Mortality in a cohort of asbestos-exposed workers...

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Mortality in a cohort of asbestos-exposed workers undergoing health surveillance

Fabiano BARBIEROa,b,c, Tina ZANINd, Federica E. PISAa,e, Anica CASETTAa, Valentina ROSOLENa, Manuela

GIANGRECOa, Corrado NEGROf , Massimo BOVENZIf, Fabio BARBONEa,e,f

aDepartment of Medical and Biological Sciences, University of Udine, Udine, Italy.

bUniversity of Parma, Department of Clinical and Experimental Medicine.

cHealth and Safety at Work Department (SPISAL), Local Health Authority No 12, Region of Veneto, Mestre, Italy.

dHealth and Safety at Work Department. Local Health Authority No 2 (ASS2), Region of Friuli Venezia Giulia,

Gorizia, Italy.

eInstitute of Hygiene and Clinical Epidemiology, University Hospital of Udine, Udine, Italy.

fDepartment of Medical Sciences, University of Trieste, Trieste, Italy.

Correspondence to: Professor Fabio Barbone, Department of Medical and Biological Sciences, University of

Udine, Piazzale Kolbe 3, Udine 33100, Italy.

phone: +39 0432559158. Email: [email protected].

Authors’ email addresses:

FABIANO BARBIERO [email protected]

TINA ZANIN [email protected]

FEDERICA E. PISA [email protected]

ANICA CASETTA [email protected]

VALENTINA ROSOLEN [email protected]

MANUELA GIANGRECO [email protected]

CORRADO NEGRO [email protected]

MASSIMO BOVENZI [email protected]

FABIO BARBONE [email protected]

mailto:[email protected]


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Abbreviations:

Attributable Risk (AR)

Computed tomography (CT)

Friuli Venezia Giulia (FVG)

Low-dose computed tomography (LDCT)

Relative Risk (RR)

Standardized Mortality Ratios (SMR)

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Abstract

Objectives. To compare the mortality in a cohort of 2,488 men previously occupationally

exposed to asbestos and enrolled in a public health surveillance program in Friuli Venezia Giulia

(FVG) region, northeastern Italy, with that of the general population of FVG and Italy, from

1989 to 2011.

Methods. Standardized Mortality Ratios (SMR), with 95% Confidence Interval (95%CI), for all

causes, all cancers, lung and malignant pleural cancer were estimated in the cohort and in

subgroups of workers employed in the shipbuilding industry between 1974 and 1994.

Results. A strong excess mortality for pleural cancer with reference both to FVG (SMR 6.87-

95%CI 4.45-10.17) and to Italian (SMR 13.95-CI 95% 9.02-20.64) populations was observed.

For lung cancer, the FVG-based SMR was 1.49 (95%CI 1.17-1.89) and the Italy-based 1.43

(95%CI 1.12; 1.81). Concurrent mortality did not exceed in the cohort for all cancers and for all

causes. Mortality among workers with first hire date in shipbuilding industry before 1985 was

particularly high for both pleural (FVG-based SMR: 8.98 95%CI 5.56-13.75; Italy-based SMR:

18.41 95%CI 11.40-28.17) and lung cancer (FVG-based SMR: 1.54 95%CI 1.14-2.03; Italy-

based SMR: 2.45 95%CI 1.06-4.82).

Conclusions. This cohort experienced an excess mortality for pleural and lung cancer,

compared to both the regional and national populations. The excess was stronger in workers

with first hire date in shipbuilding before year 1985, suggesting a key role of asbestos exposure.

Keywords: mortality, asbestos, mesothelioma, lung cancer, shipbuilding, epidemiology,

Monfalcone,

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Introduction

The increase in diseases of the respiratory system in former workers exposed to asbestos had

been detected during the course of the last century, around the seventies. The increased

incidence and mortality were evident for asbestos-related respiratory diseases, especially

cancers of the pleura and lung cancers (Magnani, Fubini et al. 2013). In particular,

mesothelioma is closely associated to exposure to asbestos, whose pathogenicity of fibers is

significantly modulated by their physico-chemical characteristics and follows the geography and

history of asbestos exposure (IARC 2011; NIOSH 2011). Asbestos was used in Italy since early

1900s in several employment sectors, such as the metalworking industry, the textile industry,

shipbuilding industry, electricity production industry, and several craft work activities and trades.

Asbestos was generally used as thermal and acoustic insulation. Damage to human health

arising from inhalation of the fibers, has affected a large part of the exposed population, both

workers and their spouses. For mesothelioma of the pleura, exposure to asbestos has a major

causal role.

Various European regulations have been written about its dangers. In the years 1991 and 1992

Italian Legislative Decrees (D.Lgs.) were approved (D. Lgs n 277 1991; Italian Law n 257 1992)

declaring the 'extreme attention to risk’ and banning use of asbestos in the work environment.

The establishment of occupational health surveillance programs for formerly exposed workers,

organized by health service agencies and managed by qualified and experienced personnel, is

recommended, although very limited evidence exists on the efficacy of such programs in

reducing disease occurrence and mortality (Pinto, Novello et al. 2013).

The coastal area of FVG has been characterized by the presence of production activities where

asbestos was used in large quantities until the years 1990-1992, particularly in the shipbuilding

industry, as well as within metalworking industries, in port or in the cotton mills. A large number

of workers were therefore exposed to asbestos; in the early months of 2014 over 9,100

individuals were enrolled in the FVG Register of Exposed to Asbestos (Regional Law n 22

2001). However, this list may underestimate the number of people formerly exposed to

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asbestos: enrollment in the register is voluntary and free (Regional Law n 22 2001; Asbestos

Regional Commission 2014).

In a case-control study conducted in the general population of Trieste, the largest city in this

coastal area and the location of shipbuilding industries, the RR of lung cancer, adjusted for

smoking and air pollution, for certain occupational exposures to asbestos was 2.0 for squamous

cell carcinoma (95% CI 1.28-3.11), 2.11 for small cell carcinoma (95% CI 1.31-3.39) and 2.16

for adenocarcinoma (95% CI 1.32- 3.53); the AR estimate for possible or definite exposure to

asbestos was 20% (95% CI 11.5-28.5)(Bovenzi, Stanta et al. 1993). The interaction between

asbestos and smoking regarding lung cancer risk is between additive and multiplicative;

association between asbestos exposure and lung cancer risk is basically linear, but may level

off at very high exposures. The RR for lung cancer increases between 1% and 4% per fiber-

year (f-y)/ml, corresponding to a doubling of the risk at 25-100 f-y/ml (Nielsen, Baelum et al.

2014).

To evaluate whether male workers with previous occupational exposure to asbestos and

enrolled in a public health surveillance program experienced an increase in mortality from all

causes, all cancers, lung cancer, and malignant neoplasm of the pleura, we conducted a

historical cohort study using as external comparisons the general population of FVG region and

the whole Italian population.

Within this cohort, internal comparisons evaluating the role of personal risk factors (smoking)

and the association of frequency and type of examinations with mortality will be presented

elsewhere.

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Materials and methods

Setting

FVG Region is located in North-East of Italy and has a total of 1,218,985 inhabitants (ISTAT

2011).

The local Health Authority “ASS 2 Isontina” (ASS2), provides health care, including preventive

occupational medicine, to residents of part of the region coastal area. Since the nineties, ASS2

has held a number of technical and health care activities, as part of an overall "asbestos

project", with the aim, on the one hand, to control the danger of asbestos-containing structures,

landfills, instruments, and on the other, to take action limiting the health effects of past

exposure, both on workers and on the general population.

As a part of this project, a public health surveillance program for persons with previous

occupational exposure to asbestos has been carried out at a dedicated outpatient clinic of the

ASS2 Occupational Medicine Center. Former workers exposed to asbestos and their spouses

have voluntary and free access to this clinic. Although some surveillance had started some

years before, 91% of medical surveillance and examinations were provided after 1991

according to Italian legislation (D. Lgs n 277 1991). Periodicity of the examinations at the Center

was defined by the doctor, but often also by the perceived needs of the subject. Exams varied

individually and included physical examination, basal spirometry, alveolar diffusion of CO

(DLCO), chest radiography and chest computerized tomography (CT).

Exposure assessment

The exposure to asbestos was individually confirmed by occupational health personnel during

the surveillance examinations. The evaluation of the level of exposure to asbestos was carried

out by an occupational doctor using a semi quantitative method. Level of exposure was

established individually based on work history and accessible documentation, such as the

employment card, acknowledgment of exposure by National Institute for Insurance against

Accidents at Work (INAIL), and/or declarations from colleagues. For each worker, the intensity

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of exposure was quantified on the basis of anamnestic data, information obtained during the

interviews, and according to job-exposure matrices available in the literature (Goldberg,

Kromhout et al. 1993; Orlowski, Pohlabeln et al. 1993; Goldberg 2002). Intensity of exposure

was considered high when there was evidence that the subject had direct or indirect contact

with friable material containing asbestos in confined spaces; medium, when the subject had

occasional contact with friable materials, worked with compact material containing asbestos or

used continuously substrates containing asbestos; low, when the subject had occasional

exposure to environmental materials containing asbestos.

Data collection

For each person enlisted in the surveillance program, the following information was recorded

electronically: demographics (name, surname, date of birth, residence and phone number);

company name and industry sector; total years of exposure to asbestos; cigarette smoking

habits (i.e., never, ex or current smoker); type, date and findings of examination. Since only 96

women enlisted in the surveillance program, their evaluation will not be presented in this report.

Follow-up

Selection cohort process is described in Figure 1. For each member of the cohort, the

residential status in FVG and the vital status, including cause of death, between 1 January 1989

and 31 December 2011 were assessed through record linkage with the regional databases of

residents and of mortality, respectively, of the regional health data repository, using an

anonymized unique personal identifier. Each member of the cohort was followed-up from the

date of the first surveillance examination or 01/01/1989, whichever last, to the date of death,

end of residence in FVG or 31/12/2011, whichever first.

Assessment of mortality

Observed deaths were identified through record linkage with the mortality database. In this

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database, the causes of death are codified according to the WHO International Classification of

Diseases, 9th edition, (ICD-9). Deaths for all cancers were identified through ICD-9 codes 140 to

239; for malignant neoplasm of the pleura through code 163 and for lung cancer through code

162.

We calculated the time difference between surveillance enrollment and death, to estimate the

possible weigh of residual prevalent cases of an often rapidly lethal disease such as malignant

neoplasm of pleura or lung cancer.

Statistical analysis

The number of observed deaths and calendar year- and age-specific mortality rates from 1989

to 2011 (Supplemental Tables 1-4) were calculated for all causes of death, all cancers,

malignant neoplasms of the pleura and lung cancer.

As measures of association, we calculated SMRs, with 95% Confidence Interval (95%CI),

through the indirect method (Breslow and Day 1987). SMR was calculated as the ratio of the

number of deaths observed in the cohort to the number expected on the basis of calendar year-

age- and sex-specific rates among the general population in FVG and in Italy.

To conduct sensitivity analyses, we used two external standards: the general population of FVG

Region and of Italy. The sources of the age-specific mortality rates for men were as follows:

- for mortality for all causes and all cancers, including lung cancer but excluding malignant

neoplasm of the pleura, the rates provided by Istituto Superiore di Sanità (ISS) for the FVG

region (years 1989-2011) and for Italy (years 1989-2011), respectively;

- for malignant neoplasm of the pleura, the rates calculated from the data of mortality

provided by the National Institute of Statistics (ISTAT) for FVG (years 1989-2011) and for Italy

(years 1989-2011).

For the years 2004 and 2005, standard rates were not available. We thus used the available

rates of the closest year: for year 2004 we used the rates of year 2003, for 2005 the rates

available of year 2006.

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Subgroup analyses restricted to subjects ever employed in the shipbuilding industry were also

conducted. Trends in supply and consumption of asbestos in Italy peaked between the 1970s

and the mid-1980s, with a rapid decrease since 1985 (Virta 2006). To account for possible

differences in the intensity of exposure over the years, the subgroup of ever shipbuilding

industry former workers was further categorized according to the hiring period in the following

three groups: (a) subject hired for the first time before year 1974, (b) those hired for the first time

between 1974 and 1984 and (c) those who were hired for the first time between 1985 and 1994.

