Occupational and Environmental Medicine 1995;52:28-32

Cancers related to exposure to arsenic at a copper

smelter

Philip E Enterline, Richard Day, Gary M Marsh

Abstract

Objective-This is an update of an earlier

study on the relation between exposure to

arsenic in air and deaths from respiratory cancer. The purpose was to verify

earlier findings of a supralinear dose

response relation and to examine relations with other cancers, particularly

those reported in studies on drinking

water.

Methods-An earlier study of 2802 men

who worked at a copper smelter for a

year or more during the period 1940-64

and who were followed up for deaths during the period 1941-76 was updated until

1986. Estimates of exposure for the

period 1977-1984 were added.

Results and conclusions-The additional

follow up confirms the earlier finding

that at low doses the increments in death

rates for respiratory cancer for a given

increment in dose are greater than at

high doses. The additional follow up also

shows significant increases in cancer of

the large intestine and bone, and SMRs

>150 for cancer of the buccal cavity and

pharynx, rectal cancer, and kidney cancer. There was a positive relation

between exposure to arsenic in air and

kidney and bone cancer, but none for the

other cancers, except respiratory.

(Occup Environ Med 1995;52:28-32)

Keywords: arsenic; cancer; dose-response

We (PE, GM) previously reported on the

mortality experience of 2802 men who were

exposed to arsenic at a copper smelter at

Tacoma, WA after a year or more of employment during the period 1940-64.' 3 These

reports showed an excess in deaths from respiratory cancer during the period 1941-76

with the excess related to cumulative airborne

exposure to arsenic. In the most recent report,

the respiratory cancer dose-response curve at

lower exposures was much steeper than at

higher exposures so that the dose-response

curve was supralinear (concave downward).

This was true for the relative as well as the

absolute response, and for follow up that

started at entry into the study, or follow up

that started at the end of exposure.3 Thus, in

the population we studied, the increments in

respiratory cancer per unit dose were greater

at low exposures than at high.

This is a report on the results of an additional 10 years of follow up, until 1986. The

purpose is to verify our previous findings and

to explore an additional question, and that is

whether inhaled arsenic is related to internal

cancers as well as to respiratory cancer.

The copper smelter where workers in this

study were exposed to arsenic started operations in 1913 and at one time was the largest in

the United States, producing about 10% of

the refined copper in the entire country. For

many years it was the source- of all ofFthe

arsenic commercially produced in the United

States. Further information about this smelter

is contained in an earlier paper.

Methods

For the entire cohort of 2802 men who

worked for a year or more during the period

1940-64 it was possible to determine vital

status at the end of 1986 for 98-5%. An additional 522 deaths were identified, which

increased the total from 1061 in the last

report to 1583. Of 1583 known deaths, death

certificates were obtained for 1530 or 96 6%.

The additional 522 deaths were traced

through the United States Social Security

Administration, the United States National

Death Index, and by personal phone contacts.

Death certificates were obtained from state

Health Departments and coded by a nosologist to the underlying cause of death according to the revision of international

classification of causes of death in effect at the

time of death. For malignant neoplasms

expected numbers of deaths were based upon

the mortality of the population of the State of

Washington.4 These are available for the

entire follow up period 1941-86 for malignant

neoplasms but only from 1960 for other

causes of death. Thus, for this report follow

up for non-malignant disease only starts in

1960 whereas follow up for malignant disease

starts in 1941.

In the calculation of expected deaths only

mortality of white men was used as all the

2802 workers in the study were men and

nearly all were white. Expected deaths were

also calculated with death rates for Pierce

County, the county where the smelter is

located.4 Results were about the same as when

Washington state rates were used. Because of

larger numbers of deaths and more stable

rates only Washington state rates are used in

this report. Excesses and deficits in mortality

are expressed as a standardized mortality ratio

(SMR). This is the ratio of the observed to the

expected number of deaths multiplied by 100.

