British Journal ofIndustrial Medicine 1988;45:766-776

Incidence of laryngeal cancer and exposure to acid

mists

K STEENLAND,' TERESA SCHNORR,' J BEAUMONT,2 W HALPERIN,' T BLOOM'

From the National Institutefor Occupational Safety and Health,' Cincinnati, Ohio 45226, and University of

California at Davis,2 Davis, California, USA

ABSTRACT To determine the relation between exposure to acid mist and laryngeal cancer, the

smoking habits, drinking habits, and incidence of laryngeal cancer of 879 male steelworkers exposed

to acid mists during pickling operations was ascertained. Sulphuric acid mist was the primary

exposure for most men in this cohort. These men had all worked in a pickling operation for a

minimum of six months before 1965, with an average duration of exposure of9 5 years. Exposures to

sulphuric acid in the 1970s averaged about 0-2 mg/m3, and earlier exposures were probably similar.

Interviews were conducted with all cohort members or their next ofkin in 1986 and medical records of

decedents were reviewed. Nine workers were identified who had been diagnosed as having laryngeal

cancer, using a conservative case definition that required medical record confirmation for any case

among decedents and confirmation by a physician for any case among live individuals. Using data

from national surveys of cancer incidence as referent rates, 3-44 laryngeal cancers would have been

expected. Excess smoking by the exposed cohort compared with the United States population

resulted in an upward adjustment of the expected number of cases of laryngeal cancer to 3'92. The

standardised incidence rate ratio for laryngeal cancer was 2-30 (9/3 92), with a one sided p value of

0O01 (assuming a Poisson distribution). The finding of excess laryngeal cancer in this cohort is

consistent with four other studies published since 1981.

Three recent reports have indicated an association

between exposure to sulphuric acid and an increase in

the incidence oflaryngeal cancer. Ahlborg et al studied

110 men exposed for at least one year to various acids

in a pickling operation and observed three incident

cases oflaryngeal cancer compared with 0-6 expected.'

No data on smoking were available. Soskolne et al

conducted a nested case-control study of 34 cases of

laryngeal cancer among men who worked in a refinery

and chemical plant.2 A 13-fold excess risk of laryngeal

cancer was found for those exposed to the highest

levels of sulphuric acid compared with those least

exposed, and a fourfold risk for the moderately

exposed versus the least exposed, after controlling for

alcohol and tobacco consumption. Cookfair et al

(reported at Society for Epidemiological Research

Conference, Chapel Hill, 1985) conducted a population based case-control study of 352 white men with

laryngeal cancer at a cancer research hospital in New

York. After coding lifetime work histories for

exposure to sulphuric acid and controlling for smokAccepted 21 September 1987

ing and drinking, they found that the risk of laryngeal

cancer increased for those with longer exposure to

sulphuric acid. Finally, Forastiere et al studied 361

soap workers in Italy who had been exposed to

sulphuric acid for a minimum of one year and

observed five cases of laryngeal cancer over the study

period compared with approximately one expected3;

there was no control for smoking in this study.

Beaumont et al at the National Institute for

Occupational Safety and Health had previously

studied the mortality of a cohort of 1156 men exposed

to sulphuric and other acids in pickling operations at

three midwestern steel mills.4 In this study two deaths

from laryngeal cancer were observed versus 1 03

expected (not significant). Mortality studies for

laryngeal cancer are relatively insensitive, however,

because the five year survival rate for laryngeal cancer

is greater than 50%,4 and many patients with laryngeal

cancer die of other diseases. Given the evidence that

sulphuric acid might be associated with an increased

risk of developing laryngeal cancer, and the relative

insensitivity of the mortality study, we conducted a

study ofthe incidence of laryngeal cancer in the cohort

assembled by Beaumont.4

766
Incidence oflaryngeal cancer and exposure to acid mists

Materind mehods

ORIGINAL COHORT DESCRIPTION

The original cohort consisted of 1156 men, all of

whom had worked for at least six months before 1965

in a pickling department at one of three midwestern

steel mills. Demographic and work history data from

company records for these men were collected in

1980-1. Most of these men began work in 1940 or

later, although a few began in the 1930s.

Ofthe entire cohort, 373 (32%) had died by the end

of 1985. The average duration of employment in an

exposed job (in the pickling area) was 8-8 years.

Twelve per cent of these men were non-white (black

and hispanic). Details ofthis study have been reported

elsewhere.4

PROCESS DESCRIPTION AND EXPOSURE LEVELS

Acids are used to remove impurities (oxides) from

newly manufactured steel. Sulphuric acid was the

predominant acid used for steel pickling until the mid1960s when it began to be replaced by other acids

(hydrochloric, nitric, hydrofluoric, and hydrocyanic,

with hydrochloric being the most common). By 1980,

sulphuric acid was no longer being used at any of the

three plants studied. Historical exposure data from

1975, 1977, and 1979 at two of the three plants in the

original study indicated that exposure levels for

sulphuric acid averaged 0-2 mg/m3 (time weighted

average), less than the current OSHA standard of 1 00

mg/n367 (table 1). Based on our observations, we

estimated that exposures at the third plant were similar

to the two from which exposure data were available.

Furthermore, given that processes had not changed

substantially over time, exposure in earlier years

probably did not differ greatly from the measured

767

levels, although this possibility cannot be excluded.

Sampling data also indicated that the pickling

process did not generate appreciable levels of metal

particulate.7 Twenty samples taken for chromium

were all non-detectable or found only trace amounts

(less than 0-01 mg/m3) whereas ten samples taken for

nickel were all non-detectable. Lead, copper, and

manganese levels were similarly negligible. The only

metal found in appreciable quantities was iron oxide,

which averaged 0-67 mg/m3 over 20 samples (range

0O2-2-7).

