MESOTHELIOMA IN EUROPE

In 1991, Wagner introduced the Mesothelioma Conference in Paris with an historical
review, from the 1870s to the 1930s, when European and American pathologists were
discussing the exact origin and nature of the so-called primary neoplasms of the pleura.
Mesothelioma as a real pathologic entity
Klemperer and Rabin used the word ‘mesothelioma’ for the first time in 1931.In this
early period, the biphasic pattern of this tumour, epithelial and mesenchymatous, had
been demonstrated by different pathologists.Thereafter, we have to wait until the
1950s to find case reports of ‘primary diffuse pleural mesotheliomas’ described by
different authors in Europe and in North America.
Finally, in the 1960s, the pioneer work of European and North American pathologists
reached a consensus for considering that diffuse malignant mesothelioma, located
mainly in the pleura and less frequently in the peritoneum, was a primary neoplasm
arising from the pluripotential mesothelial cells. The pathological diagnosis of mesothelioma
appeared difficult, so that, in most serious epidemiological studies, the diagnosis
was ascertained by a panel of national or supranational expert pathologists.At present,
most European countries have a mesothelioma panel of trained pathologists.
Discovery of the relationship with asbestos exposure
Another major step in the history of mesothelioma was the studies which demonstrated
that asbestos exposure was a strong causal factor for the development of this
malignant tumour. In fact, it took about 30 years for this to be demonstrated! While a
case of mesothelioma associated with asbestos exposure was published in 1943 by
Wedler in Germany, this tumour was very rare in Europe and North America, so its
relationship with asbestos exposure was not identified in industry, possibly in relation with the growth of asbestos uses. By contrast the
tumour was rare in females. Actually, the year 1960 is of historical note as, 5 years after
the publication by Richard Doll10 demonstrating the link between lung cancer and occupational
exposure to asbestos, Wagner et al. reported 33 cases of MM in Northwest Cape
(South Africa) among crocidolite miners and their family contacts. Thus, the causal
relationship between mesothelioma and exposure to asbestos was demonstrated. Five
years later in France, Turiaf et al. reported the first case of pleural mesothelioma in a 54-
year-old man with a 30-year history of occupational exposure to asbestos.
Incidence of malignant mesothelioma (MM)
As mesothelioma, whatever its two main locations (pleura and peritoneum), represents
a severe disease, highly related to asbestos exposure, all industrialised countries
are presently concerned with the evaluation of the true incidence of this cancer and its
relationships with the different types of asbestos exposure. This section will cover the
incidence of mesothelioma in European countries and the role played by accurate
registration of cases for assessing this fundamental parameter.
Incidence in industrialised countries
In industrialised countries, data on mortality from mesothelioma can be obtained from
death certificates and incidence rates from cancer registries. Actually, the problem is
to know the accuracy of mesothelioma cases registration.
As recently as the 1970s, in order to establish the incidence of this malignancy
and its causal relationships, several industrialised countries decided to collect data on
pleural and peritoneal cases for the whole country (United Kingdom, Scandinavian
countries) or only for some specific areas (USA, Canada). From these studies, the
‘background’ level of mesothelioma incidence could be estimated at around 1 to 2 per
million per year in industrialised countries
Incidence rates vary in different countries, apparently in relation with tonnages
and types of asbestos production and/or consumption: 28.3 cases per million among
males in Australia14 and 33 per million in South Africa, both countries being producers
of crocidolite and amosite. In European countries, various incidence rates have
been observed: for instance, the mortality rate in males was reported to be 17.5 per
million in Great Britain16 and 20.9 per million in the Netherlands.
During the past 30 to 40 years, most industrialised countries (e.g., North America,
Europe, Australia) have observed an increase in the annual incidence of MM (at about
7% to 10% per annum), with an obvious predominance among males. Such trends suggested
the causal role of specific occupational asbestos exposures (particularly to amphiboles),
no other causes having been identified in this early period, but possibly also
in relation to a real improvement in diagnosis and registration of this rare type of cancer.
In the 1960s, definite mesothelioma cases showed a marked clustering in areas
where there was substantial industrial use of asbestos. Thus, in the USA, Connelly et

al. observed that the highest rate was in shipyard areas (Seattle, San Francisco, Hawaii).
 However, from the mesothelioma register in Great Britain, Peto et al. found
that mesothelioma deaths were still increasing and will continue for at least 15 to 25
years. As the deceased’s job (probably the last one) was mentioned on United Kingdom
death certificates, the authors could calculate the trend of mesothelioma in different
jobs; workers in construction and maintenance of buildings containing asbestos
accounted for the largest proportion of these deaths. This important finding stresses
the usefulness of a nationwide mesothelioma register as the most relevant tool for the
surveillance of possible risks of malignancy related to low-dose asbestos exposures, for
instance in asbestos-containing buildings.
As a definite diagnosis of MM is difficult to establish with certitude, requiring
the opinion of trained clinicians and pathologists, it is probable that estimates
from death certificates do not match those obtained from cancer registries. It is probable
that presently this tumour is underreported, although the reverse is also possible!
Thus, for the period 1967–68, 413 cases from England, Wales and Scotland
were notified as mesothelioma to the national register. After revision of the slides by
the British panel of pathologists, 246 cases were accepted as definite and 76 cases as
definitely not mesothelioma. Such discrepancies have been reported from other
industrialised countries where both registry-based incidence data and mortality data
were available. In their review, Iwatsubo et al. have shown that, for different studies,
variations in the percentage of pathologically confirmed diagnosis of mesothelioma
ranged from 26% to 96%