Department of

Biostatistics,

Graduate School of

Public Health,

University of

Pittsburgh, PA

P E Enterline

R Day

G M Marsh

Correspondence to:

Dr Philip E Enterline,

Department of Biostatistics,

Graduate School of Public

Health, University of

Pittsburgh, Pittsburgh,

PA 15261, USA.

Accepted 6 September 1994

28
29 Cancers related to exposure to arsenic at a copper smelter

Expected deaths are age-time specific death

rates of white men for the state of Washington

multiplied by person-years lived by the cohort

in five year age-time intervals. The SMRs

were calculated with the computer program

OCMAP.5

Exposure to arsenic was estimated from

departmental measurements of arsenic in air

contained in company annual reports that

started in 1938, and measurements of urinary

arsenic identified by department and worker

started in 1948. We combined these data to

allow an analysis of the relation between the

concentrations of arsenic in air and various

cancers.

Measurements of arsenic in air were mostly

confined to departments in which arsenic was

thought to be a problem. Measurements of

urinary arsenic, on the other hand, were

offered to all workers, and they represent all

departments of the smelter. The conversion of

data of urinary arsenic to air arsenic was made

by the identification of departments and years

for which data from both air and urinary

arsenic were available and by the determination of the mathematical relation between the

two. Although a total of 34 pairs of data were

available, six pairs were deleted, one pair

because the value of arsenic in air was based

on only one sample and the other five pairs

because notations in the annual reports indicated that the measurements of arsenic in air

were not representative of normal working

conditions. The remaining 28 pairs of data

represented 11 of the 33 departments at the

smelter.

Average concentrations of arsenic in air

were weighted to reflect as closely as possible

actual exposures of workers. Before 1971,

data of arsenic in air came from spot samples

and tape samples. As far as possible these

were weighted for hours per shift at the sample location, numbers of men at that location

per shift, and frequency of operation (for samples that reflected exposure from a particular

operation). Starting in 1971, data for arsenic

in air were based on readings from personal

samples. These seem to be representative of

personal exposure for particular departments.

From these data an exposure matrix of

arsenic in air was developed by department

and year from 1938 up to the time the smelter

closed in 1984. Combined with job histories

for each worker cumulative exposure was calculated and expressed as pg/m'/y. For years

before 1938 the exposure data for 1938 were

used. Additional details on the method used

in estimations of exposure are contained in an

earlier report.3

RESULTS FOR CANCER

Table 1 shows the mortality experienced for

selected malignant neoplasms in total and by

time since first exposure. Overall, there were

significant excesses for all malignant ne oplasms taken together, cancer of the large

intestine, cancer of the respiratory system,

and bone cancer. When there were <20 years

since first exposure the only significant excess

is for respiratory cancer. For >20 years since

first exposure SMRs are generally higher but

those that are significant are the same as for

the total cohort.

As well as the cancers that were significantly in excess in table 1 there are three sites

for which there were 10 or more deaths and

for which the SMRs were >150 but were not

significant. For cancer of the buccal cavity

and pharynx the SMR was 168-7 based on 12

deaths. For rectal cancer the SMR was 176-0

based on 15 deaths, and for kidney cancer

there were 11 deaths and the SMRwas 163-5.

Ten of the 11 deaths from kidney cancer

occurred >20 years after first exposure.

Table I Observed (0) and expected (E) deaths and SMRsfor selected cancers by years since first exposure, Tacoma copper smelter

Total Exposure <20y Exposure >20y

Cancer site 0 E SMR 0 E SMR 0 E SMR

All malignant neoplasms: 395 276-06 143-1" 43 36-10 119-1 352 239-95 146-7 Buccalcavityandpharynx 12 7-12 168-7 2 1-14 175-8 10 5-98 167-3

Digestive organs and peritoneum: 95 79-08 120-1 11 10-94 100-6 84 68-14 123-3 Oesophagus 7 6-08 115-2 0 0-64 - 7 5-44 128-8 Stomach 18 16-43 109-6 2 2-79 71-8 16 13-64 117-3

