### 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 

### Safetyand

### 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 

### smokinghabits, drinkinghabits, and 

### incidence oflaryngeal 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 

### minimumofsixmonths before 1965, 

### with an average

### durationof 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

### conductedwithallcohortmembers or

### theirnext 

### ofkinin 1986 

### andmedical records of 

### decedents were 

### reviewed. Nine workers were 

### identifiedwho had

### beendiagnosed 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

### incidenceoflaryngeal cancer. 

### Ahlborget

### al

### studied 

### 110 men

### exposed for at least oneyear to 

### various acids in a 

### pickling operation 

### and observed three incident

cases 

### of

### laryngeal cancer

### comparedwith0-6

### expected.' No 

### data on 

### smoking were 

### available. Soskolne et al 

### conducted a nested case-control 

### study of 34 cases 

### of 

### laryngeal cancer amongmen

### whoworked ina

### refinery and chemical

### plant.2 A 

### 13-foldexcess 

### 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 ingand

### 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

### mortalityofa 

### cohort 

### of 1156 men

### exposed
to 

### sulphuric and 

### other acids in

### pickling 

### operations at 

### threemidwestern 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 fiveyear 

### survival rate 

### for

### laryngeal cancer isgreater than 50%,4

### andmany

### patientswith

### 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 

### studyoftheincidence

### of

### laryngeal cancerin

### thecohort 

### assembled

### by Beaumont.4
766

### Incidence of

### laryngeal cancer 

### andexposure to acid

### mists
Materind mehods

ORIGINAL COHORT DESCRIPTION The original cohort consisted of 1156 men, all of whomhadworked for at least sixmonths before 1965 in a pickling department at one of three midwestern steel mills. Demographic and work historydata from

company records for these men were collected in 1980-1. Most of these men began work in 1940 or later, although a fewbegan in the 1930s. Ofthe entire cohort, 373 (32%) haddiedbythe 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 studyhavebeenreported elsewhere.4

PROCESS DESCRIPTION AND EXPOSURE LEVELS Acids are used to remove impurities (oxides) from newly manufactured steel. Sulphuric acid was the 

### predominant acidused 

### forsteel

### picklinguntil themid1960s 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 ofthe 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 currentOSHAstandard of 1 00 mg/n367 (table 1). Based on our 

### observations, we estimatedthat exposures atthethirdplant 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 thispossibility 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

### byNIOSH 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%) ofthe 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 forwhom we had no interviewwith next ofkinbut forwhom 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 inpicklingdepartments. Area andpersonalsamples ofsulphuric acidair concentrations measuredat two studyplantsduringNIOSHandcompany industrialhygiene surveys*

Batch (B) or Concentration (mg/m3) continuous (C) No of Plant pickling Area orjobsampled samples Mean Range

Personalsamples 3 B Picklehooker 7 015 0-07-0-25 3 B Asstpickle 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 stripmill 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 etal.' Data forplant 2 fromYoung,' data forplant 3 fromPrice,7 and from 1975 companydata.768

All 

### reported cases 

### of 

### laryngeal cancer had to be confirmed 

### by a 

### physician or 

### by medical records to be 

### considered cases inthe 

### study. For

### decedents, neither a report by next of kin nor a death certificate was 

### considered 

### sufficient todefine acase. Suchreports had to be 

### confirmed

### bymedical 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 ofcancer, 

### smoking habits, and alcohol 

### consumption. Live cohort members were also 

### asked whether 

### theyhad 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

### deathcertificates 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

### theirnext 

### ofkin

### bycertifiedmail. If the 

### first 

### mailing was 

### unsuccessful a 

### follow up

### mailing

was done. If no response was 

### obtained 

### through the mailings 

### theninterviewswere

### conducted

### by

### telephone.

ANALYTICAL DESIGN We 

### analysed the data by a comparison 

### ofthe 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). TheNIOSH lifetableprogramwasusedtocalculate 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 usedbecause this studywas undertaken to test the

a priori hypothesis ofanexcess incidence oflaryngeal

cancer. Further analyses were conducted after dichotomising the cohort byduration ofexposure 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 ofthe duration ofexposure and time since first exposure of the observed cases. The cut offpoint 

### for duration of exposure (five years) was chosen to 

### distribute approximately the expected laryngeal

cancersevenlybetweenthetwo strata, whereas thatfor time sincefirstexposure (20years) was chosenbecause it is a conventional cut offpoint chosen to reflect the fact thatmost occupational agents requireat leasta 20
years 

