 mg/nr)
6
6
6
6
6
6
0
0
1956-1964
(Average Exposure
Level: .1 mg/m )
8
9
7
5
6
9
0
0
Lifetime Average
Exposure in
pgm/m
660. 8b
262.9
555.6
512.8
638.3
589.3
x = 580.1
303.8
375.7
x = 339.8
3Average exposure weighted by number of years exposed x (fraction of working year exposed = .22) v
age at death x 103 = lifetime average exposure in ngm/m3.
f\
bExample: 660.8 = (7.4 x 21 + .5 * 6 + .1 * 8) < .22 : 53 x 10 .
-------
TABLE 2
DATA USED TO ESTIMATE EFFECT OF CADMIUM EXPOSURE ON
INCREASE IN U.S. PROSTATE CANCER
Age Interval
50-54
55-59
60-64
65-69
75-79
Potts' Data
Total Deaths
1
1
1
3
2
Deaths Due to
Prostate Cancer
0
0
0
2
1
P-j = Proportional
Mortality Ratio
0
0
0
.6667
.5000
1973 U.S. Male
Death Rates < 10^
a .
J
Total
1,103.0
1,779.0
2,695.5
3,933.5
8,813.5
a2j
Prostate
Cancer3
5.1
13.6
33.7
72.0
246.0
ICD 180-187, malignant neoplasms of genital organs, x .942, where
= 18.830
•* 19,864
is the fraction of total number of deaths classified 180-187 which are attributed to
ICD 185, malignant neoplasm of prostate, based on 1973 U.S. mortality data.
-------
-36-
TABLE 3
DATA UTILIZED TO COMPUTE SLOPE OF
DOSE RESPONSE CURVE g
Age Interval
50-54
55-59
60-64
65-69
75-79
Number of
Deaths in Interval = W.
J
1
1
1
3
2
Lifetime Average
Exposure = x .
660.8
262.9
555.6
580.1
339.8
Y.
J
-1.
-1.
-1.
106.3
33.8
RESULT: 0 =
^ 206,485.1
2 2,054,940.5
= .1005
-------
TABLE 4
GOODNESS OF FIT IN x SENSE OF MODEL
Age Interval
50-54
55-59
60-64
65-69
75-79
Observed Prostate
Cancer Deaths
0
0
0
2
1
Under Assumed Model
Expected Prostate
Cancer Deaths
.238
.174
.418
1.575
1.005
2
X Deviation
.238
.174
.418
.115
.000
Under No-Ef fect-of7Exposure
Assumption7
Expected Prostate
Cancer Deaths
.375
.375
.375
1.125
.75
2
X Deviation
.375
.375
.375
.7777
.08333
-J
I
Total
.945
1.986
e = np =
.
.1005x.)
a. + .1005a2>x.
tt
e = n x 3/8
RESULT: % reduction in x is
1-98
= 52.42%
-------
TABLE 5
EXPOSURES OVER TIME AND CALCULATION OF LIFETIME
AVERAGE EXPOSURE TO CADMIUM
Individual ' s
Age at Death
71
77
79
64
Working Years of Exposure
to Cadmiuma
1925-1947
(Average Exposure
Level: 1.5 mg/m3)
4
5
17
17
1948-1973
(Average Exposure
Level: 1.0 mg/m )
0
8
1
0
Lifetime Average
Exposure in
ygm/m3
18.6
44. 3C
73.8
87.7
Average = 56.1
Based on Lemen et al., table 4.
Average exposure weighted by number of years exposed x (fraction
of working year exposed = .22) T age at death x 1Q~3 = lifetime average
exposure in ygm/m .
CExample: 44.3 = (5 x 1.5 + 8 x 1.0) x .22 T 77 x 1Q3.
oo
I
-------
I
01
to
s
TABLE 6
EXPECTED NUMBER OF PROSTATE CANCER CASES PER YEAR DUE TO
DIFFERENT SOURCES OF ATMOSPHERIC CADMIUM EXPOSURE
Source
Secondary Copper
i
Secondary Zinc
Municipal Incinerators
Primary Zinc
Primary Lead
Primary Copper
Primary Cadmium
Iron and Steel
Average Exposure
ngm/m^
1.54
.47
7.16
10.
10.
10.
10.
1.9
Lifetime Probability of
Prostate Cancer due
to Cadmium
2.90 x 10~6
8.84 x 10~7
1.35 x io~5
1.88 x 10~5
1.88 x io~5
1.88 < 10~5
1.88 x io~5
3.58 x 10~6
Expected Number of Prostate
Cancer Deaths per Year
due to Cadmium
.20
-
4.53
.01
-
.01
-
.49
Total
5.24
-------
-40-
APPENDIX I
DERIVATION OF PROBABILITY OF THREE OR MORE PROSTATE
CANCER DEATHS IN U.S. AGE-MATC1ED SAMPLE
In general, if we wish to calculate the probability of k or more
deaths of a specific type from a series of deaths from m different age
groups, we proceed as follows:
Let N. = Number of deaths in jth age group
m
N = £ N. = Total number of deaths in population of interest
r. = Number of deaths in jth age group of type of interest
m
r = £ r • = Total number of deaths of type of interest
3=1 J
o. = Age-specific death rate for jth age group
a7 . = Age-specific death rate for jth age group for cause of
interest
P. = a9./a. = Probability, given that an individual in the jth
age group died, that death was due to the cause
of interest.