Large intestine 38 23-48 161-8** 2 2-61 76-8 36 20-87 172-5

Rectum 15 8-52 176-0 4 1-33 299-9 11 7-19 153-0

Biliary passages and liver 1 4-72 21-2 0 0-58 - 1 4-13 24-2

Pancreas 14 16-26 86-1 2 2-19 91-5 12 14-07 85-3

All other digestive 2 3-59 55-7 1 0-80 125-0 1 2-79 35-8 Respiratory system: 188 89-65 209-7** 17 9-66 176 0* 171 79-99 213-8

Larynx 3 3-17 94-7 0 0-42 - 3 2-75 109-2

Bronchus, trachea, lung 182 85-03 214-1** 17 9-04 188-1* 165 75-99 217-1 All other respiratory 3 1-46 205-4 0 0-20 - 3 1-26 238-1

Breast 0 0-46 - 0 0-10 - 0 0-36 -

Prostate 28 25-62 109-3 2 1-23 163-2 26 24-39 106-6

Testes and other male genital organs 1 1-31 76-6 1 0-70 143-2 0 0-61 Kidney 11 6-73 163-5 1 1 04 95 9 10 5-69 175-9 Bladder and other urinary organs 8 9-61 83-2 1 0-94 106-7 7 8-67 80-7 Malignant melanoma of skin 1 2-56 39-1 0 0-55 - 1 2-00 49 9

Eye 1 0-28 361-6 0 0-04 - 1 0-23 428-1 Central nervous system 5 8-15 61-4 0 1-98 - 5 6-16 81-1 Thyroid and other endocrine glands 1 1-00 99-9 0 0-24 - 1 0-76 131-7

Bone 5 1-10 455-6* 0 0-28 - 5 0-82 610-2 Alllynphatic, haeatopoieeic: 24 27-21 88-2 7 5-16 135-5 17 22-05 77-1 Lymphosarcorna and reticulosaroma 3 5-36 55-9 0 1-21 - 3 4-15 72-3 Hodgkin's disease 2 2-91 68-8 2 1-20 166-4 0 1-70 Leukemia and leukemia 9 11-28 79-8 2 2-04 97-8 7 9-24 75-8 All other lymphopoietic tissue 10 7-66 130-5 3 0-70 426-8 7 6-96 100-6 All other malignant neoplasms 15 16-20 92-6 1 2-11 47-5 14 14-09 99-3

*P<0-05;**P<001.
Table 2 Observed (0) and expected (E) deaths and SMRSfor respiratory cancer by cumulative airborne arsenic and date of hire, Tacoma copper

smelter

Cumulative Mean Total cohort Hired <1940 Hired >1940

exposure exposure Person-

(ag/rM y) (total cohort) years 0 E SMR 0 E SMR 0 E SMR

<750 405 20 445 22 14-29 154-0 2 3 08 65-0 20 11-21 178 4*

750- 1305 19 III 30 17 10 175-5** 5 7-33 68-2 25 9-77 256-0**

2000- 2925 15 804 36 17 17 209-7** 22 8-93 246-2** 14 8 23 170-1

4000- 5708 13 747 36 17-00 211-7** 15 10 01 149-9 21 7 00 300-2**

8000- 12 334 10 934 39 15 48 252-0** 28 10 98 255-1** 1 1 4-50 244-4*

20 000- 28 336 4 114 20 7-04 284-0** 14 5-56 251-7** 6 1-48 405-5**

45000- 58957 761 5 1-58 315-7* 5 1-48 338-7* 0 0 11

*P < 0-05; **P <001.

Table 2 shows the relation between cumulative exposure to arsenic in air expressed as

,ug/m3/y and cancer of the respiratory system

for the entire cohort, for the cohort hired

before 1940, and for the cohort hired in 1940

or later. The reason for this stratification is

that for the cohort hired before 1940 only the

person-years accumulated from 1941 were

followed up for deaths, whereas for the cohort

hired in 1940 and later all the person-years, to

the end of the follow up period, were assessed.