Based on personnel records and knowledge of

process changes at the three plants, all men in the

cohort were classified by NIOSH industrial hygienists

into categories according to type of acid exposure.4

Sixty two per cent of the original cohort was exposed

to only sulphuric acid, 22% to sulphuric and other

acids, and 16% only to acids other than sulphuric.

INCIDENCE COHORT DEFINITION AND CASE

CONFIRMATION PROCEDURES

The incidence cohort was a subset (77%) of the study

population included in the mortality study by

Beaumont et al4 and was composed of all men for

whom we could determine whether or not they had

ever had laryngeal cancer. Such a determination was

made for all live men for whom we obtained an

interview and for all deceased men for whom next of

kin were able to answer whether they had had

laryngeal cancer. Any decedents for whom we had no

interview with next of kin but for whom we were able

to obtain medical records with a complete medical

history were also included. Medical records (admissions, pathology reports, necropsy reports, discharges) were sought from all hospitals and physicians

listed on the death certificate.

Table 1 Exposure data in pickling departments. Area andpersonal samples ofsulphuric acid air concentrations measured at

two study plants during NIOSH and company industrial hygiene surveys*

Batch (B) or Concentration (mg/m3)

continuous (C) No of

Plant pickling Area orjob sampled samples Mean Range

Personal samples

3 B Pickle hooker 7 015 0-07-0-25

3 B Asst pickle hooker 4 0-20 0-03-0-48

3 B Craneman 4 0-22 0-15-0-29

Average 0-19

Area samples

2 B Cold finishing 2 0 09 0-040-14

2 C Cold strip mill 3 0-92 0-35-1-20

3 B Pickle tanks helper 2 015 012-027

3 B Crane operator 10 0-25 0-01-0-50

3 B Lunch table 2 0-21 0-18-0-24

3 B Crane stairs 15 0-15 0-00-0-61

Average 0-29

*Table taken from Beaumont et al.' Data for plant 2 from Young,' data for plant 3 from Price,7 and from 1975 company data.
768

All reported cases of laryngeal cancer had to be

confirmed by a physician or by medical records to be

considered cases in the study. For decedents, neither a

report by next of kin nor a death certificate was

considered sufficient to define a case. Such reports had

to be confirmed by medical records. Similarly, for any

live men reporting cancer of the larynx, physician or

medical record confirmation was required.

METHODS OF OBTAINING INTERVIEWS

We attempted to contact all the members of the

original cohort used in the mortality study, or their

next of kin, to determine incidence of cancer, smoking

habits, and alcohol consumption. Live cohort

members were also asked whether they had had vocal

chord polyps, and whether they had been exposed to

asbestos, nickel, or wood dust, since these exposures

have been identified as potentially associated with

laryngeal cancer.8

Original addresses for all cohort members were

available from personnel records, but in many cases

these addresses dated back many years. Current

addresses for live members of the cohort were

obtained through the Internal Revenue Service (IRS)

and the Health Care Financing Administration

(HCFA) for those aged over 65. Addresses were also

sought for live individuals from the Motor Vehicle

Bureaus in the presumed state of residence. For

decedents, addresses of next of kin were obtained

primarily from death certificates and through HCFA.

When addresses could not be obtained, living

individuals and next of kin were also sought through

telephone directory assistance checks in cities where

cohort members were last known to live.

Mailed questionnaires were sent in 1986 to all

cohort members or their next ofkin by certified mail. If

the first mailing was unsuccessful a follow up mailing

was done. If no response was obtained through the

mailings then interviews were conducted by telephone.

ANALYTICAL DESIGN

We analysed the data by a comparison of the exposed

cohort with a non-exposed referent group, comparing

observed laryngeal cancers with expected laryngeal

cancers, based on conventional person-years analysis.

The resulting measure was a standardised incidence

ratio (SIR).

The NIOSH life table program was used to calculate

person-years at risk for the cohort.9 The appropriate

referent rates (see below), stratified by sex, age, and

calendar time, were applied to the person-years

derived from the program to determine expected

numbers of laryngeal cancer. Observed versus

expected cases were tested using a modified one sided

exact test, assuming a Poisson distribution, as

discussed by Rothman and Boice."' A one sided test

Steenland, Schnorr, Beaumont, Halperin, Bloom

was used because this study was undertaken to test the

a priori hypothesis of an excess incidence of laryngeal

cancer.

Further analyses were conducted after dichotomising the cohort by duration of exposure and time since

first exposure. Cut off points for the categories

were determined a priori, after the person-years

distribution of the cohort was known but without

knowledge of the duration of exposure and time since

first exposure of the observed cases. The cut off point

for duration of exposure (five years) was chosen to

distribute approximately the expected laryngeal

cancers evenly between the two strata, whereas that for

time since first exposure (20 years) was chosen because

it is a conventional cut off point chosen to reflect the

fact that most occupational agents require at least a 20

years latency period before resulting in solid tumours.

REFERENCE RATES FOR INCIDENCE OF

LARYNGEAL CANCER

We calculated the expected number of laryngeal

cancers using three sources of incidence data. There is

no ideal referent population for which there exist

complete incidence rates of laryngeal cancer for the

entire study period, stratified by age, sex, and calendar

time. Partial data over time, however, exist from the

Connecticut Cancer Registry (1935-79) and the New

York Cancer Registry (1950-72). These data were

kindly provided by Dr William Burnett (New York

State Health Department) and John Flannery

(Connecticut Department of Health Services). Rates

reported from the New York Registry did not include

New York City before 1973, and rates subsequent to

1973 cannot be compared with earlier rates. Neither

Connecticut nor New York rates are stratified by race.