Then
m
-------
-41-
to the cause of interest, where v is all possible combinations of the
r. that sum to r. It follows that
3
N k-1
P(r >_ k) = I (v,r)
r=k r=0
equals the probability of k or more deaths due to the cause of interest.
From section VI, table 2, we calculate the P. for prostate death
rates and show them in appendix table 1, along with all the possible
combinations that could result in two or less prostate cancer deaths.
For each combination, 4>(v,r) r = 0,1,2 is calculated where v = 18. The
probability of r >^ 3 is simply 1 minus the sum of all these probabili-
ties, or P(r >_ 3) = l-(.872032 + .120665 + .007087) = .000216.
-------
APPENDIX TABLE 1
PROBABILITY OF THREE OR MORE PROSTATE CANCER DEATHS
OUT OF EIGHT DEATHS IN SPECIFIED AGE GROUPS
BASED ON 1973 U.S. DEATH RATES
Age
Interval
50-54
55-59
60-64
65-69
75-79
Number
of
Deaths
1
1
1
3
2
Probability
Death Was Due
to Prostate
Cancer
Pj
.004624
.007645
.012502
.018304
.027912
Total Prostate Cancer Deaths r =
RESULT:
P(r > 3) - 1 - (.872032+ .120665
+ .007087)
= .000216
All Possible Combinations That Result in
Two or Less Prostate Cancer Deaths
rj
r=0
0
0
0
0
0
4
o
4
00
to
0
to
^
•
oo
hJ
o
LO
to
r=l
10000
01000
00100
00010
00001
44444
-
44444
o o o o o
O O H-" -C- <-n
f- &* )-> (X O
O ~J O *J O
M 00 O OO OO
'
to
o
Ul
r=2
111100000000
100011100000
010010011000
001001010120
000100101102
44,4.4444,4.4.414.
N)
44-^44-4-44-4-444
oooooooooooo
oooooooooooo
OOOOOOOOOMOO
Ijj {j^ [^J (j^ QQ "vj QQ |— I Jjj ^^ [\^j E__l
f— i i—1 *^j O-? O"i O^ O^ 00 •P'* H^ o^ VO
^
b
o
-J
o
OO
~J
n
O hH
l~tl tj
o M o
rt ^ sf
i P. i±
g.^
flj ^ •nd
JU i i f^
S 3 S3!
rt O cr'
re n M M
-------
-43-
*
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1. Berg, J.W. and Burbank, P., "Correlations Between Carcinogenic
Trace Metals in Water Surolies and Cancer Mortality". Ann. N.Y.
Acad. Sci. 199,, 249-261 (1972) .
2. Energy and Environmental Analysis, Inc. "Atmospheric Cadmium-
Population Exposure Analysis." Draft report prepared for U 5
Environmental Protection Agency 17 March 1978.
3 Energy and Environmental Analysis, Inc. "Sources of Atmospheric
Cadmium. " Draft reported prepared for U.S. Environmental Protection
Agency, 27 February 1978.
4 . Environmental Protection Agency, "Scientific and Technical
Assessment Report en Cadmium", EPA-600,/6-75-003, (Marcn 1975).
5. Food and Drug Administration Review, Mutagenicity of Cadmium
(May 31, 1977).
6. Fleischer, M. , A. F. Sarofim, D.W. Fassett, P. Hammond, E. T.
Shacklette, I. C. T. Nisbet, ard S. Epstein, " Envirorer-ental
Impact o£ Cadmium: A Review bv the Panel on Hazardous Trace
Substances" , . Environmental Healtn Perspectives, 7_, 253-323, (1974).
7. Friberg, L. , Piscatcs, M. , and Nordberg, G. "Cadmium in the
Environment" Chemical Rubber Press, Cleveland (1971).
8. International Agency for Research on Cancer, "IARC Mcnccrachs
on the Evaluations of Carcinogenic Risk of Chemicals to Man" ,
U, 39-74 (1976).
9. Kipling, M.D. and J. A. H. Watsrhouse, "Cadmium and Frostatic
Carcincma" , Lancet, 730-731, (April 1,1967).
10. Knorre, Von P.," Introduction of interstitial cell tumors bv
caamiap chloride in albino rats1', Arch. Geschwulstforscn, 3S:
257-263, 1971.
-
11. Lemen, R.A.;0^. d. Lee; J. K. Wagoner, H. P. Blejer, "Cancer
Mortality Among Cadmidn Production Workers", Ann. N. Y. Acad.
Science, 271, 273-279, (1976).
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