All analyses were performed using SAS© software, Version 9.3 (SAS Institute Inc., Cary, N.C.,

USA) and Microsoft®Excel 2013 spreadsheet.

Results

Table 1 shows the characteristics of the cohort. The cohort included 2,488 men, with 26,415.78

person-years of follow-up during period 1989-2011, and a mean follow-up of 10.62 years per

subject. About 68% of the subjects had a medium exposure to asbestos and 70% was

represented by workers employed in the shipbuilding industry.

Over 94% of deaths for all causes, 92% of deaths for malignant neoplasm of the pleura, and

over 98% for lung cancer, occurred after 12 months from surveillance enrollment (Supplemental

Table 5). Measures of frequency and SMRs for all causes, all cancers, malignant cancer of

pleura, lung and other individual cancers and for groups of non-neoplastic causes are presented

in Table 2. A total of 388 deaths were observed. The SMRs for all causes were 0.89 (95%CI

0.80-0.98) and 0.94 (95%CI 0.85-1.03), based on FVG and Italian rates, respectively. Mortality

for non-neoplastic causes was lower than expected: SMR was 0.88 (95%CI 0.76-1.01), based

on FVG rates and 0.90 (95%CI 0.78-1.03), based on Italian rates (data not shown). The

observed deaths for all cancers did not exceed expected deaths: the SMR was 0.96 (95%CI

0.83-1.11) based on FVG rates and 1.07 (95%CI 0.92-1.24) based on Italian rates.

A total of 25 deaths for malignant neoplasm of the pleura were observed, compared with 3.64

and 1.79 expected according to the rates in FVG and Italian general population, respectively.

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The corresponding SMRs were 6.87 (95%CI 4.45-10.17) and 13.95 (9.02-20.64). A total of 70

deaths for lung cancer were observed and the SMRs were 1.49 (95%CI 1.17-1.89) and 1.43

(95%CI 1.12-1.81), respectively.

An increased, albeit not significant, mortality was also found for esophageal cancer

standardizing for Italian rates. Colorectal cancer mortality was significantly lower than expected

as compared with FVG general population. A highly significant reduction in prostate cancer

mortality was also found (SMR = 0.09, 95%CI 0.00-0.49 based on FVG rates; SMR = 0.10,

95%CI 0.00-0.55 based on Italian rates).

The SMRs stratified by age group are presented in Table 3. As expected, deaths under age 50

years were sparse. The SMRs for age 50-59 were lower than 1, with a borderline significant

reduction of mortality for all cancers. An excess mortality was found at ages 50 and over for

malignant pleural cancer (with an SMR from 4.84 95%CI 1.58-10.54 based on FVG rates, to an

SMR of 29.14 95%CI 9.44-67.69 based on Italian rates) and 70 and over for lung cancer (with

an SMR from 1.55 95%CI 1.03-2.25, to an SMR of 2.02 95%CI 1.01-3.62 based on Italian

rates).

Table 4 displays the results for subgroups of former workers exposed to asbestos in the

shipbuilding industry, by period at first hiring. The results pertaining to the group with

hypothesized highest level of exposure to asbestos (first hiring before 1985) and longer latency

show a particularly high mortality for lung cancer (with an SMR from 1.54 95%CI 1.14-2.03

based on Italian rates, to an SMR of 2.45 95%CI 1.06-4.82 based on FVG rates) and malignant

neoplasm of the pleura (with an SMR from 8.98 95%CI 5.56-13.75 based on FVG rates, to an

SMR of 18.41 95%CI 11.40-28.17 based on Italian rates) but not for all causes and all cancers.

Also subjects hired for the first time in shipbuilding between 1985 and 1994 were associated to

increased mortality, although not significantly, for lung (SMR = 1.26, 95%CI 0.15-4.56 based on

FVG rates; SMR = 1.22, 95%CI 0.15-4.39 based on Italian rates) and pleura (SMR = 8.40,

95%CI 0.21-46.81 based on FVG rates; SMR = 16.88, 95%CI 0.43-94.04 based on Italian rates)

and not for all cancers nor for all deaths.

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Discussion

Strengths of the study

Under certain circumstances, epidemiologic studies of asbestos-exposed workers undergoing

health surveillance may fulfill several criteria relevant to etiologic objectives: (a) the observation

is conducted longitudinally, i.e., the direction of the observation goes from exposure to disease

occurrence; (b) the hypothesis and related study inclusion criteria are exposure specific, i.e.,

cohort members are selected only under the condition of confirmed asbestos exposure; (c) the

study allows for the evaluation of associations with multiple outcomes, i.e., mortality for

malignant neoplasm of the pleura and lung cancer are the main outcomes, but the concurrent

opportunity exists to estimate also all causes and all cancers mortality; (d) the cohort may be a

representative sample of all the asbestos-exposed persons within a specific area and time

period and, therefore, its disease experience may reflect the effects of the exposure in that area;

in our case the group of exposed subjects (the study cohort) was established as population-

based and all the asbestos-exposed workers residing in the territory of the local Health Authority

“ASS 2 Isontina” were eligible for inclusion in the dedicated clinic at the local Occupational

Medicine Center; (e) a valid comparison group of unexposed subjects can be identified and its

sex-, age- and time period-specific mortality rates are compared with the rates of the exposed.

In fact, in this study we used two comparisons: the first one was the regional population that

reflects the underlying morbidity and mortality of cancer due to factors other than asbestos

exposure, the second was the whole Italian population which represents baseline rates

(particularly of lung cancer and pleural neoplasms) not influenced by the asbestos experience of

the index population.

The choice of analyzing workers undergoing health surveillance also avoids the limitations that

may be present when an occupational cohort coincides with the workers of a single company. In

the latter case sometimes subjects’ inclusion in the cohort study fully depends on the company

collaboration and on data completeness, i.e., access to complete personnel records. Indeed, in

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the study area for a number of decades such an access has not been possible, and the study of

workers under public health surveillance has now overcome this limitation. In addition, a

population-based approach to asbestos-exposed workers allows also for the inclusion of

individuals whose job has been outsourced (subcontracted) and not included directly under the

main shipyard payroll. Outsourcing jobs in different areas and historical periods may represent a

large proportion of exposed workers.

Possible limitations

The use of asbestos-exposed workers undergoing health surveillance has also limitations. In

particular, selection bias may arise whenever observation-time in the study doesn’t include the

whole pool of data related to every person who ever experienced occupational exposure to

asbestos in the study area, with each person followed to the end of life (Rothman 2008). It is

well known that most studies use a subset of this person-time experience, and hence bias may

occur (Checkoway 2004). Indeed, in our study, follow-up started only when asbestos-exposed

workers entered health surveillance. Therefore, the follow-up period (observation) from age at

hire in the first job entailing asbestos exposure till entry in health surveillance is missing. It might

have occurred that subjects who died or left the study area before the establishment of the

surveillance clinic, or before start of follow-up, experienced an exposure that was qualitatively

(type of asbestos materials, other carcinogens or toxicants) or quantitatively (concentration or

duration) different as compared with the subjects who enrolled in the surveillance program. This

selection bias might under or overestimate mortality rates of conditions with short induction

period (injuries, cardiovascular diseases, respiratory diseases, certain neoplasms). About the

main outcomes of interest of this study, i.e., lung and pleural cancers, we assume that the

induction period for the study subjects exposed in the 1960s, 1970s, and 1980s was not

completed at their time of surveillance enrollment and, indeed, the descriptive epidemiology of

mesothelioma showed, as of 2014, still increasing mortality rates in the study area and in the

whole Country (Puntoni, Merlo et al. 2001). In terms of possible differential exclusion from

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follow-up of individuals due to migration out of the study area, this might have occurred,

although the FVG enjoyed a wealthy period from the 1960s to year 2008; therefore, it is unlikely

that many of them actually moved becoming ineligible for enrollment in the surveillance

program. Another possible selection bias to consider is enrollment in the surveillance program

depending on health status rather than on likelihood of asbestos exposure. Bias might have

occurred if subjects enrolled because symptomatic or because they had received a diagnosis of

any type, a cancer, or specifically lung or pleural cancers. To avoid such a bias we excluded

subjects who had received any diagnosis of cancer during the period of operation of the

regional cancer registry (1995-2009). In addition, for the purpose to estimate the weight of latent

cancers, we conducted a sensitivity analysis that calculated the number of deaths occurring

within the first 12, 24, 36, 48 and 60 months from enrollment in the surveillance program

(Supplemental Table 5). Considering the poor prognosis of lung and pleural cancers, it is likely

that selection bias due to preferential selection associated with a latent cancer condition played

a minor, if any, role in the study results and that large overestimation of the SMRs are not

present.

On the other hand, it is possible that, while we excluded from the cohort prevalent cancer cases,

in this way we may have reduced for other cancers, the comparability of the cohort versus the

general population mortality rates. In fact, the general population (which is an external

comparator) does include persons with long-lasting diagnosis of cancer, especially as it relates

to less lethal sites such as colon and prostate. All these things considered, we may conclude

that the SMR for all cancers in this analysis may be slightly underestimated lending even more

credit to the interpretation that occupational exposure to asbestos in this cohort is causally

associated both to mesothelioma and to lung cancer. Instead, results about other cancer sites

should be interpreted with caution.

From this cohort of asbestos-exposed workers undergoing health surveillance, 25 deaths for

malignant neoplasm of the pleura were observed and a consequent large excess of mortality

was estimated with mortality ratios between 7 and 14, according to two comparison general

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populations (the local region and Italy). In addition, a total of 70 deaths for lung cancer was

observed displaying SMRs around 1.5 in the overall cohort.

Internal consistency

Although these results are upheld for all subgroups within the cohort, the increase in mortality

from lung cancer and malignant neoplasm of the pleura showed to be stronger among former

workers exposed to asbestos in the shipbuilding industry. In our study results are even stronger

among subjects with known hiring in shipbuilding before the year 1974 for malignant neoplasm

of the pleura and between 1974 and 1984 for lung cancer. The excess of mortality from

malignant neoplasm of the pleura is not statistically significant in the cohort of former workers

hired for the first time in shipbuilding between 1985 and 1994: this fact may be explained by a

low number of subjects of the sub cohort and the low number of observed cases (cohort=136

men; observed=1). These results can be explained also by the long latency of the malignant

neoplasm of the pleura: likely, former workers exposed to asbestos, hired for the first time since

the middle 1980s, could become cases until 2020 or later.

Results for cancers other than lung and pleura showed some mortality decrease for several

cancer sites, notably stomach, colorectal, prostate and leukemia as well as a non-statistically

significant excess mortality observed for esophageal cancer (based on Italian not Regional

standard rates). The latter result on the esophagus may be due to the strong and the well-

known mortality excesses for esophageal cancer of the whole FVG region when compared to

the rest of Italy. These results may be explained by the regional higher prevalence of risky

behaviors related to alcohol drinking (Franceschi, Talamini et al. 1990; Zambon, Talamini et al.

2000), therefore, it is unlikely that this reportedly positive association be explained as an effect

of asbestos exposure. Rather, it is worth noting that in this cohort we did not find an association

with cancer of the larynx, another target organ of both asbestos and alcohol exposure. More

evident, on the other hand, is the reduced mortality for stomach, colorectal, and especially

prostate cancer as compared both with Regional and Italian standard rates.

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Mortality for all causes of death did not differ from that of the general population, not even when

standardization was performed on sub cohorts of former workers exposed to asbestos in

shipbuilding industries, in different periods. This finding may be partially explained by a healthy

worker effect; in fact, 58.27% of the cohort was in working-age with less than 60 years, at first

examination.

External consistency

Two preliminary, descriptive reports about workers from the same local shipyard who were hired

in 1942 and in 1950-1959 were published previously, showing high mesothelioma occurrence

(Bianchi and Bianchi 2012; Bianchi and Bianchi 2012). One Italian historical cohort mortality

study was conducted previously among 3,984 shipyard workers in the harbor of Genoa, Italy,

between 1960 and 1981 (Puntoni, Merlo et al. 2001). In this cohort, SMRs were computed using

male residents in the Province of Genoa as the referent population. For the whole cohort,

significantly increased SMRs were detected for all causes, all cancers, liver, larynx, lung, pleural

and bladder cancers, respiratory tract diseases, and cirrhosis of the liver. In particular, for

malignant pleural neoplasm the observed number of deaths was 60, the expected number was

11.5 with an SMR of 5.24, 95%CI: 4.00-6.74. For lung cancer the observed number of deaths

was 298, the expected number was 168.7, with an SMR of 1.77, 95%CI: 1.57-1.98.