The stratification to some extent also separated workers before 1940 with relatively high

exposure and with poor respiratory protection

from workers with lower exposure, but with

better exposure data and perhaps better respiratory protection.

Table 2 shows the data that are plotted

with dose on a log scale in fig 1. For the entire

cohort the SMRs are almost a straight line.

When the cohort was separated into those

hired before 1940, and 1940 or later the plots

are more irregular, but trends are roughly

similar to that for the entire cohort. Some of

the differences are probably related to the

smaller numbers upon which the divided

cohort is based and it does not seem that the

combination of the two cohorts is inappropriate for determination of the shape of the doseresponse relation between arsenic and

respiratory cancer.

When absolute rather than relative

increments in mortality are calculated the

plots for the entire cohort are similar to those

in fig 1. If, for the entire cohort, dose is plotted

500 r

2 400

en

it

c 300

(a

° 200

(D 100

---- Hired 1940+

---- Hired <1940

All-,-A-lre

on an arithmetic scale rather than on a

logarithmic scale the dose-response curve is

concave downward- like the relation previously reported for the years 1941-76.3 For the

entire cohort, the linear correlation between

log dose and SMRs in fig 1 is highly significant (P <0-001). The fitted regression equation between dose and SMRs is a power

function:

SMR = 100 + 10-5 (cumulative exposure) 1279

Compared with the regression equation

reported for the years 1941-76 this new

equation, which includes 10 years additional

follow up, has slightly more curvature than

the old equation and strengthens the evidence

for relatively large increments in respiratory

cancer at low exposures. Figure 2 compares

the dose-response curve for the period

1941-86 with the curve previously reported

for the period 1941-76. Note that the horizontal scale is arithmetic. The power function

for follow up to 1986 is an almost perfect

fit.

Table 3 shows the relation of the other

cancer sites already discussed with cumulative

exposure to arsenic in air. Here cancer of the

large intestine has been combined with colon

cancer as these are sometimes confused

diagnostically and, moreover, the aetiology of

these cancers is likely to be the same. There

does not seem to be any relation between

cumulative exposure to arsenic in air and

either colorectal or buccal cancer. There is a

weak relation for kidney and bone cancers.

400

C 350

Cl)

I, 300

0o 250

c 200 C.

it

z 150!

0

75 750 7 500 75 000

Cumulative air arsenic (ig/rmn y)

Figure I The SMRsfor respiratory cancerfor cumulative

airborne arsenic and date of hire. Copper smelter workers

from Tacoma 1941-86. Data are plotted at the means of

exposure intervals.

Cumulative air arsenic (igg/m3 y)

Figure 2 The SMRs for respiratory cancerfor cumulative

airborne arsenic. Copper smelter workers from Tacoma

1941-76 and 1941-86. Data are plotted at the means of

exposure intervals. Fitted lines are from corresponding

powerfunctions.

30 Enterline, Day, Marsh

All worKers I

-------

I

,

.1

I

I

I

I

-------

Jr
Table 3 Observed (0) and expected (E) deaths and SMRSfor selected cancers by cumulative exposure to airborne arsenic, Tacoma copper smelter

Cumulative Buccal Colorectal Kidney Bone

exposure (pg9/mY) 0 E SMR 0 E SMR o E SMR 0 E SAtR

<750 2 1*07 186-7 5 4 23 118-2 0 1*03 - 0 0-17 -

750- 2 1 29 154-8 9 5 30 169-8 2 1-23 162-5 0 0-19 -

2000- 5 1-37 366-2 12 6-02 199-3 1 1-38 78-2 0 0 21 -

4000- 3 1-36 220 3 13 6-34 205 0 3 1-29 232 2 1 0.21 470-0

8000- 0 1-30 - 10 6-32 158 2 2 1-21 165 6 4 0 20 1969-8**

20 000- 0 0-60 - 3 3-07 97-7 3 0-56 538-0* 0 0 09 -

45 000- 0 0-13 - 1 0-70 137-0 0 0-13 - 0 002

*p<005; **P<0-01.