Incidence of mesothelioma in Europe from case registration
The background level of mesothelioma was assumed to be as low as 1 to 2 per million
inhabitants, but since the 1950s, this incidence has been increasing in the general
population of most industrialised countries.
Since mesothelioma is usually a rapidly fatal malignancy, mortality rates based on
the underlying cause of death, as recorded on death certificates, have often been used as a
close approximation of incidence rates. But large discrepancies have been observed in some
cases,19 so that we should distinguish the studies according to the origins of the data:
either mesothelioma registries, general cancer registries or death certificates.
In non-asbestos-producing European countries, it appears that an accurate evaluation
of the true incidence of mesothelioma cases and their causal relationships was
the best epidemiological tool for assessing the types (amphiboles versus chrysotile) of
imported asbestos and determining the cumulated tonnes of past exposures. Nevertheless,
this aim had some limitations, as only a limited number of European countries
(Scandinavian countries, United Kingdom) decided early in the 1970s to register
all pleural and peritoneal mesotheliomas cases.
In the United Kingdom, a mesothelioma register was set up in 1967.Mesothelioma
cases were identified from the death certificates mentioning ‘pleural or peritoneal
mesothelioma’, information provided by registrations from the Cancer Bureaux,
the Pneumoconiosis Panel and also from chest physicians, surgeons, pathologists and

to the UICC Panel of Pathologists. For the year 1967–68, 412 cases were notified to
the register, of which 245 were considered as definite mesothelioma, leading to a rate
of 2.29/million/year for England, Wales and Scotland.
Gardner et al. examined the time trend of mortality by pleural cancer, i.e., death
coded into the category 163 of the ICD, 9th revision, in England and Wales for the
period 1968–78 from the death records (Office of Population Censuses and Surveys).27
For the entire period, the mortality rate by pleural cancer was 5 per million in men
and 2 per million in women.
A later publication of the mesothelioma register concerning the period 1968–
8316 showed an increase of about 10% in men. The mesothelioma mortality in 1983
was 17.5 per million in men and 3.2 per million in women.
In the Netherlands, Meijers et al. examined the mortality trend of pleural malignancies
between 1970 and 1987.17 The coded underlying cause of death was provided from the
Dutch Central Bureau of Statistics. In men, the average pleural cancer mortality increased
from 10.7 per million for the period 1970–78 to 20.9 per million for the period 1979–87. In
women, these rates were, respectively, 2.5 per million and 3.6 per million.
In Scandinavian countries (Finland, Sweden, Denmark, Norway), the existence
of a national cancer register of all deaths from cancer facilitated the task of
examining the time trend of cancer incidence.
In Finland, a nationwide Finnish Cancer Registry was established in the 1950s.
This Cancer Registry allowed Karjalainen et al. to study the trend of mesothelioma incidence
in Finland between 1960 and 1995.29 In that country, anthophyllite asbestos was
produced and widely used from 1918 to 1975. The age-adjusted incidence of mesothelioma
was under 1 per million in both sexes around 1960, and then rose steeply in 1975–
90. In 1990–94, the age adjusted incidence of mesothelioma was 10 per million in men
and 2.9 per million in women. The overall pattern of mesothelioma seems to be stable in
the very recent period. This plateauing could be related to a significant decrease in the
use of amphiboles. Nevertheless, it seems that the mesothelioma risk related to
anthophyllite asbestos is low,30 but crocidolite was also used from the late 1960s.
In Sweden, Järvholm et al. studied the incidence of pleural mesothelioma between
1958 and 1995 with respect to preventive measures taken to reduce occupational
exposure to asbestos. There were about 10 cases of pleural mesothelioma in
men and no case in women in 1958. In 1995, 92 cases in men and 15 in women were
observed. An increasing incidence was found in recent birth cohorts in men.
In Denmark, Andersson and Olsen described the time trend and the distribution
of MM since 1942. The registration to the National Cancer Registry was based
on reports from hospital departments, pathology institutes, notifications from practising
physicians and death certificates. For the entire period, the authors observed a
regular increase in both sexes. The incidence rates for the latest period, 1978–80,
were 14.7 per million in men and 7 per million in women.
In Norway, Mowé et al. examined the time trends of mesothelioma incidence
between 1960 and 1988.34 The investigation was based on data from the Cancer Registry