The International epidemiological evidence of health problems caused by asbestos exposure

among shipyard workers is profuse. In particular, the association between asbestos and pleural

and lung neoplasms have been the subject of a number of original studies and multiple reviews

(Krstev, Stewart et al. 2007; Tomioka, Natori et al. 2011; McCormack, Peto et al. 2012; Pinto,

Novello et al. 2013). Supported by strong evidence from studies among shipyard workers, the

association between occupational asbestos exposure and malignant neoplasm of the pleura

has been demonstrated (Neumann, Loseke et al. 2013) and findings suggest that the

association between asbestos exposure and lung cancer risk is linear (Nielsen, Baelum et al.

2014).

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According to ‘The Helsinki Declaration on Management and Elimination of Asbestos-Related

Diseases’ adopted by the International Conference on Monitoring and Surveillance of Asbestos-

Related Diseases, for medical, legal, and social reasons asbestos-related diseases should be

diagnosed at the earliest possible stage(Diseases 2014). For minimizing the adverse health

effects of asbestos, as well as for compensation of disease and disability. In addition, since new

scientific evidence provides support to the health benefits of low-dose computed tomographic

screening in people with a high risk of smoking-related lung cancer (Aberle, Adams et al. 2011),

by analogy, the Helsinki Declaration also recommended such screening programs for workers

with a history of asbestos exposure who are at high risk of lung cancer. Presently, such a

recommendation is based on the evidence that T scan screening in asbestos-exposed workers

is effective in detecting asymptomatic lung cancer (Fasola, Belvedere et al. 2007; Ollier,

Chamoux et al. 2014), although evidence of reduced mortality among asbestos-exposed

workers enrolled in organized screening programs is scanty. With respect to this, Pesch et al.

(2010) estimated the cancer risk of asbestos in a surveillance cohort of 576 German workers

highly exposed to asbestos in a variety of industrial sectors (Pesch, Taeger et al. 2010). They

were selected for high-resolution computer tomography of the chest in 1993-1997 and were

followed up to 15 years. In this cohort SMRs were 28.1 (95%CI: 15.73-46.36) for pleural

mesothelioma, 0.39 (0.17-0.77) for lung cancer, 0.59 (0.49-0.70) for all causes and 0.82 (0.63-

1.07) for all cancers.

Mastrangelo et al. (2013) showed preliminary results of mortality from post-occupational health

surveillance of asbestos workers recruited in the Veneto Region (about 1,700 asbestos workers)

and monitored either with chest x-ray or LDCT (Mastrangelo, Marangi et al. 2013). Compared to

the general population the SMRs for lung cancer were 1.05 (95% confidence interval 0.48-1.99)

in workers without pleural plaques, 1.05 (0.48-2.00) in workers with pleural plaques but not

asbestosis and 4.62 (0.56-16.7) in workers with asbestosis. Pleural mesothelioma mortality was

not reported.

In summary, whereas results from both our cohort and the German cohort described by Pesch

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et al. (2010) are consistent in demonstrating a still very strong association with neoplasm of the

pleura during asbestos-exposed surveillance, lung cancer relative mortality varies across

surveyed monitored cohorts. We believe that such surveillance programs vary widely in terms of

efficacy of these interventions, mostly because of surveillance protocol, image technology used

and monitoring adherence. Because of such a scant evidence on relative mortality among

screened asbestos-exposed workers, the Helsinki Declaration also recommends that such

screening programs include quality control to allow assessment of lung cancer mortality.

Conclusions

When compared to the general population of FVG and of Italy, this cohort of subjects enrolled in

a surveillance program for exposure to asbestos showed a very strong excess of mortality for

malignant neoplasm of the pleura. Lung cancer mortality was also significantly increased.

Relative mortality was stronger when we considered sub cohorts of former workers exposed to

asbestos in shipbuilding industries. Mortality for all causes did not differ from that of the general

population; this finding may be partially explained by a healthy worker effect. Future internal

analyses of this cohort should evaluate whether any of the surveillance activities conducted

within subgroups such as periodic LDCT demonstrate any relative reduction in lung cancer and

mesothelioma mortality.

Author Declaretion

We wish to confirm that there are no known conflicts of interest associated with this publication

and there has been no significant financial support for this work that could have influenced its

outcome.

18

References

Aberle, D. R., A. M. Adams, et al. (2011). "Reduced lung-cancer mortality with low-dose computed tomographic screening." N Engl J Med 365(5): 395-409. Asbestos Regional Commission (2014). Friuli Venezia Giulia region, Italy. Bianchi, C. and T. Bianchi (2012). "Mesothelioma among shipyard workers in Monfalcone, Italy." Indian J Occup Environ Med 16(3): 119-123. Bianchi, C. and T. Bianchi (2012). "Shipbuilding and mesothelioma in Monfalcone, Italy." Indian J Occup Environ Med 16(1): 14-17. Bovenzi, M., G. Stanta, et al. (1993). "Occupational exposure and lung cancer risk in a coastal area of northeastern Italy." Int Arch Occup Environ Health 65(1): 35-41. Breslow, N. E. and N. E. Day (1987). "Statistical methods in cancer research. Volume II--The design and analysis of cohort studies." IARC Sci Publ(82): 1-406. Checkoway, H., Pearce, N., Kriebel D. (2004). Research methods in occupational epidemiology, 2nd ed. D. Lgs n 277 (1991). D. Lgs n. 277 of August 15, 1991. Implementation of directives n. 80/1107 / EEC, n. 82/605 / EEC, n. 83/477 / EEC, n. 86/188 / EEC and n. 88/642 / EEC, concerning the protection of workers against the risks related to exposure to chemical, physical and biological agents during work , a provision of Art . 7 of the Law of 30 July 1990, n. 212. Diseases, I. C. o. M. a. S. o. A.-R. (2014). Helsinki. Fasola, G., O. Belvedere, et al. (2007). "Low-dose computed tomography screening for lung cancer and pleural mesothelioma in an asbestos-exposed population: baseline results of a prospective, nonrandomized feasibility trial--an Alpe-adria Thoracic Oncology Multidisciplinary Group Study (ATOM 002)." Oncologist 12(10): 1215-1224. Franceschi, S., R. Talamini, et al. (1990). "Smoking and drinking in relation to cancers of the oral cavity, pharynx, larynx, and esophagus in northern Italy." Cancer Res 50(20): 6502-6507. Goldberg, M., H. Kromhout, et al. (1993). "Job exposure matrices in industry." Int J Epidemiol 22 Suppl 2: S10-15. Goldberg, M. I., E. (2002). "The use of job exposure matrices for cancer epidemiology research and surveillance." Arch. Pub. Health. 60: 173-185. IARC (2011). International Agency for Research on Cancer. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. A review of Human carcinogens: Metals, arsenic, dusts, and fibres., WHO press. Vol. 100 Part C, WHO, IARC, Lyon. ISS "Istituto Superiore di Sanità, Italy. Available at: http://www.iss.it/site/mortalita/Scripts/SelCause.asp [last access: 03/11/2014].". ISTAT (2011). Italian National Institute of Statistics, 15th Census of Population and Housing, 2011. Available at: http://dati-censimentopopolazione.istat.it/ [last access: 03/11/2014]. Italian Law n 257 (1992). Italian Law n. 257 of March 27, 1992. Rules relating to the cessation of asbestos. . Italy. Krstev, S., P. Stewart, et al. (2007). "Mortality among shipyard Coast Guard workers: a retrospective cohort study." Occup Environ Med 64(10): 651-658. Magnani, C., B. Fubini, et al. (2013). "Pleural mesothelioma: epidemiological and public health issues. Report from the Second Italian Consensus Conference on Pleural Mesothelioma." Med Lav 104(3): 191-202. Mastrangelo, G., G. Marangi, et al. (2013). "Post-occupational health surveillance of asbestos workers." Med Lav 104(5): 351-358. McCormack, V., J. Peto, et al. (2012). "Estimating the asbestos-related lung cancer burden from mesothelioma mortality." Br J Cancer 106(3): 575-584. Neumann, V., S. Loseke, et al. (2013). "Malignant pleural mesothelioma: incidence, etiology, diagnosis, treatment, and occupational health." Dtsch Arztebl Int 110(18): 319-326. Nielsen, L. S., J. Baelum, et al. (2014). "Occupational asbestos exposure and lung cancer--a systematic review of the literature." Arch Environ Occup Health 69(4): 191-206.

http://www.iss.it/site/mortalita/Scripts/SelCause.asp

http://dati-censimentopopolazione.istat.it/

19

NIOSH (2011). National Institute for Occupational Safety and Health. Department of Health and Human Services, Centers for Disease Control and Prevention. Current intelligence bulletin: asbestos fibers and other elongate mineral particles: state of the science and roadmap for research, version 4. April 2011. . Ollier, M., A. Chamoux, et al. (2014). "Chest CT scan screening for lung cancer in asbestos occupational exposure: a systematic review and meta-analysis." Chest 145(6): 1339-1346. Orlowski, E., H. Pohlabeln, et al. (1993). "Retrospective assessment of asbestos exposure--II. At the job level: complementarity of job-specific questionnaire and job exposure matrices." Int J Epidemiol 22 Suppl 2: S96-105. Pesch, B., D. Taeger, et al. (2010). "Cancer mortality in a surveillance cohort of German males formerly exposed to asbestos." Int J Hyg Environ Health 213(1): 44-51. Pinto, C., S. Novello, et al. (2013). "Second Italian consensus conference on malignant pleural mesothelioma: state of the art and recommendations." Cancer Treat Rev 39(4): 328-339. Puntoni, R., F. Merlo, et al. (2001). "A historical cohort mortality study among shipyard workers in Genoa, Italy." Am J Ind Med 40(4): 363-370. Regional Law n 22 (2001). Measures on surveillance, prevention and information from asbestos risk situations and regional interventions related to it. Text coordinated with Regional Law 21/2005. Italy. Rothman, K. J., Greenland, S., Lash, T.L. (2008). Modern Epidemiology, 3rd Edition. Tomioka, K., Y. Natori, et al. (2011). "An updated historical cohort mortality study of workers exposed to asbestos in a refitting shipyard, 1947-2007." Int Arch Occup Environ Health 84(8): 959-967. Virta, R. L. (2006) "Worldwide asbestos supply and consumption trends from 1900 through 2003: U.S. Geological Survey Circular 1298. Available at: http://pubs.usgs.gov/circ/2006/1298/c1298.pdf. [last access: 03/11/2014]." 80. Zambon, P., R. Talamini, et al. (2000). "Smoking, type of alcoholic beverage and squamous-cell oesophageal cancer in northern Italy." Int J Cancer 86(1): 144-149.

http://pubs.usgs.gov/circ/2006/1298/c1298.pdf

Figure 1. Selection cohort process

3,136 subjects obtained

Deleting records of subjects for whom it was not possible to link with the Regional Repository of micro-data


Deleting records of subjects without residence in FVG during the study period (1989-2011)


96 women 2,488 men

3,293 total records entered by Local Health Authority

Deleting records of subjects without visits, without information, duplicate, or reported as 'to remove'

Deleting prevalent cases of cancer disease, after record linkage with Regional Cancer Registry - period 1995-2009

1

Table 1. Characteristics of the study cohort (N= 2,488)

N %

Age at Surveillance Enrollment (years)