RESULTS FOR OTHER CAUSES OF DEATH

Data on non-malignant diseases (table 1)

were calculated for the period 1960-86. As

already noted, expected deaths are based on

the mortality in the state of Washington for

the years 1960-86. There were a total of 1234

deaths for all causes during these years and

the SMR was 118-8 (P < 0-01). When

selected causes were examined there were significant excesses for ischemic heart disease

(P < 0-01) and for non-malignant respiratory

disease, excluding bronchitis, emphysema,

and asthma (P < 0 05). There were 428

deaths from ischemic heart disease and the

SMR was 115-0. This was weakly related to

cumulative exposure to arsenic. For the exposure categories shown on table 2, the SMRs

and number of deaths were: 107-6 (55), 103-2

(67), 106-6 (74), 121-6 (87), 127-5 (91; P <

0 05), 131-7 (46), and 89-5 (8). For nonmalignant respiratory disease there were 41

deaths and a slight negative relation, with the

less exposed workers having the highest SMR.

COMPARISONS WITH OTHER STUDIES

An association between exposure to arsenic in

air and respiratory or lung cancer has been

reported for several other occupationally

exposed populations.i" Evidence for the kind

of dose-response relation reported here for

respiratory cancer has recently been summarised and commented upon by HertzPicciotto and Smith with data from one of our

600F --

5007 - Ronnskar

E ---- Anaconda

Cl)

aI 400 - Tacoma

c In

(D 40 CL

0

X 200 _

75 750 7 500

Cumulative air arsenic (pg/m

Figure 3 The SMRsfor respiratory cancer (A

and Tacoma) and lung cancer (Ronnskar) for

airborne arsenic. To facilitate presentation the a

exposure categories for Ronnskar have been con

Tacoma plots are as forfig 1. Anaconda and R

are plotted at the midpoint of exposure intervals

upper intervals 30 000 and 57 000, which were

in part on the exposure distributions in the data

Tacoma.

earlier reports.36 There are data from two

copper smelters that seem to be comparable

with our study. Figure 3 shows the doseresponse relation reported for a United States

copper smelter at Anaconda, MT and for a

copper smelter at Ronnskar, Sweden along

with data from our study.'4 '5 As in fig 1, the

horizontal scale is logarithmic. Only data

reported by one of the investigators of the

Anaconda smelter are shown.'4 Other data for

the Anaconda smelter have been reported by

Lee-Feldstein but the shape of the doseresponse curves is similar to that in fig 2.'3

There are also exposure data for the

Anaconda smelter that have been adjusted

downward, and thus higher SMRs for each

exposure category can be calculated. '4 This

raises the dose-response curve, particularly at

higher doses where it is nearly midway

between the Tacoma and the Ronnskar data.

The dose-response curves for the two copper smelters located in the United States are

similar. For the Swedish smelter the response

in terms of lung cancer is higher at each level of

exposure than for the United States smelters.

The authors of the report on the Swedish

smelter thought that some of the excess in

lung cancer might be due to an excess in

smoking when compared with the general

population. A more recent report shows that

smoking probably was not a factor in the high

death rate from lung cancer.'7

Discussion

Studies of cancer related to arsenic in drinking water indicate increases in cancer of the

lung, bladder, kidney, skin, liver, and colon.'8 19

Gibb and Chen have compared studies of

sites with excessive cancer between arsenic

inhalation (like our study) and arsenic ingestion, and have concluded that there is some

agreement. Our study lends some support

for a relation between exposure to arsenic in

air and kidney cancer but little support for the

other cancers except lung cancer.