### latencyperiodbefore resulting in solid tumours.

REFERENCE RATES FOR INCIDENCE OF
LARYNGEAL CANCER We calculated the expected number of laryngeal

cancers 

### using three sources 

### ofincidence data. There is

no ideal 

### referent 

### population for which there exist complete incidence rates 

### of 

### laryngeal cancer 

### for the entire 

### studyperiod, stratifiedbyage, sex, andcalendar 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 fromthe New

### York Registrydidnot 

### include New York 

### City before 1973, 

### and rates 

### subsequent to 1973 cannot be 

### compared with earlier rates. 

### Neither ConnecticutnorNewYork rates are stratified

### byrace. In 

### addition, rates 

### corresponding to a 

### sample of all 

### United States 

### geographical areas 

### exist for 1938 and 1948 

### (1stand 2nd

### NationalCancer

### Surveys"), for 1970 

### (3rd National Cancer 

### Survey),'2 and 

### for 1973-7 and 1978-81 

### (1st and 2nd surveillance, 

### epidemiology, and 

### endresults 

### (SEER) 

### surveys).'3 The 

### United States rates

arebased on cancer 

### registrydata 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 arequite small andunstable. Wehaveused rates for all races 

### combined in calculating 

### expected laryngeal cancers in our cohort. We have calculated the 

### slope ofthe increase in rates

over time for each source of rates (Connecticut, New 

### York, United States, 

### using linear regression. These regressionswereused toestimateratesduringfiveyear 

### 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 andexposure to 

### acidmists

'10.5-

a,

a 9.0- 

### <8 1.5-

a

_ 

### TU4 26.0



### 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 UnitedStatespopulation except forfirst two UnitedStates datapoints which were adjusted to the 1950 UnitedStatespopulation).

ages over 85. Five year age andcalendar 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 beenplotted

overcalendar time, thenumber ofrates that needed to be estimatedvaried. For Connecticut, rates for only one time point (out of 10) needed to be estimated. ForNewYork, and the United States, dataneeded to be estimated forfive 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 oftrendwith time, gave us some confidence that our regression estimates were reasonable.

ADJUSTMENT FOR CONFOUNDING BY TOBACCO

AND ALCOHOL CONSUMPTION Smokingdata The strongestknownrisk factor forlaryngeal 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 ordownwarddepending 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 

### studybyWynder 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, alsomake

a 

### secondAxelson

### adjustmentusing 1976 

### UnitedStates 

### 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 

### thepublished 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 

### byamount 

### smoked a

### day (a 

### pack or

### less, ormore 

### thanone

### 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. Expectedcases 

### of

### laryngeal cancer arederived 

### from rates

### which arenot 

### stratified

### byrace (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

### calculatedusinganage

### 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 

### smokingcategories. To account 

### for the effect ofpipe 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 with770

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 ofthe 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 suggestedbyAxelson'4 and the 

### relative risks for 

### laryngeal cancer were taken from the studybyWynder 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 

### populationandstratifiedby ageand sex, have notbeen 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 studyperiod, ourcomparison was restricted to cohort members who were alive at the time of our interviews. Whereasdrinkinghabits some time agomightbe 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 havemade 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 aweek 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 onlyoccasionally 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 forwhich relative risks for laryngeal cancer

were estimated by Wynder et al' and could also be 

### Steenland, Schnorr, Beaumont, Halperin, Bloom 

### derived

### both

### fromour

### cohort'sdataand theHISdata. To 

### compare our cohort 

### with the 

### national 

### population, we 

### considered

### theirage 

### and their

### drinkinghabits

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

### drinkinghabits. 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

### weightedaverage 

### ofthe

### proportions ofvarious 

### drinking categories.

Results

RESPONSE RATE FOR FOLLOW UP OF ORIGINAL
COHORT 

### Usingthemailed

### questionnaire followedby

### telephone interviews for 

### non-respondents, responses were 

### obtained 

### from 841 (73%) 

### ofthe

### original cohort. Table 2 

### indicates the percentage of 

### telephone and self 

### administered (mailed) questionnaires completed
among 

### each group. In

### addition to 

### the interviews withnext ofkin, forall 

### 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 

### historywas 

### available. This 

### ledto the inclusion 

### ofan

### additional 45 

### forwhomwehadno 

### interviewwith next 

### ofkin.

DESCRIPTION OF INCIDENCE COHORT We were 

### able to determine the incidence ofcancer 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% ofdead) Mailed interview 480 146 Telephone interview 141 74 Non-response: 162 153

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

### acidmists

77% of the original cohort and these men were includedinthe "incidence" cohort forfurtheranalysis. The incidence cohort consisted of 879 men, ofwhom 621 were alive and 258 were dead. We hadreceived an interview from all live men. Interviews were available 

### fromnext ofkin 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% oftheoriginal cohort (79-2% ofthe 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

wereexposedonlyto sulphuricacid, 17% toonlyother acids, and the remainder were exposed to sulphuric and other acids. Fourteen per cent of the men had worked atplant 1, 31% atplant 2, and 55% atplant 3. Bycomparisonwith the original mortality cohort (see sections 1 and 2 ofthematerials andmethods 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 theincidencecohort andtheoriginalmortalitycohort.