MEAN (SD) 56.76 (11.99) -

0-54 970

38.99

55-59 491 19.73

60-64 430 17.28

65-69 284 11.41

70-74 170 6.83

75-79 96 3.86

80 + 47 1.89

Exposure Level Low 477 19.17

Medium 1691 67.97

High 320 12.86

Years of Exposure Mean (SD) 18.28 (9.97) -

<10 481 19.33

10-19 837 33.64

20-29 796 31.99

30 + 374 15.03

Industry Sector Metalworking 294 11.89

Shipbuilding 1740 70.39

Electric 96 3.88

Insulation 89 3.60

Other 253 10.23

Person-years of observation before year 2000

4588.56 17.37

2000-2002 3168.67 12.00

2003-2005 5650.95 21.39

2006-2008 6592.78 24.96

2009-2011 6414.82 24.28

2

Table 2. Observed (O) and Expected (E.) Deaths, Standardized Mortality Ratios (SMR) for Causes of Death and 95% Confidence Interval (95% CI) among 2,488 men enrolled in an asbestos surveillance program. Follow Up Period 1989 – 2011*

FVG Standard Rates1 Italian Standard Rates2

Cause of Death ICD9 ICD10 O E SMR 95% CI E SMR 95% CI

All Cause 0-99 A00-T98 388 437.30 0.89 0.80; 0.98 414.38 0.94 0.85; 1.03

All Cancers 140-239 C00-D48 181 188.99 0.96 0.83; 1.11 169.33 1.07 0.92; 1.24

Esophagus 150 C15 5 5.36 0.93 0.30; 2.17 2.77 1.81 0.59; 4.21

Stomach 151 C16 11 12.63 0.87 0.43; 1.56 10.63 1.03 0.52; 1.85

Colorectal 153-154;159.0 C18-C21 11 20.53 0.54 0.27; 0.96 17.07 0.64 0.32; 1.15

Liver 155.0-155.1 C22 9 18.89 0.65 0.30; 1.23 10.97 0.82 0.38; 1.56

Pancreas 157 C25 10 0.94 0.94 0.45; 1.74 8.76 1.14 0.55; 2.10

Larynx 161 C32 1 3.19 0.31 0.01; 1.74 3.04 0.33 0.01; 1.83

Trachea, bronchus, lung 162 C33-C34 70 47.05 1.49 1.17; 1.89 48.99 1.43 1.12; 1.81

Malignant neoplasm of pleura3 163 C45 25 3.64 6.87 4.45; 10.17 1.79 13.95 9.02; 20.64

Prostate 185 C61 1 11.30 0.09 0.00; 0.49 10.10 0.10 0.00; 0.55

Bladder 188 C67 3 5.31 0.56 0.12; 1.65 6.73 0.45 0.09; 1.30

Kidney 189 C64 2 4.47 0.45 0.05; 1.61 3.69 0.54 0.07; 1.96

Central Nervous System 191 C71 4 3.84 1.04 0.28; 2.66 3.40 1.18 0.32; 3.01

Leukemia 204-208 C91-C95 2 4.17 0.48 0.06; 1.73 4.99 0.40 0.05; 1.45

Mental disorders 290-303 E 305-319 F00-F99 4 6.41 0.62 0.17; 1.60 4.14 0.97 0.26; 2.47

Diseases of nervous system and sense organs 320-389 G00-G99 7 11.03 0.63 0.25; 1.31 11.43 0.61 0.25; 1.26

Diseases of digestive system 520-579 K00-K93 23 24.31 0.95 0.60; 1.42 19.21 1.20 0.76; 1.80

Diseases of genitourinary system 580-629 N00-N99 5 4.88 1.02 0.33; 2.39 5.80 0.86 0.28; 2.01

Symptoms, signs, and ill-defined conditions 780-799 R00-R99 5 3.78 1.32 0.43; 3.08 3.84 1.30 0.42; 3.03

Injury and poisoning 800-999 S00-T98 14 19.42 0.72 0.39; 1.21 16.27 0.86 0.47; 1.45

Diseases of circulatory system 390-459 I00-I99 112 128.60 0.87 0.73; 1.05 133.34 0.84 0.70; 1.01

Diseases of respiratory system 460-519 J00-J99 28 27.14 1.03 0.69; 1.50 26.37 1.06 0.71; 1.54

*Cohort of study: 2,488 subjects for 26,415.77 total person-years; we used for standardization available rates of ICD-9 code (1980-2002). 1Standard rate: age-specific mortality rates of FVG for years 1989-2003 and 2006-2011, provided by the Istituto Superiore di Sanità (ISS); 2Standard rate: age-specific mortality rates of Italy for years 1989-2003 and 2006-2011, provided by the Istituto Superiore di Sanità (ISS); 3Standard rate: age-specific mortality rates of FVG and Italy for years 1989-2003 and 2006-2011 calculated from the data of mortality provided by the National Institute of Statistics (ISTAT).

3

Table 3. Standardized Mortality Ratios by Cause of Death and Age Group. Observed (O) and Expected (E) Cases, SMR and 95% Confidence Interval (LL, UL; 95% CI)

FVG Standard Rates* Italian Standard Rates**

Cause of Death by age group O E SMR LL UL E SMR LL UL

All Causes1

≤ 39 1 2.39 0.42 0.01 2.33 2.57 0.39 0.01 2.17

40-49 4 5.71 0.70 0.19 1.79 5.41 0.74 0.20 1.89

50-59 35 46.43 0.75 0.53 1.95 42.34 0.83 0.58 1.15

60-69 121 131.16 0.92 0.77 1.11 118.90 1.02 0.85 1.22

70-79 137 152.76 0.90 0.76 1.06 146.36 0.94 0.79 1.11

80 + 90 98.84 0.91 0.74 1.13 98.79 0.91 0.74 1.13

All Cancers1

≤ 39 0 0.31 0.00 - - 0.33 0.00 - -

40-49 2 2.01 0.99 0.12 3.58 1.78 1.12 0.14 4.05

50-59 13 22.22 0.59 0.31 1.00 19.97 0.65 0.35 1.11

60-69 74 68.40 1.08 0.85 1.37 60.04 1.23 0.97 1.56

70-79 67 69.11 0.97 0.76 1.23 61.73 1.08 0.85 1.38

80 + 25 26.94 0.93 0.60 1.37 25.48 0.98 0.63 1.45

Malignant Neoplasm of Pleura2

≤ 39 - 0.00 - - - 0.00 - - -

40-49 - 0.02 - - - 0.02 - - -

50-59 3 0.47 6.40 1.32 18.69 0.22 13.71 2.82 40.04

60-69 11 1.56 7.04 3.51 12.60 0.76 14.37 7.17 25.73

70-79 6 1.24 4.84 1.58 10.54 0.62 9.70 3.17 21.14

80 + 5 0.35 14.45 4.68 33.68 0.17 29.14 9.44 67.89

Lung Cancer1

≤ 39 - 0.06 - - - 0.03 - - -

40-49 1 0.40 2.49 0.06 13.85 0.42 2.40 0.06 13.38

50-59 4 5.57 0.72 0.20 1.84 6.06 0.66 0.18 1.69

60-69 26 17.66 1.47 0.96 2.16 18.97 1.37 0.89 2.01

70-79 28 17.82 1.57 1.04 2.28 18.06 1.55 1.03 2.25

80 + 11 5.55 1.98 0.99 3.55 5.44 2.02 1.01 3.62 1Standard rate: age-specific mortality rates of FVG and Italy for years 1989-2003 and 2006-2011, provided by the Istituto Superiore di Sanità (ISS); 2Standard rate: age-specific mortality rates of FVG and Italy for years 1989-2003 and 2006-2011 calculated from the data of mortality provided by the National Institute of Statistics (ISTAT); Follow Up Period: 1989 – 2011. Cohort included 2,488 subjects, for 26,415.77 total person-years.

4

Table 4. Standardized Mortality Ratios by Cause of Death, Industrial Sector and Year of Hire. Observed (O) and Expected (E) Cases, SMR and 95% Confidence Interval (LL, UL; 95% CI)

FVG Standard Rates* Italian Standard Rates**

Cause of Death O E SMR LL UL E SMR LL UL

All Causes

All industrial sectors1 388 437.30 0.89 0.80 0.98 414.38 0.94 0.85 1.03

Shipbuilding2 301 336.86 0.89 0.80 1.00 319.93 0.94 0.84 1.05

Shipbuilding hired < 19743 257 295.02 0.87 0.77 0.99 280.92 0.91 0.81 1.04

Shipbuilding hired 1974-19844 30 27.78 1.08 0.73 1.54 25.89 1.16 0.78 1.66

Shipbuilding hired 1985+5 14 14.06 1.00 0.54 1.67 13.12 1.07 0.58 1.79

All Cancers


Shipbuilding2 144 143.01 1.01 0.85 1.19 128.17 1.12 0.95 1.33




Malignant neoplasm of pleura***


Shipbuilding2 22 2.71 8.12 5.09 12.26 1.33 16.60 10.41 25.06


Shipbuilding hired 1974-19844 0 0.25 - - - 0.13 - - -


Lung Cancer


Shipbuilding2 59 35.56 1.66 1.28 2.16 36.86 1.60 1.23 2.08




*Standard rate: age-specific mortality rates of FVG for years 1989-2003 and 2006-2011, provided by the Istituto Superiore di Sanità (ISS); **Standard rate: age-specific mortality rates of Italy for years 1989-2003 and 2006-2011, provided by the Istituto Superiore di Sanità (ISS); *** Standard rate: age-specific mortality rates of FVG and Italy for years 1989-2003 and 2006-2011 calculated from the data of mortality provided by the National Institute of Statistics (ISTAT); 1Follow Up Period: 1989 – 2011. Cohort included 2,488 subjects, for 26,415.77 total person-years; 2Follow Up Period: 1989 – 2011. Cohort included 1,740 subjects, for 18,972.65 total person-years; 3Follow Up Period: 1989 – 2011. Cohort included 1,370 subjects, for 1713,206.14 total person-years; 4Follow Up Period: 1989 – 2011. Cohort included 234 subjects, for 3,176.32 total person-years; 5Follow Up Period: 1989 – 2011. Cohort included 136 subjects, for 2,590.19 total person-year

1

Supplemental Tables Supplemental Table 1. Standardized Mortality Ratios for All Causes by calendar year. Observed (O) and

Expected (E) Cases, SMR and 95% Confidence Interval (95% CI) Follow Up Period 1989 – 2011*


Year O E SMR LL UL E SMR LL UL

1989 - 0.97 - - - 0.84 - - -

1990 - 1.17 - - - 1.02 - - -

1991 - 1.40 - - - 1.21 - - -

1992 - 1.74 - - - 1.52 - - -

1993 - 1.98 - - - 1.78 - - -

1994 - 2.66 - - - 2.36 - - -

1995 2 3.75 0.53 0.06 1.93 3.37 0.59 0.07 2.14

1996 3 4.86 0.62 0.13 1.80 4.39 0.68 0.14 2.00

1997 6 5.93 1.01 0.33 2.21 5.52 1.09 0.36 2.37

1998 4 7.57 0.53 0.14 1.35 7.01 0.57 0.16 1.46

1999 5 9.13 0.55 0.18 1.28 8.40 0.60 0.19 1.39

2000 9 11.09 0.81 0.37 1.54 10.36 0.87 0.40 1.65

2001 16 14.99 1.07 0.61 1.73 13.97 1.14 0.65 1.85

2002 23 19.48 1.18 0.75 1.77 18.25 1.26 0.80 1.89

2003 20 26.53 0.75 0.46 1.16 24.51 0.82 0.50 1.26

2004 27 33.00 0.82 0.54 1.19 30.48 0.89 0.58 1.29

2005 30 32.56 0.92 0.62 1.32 30.92 0.97 0.65 1.39

2006 31 36.73 0.84 0.57 1.21 34.95 0.89 0.60 1.27

2007 44 38.65 1.14 0.83 1.53 37.96 1.16 0.85 1.55

2008 42 43.44 0.97 0.69 1.31 41.30 1.02 0.73 1.38

2009 41 45.20 0.91 0.65 1.23 43.54 0.94 0.67 1.28

2010 41 46.50 0.88 0.63 1.20 44.36 0.92 0.66 1.26

2011 44 47.97 0.92 0.67 1.23 46.36 0.95 0.69 1.27

1Standard rate: age-specific mortality rates of FVG for years 1989-2003 and 2006-2011, provided by the Istituto Superiore di Sanità (ISS); 2Standard rate: age-specific mortality rates of Italy for years 1989-2003 and 2006-2011, provided by the Istituto Superiore di Sanità (ISS). Follow Up Period: 1989 – 2011. Cohort included 2,488 subjects, for 26,415.77 total person-years.