In addition, rates corresponding to a sample of all

United States geographical areas exist for 1938 and

1948 (1st and 2nd National Cancer Surveys"), for 1970

(3rd National Cancer Survey),'2 and for 1973-7 and

1978-81 (1st and 2nd surveillance, epidemiology, and

end results (SEER) surveys).'3 The United States rates

are based on cancer registry data in several large cities

and some entire states. Although United States rates

are stratified by race, there is little difference in rates

between whites and non-whites and the numbers for

non-whites are quite small and unstable. We have used

rates for all races combined in calculating expected

laryngeal cancers in our cohort.

We have calculated the slope of the increase in rates

over time for each source of rates (Connecticut, New

York, United States, using linear regression. These

regressions were used to estimate rates during five year

calendar periods when actual rates were missing. For

each of the three sources of rates 15 regression lines

were calculated, corresponding to five year age

intervals beginning with 15-19 and ending with all
Incidence oflaryngeal cancer and exposure to acid mists

'10.5-

a,

<8a 9.0- 1.5-

a _

TU426.0

B c 3.0

-T 1.51

Connecticut

_ -----f ~United States

New Ybrk

v I I I .1 I I I

--

1940 1945 1950 1955 1960 1965 1970 1975 1980

War

Age adjusted incidence rates ofmale laryngeal cancer per

100 000 (adjusted to 1970 United States population except

forfirst two United States data points which were adjusted to

the 1950 United States population).

ages over 85. Five year age and calendar time intervals

were used because person-years at risk in the NIOSH

life table system are broken down into these same

intervals.9 Referent rates were derived for the period

1940-85. As may be seen from the figure in which the

available age adjusted referent rates have been plotted

over calendar time, the number of rates that needed to

be estimated varied.

For Connecticut, rates for only one time point (out

of 10) needed to be estimated. For New York, and the

United States, data needed to be estimated for five out

of 10 time points. As the figure illustrates, the

similarity of the plots of the rates from the three data

sources, as well as the apparent linearity of trend with

time, gave us some confidence that our regression

estimates were reasonable.

ADJUSTMENT FOR CONFOUNDING BY TOBACCO

AND ALCOHOL CONSUMPTION

Smoking data

The strongest known risk factor for laryngeal cancer is

smoking, with a relative risk on the order of 15 for

smokers versus non-smokers.'4 In our reference rates

laryngeal cancer incidence data are not available

separately for smokers and non-smokers. Therefore,

we were unable to calculate the expected number of

laryngeal cancers for different smoking categories in

our cohort. Instead, we used a technique first

described by Axelson, which adjusts the expected

laryngeal cancers upward or downward depending on

the prevalence of smoking in our incidence cohort

compared with the prevalence of smoking in the

United States. This adjustment assumes that there are

known relative risks for the different smoking

categories considered, and calculates the incidence

rates of laryngeal cancer, as a weighted average of

769

rates for different smoking categories. We obtained

the known relative risks from a large case-control

study by Wynder et al.5

Smoking prevalence in the United States was

estimated using data from the 1965 Health Interview

Survey (HIS) conducted by the National Center for

Health Statistics.'6 The 1965 United States data were

chosen because such data were situated at about the

midpoint of our study period and because smoking

habits of earlier periods were more relevant than

current data when considering the subsequent

development of laryngeal cancer. Furthermore, dead

cohort members, who might be expected to have

smoked more,' would be less well represented in a

more recent comparison. We did, however, also make

a second Axelson adjustment using 1976 United States

smoking prevalence data, by way of checking how

much effect such a change in calendar time would

make.

The 1965 HIS survey included data from about

35-000 men stratified into five age groups (20-24,

25-34, 35-44, 45-64, A65). In the published HIS data

this sample population was weighted to obtain

estimates for the entire United States. The HIS data

refer to cigarette smoking only, without reference to

pipes or cigars. We have made comparisons between

our cohort and the HIS data for cigarette smoking

status (current, former, and never). We further

stratified current smokers by amount smoked a day (a

pack or less, or more than one pack). Former smokers

were those who had smoked regularly but were not

currently smoking.

Lifetime smoking histories of the cohort were

obtained in early 1986. We used these data to

determine the cohort's smoking habits as of 1965, the

same year as the HIS survey. All 46 men who died

before 1965 were excluded from the comparison for

the smoking adjustment.

Expected cases of laryngeal cancer are derived from

rates which are not stratified by race (see above). Thus

in our smoking prevalence comparison we have not

stratified the data on race.

Expected proportions of the different categories of

cigarette smokers, based on the United States data,

were calculated using an age adjustment. In 1965 3-3%

of our cohort was aged 20-24, 19-1% were 25-34,

30 3% were 35-44, 42-4% were 45-64, and 4 9% were

65 or older. Age adjusted smoking prevalences in the

United States were calculated by using the above

proportions to weight an average of the age specific

United States smoking prevalence rates, for the

various smoking categories.

To account for the effect of pipe and cigar smoking,

we have also calculated the numbers of men in our

cohort who did not smoke cigarettes but did smoke

pipes and cigars, and compared this proportion with
770

the expected number based on data gathered by the

American Cancer Society.'8

Alcohol data

Alcohol is a much weaker determinant of laryngeal

cancer than smoking. The relative risk for drinkers

versus non-drinkers is of the order of 2-3. To adjust

for possible confounding by divergent alcohol

consumption patterns between the incidence cohort

and the United States referent population, we again

used an adjustment of the expected laryngeal cancers

according to the technique suggested by Axelson'4 and

the relative risks for laryngeal cancer were taken from

the study by Wynder et al.'5

Alcohol histories of the cohort were obtained in

early 1986. Good historical data on United States

alcohol consumption, based on a sample of the entire

population and stratified by age and sex, have not been

available until recently. As a comparison with our

cohort we used the drinking habits of the national

population obtained in 1983 in the HIS conducted by

the National Center for Health Statistics.'9 Because

the HIS survey was conducted toward the end of our

study period, our comparison was restricted to cohort

members who were alive at the time of our interviews.