One important difference between studies

of occupationally and environmentally

75000 exposed cohorts is that for most of the envi-

~' y) ronmentally exposed cohorts exposure starts

Inaconda at birth, whereas for the occupationally

cumulative exposed cohorts exposure of interest starts 4pper three

ibined. much later in life. In our study the mean age otonskar at first exposure was about 30 years. If the

ue exceptfor

used based latent period for some cancers caused by

from ingestion is very long these might be missed

in a study of occupationally exposed

Cancers related to exposure to arsenic at a copper smelter 31

II
Enterline, Day, Marsh

populations. We looked for skin cancers in the

smelter population of Tacoma and found no

excess.2' These are rarely fatal and could only

be found at work, not very long after the onset

of exposure. Skin cancer related to arsenic in

drinking water does not usually appear until

after the age of 30 and the incidence rises

rapidly with age.22 Thus, the latent period for

skin cancer and perhaps other cancers related

to ingested arsenic could be very long, so perhaps this is the reason these were not seen in

the smelter worker population of Tacoma. It

may also be that, as noted by Bates et al, in

comparison with populations exposed to

arsenic in drinking water the exposure of our

population, and perhaps other populations

exposed to arsenic in air is relatively low.'9

One cancer with an apparently short latent

period in this study is respiratory cancer. As

table1 shows,

a significant excess (SMR

=

203 3) occurred in <20 years. The SMR

remained around 200 in successive 10 year

periods and was 151-9 >,50 years since first

exposure. We are not aware of published

studies of other workers from copper smelters

that report increments in respiratory or lung

cancer by time from first exposure. Ott et al

reported no deaths from respiratory cancer in

a

population occupationally exposed to insecticides containing arsenic <15 years from first

exposure (0

4 expected), but did report

excesses for the subsequent time since first

exposure categories." In

a study by us (PE,

GM) of workers at

a copper smelter at Salt

Lake City, UT where there was exposure to

arsenic the SMR for respiratory cancer <20

years since first exposure was 170-0 (11

deaths) and >20 years 107-8 (39 deaths).'221

Perhaps

a short latent period is somehow

related to the way exposure occurs in the lung

as inhaled arsenic seems to be retained in the

lung for long periods.24 On the other hand,

perhaps the lung has

a particular susceptibility. One curious finding in studies of arsenic

in drinking water is

a dose related excess in

mortality from lung cancer-an excess surpassed only by an excess in urinary cancer."

We are not aware of any other ingested substance that may cause lung cancer.

The dose-response relation between airborne arsenic and respiratory cancer found in

this study is unusual. As noted in our earlier

report, this could be because air measurements are not good measures of biological

dose.3 The relation is not likely to be due to

confounding, but this needs further study.

Smoking can be an important confounder in

respiratory cancer and data on the histories of

the study population for smoking are being

collected. These will be modelled along with

other covariates in

a future publication.

The excess we found in bone cancer has

not, to our knowledge, been reported in other

studies. As arsenic is stored in the bone, however, this may be an important finding.25 26 Of

the five deaths coded by our nosologist to

bone cancer, two were mandible, one hip, one

spine, and one ribs. For the spine and ribs

information on the death certificate indicated

that these may not have been the primary

sites. If we had recoded these, however, it

would have invalidated our comparison with

the external control population.

This research was supported in part by the US Environmental

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smelter workers. AmjInd Med 1980;1:251-9.

2 Enterline PE, Marsh GM. Cancer among workers exposed

to arsenic and other substances ina copper smelter. AmJ

Epidemiol 1982;116:895-91 1.

3 Enterline PE, Henderson VL, Marsh GM. Exposure to

arsenic and respiratory cancer-a reanalysis. Am

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Epidemiol 1987;125:929-38.

4 Marsh GM, Ehland J, Sefcik S. Mortality and population

data system (MPDS). Pittsburgh: University of

Pittsburgh, Department of Biostatistics, Technical

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man: an occupational study.

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copper smelter.

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a metal

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32