2

Supplemental Table 2. Standardized Mortality Ratios for All Cancers by calendar year. Observed (O)

and Expected (E) Cases, SMR and 95% Confidence Interval (95% CI) Follow Up Period 1989 – 2011*



1989 - 0.39 - - - 0.32 - - -

1990 - 0.49 - - - 0.39 - - -

1991 - 0.57 - - - 0.46 - - -

1992 - 0.74 - - - 0.59 - - -

1993 - 0.86 - - - 0.70 - - -

1994 - 1.17 - - - 0.96 - - -

1995 0 1.58 0.00 - - 1.34 0.00 - -

1996 2 2.08 0.96 0.12 3.47 1.74 1.15 0.14 4.15

1997 1 2.45 0.41 0.01 2.27 2.20 0.46 0.01 2.53

1998 2 3.22 0.62 0.08 2.24 2.77 0.72 0.09 2.61

1999 2 3.93 0.51 0.06 1.84 3.33 0.60 0.07 2.17

2000 5 4.67 1.07 0.35 2.49 4.13 1.21 0.39 2.82

2001 10 6.52 1.53 0.74 2.82 5.69 1.76 0.84 3.23

2002 9 8.75 1.03 0.47 1.96 7.51 1.20 0.55 2.28

2003 12 11.27 1.06 0.55 1.86 10.12 1.19 0.61 2.08

2004 14 13.95 1.00 0.55 1.69 12.53 1.12 0.61 1.88

2005 11 14.69 0.75 0.37 1.34 13.27 0.83 0.41 1.48

2006 15 16.45 0.91 0.51 1.50 14.85 1.01 0.57 1.67

2007 22 17.08 1.29 0.81 1.95 15.95 1.38 0.86 2.08

2008 20 18.99 1.05 0.64 1.62 16.92 1.18 0.72 1.82

2009 18 18.93 0.95 0.56 1.50 17.53 1.03 0.61 1.62

2010 20 19.89 1.01 0.61 1.55 17.83 1.12 0.69 1.73

2011 18 20.31 0.89 0.53 1.40 18.21 0.99 0.59 1.56


3

Supplemental Table 3. Standardized Mortality Ratios for Malignant Pleural cancer by calendar year. Observed (O) and Expected (E) Cases, SMR and 95% Confidence Interval (95% CI) Follow Up Period 1989 – 2011*



1989 - 0.00 - - - 0.00 - - -

1990 - 0.01 - - - 0.00 - - -

1991 - 0.00 - - - 0.00 - - -

1992 - 0.01 - - - 0.00 - - -

1993 - 0.01 - - - 0.01 - - -

1994 - 0.01 - - - 0.01 - - -

1995 - 0.02 - - - 0.01 - - -

1996 1 0.04 22.32 0.56 124.33 0.01 78.41 1.98 436.74

1997 - 0.03 - - - 0.02 - - -

1998 - 0.04 - - - 0.02 - - -

1999 1 0.06 17.73 0.45 98.77 0.03 32.01 0.81 178.30

2000 - 0.09 - - - 0.04 - - -

2001 2 0.14 13.81 1.67 49.86 0.05 37.27 4.51 134.55

2002 3 0.21 14.33 2.95 41.83 0.08 39.57 8.15 115.55

2003 - 0.14 - - - 0.10 - - -

2004 2 0.17 11.92 1.44 43.03 0.12 17.12 2.07 61.79

2005 1 0.32 3.13 0.08 17.45 0.15 6.77 0.17 37.68

2006 2 0.35 5.69 0.69 20.55 0.16 12.29 1.49 44.36

2007 3 0.31 9.73 2.00 28.41 0.18 16.51 3.40 48.21

2008 4 0.53 7.48 2.04 19.16 0.19 21.33 5.80 54.62

2009 3 0.43 7.01 1.44 20.48 0.21 14.62 3.01 42.69

2010 2 0.49 4.08 0.49 14.71 0.20 9.90 1.20 35.75

2011 1 0.22 4.59 0.12 25.59 0.20 4.93 0.12 27.47

1Standard rate: age-specific mortality rates of FVG for years 1989-2003 and 2006-2011 calculated from the data of mortality provided by the National Institute of Statistics (ISTAT); 2Standard rate: age-specific mortality rates of Italy for years 1989-2003 and 2006-2011 calculated from the data of mortality provided by the National Institute of Statistics (ISTAT); Follow Up Period: 1989 – 2011. Cohort included 2,488 subjects, for 26,415.77 total person-years.

4

Supplemental Table 4. Standardized Mortality Ratios for Lung cancer by calendar year. Observed (O)

and Expected (E) Cases, SMR and 95% Confidence Interval (95% CI) Follow Up Period 1989 – 2011*



1989 - 0.12 - - - 0.11 - - -

1990 - 0.14 - - - 0.13 - - -

1991 - 0.16 - - - 0.15 - - -

1992 - 0.22 - - - 0.19 - - -

1993 - 0.26 - - - 0.23 - - -

1994 - 0.33 - - - 0.31 - - -

1995 - 0.44 - - - 0.43 - - -

1996 - 0.58 - - - 0.55 - - -

1997 1 0.73 1.37 0.03 7.62 0.69 1.45 0.04 8.06

1998 - 0.89 - - - 0.85 - - -

1999 - 1.06 - - - 1.03 - - -

2000 2 1.20 1.67 0.20 6.03 1.26 1.59 0.19 5.75

2001 2 1.74 1.15 0.14 4.16 1.71 1.17 0.14 4.23

2002 3 2.12 1.41 0.29 4.12 2.28 1.32 0.27 3.84

2003 5 2.87 1.74 0.57 4.06 3.01 1.66 0.54 3.87

2004 6 3.55 1.69 0.55 3.69 3.73 1.61 0.53 3.51

2005 7 3.73 1.88 0.75 3.86 3.86 1.81 0.73 3.73

2006 4 4.16 0.96 0.26 2.46 4.31 0.93 0.25 2.38

2007 10 4.15 2.41 1.16 4.43 4.56 2.19 1.05 4.04

2008 6 4.35 1.38 0.45 3.00 4.77 1.26 0.41 2.74

2009 9 4.36 2.06 0.95 3.92 4.88 1.84 0.84 3.50

2010 9 5.12 1.76 0.81 3.34 4.95 1.82 0.83 3.45

2011 6 4.79 1.25 0.41 2.73 4.98 1.20 0.39 2.63


5

Supplemental Table 5. Number of observed deaths since first surveillance enrollment, by months, for all causes of death, lung cancer and malignant neoplasm of the pleura

Months since surveillance enrollment

(N) by cause of death N. of Obs. deaths (%) Cumulative freq. (%)

All cause of death

≤12 22 (5.67) 22 (5.67)

13 - 24 24 (6.19) 46 (11.86)

25 - 36 25 (6.44) 71 (18.30)

37 - 48 43 (11.08) 114 (29.38)

49 - 60 30 (7.73) 144 (37.11)

60+ 244 (62.89) 388 (100.00)

All cancers

≤12 8 (4.42) 8 (1.43)

13 - 24 12 (6.63) 20 (8.57)

25 - 36 11 (6.08) 31 (17.13)

37 - 48 20 (11.05) 51 (28.18)

49 - 60 13 (7.18) 64 (35.36)

60+ 117 (64.64) 181 (100.00)

Lung cancer

≤12 1 (1.43) 1 (1.43)

13 - 24 5 (7.14) 6 (8.57)

25 - 36 - -

37 - 48 11 (15.71) 17 (24.29)

49 - 60 6 (8.57) 23 (32.86)

60+ 47 (67.14) 70 (100.00)

Malignant neoplasm of pleura

≤12 2 (8.00) 2 (8.00)

13 - 24 2 (8.00) 4 (16.00)

25 - 36 2 (8.00) 6 (24.00)

37 - 48 4 (16.00) 10 (40.00)

49 - 60 2 (8.00) 12 (48.00)

60+ 13 (52.00) 25 (100.00)

1

Analisi di sensibilità per la stima dei rapporti standardizzati di incidenza in

mancanza di tassi standard nazionali in una coorte di ex esposti ad amianto sotto

sorveglianza sanitaria

A sensitivity analysis for estimating standardized incidence rates in the absence of national

standards in a cohort of formerly exposed to asbestos undergoing health surveillance

Fabiano BARBIEROa,b,c, Manuela GIANGRECOa, Federica E. PISAa,d, Valentina ROSOLENa, Fabio

BARBONEa,d,e,

aDipartimento di Scienze Mediche e Biologiche, Università di Udine, Udine, Italia.

bDipartimento di Medicina Clinica e Sperimentale, Università di Parma, Parma, Italia.

cServizio Prevenzione Igiene e Sicurezza negli Ambienti di Lavoro (SPISAL), ULSS n. 12, Mestre, Italia.

dIstituto di Igiene ed Epidemiologia Clinica, Azienda ospedaliero-universitaria di Udine, Udine, Italia.

eDipartimento di Scienze Mediche, Università di Trieste, Trieste, Italia.

Corrispondenza: Professore Fabio Barbone, Dipartimento di Scienze Mediche e Biologiche, Università di

Udine. Piazzale Kolbe 3, Udine 33100, Italia.

telefono: +39 0432559158. Email: [email protected].

Contatti:

FABIANO BARBIERO [email protected]

MANUELA GIANGRECO [email protected]

FEDERICA E. PISA [email protected]

VALENTINA ROSOLEN [email protected]

FABIO BARBONE [email protected]




2

Cosa si sapeva già

L’incidenza di mesotelioma mostra in Italia una notevole variabilità geografica;

per il mesotelioma non sono disponibili tassi di incidenza italiani sesso, età e

anno specifici precedenti all’anno 2006

Il confronto della popolazione di studio con una popolazione non adeguata può

generare una distorsione nella stima delle misure di associazione.

Cosa si aggiunge di nuovo

L’utilizzo di un tasso di incidenza standard mediano, che tenga conto della

variabilità geografica per malattia, può rappresentare uno strumento utile per la

stima dei SIR qualora non siano disponibili tassi nazionali;

Si conferma l’ipotesi che i SIR della nostra coorte, se ottenuti con l’utilizzo di tassi

standard del Friuli Venezia Giulia, risultano sottostimati.

RIASSUNTO

OBIETTIVI. Stimare i Rapporti Standardizzati di Incidenza (SIR) di mesotelioma in una

coorte di ex lavoratori esposti ad asbesto sotto sorveglianza sanitaria, nel caso in cui i

tassi standard nazionali sesso-età e anno specifici non siano disponibili e il numero di casi

attesi calcolato a partire dai tassi regionali sia distorto considerata la dimensione della

coorte di studio.

DISEGNO. Analisi di sensibilità che confronta tutti i tassi standard disponibili dalla rete dei

registri tumori italiani nel periodo 1995-2007.

SETTING E PARTECIPANTI. L’incidenza di mesotelioma in Italia mostra una forte

variazione geografica, con i tassi di incidenza più elevati per le aree di Genova e Friuli

Venezia Giulia. Per il mesotelioma non sono disponibili tassi di incidenza standard, riferiti

3

all’intero territorio italiano, età-sesso e anno specifici antecedenti al 2006. Abbiamo

condotto un’analisi di sensibilità in una coorte di 2.488 uomini. Abbiamo considerato tutti i

registri tumori italiani disponibili e con i dati completi nel periodo 1995-2007 (N=14).

Abbiamo individuato, per ciascuna classe d’età e anno di calendario, il tasso

corrispondente al valore minimo, al primo quartile, alla media, alla mediana, al terzo

quartile e al valore massimo.

RISULTATI. Nel periodo 1995-2007 abbiamo osservato 25 casi incidenti di mesotelioma. I

casi attesi di mesotelioma erano 0.45, 1.77, 2.05 and 7.05 corrispondenti rispettivamente

al valore minimo, alla media, alla mediana e al valore massimo dei tassi individuati. Il SIR,

sulla base del valore mediano dei tassi standard è stato 14,10; (95% CI: 9,12 to 20,87)

mentre il SIR basato sul valore massimo è stato 3,55 (95% CI 2,29 to 5,25).