Whereas drinking habits some time ago might be more

relevant than current data when considering the

subsequent development of laryngeal cancer, these

data were not available for the United States.

Although this could be considered a disadvantage,

the relative importance of alcohol as a potential

confounder is much less than the importance of

smoking, and only an extreme divergence between

drinking habits between our cohort and the United

States could cause much of an effect on the expected

number of laryngeal cancers.

The 1983 HIS survey obtained data from about

9000 men. We stratified them into three age groups

(18-44, 45-64, and > 65). We have made comparisons

between our cohort and the HIS data for drinking

status (current, former, and never/occasional).

Current drinkers were those who drank three to four

times a week or more often and were further stratified

by amount drunk a day ( < 3 drinks, 3-6 drinks, > 7

drinks). Former drinkers were those who had drunk

alcohol regularly but were not current drinkers. Men

who had never drunk or who did currently drink

occasionally (<3-4 times a week) were defined as

never/occasional drinkers. An exception to this

classification were those current drinkers who drank

only occasionally but who consumed more than seven

drinks on a given day (binge drinkers). These binge

drinkers were added to the heavy drinker category.

This categorisation corresponded to the drinking

categories for which relative risks for laryngeal cancer

were estimated by Wynder et al' and could also be

Steenland, Schnorr, Beaumont, Halperin, Bloom

derived both from our cohort's data and the HIS data.

To compare our cohort with the national population, we considered their age and their drinking habits

as of 1983, about the same time as the HIS survey. As

in the adjustment for smoking, no attempt was made

to stratify our cohort or the United States by race in

considering drinking habits. We have age adjusted the

HIS data to our cohort's age distribution. In 1985

6-6% of our cohort were 18-44, 59 5% were 45-64,

and 33 9% were 65 or older. The age adjusted United

States data were calculated by assuming that the men

in the United States had this same age distribution,

and calculating a weighted average of the proportions

of various drinking categories.

Results

RESPONSE RATE FOR FOLLOW UP OF ORIGINAL

COHORT

Using the mailed questionnaire followed by telephone

interviews for non-respondents, responses were

obtained from 841 (73%) of the original cohort. Table

2 indicates the percentage of telephone and self

administered (mailed) questionnaires completed

among each group.

In addition to the interviews with next of kin, for all

decedents in the cohort we sought medical records

from the hospitals and doctors listed on the death

certificate. Some medical record was obtained for

72%. Nevertheless, a medical history sufficient to

determine the incidence of cancer was obtained for

only 42%. Those for whom we had no next of kin

interview were included in the cohort if an adequate

medical history was available. This led to the inclusion

ofan additional 45 for whom we had no interview with

next of kin.

DESCRIPTION OF INCIDENCE COHORT

We were able to determine the incidence of cancer for

Table 2 Cohort interview response rate, by vital status*

Live Next of kin

Total sought 783 373

Completed interview: 621 220

(79-3% of live) (59 0% of dead)

Mailed interview 480 146

Telephone interview 141 74

Non-response: 162 153

(20 7% of live) (41 0% of dead)

No address found 106 122

Some address found 56 31

*For seven decedents the interview with next of kin was insufficient

to determine the incidence of laryngeal cancer, and these men were

subsequently excluded from the incidence study. On the other hand,

medical record information sufficient to determine the incidence of

laryngeal cancer was available for 45 men for whom we had

obtained no interview with next of kin and these men were added to

the incidence study.
Incidence oflaryngeal cancer and exposure to acid mists

77% of the original cohort and these men were

included in the "incidence" cohort for further analysis.

The incidence cohort consisted of 879 men, of whom

621 were alive and 258 were dead. We had received an

interview from all live men. Interviews were available

from next of kin for 220 decedents; however, for seven

the next of kin were unable to provide a history of

cancer and these were excluded. In addition, 45

decedents for whom we did not receive any interview

with next of kin, but for whom we obtained an

adequate medical history from medical records, were

included. The 879 men in the incidence cohort

represented 76-9% of the original cohort (79-2% of the

live cohort members and 69-4% of dead cohort

members).

The average duration of exposure of the incidence

cohort was 9 5 years. Fifteen per cent of these men

were non-white (black and hispanic). Sixty per cent

were exposed only to sulphuric acid, 17% to only other

acids, and the remainder were exposed to sulphuric

and other acids. Fourteen per cent of the men had

worked at plant 1, 31% at plant 2, and 55% at plant 3.

By comparison with the original mortality cohort (see

sections 1 and 2 ofthe materials and methods section),

the men in the incidence cohort had been exposed

slightly longer (9 5 versus 8-8 years). Distributions by

race, type of acid exposure, and plant were similar in

the incidence cohort and the original mortality cohort.

DETERMINATION OF EXPECTED LARYNGEAL

CANCERS

The incidence of laryngeal cancer has increased over

time, possibly due to the effects of increasing

prevalence of smoking, a strong risk factor. The figure

shows the age adjusted summary rates for the different

time points for all three sources ofrates. There is some

771

distortion because the two early United States data

points (1938 and 1948) are age adjusted to the United

States population in 1950, whereas the other data

points are all adjusted to the United States population

in 1970.

It is apparent that the United States data fit roughly

between the lower rates of New York (without New

York City) and the higher rates of Connecticut for

most ofthe study period. Although we have calculated

the expected laryngeal cancers using all three sets of

rates, we believe the expected cancers based on United

States rates are the most appropriate, for two reasons.