DETERMINATION OF EXPECTED LARYNGEAL
CANCERS The incidence of laryngeal cancer has increased over time, possibly due to the effects of increasing prevalence ofsmoking, a strong risk factor. The figure shows the ageadjusted summary rates forthedifferent timepoints forall 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 theUnited States

### population in 1970. It is apparent that theUnited States datafit

### roughly between the lower rates of New York 

### (without New York 

### City) and the 

### higher rates of Connecticut for
most ofthe studyperiod. Although wehavecalculated the expected laryngeal cancers using all three sets of rates, webelieve theexpected cancers based onUnited States rates are themost appropriate, for two reasons. Firstly, our study population is from the 

### midwestern United States, and the general United States rates probablyprovide abettercomparisonthaneitherNew 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 

### (JHorm, NCI, personal 

### communication, 1986). The lifetableanalysisyielded 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% bymenaged40-59, and 16% bymenaged 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 fromfirst Vital status Age (late) of first exposure Years Aci(ltpe Snmokinzg Driniking No Source* (date ofdeath) 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 ofdiagnosis. 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, drinkinghabits, and type of acid exposure. Three of the five decedents with laryngeal cancer had no indication of the disease on theirdeathcertificate. Conversely, one individual who

was listed as having died of laryngeal cancer was subsequently found, throughmedical records, to have actually had pharyngeal cancer and was not considered a case in this study. The average age atdiagnosis forthese 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, theproportion 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 incidencecohort), 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 ofpolyps. 

### 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 andpolyps. With the exception of one benign 

### laryngeal tumour found through medical records, table 4 

### reflects incidence only among the livemembers 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 smok

### ing 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 fromwhich we coulddetermine smoking habits as of 1965. Nevertheless, 46 menhad to be excluded because theyhaddied before 

### 1965, leaving 795 men to 

### be considered 

### in our comparisonofsmokinghabits (22% ofthese menwere 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% ofthe incident cohort. Results for cigarette smoking prevalence, comparing the incidence cohortwiththeUnited 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, reflectingwell known national trends that blue collar workers smoke more than the United 

### States 

### average.' It is also apparent thatwhereas menwho 

### subsequentlydiedandmenwho survived werevirtuallythe same regardingthe 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 Benigngrowths andpolyps on vocal cords*

Years Age at Date of Yearfirst fromfirst 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 of

### laryngeal cancer and

### exposure to 

### acidmists

Table 5 Comparison ofsmoking habits, UnitedStatespopulation versus sulphuric acidcohort, 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 fromthedata

### byWynder 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 ofmen 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 

### thanbackground 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 non

### exposed due to 

### cigarette smoking. We also 

### conducted this same 

### adjustment using a 

### comparison between the 

### prevalence of 

### cigarette 

### smokingofour

### cohortversus 

### theUnitedStates in 1976 to

### determine howmucha 

### change calendar timewould effectthe

### adjustment. Results

### using 1976 

### smokingdata 

### indicated an 

### upward adjustment of the 

### expected laryngeal cancers of 

### 13%, which 

### compared well with the 15% 

### based on 1965 

### smokingdata. For the reasons outlinedabove intheMethods section 

### (morerelevance to later

### disease, more of the 

### dead 

### included), we 

### chose to use the 

### adjustment based on 1965 data. 

### Pipeand

### cigarsmokingalso

### involveanexcess

### riskof 

### lung cancer, 

### although such risk 

### is 

### considerably less than that of

### cigarettes, and

### could

### confoundour

### 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 thosewho 

### 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 

### fourfoldexcess risk of

### laryngeal cancer. 

### Hence, poten

### tially, if in our 

### cohort a 

### large 

### percentage ofmen 

### who didnot smoke

### cigarettes did 

### smokepipes 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, theHIS 

### surveysdonot

### 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% ofnon-smokers of

### cigarettes smokedpipes 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

### bydrinking status was available for 593. 

### Table 6 shows the results 

### comparingthealcohol

### consumptionofourcohortand 

### the United States 

### population. 

### Clearly in our 

### cohort 773774

Table 6 Comparison ofalcohol consumption, UnitedStates 

### population versus 

### sulphuric acidcohort, 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 comparedwith all United States men. The prevalence ofboth 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 ofWynder et al,'5 were assumed to be 1 for 