CONCLUSIONI. L’utilizzo di un tasso di incidenza mediano quale standard può essere

una valida seppur prudente alternativa per il calcolo dei SIR qualora i tassi standard

nazionali non fossero disponibili. Questi risultati supportano l’ipotesi che il SIR della nostra

coorte, se ottenuto dall’utilizzo della popolazione del FVG quale standard di riferimento

(SIR=9,76; IC 95% 6,32-14,45), potrebbe essere sottostimato.

PAROLE CHIAVE: Analisi di sensibilità, SIR, mesotelioma, asbesto.

4

ABSTRACT OBJECTIVES. To estimate the Standardized Incidence rate Ratio (SIR) of mesothelioma

in a cohort of former workers undergoing health surveillance because of previous asbestos

exposure, when sex-, age-, and calendar year-specific rates of the national standard are

not available and the number of expected cases calculated from the regional rates is

biased by the size of the study cohort.

DESIGN. A sensitivity analysis that compares all standard rates available from the network

of the Italian cancer registries in the period 1995-2007.

SETTING AND PARTICIPANTS. The incidence of mesothelioma in Italy shows strong

geographical variation, with the highest incidence rates for the geographic areas of Genoa

and Friuli Venezia Giulia. For mesothelioma, standard incidence rates are not available for

Italy prior to the year 2006. We conducted a sensitivity analysis in a cohort of 2,488 men.

We considered every Italian cancer registry available with complete data in the period

1995-2007 (N = 14). We assembled, for each year and age group, the corresponding

minimum, first quartile, mean, median, third quartile and maximum rate.

MAIN OUTCOME MEASURES. We estimated the expected number of mesothelioma

cases and the SIR with 95% confidence interval (95%), using as standard the rate

corresponding to the median and the maximum value.

RESULTS. During the period 1995-2007, we observed 25 incident cases of mesothelioma.

The expected cases of mesothelioma were 0.45, 1.77, 2.05 and 7.05, according to the

minimum, median, mean and maximum standard rate, respectively. The SIR based on the

5

median standard rates was 14.10; (95% CI: 9.12 to 20.87) while the SIR based on the

maximum rate was 3.55 (95% CI 2.29 to 5.25).

CONCLUSIONS. Using a standard median incidence rate may be a cautious alternative

for the estimated SIR if national standard rates are not available. These results support the

hypothesis that the SIR of the study cohort, if obtained from the use of the population of

FVG as standard (SIR=9.76; 95% CI 6.32-14.45), would be underestimated.

Keywords: Sensitivity analysis, SIR, mesothelioma, asbestos.

6

INTRODUZIONE

La stima del rapporto standardizzato di incidenza (SIR) è comunemente utilizzata per il

confronto esterno tra una coorte, per esempio occupazionale o su base geografica, ed una

popolazione di riferimento, per esempio la popolazione generale.1,2 Tale confronto tiene

conto della distribuzione per età, genere e periodo storico: per il calcolo dei casi attesi è

infatti necessario disporre dei tassi età-anno e genere specifici per la popolazione

standard.

Nel caso di popolazioni di modeste dimensioni e/o per numeri modesti di eventi,

utilizzando il metodo della standardizzazione indiretta, è opportuno scegliere una

popolazione standard di grandi dimensioni e con tassi anno ed età specifici molto stabili.3

Inoltre la popolazione standard deve essere simile alla popolazione di studio e non

cambiare frequentemente nel corso del tempo.4

Popolazioni standard di riferimento appartenenti a aree geografiche caratterizzate ad

esempio da particolari attività lavorative, condizioni di esposizione ambientale, o aree

geografiche ridotte (ad esempio singole aree regionali) possono, se prese come

popolazione di riferimento, presentare tassi crudi età, genere e malattia specifici

particolarmente alti o bassi rispetto ai tassi di una più ampia popolazione di riferimento, e

generare delle stime distorte soprattutto in presenza di coorti di studio sufficientemente

numerose.

La provincia di Gorizia presenta realtà produttive industriali, in cui l’asbesto è stato

utilizzato in larga quantità fino agli anni 1990-1992, nel settore della navalmeccanica,

metalmeccanica e nei cotonifici. L’area ospita fin dai primi anni del 1900, uno dei più

grandi cantieri navali del Paese.

Abbiamo analizzato una coorte di uomini con esposizione occupazionale ad amianto e

7

seguiti da un programma di sorveglianza sanitaria, per valutare se vi fosse un incremento

o decremento di incidenza di mesotelioma rispetto alla popolazione generale del Friuli

Venezia Giulia (FVG). I risultati di tale studio saranno presentati nel dettaglio altrove.

L’incidenza di mesotelioma mostra in Italia una notevole variabilità geografica, che

rispecchia la mappa dell’utilizzo industriale dell’asbesto.5 Infatti le aree geografiche di

Genova e FVG presentano i tassi di incidenza di mesotelioma più alti, circa 10-20 volte più

elevati dei tassi minimi delle altre aree italiane.6 Da qui nasce la necessità di calcolare SIR

basati su una popolazione esterna di riferimento che tenga conto della diversa variabilità

geografica. Per il periodo di follow-up di nostro interesse (1995-2007) non sono ad oggi

disponibili tassi età-genere e anno specifici per l’intera popolazione italiana quale standard

di riferimento. Presso l’Associazione Italiana Registri Tumori (AIRTUM), infatti, tali tassi

riferiti al Pool di tutti i 38 registri, sono disponibili solamente per il periodo 2006-2009.7 Il

Registro Nazionale dei Mesoteliomi (ReNaM) fornisce tali tassi aggregati per età, e riferiti

ad un periodo temporale (2005-2008) non coincidente con il periodo di follow-up di nostro

interesse.8

È stata quindi condotta un’analisi di sensibilità per valutare se e quanto variava il numero

di casi attesi di mesotelioma, e di conseguenza il SIR, al variare del tasso standard

utilizzato tra quelli delle aree italiane disponibili per il periodo 1995-2007.

8

Materiali e metodi

La popolazione di questo studio consiste in una coorte di 2 488 soggetti, ex lavoratori

maschi, con esposizione ad asbesto confermata individualmente da medici del lavoro.

Questi soggetti sono stati seguiti da un programma di sorveglianza sanitaria pubblico

organizzato dall’azienda per i Servizi Sanitari n. 2 Isontina (ASS2) della Regione FVG tra il

1989 e il 2008. Il bacino di competenza dell’ASS2 coincide con l’intero territorio della

Provincia di Gorizia, situata nel nord-est dell’Italia, con una popolazione di 140.143 abitanti

distribuiti in 25 comuni.9 Il periodo di follow-up per ciascun soggetto è iniziato dall’ultima in

ordine cronologico tra la data di prima visita medica e il 1/1/1995, ed è terminato alla prima

tra la data di incidenza, di fine residenza in FVG, data di decesso o il 31/12/2009. Attraverso

record linkage con il Registro Tumori (RT) della Regione FVG, disponibile per il periodo

1995-2009, sono stati identificati i casi incidenti di tumore tramite la codifica dell’International

Classification of Disease decima edizione (ICD-10). Al fine di ridurre il più possibile eventuali

bias di selezione coorte di studio sono stati identificati ed esclusi i casi prevalenti di tumore

all’inizio del follow-up.

Sono state calcolate le percentuali di casi incidenti per le principali sedi tumorali rilevati nella

coorte ASS2 e nell’intera popolazione del FVG per il periodo 1995-2009. Dal confronto

emergeva che tali percentuali erano simili per quasi tutte le sedi tumorali esaminate: per il

mesotelioma, tuttavia, i casi incidenti risultavano circa 8 volte più frequenti nella coorte

ASS2. Per il mesotelioma non sono disponibili tassi di incidenza età-genere e anno specifici

riferiti all’Italia e precedenti all’anno 2006. Sono tuttavia disponibili i tassi di incidenza età,

genere e anno specifici, per periodi temporali diversi, dei 38 registri tumori che coprono varie

regioni o aree d’Italia. Il FVG, dopo la provincia di Genova, risulta per il periodo 1998-2002

l’area Italiana con i tassi di incidenza per mesotelioma più elevati.6

9

È stata quindi condotta un’analisi di sensibilità per valutare se e quanto varia il numero di

casi attesi, e di conseguenza il SIR, al variare del tasso standard utilizzato tra quelli

disponibili per le diverse aree o regioni italiane. Nonostante il periodo di follow-up della

coorte ASS2 terminasse al 2009 è stato scelto di ridurlo al 2007 per garantire l’utilizzo di

un maggior numero di registri tumori. Sono stati considerati, quindi, tutti i registri che

coprono per intero il periodo 1995-2007: Varese, Parma, Ragusa, Torino, Genova,

Romagna, Modena, Latina, Ferrara, Sassari, Umbria, Biella, Friuli Venezia Giulia e Alto

Adige (i periodi coperti dai singoli RT sono mostrati nella tabella supplementare 1).

Per ciascuno di questi RT sono stati estratti i tassi di incidenza per mesotelioma specifici

per ciascun anno e classe di età dalla banca dati AIRTUM. È stato quindi definito, per ogni

anno e classe di età, quale fosse il tasso con valore minimo e quello massimo (Tabella

supplementare 2). Inoltre sono stati calcolati i tassi corrispondenti al primo quartile, alla

mediana, al terzo quartile e alla media. Per ciascuno di questi scenari sono stati calcolati i

casi attesi.

Sono stati stimati, attraverso metodo indiretto,2 i SIR e l’intervallo di confidenza di

Poisson10 corrispondente al 95% (IC 95%), utilizzando come tasso standard

rispettivamente: il valore corrispondente alla mediana, che tiene conto della variabilità dei

tassi dei 14 registri, e il valore massimo, per confrontare i tassi utilizzati nelle analisi

riguardanti lo studio di coorte ASS2 con i più elevati tassi di incidenza rilevati sul territorio

Italiano.

Le analisi di sensibilità per il mesotelioma sono state condotte anche per sottogruppi,

ristrette ai lavoratori impiegati nel settore navalmeccanico. Tra questi abbiamo classificato

coloro che sono stati assunti nel settore della navalmeccanica prima del 1974, negli anni

compresi tra il 1974 e il 1984 e coloro che sono stati assunti tra il 1985 e il 1994: la

tendenza del consumo e utilizzo di amianto registra, in Italia, il più alto livello a partire dagli

10

anni '70 fino alla metà degli anni '80, con una rapido decremento dal 1985.11 Infine i SIR

sono stati calcolati, per il periodo 1995-2007, anche utilizzando come tassi standard quelli

della popolazione del FVG e forniti da AIRTUM, allo scopo di confrontarli con i risultati

ottenuti dall’analisi di sensibilità.

Tutte le analisi sono state effettuate con l’utilizzo del software SAS© versione 9.3 (SAS

Institute Inc., Cary, N.C., USA).

RISULTATI

La coorte include 2.488 uomini, per un totale di 16.505,32 anni-persona di osservazione

nel periodo 1995-2007, con una media di 6,63 anni di follow-up per ciascun soggetto.

Sono stati calcolati i tassi corrispondenti al primo quartile, alla mediana, al terzo quartile e

alla media, per classe d’età e per l’intero periodo 1995-2007. Vengono contestualmente

presentati i valori minimo e massimo: i risultati sono riportati in tabella 1. In tabella 2 sono

presentate le distribuzioni percentuali dei casi incidenti, per i maschi, per specifica causa

nella coorte ASS2 e nel RT della Regione FVG 1995-2009. Tale confronto evidenzia che

le percentuali di casi di tumore maligno di polmone, trachea e bronchi (19,6% vs 13,2%),

della prostata (26,1% vs 20,2) e del mesotelioma (8,9% vs 0,6%) sono sensibilmente più

elevate nella coorte ASS2.

Nella tabella 3 sono riportati i casi attesi calcolati utilizzando come tassi standard

rispettivamente: il valore minimo; il primo quartile; la mediana; il terzo quartile; il valore

massimo; la media, data la distribuzione dei tassi per anno e per classi d’età dei 14 registri

utilizzati. Nell’intero periodo 1995-2007 sono stati osservati 25 casi incidenti di

mesotelioma; i casi attesi di mesotelioma variano da 0,45 a 7,05 con un valore medio di

2,05 e una mediana pari a 1,77.