Firstly, our study population is from the midwestern

United States, and the general United States rates

probably provide a better comparison than either New

York or Connecticut. Secondly, United States rates

are based on larger numbers and are somewhat more

stable. Disadvantages to the United States rates come

primarily from a lack of confidence in the early data

points (1938 and 1948), at which time the surveys

suffered from several methodological problems and

covered somewhat different geographical areas than

later surveys (J Horm, NCI, personal communication,

1986).

The life table analysis yielded 27 476 person-years at

risk for the total cohort, almost all of which were

accumulated after 1940 (97-0%). Twenty one per

cent were accumulated between 1950 and 1959, 28%

between 1960 and 1969, 27% between 1970 and 1979,

and 12% between 1980 and 1986. Thirty four per cent

of the person-years were accumulated by men aged

20-39,50% by men aged 40-59, and 16% by men aged

60 and older.

We calculated that 3-44 cases of laryngeal cancer

were expected after applying the United States rates

specific to five year calendar time and age intervals to

Table 3 Cases oflaryngeal cancer

Years

Year from first

Vital status Age (late) of first exposure Years Aci(l tpe Snmokinzg Driniking

No Source* (date of death) diagnosis exposed to cancer evposedt (plant) statust staitust

I MR, DC Dead 1980 52 (1977) 1947 30 7-2 Sulphuric (2) Current Unknown

2 MR,DC Dead 1979 45(1978) 1962 16 7-6 Mixed (3) Former Occ

3 NOK, MR Dead 1975 63 (1972) 1933 39 38-5 Sulphuric (3) Current Never

4 NOK, MR Dead 1977 44 (1952) 1940 12 5-3 Other (2) Unknown Unknown

5 NOK, MR Dead 1983 57(1970) 1945 25 0 9 Other (2) Former Heavy

6 INT, PHY Live 59 (1981) 1947 34 28-9 Mixed (3) Current Occ

7 INT, PHY Live 56 (1979) 1951 28 2-2 Sulphuric (3) Current Mod

8 INT, PHY Live 61 (1971) 1939 32 2-0 Sulphuric (3) Current Never

9 INT, PHY Live 46 (1976) 1958 18 17 3 Mixed (3) Current Mod

*Source of information about laryngeal cancer. For a dead person to be confirmed as a case, medical record confirmation was required. For

a live person to be confirmed, his own interview and confirmation by a physician were required. MR: medical record; DC: death certificate;

NOK: next of kin; INT: interview; PHY: physician.

tYears exposed are calculated before diagnosis. Smoking and drinking status are self reported or reported by next of kin. Smoking status is

determined as of the date of diagnosis. For drinkers: occ, occasional/less than three to four times a week, consumes six or fewer drinks when

drinking; mod: moderate/current drinker (at least three to four times a week or more) consuming three to six drinks when drinking; heavy:

current drinker consuming seven or more drinks when drinking.
772

these person-years. The expected cases using New

York and Connecticut rates were 2-94 and 3-89

respectively.

LARYNGEAL CANCER INCIDENCE, BENIGN

GROWTHS, AND POLYPS

Nine men in our cohort were found to have had

laryngeal cancer, five of whom had died. Table 3

provides details on the source of information about

laryngeal cancer, dates of diagnosis, employment

history, smoking history, drinking habits, and type of

acid exposure. Three of the five decedents with

laryngeal cancer had no indication of the disease on

their death certificate. Conversely, one individual who

was listed as having died of laryngeal cancer was

subsequently found, through medical records, to have

actually had pharyngeal cancer and was not

considered a case in this study.

The average age at diagnosis for these men was 53 2

years and the average number of years between first

exposure and diagnosis was 26-0. The proportion of

these nine men exposed to each of the three acid types

(only sulphuric, only other types, and mixed) did not

differ appreciably from the proportion in the entire

cohort (see table 3). Similarly, the proportion of cases

working at the three plants was similar to the entire

cohort. Although no cases occurred at plant 1, only

14% of the incidence cohort worked there.

The average duration of exposure for the cases was

12-2 years (compared with 9 5 years for the entire

incidence cohort), with a range of09 to 38 5 years. All

of the cases were either current or former smokers

(laryngeal cancer is extremely rare among nonsmokers). Drinking habits varied. All four live

laryngeal cases were asked about past exposure to

asbestos, wood dust, and nickel, and all denied any

past exposure.

In addition to the cases of laryngeal cancer other

men in the incidence cohort had benign laryngeal

growths (table 4). There were two reported benign

growths on the vocal cords and seven cases of polyps.

Steenland, Schnorr, Beaumont, Halperin, Bloom

One of the men with polyps subsequently developed

laryngeal cancer (he is one of the nine cases). Table 4

probably underestimates the incidence of benign

growths and polyps. With the exception of one benign

laryngeal tumour found through medical records,

table 4 reflects incidence only among the live members

of the incidence cohort. Next of kin were not asked

about benign growths and polyps for cohort

decedents.

ADJUSTMENT FOR SMOKING

As explained above, we sought to compare the smoking habits of our incidence cohort with the smoking

habits of the United States population as of 1965. In

1986 we had obtained 841 interviews with men (or

their next of kin) in our incidence cohort. These

interviews included a smoking history from which we

could determine smoking habits as of 1965. Nevertheless, 46 men had to be excluded because they had died

before 1965, leaving 795 men to be considered in our

comparison ofsmoking habits (22% ofthese men were

dead by 1985). The average age of these 795 men in

1965 was 441. Of these 795, smoking information

sufficient to categorise them by smoking status was

available for 752, 86% of the incident cohort. Results

for cigarette smoking prevalence, comparing the

incidence cohort with the United States as of 1965, are

shown in table 5. Clearly in our cohort there was a

similar overall prevalence of smoking compared with

all United States men but cohort members who did

smoke smoked more than the United States average.