### never/occasional drinkers (less than three days aweek), 125 for lightdrinkers (one to threedrinks aday), 1-75 formoderatedrinkers (fourto 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 themethod 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 thepercentages 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 thenon-exposed, againbased ontheirknowndrinking 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 oflaryngeal cancer 1-32 times greater thanbackgrounddue 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 leadus toexpect anapproximately 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 

### drinkingwould 

### indicatea

### downwardadjustment of 

### 1%. Anet

### upward 

### adjustment 

### of 14% 

### yields an 

### adjusted expected number 

### of 

### laryngeal cancers 

### of 3-92 

### (the 

### corresponding figuresusingConnecticut andNew

### Yorkratesare4-43 

### and 3 35). 

### Theobservednumberofcancers

### is

### nine, and 

### hencethe

### ratio ofobserved to

### expected (SIR) 

### is 2X30. 

### If

a

### Poisson

### distributionisassumedthe one 

### sidedp

### value 

### forthisratio is 

### 0X013. The SIRs

### usingConnecticutand 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 

### ( < 5years, > 5

### years). The SIRs 

### (observed

versus

### expected, aftera 

### 14% 

### upward

### adjustment ofthe 

### expected) were 1-70 

### (3/1-77) and 2-76 

### (6/2-17), respec

### tively. 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

### decreasingwith

### latency) is 

### statistically

### significant, given 

### the small 

### numbers 

### concerned. It 

### should also be noted that these 

### findings are 

### highly

### dependent on 

### the
cut

### off

### points. For

### example, twocases

### developedat 16- 18 years from first exposure, so that 

### had the cut 

### off 

### point fortime sincefirstexposurebeen 15 

### insteadof20
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 

### ofConnecticut 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 tobaccoIncidence 

### oflaryngeal cancer andexposure to acidmists



### 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

### ofsmokers anddrinkers. 

### 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 

### comparingthe

### highexposedand 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 neces

### sarily 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. Ifone canassumeaPoisson

### distribution forthe 

### 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 

### hadwe 

### 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 theAxelson type

### adjustment. For

### example, in

### theoryit 

### might have 

### been 

### possible to 

### combine alcohol and 

### tobacco 

### consumption categories and do one 

### adjustment 

### insteadoftwo. 

### Thereareseveral

### 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 

### approachwoulddiffer 

### 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

### byWynder 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 thecohortwere 

### better 

### represented. 

### Smokingis a far 

### stronger risk factor than 

### alcohol, andwewantedthe

### adjustment for 

### smoking to be as accurate as 

### possible. We 

### have used 

### fairly strictcriteria forcase

### definition in this 

### study; the 

### decedents had to have had case 

### confirmation 

### bymedical 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 

### theydidnot

### have laryngeal cancer. 

### Some ofthesemen 

### may have had 

### laryngeal cancer despite the assertions ofnext ofkin. The

### findingof

### polypsprecedingthe

### laryngeal cancer of one of 

### the cases 

### is 

### noteworthy given 

### published hypotheses that 

### irritation to 

### thevocal cordmay

### result in the 

### formation of 

### non-malignant nodules, which maythen

### progress to

### malignancies under the influence of

### other

### carcinogens (suchas 

### tobacco smoke).2' In our cohort seven livemen (out of621) 

### reportedvocal cord 

### nodules. 

### Unfortunately, we know of no referent 

### population with

### which to compare this 

### incidence. The

### particle size ofacidmist in an 

### industrial setting averages about 

### five

### microns,' and

### particles ofthis size

are 

### primarily deposited in 

### the upper 

### airways, where 

### theyhave an 

### irritating effect.23 Possibly such 

### irritation may 

### damage the 

### epithelium, making subsequent car

### cinogenic effects of other 

### substances such as cigarette 

### smoke morepotent. 

### 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 acidmist. 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 inthework

### environment, rather thanacid 

### mists, caused the 

### observed excess in 

### cancer of the 

### larynx. There is some evidence that 

### exposure to nickel776

is associated with laryngeal 

### cancer,8 but industrial hygiene samplingdataindicatednodetectable levelsof nickel in thepickling 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 

### ofcases 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). 

### Ourdata did not 

### show strong evidence 

### ofa 

### 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 

### ofthe 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 respec

### tively.' 3 

### The case-control 

### study by Soskolne et alwas 

### nested in a cohort in a 

### refinery and had greaterpower 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

### increasedriskin

### thosewho

### had

### workedin 

### 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.

References
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