11

Nella tabella 4 sono riportati i risultati dei SIR, stimati con un intervallo di confidenza di

Poisson del 95% (IC 95%), ottenuti nell’intera coorte ASS2 e nei sottogruppi di ex

lavoratori esposti ad amianto nel settore della navalmeccanica, per periodo di impiego. Si

ottiene un SIR minimo di 2,90 (attesi: 0,35; IC 95 % 0,07-16,13) e un massimo di 4,23

(attesi: 4,26; IC 95 % 2,51-6,68) rispettivamente nelle sotto coorti di lavoratori assunti nel

settore della navalmeccanica dal 1985 in poi e assunti nel settore della navalmeccanica

prima del 1974 (tabella 4).

Applicando i valori mediani dei tassi disponibili nei 14 registri con copertura temporale

1995-2007 il SIR varia da un minimo di 10,48 (attesi: 0,10; IC 95 % 0.27-58.35) e un

massimo di 17,19 (attesi: 1,05; IC 95 % 10,19-27,15) rispettivamente nelle sotto coorti di

lavoratori assunti nel settore della navalmeccanica dal 1985 in poi e in quelli impiegati nel

comparto della navalmeccanica indipendentemente dal periodo di assunzione. In tutti i

casi, i tassi di incidenza stimati confermano, un forte aumento dell’incidenza di

mesotelioma in ex lavoratori esposti ad asbesto; tuttavia nella coorte di lavoratori impiegati

nel settore della navalmeccanica e assunti dal 1985 in poi le stime dei SIR ottenute

utilizzando il valore mediano (attesi=0,1; SIR= 10,48 IC 95% 0,27-58,35) e massimo

(attesi=0,35; SIR= 2,90 IC 95% 0,07-16,13) dei tassi disponibili nei 14 registri con

copertura temporale 1995-2007 risultano instabili e non statisticamente significativi

(Tabella 4).

I risultati dei SIR ottenuti applicando i tassi della popolazione del FVG come standard di

riferimento, nel periodo 1995-2007, variano da un minimo di 9,76 (attesi= 2,56; IC 95%

6,32-14,45) ad un massimo di 11,27 (attesi= 1,60; IC 95% 6,68-17,80) rispettivamente

nell’intera coorte di studio e nella sotto coorte di lavoratori assunti nel settore della

navalmeccanica prima del 1974.

12

Discussione e conclusioni

I risultati ottenuti attraverso analisi di sensibilità dimostrano che all’interno della coorte

ASS2 i SIR risultano elevati (3,15 volte superiori), con significatività statistica, anche

applicando i tassi standard massimi osservati nelle aree geografiche dei 14 registri

considerati. Questo risultato rafforza l’evidenza di un eccesso di incidenza di mesotelioma

nella nostra coorte di ex lavoratori esposti ad asbesto rispetto alla popolazione di

riferimento.

L’utilizzo di un tasso di incidenza standard mediano, che tenga conto della variabilità

geografica per malattia, può rappresentare uno strumento utile per la stima dei SIR

qualora non siano disponibili tassi standard nazionali. La Regione FVG conta un totale di

1.218.985 abitanti,9 è caratterizzata dalla presenza di realtà produttive industriali in cui

l’asbesto è stato utilizzato in larga quantità fino agli anni 1990-1992 ed è sede di uno dei

più grandi cantieri navali del Paese. Questo contribuisce verosimilmente alla registrazione

dei tassi di incidenza di mesotelioma tra i più alti nel territorio italiano. Visto quanto sopra,

pertanto, l’utilizzo dei tassi standard di riferimento necessari alla stima dei SIR di

mesotelioma nella nostra coorte di studio determina verosimilmente un bias nella stima

delle misure di associazione: questo, nel caso specifico dei risultati ottenuti nella coorte

ASS2, si traduce in una ipotesi di sottostima dei SIR Nel nostro caso la stima dei SIR del

mesotelioma attraverso l’utilizzo dei valori mediani de tassi presenti nei 14 registri utilizzati

può quindi essere considerata una soluzione al fine di attenuare il bias di selezione

determinato dall’utilizzo della popolazione del solo FVG quale standard di riferimento.

I SIR di mesotelioma ottenuti nella nostra coorte di ex lavoratori esposti ad asbesto

attraverso analisi di sensibilità, e nello specifico attraverso i valori mediani anno ed età

specifici dei tassi dei 14 registri utilizzati e disponibili per il periodo 1995-2007 evidenziano

13

un eccesso di incidenza rispetto allo standard di riferimento che varia da 10,48 a 17,19.

Nella coorte di lavoratori impiegati nel settore della navalmeccanica e assunti dal 1985 in

poi le stime dei SIR ottenute utilizzando il valore mediano e massimo dei tassi disponibili

nei 14 registri con copertura temporale 1995-2007 risultano instabili e non statisticamente

significativi: questo è verosimilmente spiegato dal ridotto numero di soggetti della coorte e

dal ridotto numero di casi osservati all’interno della stessa (osservati=1). Questi risultati

supportano l’ipotesi che, nel caso specifico, i SIR della nostra coorte, se ottenuti con

l’utilizzo della popolazione del FVG quale standard di riferimento (attesi= 2,56; SIR=9,76;

IC 95% 6,32-14,45) potrebbero risultare sottostimati (Tabella 4).

14

Bibliografia

1. Rothman, K.J., Greenland, S., Lash, T.L., Modern Epidemiology, 3rd Edition. 2008.

2. Breslow, N.E. and N.E. Day, Statistical methods in cancer research. Volume II--The

design and analysis of cohort studies. IARC Sci Publ, 1987(82): p. 1-406.

3. Faggiano F., Donato.F., Barbone F., Manuale di epidemiologia per la sanità

pubblica2005. 338.

4. Choi, B.C., N.A. de Guia, and P. Walsh, Look before you leap: stratify before you

standardize. Am J Epidemiol, 1999. 149(12): p. 1087-96.

5. Corfiati, M., et al., Epidemiological patterns of asbestos exposure and spatial

clusters of incident cases of malignant mesothelioma from the Italian national registry.

BMC Cancer, 2015. 15(1): p. 286.

6. I tumori in Italia - Rapporto AIRTUM 2006: incidenza, mortalità e stime. Epidemiol

Prev 2006; 30(1) suppl 2. URL: http://www.registri-tumori.it/incidenza1998-

2002/rapporto/Schede%20specifiche%20per%20tumore/Mesotelioma.pdf [ultimo accesso:

15/09/2015].

7. Associazione Italiana registri Tumori. Banca dati accessibile presso:

http://itacan.ispo.toscana.it/italian/itacan.htm. [Ultimo accesso: 15/09/2015].

8. Marinaccio, A., et al. Registro Nazionale dei Mesoteliomi, quarto rapporto, Registro

Nazionale dei Mesoteliomi, IV Rapporto. URL:

http://www.inail.it/internet_web/wcm/idc/groups/internet/documents/document/ucm_08581

5.pdf. [Ultimo accesso: 15/09/2015]. 2012.

9. Istituto Nazionale di Statistica, 15° Censimento, 2011. Disponibile presso:

http://dati-censimentopopolazione.istat.it/ [ultimo accesso: 03/11/2014].

10. Haenszel, W., D.B. Loveland, and M.G. Sirken, Lung-cancer mortality as related to

residence and smoking histories. I. White males. J Natl Cancer Inst, 1962. 28: p. 947-

1001.

11. Virta, R.L. Worldwide asbestos supply and consumption trends from 1900 through

2003: U.S. Geological Survey Circular 1298. Available at:

http://pubs.usgs.gov/circ/2006/1298/c1298.pdf. [Ultimo accesso: 03/11/2014]. 2006. 80.

http://itacan.ispo.toscana.it/italian/itacan.htm

15

Tabella 1. Valori minimi, massimi, primo quartile (Q1), mediani, terzo quartile (Q3), range interquartile (IRQ),

medi e relative deviazioni standard dei tassi, età specifici, dei 14 registri utilizzati. Periodo 1995-2007

Table 1. Minimum, maximum , first quartile ( Q1 ) , median , third quartile ( Q3 ) , interquartile range (IQR ) ,

average and relative standard deviations of the age specific rates , of the 14 registers used . Period 1995-

2007

Classi-età Minimi Q1 Mediani Q3 Massimi Medi IQR Dev.st.

0-4 - - - - - - - -

5-9 - - - - - - - -

10-14 - - - - - - - -

15-19 4,8 4,8 4,8 4,8 4,8 4,8 0

20-24 - - - - - - - -

25-29 - - - - - - - -

30-34 2,1 2,5 2,9 5,3 14 5,4 2,8 4,8

35-39 2,4 2,8 3 3,3 5,2 3,2 0,5 0,8

40-44 2,5 3,6 5,8 7,7 15,8 6,4 4,1 3,4

45-49 2,3 3,3 4,45 6,8 15,8 5,3 3,5 2,9

50-54 2,5 3,5 6,35 8 21 6,9 4,5 4,3

55-59 2,3 5,35 7,8 13,25 45,4 10,1 7,9 7,2

60-64 2,8 7,4 13,1 16,9 36,3 13,2 9,5 8,0

65-69 3,7 8,4 14,6 20,7 59,5 17,2 12,3 12,5

70-74 3,2 9,9 16,8 26,5 67,1 20,3 16,6 15,0

75-79 4,3 13,9 22 31,9 98,2 26,0 18 17,1

80-84 2,1 14,2 26,7 40,3 130,7 32,3 26,1 23,7

85+ 1,6 17,9 28,55 39,2 87,4 32,8 21,3 19,8

16

Tabella 2. Distribuzione percentuale dei casi incidenti nei maschi, in Friuli Venezia Giulia nel periodo 1995-2009 e nella coorte di studio nel periodo di

follow-up 1995-2009 (COORTE ASS2)

Table 2. Percentage distribution of incident cases in males, in Friuli Venezia Giulia in the period 1995-2009, and into the cohort (cohort ASS2) during

the follow –up period 1995-2009

RT 1995-2009 COORTE ASS2

Cause ICD-10 Casi incidenti (N) Casi incidenti % Casi incidenti (N) Casi incidenti %

T.M. Bocca C03-C06 621 0,8 4 1,2

T.M. Colon, retto e ano C18-C21 9.203 12,3 46 13,6

T.M. Fegato C22 3.279 4,4 15 4,5

T.M. Pancreas C25 1.967 2,6 10 3,0

T.M. Laringe C32 1.697 2,3 6 1,8

T.M. Polmone e bronchi C33-C34 9.888 13,2 66 19,6

T.M. Esofago C15 1.205 1,6 5 1,5

T.M. Stomaco C16 3.641 4,9 22 6,5

T.M. Prostata C61 15.082 20,2 88 26,1

T.M. Vescica C67, D09.0, D30.3, D41.4 3.340 4,5 8 2,4

T.M. Rene e altri organi urinari C64-C66, C68 2.831 3,8 11 3,3

T.M. Cervello e SNC C70-C72 962 1,3 5 1,5

Linfoma di Hodgking C81 322 0,4 0 0,0

Leucemie C91-C95 1.442 1,9 2 0,6

Mesotelioma C45 691 0,9 30 8,9

Totale casi incidenti 74.672 100,0 337 100,0

17

Tabella3. Casi incidenti osservati (O) ed attesi calcolati applicando come tassi standard rispettivamente: il valore minimo, il primo quartile, la

mediana, il terzo quartile, il valore massimo e la media, disponibili, per anno e classi d’età, nei 14 registri utilizzati con copertura temporale 1995-2007.

Table 3. Incident cases observed (O) and expected as calculated by application respectively, of the minimum value, the first quartile, the median, the

third quartile, the maximum value and the average value of standard rates available, by calendar year and age group, in the 14 registers used with

data coverage from 1995 to 2007.