These results are not surprising, reflecting well known

national trends that blue collar workers smoke more

than the United States average.' It is also apparent

that whereas men who subsequently died and men who

survived were virtually the same regarding the proportions of never smokers, current smokers, and former

smokers, the current smokers who subsequently died

smoked more than the current smokers who survived.

Relative risks (by cigarette smoking status), based

on the data in the study by Wynder et al' were

Table 4 Benign growths andpolyps on vocal cords*

Years

Age at Date of Year first from first

Outcome diagnosis diagnosis exposed exposure Acid type Surger.v?

Benign tumour 76 1962 1926 36 Other Yes

Leukoplakia 33 1950 1937 13 Mixed No

Polypst 31 1952 1950 2 Sulphuric Yes

Polyps 48 1972 1955 17 Sulphuric Yes

Polyps 38 1969 1948 21 Sulphuric No

Polyps 48 1972 1950 22 Sulphuric Yes

Polyps 41 1960 1948 12 Sulphuric No

Polyps 45 1970 1948 22 Sulphuric Yes

Polyps 51 1972 1939 33 Sulphuric Yes

*As reported on interview with live incidence cohort members (n = 621) with the exception of first individual in the table who had died and

whose benign tumour was discovered through medical records. There are nine distinct men in this table.

tThis individual developed laryngeal cancer in 1979.
Incidence oflaryngeal cancer and exposure to acid mists

Table 5 Comparison ofsmoking habits, United States population versus sulphuric acid cohort, as of 1965

US age

adjusted* Cohort (all)t Cohort (live) t Cohori (deal)

Percent neversmoked regularly 24-5 24-1 (n = 185) 242(n = 148) 237(n= 37) Per cent current smoking one pack or less 39-9 34 3 (n = 255) 35 6 (n = 215) 28X9 (n = 40)

Per cent current, smoking more than one pack 14 8 270 (n = 200) 25-5 (n = 154) 33-7 (n = 46)

Percent former 209 146(n = 112) 147(n = 90) 141 (n = 22)

Total 1000 100 (n = 752) 100 (n = 607) 100 (n = 145)

*United States proportions weighted according to the age distribution of our cohort.

tSubjects for whom sufficient information for smoking categorisation was available

$Vital status determined as of end of study.

assumed to be one for non-smokers, about 11 for

smokers of one pack or less, about 21 for smokers of

more than one pack, and about eight for former

smokers. The risks for current cigarette smokers are

available directly from the data by Wynder et al.5 The

eightfold risk for former smokers, however, is an

estimate based on the stratified data presented by

Wynder et al for former smokers.5

Applying these relative risks to the smoking

categories for both our cohort and the United States,

according to the method of Axelson,'4 the following

results are obtained. In these equations 1o represents

the background laryngeal cancer incidence rate

for non-exposed, non-smokers. The numbers in

parentheses (see table 5) are the percentages of men in

different smoking categories. I,p represents the

incidence rate of laryngeal cancer for the exposed (the

incidence cohort), based on their smoking habits and

known relative risks, assuming no effect of exposures.

iion-ex represents the incidence rate of laryngeal cancer

for the non-exposed (in this case the United States

population), again based on their known smoking

habits and known relative risks.

inon-exp = 1(0-245)Io + 11 (O399)Io + 21(0148)Io +

8(0209)Io = 9-41I0

I.p = 1(0-241)Io + 11(0-343)I1 + 21(0-270)Io +

8(0-146)Io= 108510

Hence, the non-exposed group would be expected to

experience an incidence of laryngeal cancer 9-41 times

greater than background due to smoking, whereas the

exposed group would be expected to show an

incidence 1085 times greater than background. The

divergence in smoking habits between exposed and

non-exposed, then, would lead us to expect an

approximately 15% (10-85/9-41) increase in laryngeal

cancers among the exposed compared with the nonexposed due to cigarette smoking.

We also conducted this same adjustment using a

comparison between the prevalence of cigarette

smoking of our cohort versus the United States in 1976

to determine how much a change calendar time would

effect the adjustment. Results using 1976 smoking data

indicated an upward adjustment of the expected

laryngeal cancers of 13%, which compared well with

the 15% based on 1965 smoking data. For the reasons

outlined above in the Methods section (more relevance

to later disease, more of the dead included), we chose

to use the adjustment based on 1965 data.

Pipe and cigar smoking also involve an excess risk of

lung cancer, although such risk is considerably less

than that ofcigarettes, and could confound our results

correspondingly less. The study of Wynder et al

indicated that cigarette smokers who also smoke

cigars or pipes have less risk of laryngeal cancer than

those who smoke cigarettes alone, possibly because of

a decreased amount of cigarettes smoked.'" Among

non-smokers of cigarettes, however, Wynder et al

found that men who smoked pipes or cigars had a

fourfold excess risk oflaryngeal cancer. Hence, potentially, if in our cohort a large percentage of men who

did not smoke cigarettes did smoke pipes or cigars this

could possibly confound our results.

While we did collect information on whether our

cohort members had ever regularly smoked pipes or

cigars, the HIS surveys do not collect such information

and hence provide no comparison group. We have

compared our data with a more recent American

Cancer Society survey of 521 000 United States men

conducted in 1982."8 In this population, which had a

similar age distribution to our cohort in 1982 (mean

ages of 58 and 59, respectively), 25% of non-smokers

of cigarettes smoked pipes or cigars. In our cohort the

corresponding figure was a similar 22%. Given these

data, no substantial confounding by pipe or cigar

smoking appears likely.