Casi attesi calcolati applicando:

Anno di Incidenza Anni persona O Minimo Q1 Mediana Q3 Massimo Media

1995 494,89 1 0,01 0,02 0,03 0,05 0,08 0,03

1996 533,58 - 0,01 0,02 0,04 0,06 0,07 0,04

1997 588,80 - 0,02 0,03 0,04 0,06 0,11 0,05

1998 663,09 1 0,02 0,03 0,05 0,09 0,14 0,06

1999 754,99 2 0,03 0,04 0,06 0,09 0,16 0,07

2000 882,55 - 0,03 0,05 0,07 0,14 0,21 0,10

2001 1 082,24 4 0,05 0,07 0,12 0,19 0,28 0,14

2002 1 326,35 1 0,06 0,10 0,16 0,20 0,35 0,17

2003 1 697,83 1 0,07 0,11 0,16 0,25 0,40 0,19

2004 1 969,37 1 0,10 0,15 0,21 0,29 0,60 0,25

2005 2 102,77 5 0,09 0,16 0,28 0,37 0,75 0,31

2006 2 201,07 2 0,09 0,15 0,20 0,37 0,76 0,28

2007 2 207,79 7 0,12 0,17 0,27 0,44 0,77 0,33

1995-2007 16 505,32 25 0,45 1,07 1,77 2,57 7,05 2,05

18

Tabella 4. Casi incidenti osservati (O) ed attesi (A) applicando come tasso standard il valore mediano e quello massimo, rispettivamente, dei 14

registri disponibili e il tasso standard della Regione FVG. Rapporto standardizzato di incidenza (SIR) ed intervalli di confidenza al 95% (IC 95%),

nell’intera coorte e negli impiegati in settore navalmeccanica, per periodo di impiego. Periodo di follow-up 1995-2007

Table 4. Incident cases observed (O) and expected (A) by applying standard rate as the median and maximum values, respectively, of the 14 registers

available and the standard rate of the Friuli Venezia Giulia region. Standardized incidence ratio (SIR) and 95% confidence intervals (IC 95%), of the

whole cohort and by period of hire in shipbuilding. Follow-up period 1995-2007.

Tassi Standard FVG* Mediana

del Tasso Standard

Valore massimo

del Tasso Standard

Coorte Anni persona O A SIR IC95%* A SIR IC95%* A SIR IC95%*

Tutti i settori industriali (n=2,488) 16.505,32 25 2,56 9,76 6,32-14,45 1,77 14,10 9,12-20,87 7,05 3,55 2,29-5,25

Navalmeccanica (n=1,740) 12.085,58 19 1,93 9,84 5,92-15,35 1,33 14,25 8,58-22,23 5,33 3,56 2,14-5,56

Navalmeccanica <74 (n=1370) 8.200,38 18 1,60 11,27 6,68-17,80 1,05 17,19 10,19-27,15 4,26 4,23 2,51-6,68

Navalmeccanica 74-84 (n=234) 1.868,12 0 0,19 - - 0,15 - - 0,59 - -

Navalmeccanica 85-94 (n=136) 1.634,14 1 0,09 10,62 0,27-59,14 0,10 10,48 0,27-58,35 0,35 2,90 0,07-16,13

* Sono stati utilizzati i tassi AIRTUM del Friuli Venezia Giulia. Periodo di follow-up 1995-2007. * Age-specific mortality rates of FVG provided by AIRTUM. Follow-up period: 1995-2007.

Tabella Supplementare 1. Disponibilità dei Registri Tumori in Italia, per periodo.

Supplemental Table 1. Availability of cancer registries in Italy, by the period.

N. REGISTRO TUMORE DISPONIBILITA'

1. Varese* 1976/2009

2. Parma* 1978/2011

3. Ragusa 1981/2007

4. Torino 1985/2008

5. Genova 1986/2007

6. Romagna 1986/2008

7. Modena* 1988/2010

8. Latina* 1990/2009

9. Ferrara 1991/2008

10. Sassari* 1992/2009

11. Umbria* 1994/2009

12. Biella 1995/2007

13. Friuli Venezia Giulia 1995/2007

14. Alto Adige 1995/2007

15. Firenze Prato 1985/2005

16. Veneto 1987/2006

17. Macerata 1991/2001

18. Trento 1995/2006

19. Napoli* 1996/2009

20. Reggio Emilia* 1996/2009

21. Salerno* 1996/2009

22. Sondrio 1998/2010

23. Brescia 1999/2006

24. Milano 1999/2006

25. Siracusa 1999/2007

26. Mantova 1999/2010

27. Trapani 2002/2007

28. Lecce 2003/2005

29. Catanzaro 2003/2007

30. Palermo 2003/2007

31. Catania/Messina 2003/2008

32. Como 2003/2008

33. Nuoro 2003/2008

34. Cremona 2005/2009

35. Taranto 2006/2008

36. Piacenza 2006/2010

37. Bergamo 2007/2009

38. Milano 1 2007/2009

*Pool 9 registri

Tabella supplementare 2. Tassi minimo e massimo, per anno di calendario e classe d’età. Periodo

1995-2007.

Supplemental Table 2. Minimum and maximum rates, per calendar year and age group. Period 1995-

2007.

Classi d’età per anno Min Max Registro valore min Registro valore max

1995

00-04 - - - -

05-09 - - - -

10-14 - - - -

15-19 - - - -

20-24 - - - -

25-29 - - - -

30-34 2.8 2.8 GENOVA GENOVA

35-39 3.0 3.0 TORINO TORINO

40-44 2.5 11.4 FRIULI VENEZIA GIULIA RAGUSA


50-54 3.3 12.5 TORINO FRIULI VENEZIA GIULIA

55-59 3.0 36.7 TORINO GENOVA

60-64 3.4 23.1 ROMAGNA GENOVA



75-79 8.5 35.3 UMBRIA FRIULI VENEZIA GIULIA

80-84 8.7 100.3 ROMAGNA BIELLA

85+ 28.4 33.4 MODENA PARMA

1996

00-04 - - - -

05-09 - - - -

10-14 - - - -

15-19 - - - -

20-24 - - - -

25-29 - - - -

30-34 - - - -

35-39 - - - -

40-44 4.7 10.3 MODENA GENOVA

45-49 2.3 6.2 FRIULI VENEZIA GIULIA GENOVA

50-54 3.3 17.1 TORINO BIELLA


60-64 4.1 18.0 UMBRIA SASSARI

65-69 4.1 20.7 UMBRIA GENOVA


75-79 7.5 50.7 UMBRIA / ROMAGNA ALTO ADIGE

80-84 19.9 62.7 PARMA GENOVA

85+ 14.3 79.8 GENOVA FRIULI VENEZIA GIULIA

<CONTINUA>

<CONTINUA>


1997

00-04 - - - -

05-09 - - - -

10-14 - - - -

15-19 - - - -

20-24 - - - -

25-29 - - - -

30-34 - - - -

35-39 2.9 3.3 TORINO VARESE

40-44 2.5 15.8 FRIULI VENEZIA GIULIA BIELLA

45-49 2.4 3.5 FRIULI VENEZIA GIULIA UMBRIA

50-54 3.2 16.3 TORINO / ROMAGNA GENOVA


60-64 4.4 17.0 VARESE FERRARA

65-69 9.1 45.1 LATINA GENOVA


75-79 15.8 57.4 FERRARA GENOVA


85+ 12.3 27.9 FRIULI VENEZIA GIULIA VARESE

1998

00-04 - - - -

05-09 - - - -

10-14 - - - -

15-19 - - - -

20-24 - - - -

25-29 - - - -

30-34 - - - -

35-39 - - - -

40-44 3.6 7.5 VARESE PARMA

45-49 5.0 5.0 FRIULI VENEZIA GIULIA FRIULI VENEZIA GIULIA



60-64 2.8 17.4 FRIULI VENEZIA GIULIA VARESE



75-79 18.3 37.7 MODENA ALTO ADIGE


85+ 11.7 37.5 FRIULI VENEZIA GIULIA FERRARA

<CONTINUA>

<CONTINUA>


1999

00-04 - - - -

05-09 - - - -

10-14 - - - -

15-19 - - - -

20-24 - - - -

25-29 - - - -

30-34 2.9 2.9 GENOVA GENOVA

35-39 2.6 2.6 ROMAGNA ROMAGNA

40-44 3.5 3.5 VARESE VARESE

45-49 3.4 5.0 GENOVA FRIULI VENEZIA GIULIA

50-54 4.6 15.8 MODENA / FRIULI VENEZIA

GIULIA

GENOVA


60-64 5.4 17.0 MODENA FERRARA





85+ 11.8 67.2 ROMAGNA FRIULI VENEZIA GIULIA

2000

00-04 - - - -

05-09 - - - -

10-14 - - - -

15-19 - - - -

20-24 - - - -

25-29 - - - -



40-44 3.2 10.4 GENOVA RAGUSA

45-49 3.2 8.0 ROMAGNA PARMA

50-54 3.0 11.2 ROMAGNA FRIULI VENEZIA GIULIA


60-64 3.2 35.9 TORINO / ROMAGNA GENOVA


70-74 4.1 44.7 ROMAGNA VARESE



85+ 17.0 77.4 TORINO FRIULI VENEZIA GIULIA

<CONTINUA>

<CONTINUA>


2001

00-04 - - - -

05-09 - - - -

10-14 - - - -


20-24 - - - -

25-29 - - - -



40-44 5.8 7.8 LATINA FERRARA





65-69 6.0 42.1 MODENA FRIULI VENEZIA GIULIA


75-79 5.5 54.1 UMBRIA FERRARA

80-84 10.2 43.8 ROMAGNA RAGUSA

85+ 8.2 84.4 FRIULI VENEZIA GIULIA GENOVA

2002

00-04 - - - -

05-09 - - - -

10-14 - - - -

15-19 - - - -

20-24 - - - -

25-29 - - - -

30-34 - - - -


40-44 5.5 7.7 SASSARI FERRARA









85+ 18.0 74.9 TORINO FERRARA

<CONTINUA>

<CONTINUA>


2003

00-04 - - - -

05-09 - - - -

10-14 - - - -

15-19 - - - -

20-24 - - - -

25-29 - - - -

30-34 - - - -

35-39 5.2 5.2 SASSARI SASSARI

40-44 5.1 5.1 ALTO ADIGE ALTO ADIGE

45-49 2.4 7.2 FRIULI VENEZIA GIULIA UMBRIA

50-54 2.8 8.5 ROMAGNA FERRARA


60-64 3.9 23.6 VARESE GENOVA


70-74 4.3 41.7 TORINO BIELLA

75-79 12.3 31.8 TORINO / PARMA GENOVA


85+ 23.5 52.2 VARESE FRIULI VENEZIA GIULIA

2004

00-04 - - - -

05-09 - - - -

10-14 - - - -

15-19 - - - -

20-24 - - - -

25-29 - - - -

30-34 14.0 14.0 BIELLA BIELLA

35-39 - - - -

40-44 - - - -




60-64 5.5 36.3 MODENA FERRARA


70-74 11.1 48.3 SASSARI GENOVA



85+ 39.1 40.1 FERRARA GENOVA

<CONTINUA>

<CONTINUA>


2005

00-04 - - - -

05-09 - - - -

10-14 - - - -

15-19 - - - -

20-24 - - - -

25-29 - - - -


35-39 - - - -

40-44 4.0 4.0 FRIULI VENEZIA GIULIA FRIULI VENEZIA GIULIA

45-49 2.3 6.8 FRIULI VENEZIA GIULIA PARMA





70-74 9.2 61.3 UMBRIA FERRARA


80-84 19.0 84.0 FERRARA LATINA

85+ 10.5 53.8 ROMAGNA GENOVA

2006

00-04 - - - -

05-09 - - - -

10-14 - - - -

15-19 - - - -

20-24 - - - -

25-29 - - - -

30-34 3.1 3.1 UMBRIA UMBRIA

35-39 - - - -

40-44 - - - -

45-49 2.3 5.5 FRIULI VENEZIA GIULIA ALTO ADIGE

50-54 2.5 7.4 FRIULI VENEZIA GIULIA VARESE

55-59 3.5 16.8 VARESE FRIULI VENEZIA GIULIA

60-64 5.5 28.0 MODENA RAGUSA





85+ 1.6 87.4 FRIULI VENEZIA GIULIA GENOVA

<CONTINUA>

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