ADJUSTMENT FOR ALCOHOL CONSUMPTION

Of the 621 men who were alive in 1985 and for whom

we had an interview, information on alcohol

consumption sufficient to categorise them by drinking

status was available for 593. Table 6 shows the results

comparing the alcohol consumption of our cohort and

the United States population. Clearly in our cohort

773
774

Table 6 Comparison ofalcohol consumption, United States

population versus sulphuric acid cohort, as of 1985

US age

Drinking status (%) adjusted Cohort (live)

Never/occasional drinkers, fewer

than 3 days a week 62 1 60-5 (n = 359)

Current drinkers, 3 or fewer a day 10-6 6 7 (n = 40)

Current drinkers, 3-6 a day 7-9 8-6 (n = 51)

Current drinkers, > 7 a day 9 3 4-4 (n = 26)

Former drinkers 9 8 197 (n = 117)

Total 100 0 100-0 (n = 593)

there was a lower prevalence of current drinkers

compared with all United States men. The prevalence

of both heavy drinkers and light drinkers among the

cohort was less than the United States average. The

cohort had a higher prevalence of former drinkers

than did the United States population.

Relative risks (by alcohol consumption status),

based on the data in the study of Wynder et al,'5 were

assumed to be 1 for never/occasional drinkers (less

than three days a week), 125 for light drinkers (one to

three drinks a day), 1-75 for moderate drinkers (four to

six drinks a day), 2-8 for heavy/binge drinkers (seven

or more drinks a day), and 1b75 for former drinkers.

The risks for current drinkers are calculable from the

data in the study by Wynder et al. Relative risks for

former drinkers were not estimated by them. Hence,

the 1 75-fold risk for former drinkers is an estimate.

Since the relative risk for moderate drinkers was

midway between the highest relative risk (2.8) and 1,

we selected 175 as an appropriate risk for former

drinkers.

Applying these relative risks to the drinking

categories for both our cohort and the United States,

according to the method ofAxelson,'4 we obtained the

following results. In these equations Io represents the

background incidence rate of laryngeal cancer for

non-exposed, non-drinkers. The numbers in parentheses (see table 6) represent the percentages ofmen in

the various drinking categories. I..p represents the

incidence rate of laryngeal cancer for the exposed,

based on their drinking habits and known relative

risks, assuming no effect of exposures. I.O,,,p

represents the incidence rate of laryngeal cancer for

the non-exposed, again based on their known drinking

habits and known relative risks.

inonexp= (1) (0-621)Io + 1-25 (0-106)I1 + 1-75 (0-079)Io

+ 2-8 (0-093)I1 + 1X75 (0-098)Io = 1-32Io

Iep = (1) (0-605)Io + 125 (0-067)Io + 1-75 (0-086)Io +

2-8)(0-044)Io+ 1-75(0-197)Io= 1-31lo

Hence, the non-exposed group would be expected to

experience an incidence of laryngeal cancer 1-32 times

greater than background due to drinking, whereas the

Steenland, Schnorr, Beaumont, Halperin, Bloom

exposed group would be expected to show an

incidence 1-31 times greater than background. The

divergence in drinking habits between exposed and

non-exposed, then, would lead us to expect an approximately 1% (1-31/1-32) decrease in laryngeal cancers

among the exposed compared with the non-exposed

due to alcohol consumption.

OBSERVED VERSUS EXPECTED LARYNGEAL

CANCERS

The expected number of laryngeal cancers, based on

United States rates, was 3-44. The data on smoking

would indicate that this figure should be adjusted

upward by 15%, whereas the data on drinking would

indicate a downward adjustment of 1%. A net upward

adjustment of 14% yields an adjusted expected number of laryngeal cancers of 3-92 (the corresponding

figures using Connecticut and New York rates are 4-43

and 3 35). The observed number ofcancers is nine, and

hence the ratio of observed to expected (SIR) is 2X30. If

a Poisson distribution is assumed the one sided p value

for this ratio is 0X013. The SIRs using Connecticut and

New York rates are 2-04 and 2-70 respectively, with

corresponding one sided p values of 0-025 and 0 005.

We also analysed the cohort according to duration

ofexposure ( < 5 years, > 5 years). The SIRs (observed

versus expected, after a 14% upward adjustment ofthe

expected) were 1-70 (3/1-77) and 2-76 (6/2-17), respectively. Analysis by time since first exposure (< 20

years, > 20 years) resulted in incidence ratios of 3 27

(3/0 92) and 2-03 (6/2.95), respectively. Neither of

these trends (increasing with duration of employment

and decreasing with latency) is statistically significant,

given the small numbers concerned. It should also be

noted that these findings are highly dependent on the

cut offpoints. For example, two cases developed at 16-

18 years from first exposure, so that had the cut off

point for time since first exposure been 15 instead of 20

years, a significant positive trend would have been

observed.

Discussion

The data from this study indicate that the exposed

(incidence) cohort has experienced an approximately

2*3-fold excess of laryngeal cancer compared with the

United States referent population. The use of Connecticut or New York state rates as referent rates change

this result only slightly and, assuming a Poisson

distribution, the results are statistically significant

regardless of which referent rates are used. We have

used a one sided test given our a priori hypothesis, but

all results would have still been significant with a two

sided test.

Some uncertainty in these results arises due to the

adjustment for confounding by alcohol and tobacco
Incidence oflaryngeal cancer and exposure to acid mists

consumption. Given the lack of a referent population

with known smoking specific (or alcohol specific)

laryngeal incidence rates, it was not possible to

calculate expected cancers among the exposed by

different strata of smokers and drinkers. Furthermore,

a case-control approach was not appropriate because

of (1) the lack of any non-exposed group within the

cohort permitting an internal analysis comparing

exposed with non-exposed and (2) the lack of any

quantitative exposure data permitting an internal

analysis comparing the high exposed and low exposed.

Hence, we have used the technique suggested by

Axelson'4 to account for known differences between

the exposed and referent groups for smoking and

drinking habits. Whereas this adjustment is necessarily somewhat imprecise, it probably provides a

reasonable estimate of the expected number of laryngeal cancers. Given that the observed number of

cancers is more than double the expected, slight

changes in the expected will not change the overall

result. If one can assume a Poisson distribution for the

observed cancers, with the expected taken as the

population mean, a one sided test would find significance even if the expected number of cancers was

5-0, instead of the 3-92 we have used. An expected

number of five could result only from a much more

extreme disparity in smoking habits between our

cohort and the United States than was actually

observed. For example, in our cohort we observed

24% non-smokers, 34% light smokers, 27% heavy

smokers, and 15% former smokers (as of 1965). Even

had we observed 20% non-smokers, 35% light smokers, 45% heavy smokers, and no former smokers, our

result would still have been statistically significant.

Various methods could have been used to perform

the Axelson type adjustment. For example, in theory it

might have been possible to combine alcohol and

tobacco consumption categories and do one adjustment instead oftwo. There are several justifications for

separate adjustments, however. Firstly, in the light of

the fact that the overall drinking habits of the cohort

differed scarcely at all from that of the referent

population, it is unlikely that such a combined

approach would differ substantially from the separate

one we have presented. Secondly, while doing a single

combined adjustment might have a tbeoretical advantage of using known relative risks appropriate to

combined categories of both smoking and drinking

(using information on synergism or interaction), in

practice the categories of smoking and drinking used

in the few large case-control studies available did not

correspond to our own or to the available HIS

categories for the United States population, making it

difficult to know what relative risks to use. For

example, in the study by Wynder et al, which we have

used to estimate risks, the relative risks presented for

775

combined smokers and drinkers reflect only current

smoking and drinking, excluding former smokers and

drinkers from consideration.'" Finally, combined

categories would have required using smoking

prevalence in 1983 in order to conform to the alcohol

comparison which of necessity relied on 1983 data

(HIS). As we have argued earlier, it was preferable to

compare smoking habits as of 1965, when they were

more important for subsequent cancer incidence, and

when (subsequent) decedents in the cohort were better

represented. Smoking is a far stronger risk factor than

alcohol, and we wanted the adjustment for smoking to

be as accurate as possible.

We have used fairly strict criteria for case definition

in this study; the decedents had to have had case

confirmation by medical record and live cohort members were required to have the case confirmed by a

physician or medical record. As a result, it is unlikely

that we have overestimated the number of incident

cases of laryngeal cancer. On the other hand, we may

have underestimated the number of cases. Decedents

for whom their next of kin said they had not had

laryngeal cancer were included in the cohort as noncases and contributed to the person-years at risk, even

if no medical records were available to confirm that

they did not have laryngeal cancer. Some of these men

may have had laryngeal cancer despite the assertions

of next of kin.

The finding ofpolyps preceding the laryngeal cancer

of one of the cases is noteworthy given published

hypotheses that irritation to the vocal cord may result

in the formation of non-malignant nodules, which

may then progress to malignancies under the influence

of other carcinogens (such as tobacco smoke).2' In our

cohort seven live men (out of 621) reported vocal cord

nodules. Unfortunately, we know of no referent

population with which to compare this incidence.

The particle size of acid mist in an industrial setting

averages about five microns,' and particles of this size

are primarily deposited in the upper airways, where

they have an irritating effect.23 Possibly such irritation

may damage the epithelium, making subsequent carcinogenic effects of other substances such as cigarette

smoke more potent. Soskolne et al found a significant

positive association between laryngeal cancer and

prior history of ear, eye, or nose conditions in the

medical record.2 Such an argument would implicate

not just sulphuric acid but any acid mist. In our study

men were exposed not only to sulphuric acid but also

to other acids, and the observed cases of laryngeal

cancer were not uniquely exposed to any particular

acid.

It is possible but unlikely that other occupational

carcinogens in the work environment, rather than acid

mists, caused the observed excess in cancer of the

larynx. There is some evidence that exposure to nickel
776

is associated with laryngeal cancer,8 but industrial

hygiene sampling data indicated no detectable levels of

nickel in the pickling area. It remains possible that the

pickling workers worked in other areas of the steel

mills where they were exposed to nickel or other

unknown occupational carcinogens. The 11 pickling

workers who had also worked on coke ovens were

excluded from our cohort.

The findings of this study parallel those of four

studies in the past few years indicating that exposure

to sulphuric acid, or to acid mist in general, is

significantly associated with laryngeal cancer. Three

of these studies have been based on occupational

cohorts.'`3 Observed numbers of cases in two of these

studies were quite small,'3 however, and only two of

these studies have been able to control for cigarette

smoking2 (and D Cookfair et al, Chapel Hill, 1985).

Our data did not show strong evidence of a relation

between excess risk of laryngeal cancer and either

duration of exposure or time since first employment,

two relations often present for occupational carcinogens. Given the small numbers of observed and

expected cases in this study, however, such analyses

have low power to detect trends. Furthermore, duration of exposure may be a poor surrogate for dose if

men with higher exposures worked less time.

Most of the other published studies have also failed

to show any type of dose response, again possibly

because of insufficient power. The two cohort studies

were based on five and three observed cases respectively.' 3 The case-control study by Soskolne et al was

nested in a cohort in a refinery and had greater power

but cases and controls were matched on duration of

employment, and the authors did not conduct an

analysis by duration of exposure.2 They did observe,

however, an increased risk in those who had worked in

jobs with higher exposure to sulphuric acid compared

with those with lower exposures. Finally, the hospital

based case-control study by Cookfair et al (Chapel

Hill, 1985) found a slight trend with duration of

potential exposure, but this finding was limited

because duration of exposure to sulphuric acid was

estimated based on job titles.

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