of Norway to which all new cases of cancer are reported from hospitals and pathology
departments. The age-adjusted incidence of mesothelioma increased during the observed
period in men: 4 per million for 1960–69 to 13 per million for 1980–87. In women, mesothelioma
incidence remained at the same level, 1 per million, during the whole period.
In several other European countries (France, Germany, Italy), up to now, case
registration was limited to some specific areas.
In France, all data obtained from death certificates are collected by the Service
Commun N°8 (SC8) of Institut National de la Santé et de la Recherche Médicale
(INSERM). Since 1968, information on the underlying medical causes of death mentioned
by the practitioners on death certificates has been coded by INSERM SC8 according
to the International Classification of Diseases (ICD 8 or 9). The numbers of deaths due to
pleural malignancies were those classified in category 163 of the ICD 8 (i.e., malignant
neoplasm of pleura, stated or presumed to be primary) and category 158 of the ICD 9
(i.e., malignant neoplasm of peritoneum, stated or presumed to be primary).
A ‘registration’ of mesothelioma cases was set up in 1975. Actually, as death
certificates were totally confidential, MM cases could only be collected through pathologists
and clinicians. Thus, this ‘register’ was mainly made up of a panel of French pathologists
(still working) trained to confirm the diagnosis of mesothelioma, eventually
with the contribution of the EEC mesothelioma panel. From the death certificates, for
the period 1968–92, the mortality with mention of pleural malignancies increased from
8.2 per million to 22.5 per million in men and 4.7 per million to 9.2 per million in women.
The average increase during this period was 4.3% in men and 2.8% in women.
In such conditions, the French ‘register’ was not able to provide valid information
on the true incidence of MM. In January 1987, the mesothelioma panel interrupted
its random case collection on a national basis, to conduct a case-control study
in 5 regions of France, with a double objective: evaluation of the dose–response for
different occupational exposures and, eventually, identification of other asbestos-related
jobs (cf. below).
Recently, Ménegoz et al. (Réseau France CIM) examined the trend of mesothelioma
incidence from data obtained by 7 departmental registries for the period 1979–
93.37 These registries cover about 9.5% of the French population. For the entire period,
the increase was 25% over 3 years. In men, the incidence increased from 7 per million/
year for the period 1979–81 to 16 per million/year for 1991–93.
The progression of MM in France was estimated at around 7 to 8% per year. It
is worth comparing these data to the trend observed in the UK, the national register
of this country indicating a mesothelioma rate about three times higher than F rance.
This difference correlates with a much lower consumption of amphiboles in France
than in the UK

Relationship of mesothelioma to asbestos
exposure
As underlined by Howell et al., there are several routes of exposure to asbestos fibres:
occupational, paraoccupational (domestic contamination from asbestos workers), residential
contamination near dusty industrial sources, incidental, related contact with
asbestos products for domestic uses or hobbies, and general environmental exposure
from asbestos sediments at the surface of soil.
Occupational exposures
In Europe, most mesothelioma cases are related to asbestos exposures in occupational
activities in various industries, some of them not apparent. However, staff
in two industries were particularly exposed to asbestos dusts: shipyard workers
and construction workers.
The excess number of mesothelioma cases in coastal areas of European countries
is consistent with shipyard-related exposures (workers involved in shipbuilding
and repair). The situation applied in the Scandinavian countries (Sweden, Norway,
Finland, Denmark), The Netherlands, the United Kingdom, the Loire–Atlantique
and Normandy areas of France,and the Province of Trieste in Italy.
On the other hand, recently, Peto et al. identified from the UK mesothelioma
register an excess of mesothelioma in workers involved in construction and building
maintenance, particularly plumbers, gas fitters, carpenters and electricians, who appeared
as the largest high-risk group.

Dose–response relationships
Several authors, when evaluating cohort studies and case-control studies focusing
on mesothelioma, have reported a dose–response relationship.
Jones et al. examined the occurrence of respiratory malignancies among workers
in a gas-mask factory in the UK. The production of gas masks lasted 4.5 years from
September 1940. Crocidolite as well as chrysotile was used in production. A total of
951 women were known to have worked in this job. Up to the end of 1978, 17 cases of
mesothelioma were observed,  in those exposed to crocidolite only and one in those
exposed to both crocidolite and chrysotile. Among the 16 cases exposed to crocidolite
only, a dose–response relationship was observed with duration of exposure.
Raffn et al. studied the incidence of cancer and the mortality among employees
in the asbestos cement industry in Denmark for the period 1943–84.53 Subjects included
were those exposed between 1928 and 1984. The estimated exposure levels
varied greatly during the study period: in 1948, between 50 and 800 fibres per millilitre
(f/mL); in 1957, between 10 and 100 f/mL; in 1973, 41% of the measurements were
above 2 f/mL. Among the 7996 men and 517 women studied, 10 pleural mesotheliomas
were observed. The incidence of pleural mesothelioma increased with the duration
of exposure among subjects with 15 years or more of latency (SIR=3.77 for less
than 5 years of exposure versus 13.56 for more than 5 years of exposure).
Peto et al. observed that the risk of mesothelioma in an occupationally exposed
cohort (north American insulators) was best described by a mathematical model in which
the risk increases with the third or fourth power of time since first exposure;20 their data
were compatible with a linear dose–response relationship. Peto et al. found also this type of
relationship when considering the mortality of subjects (men and women) employed at the
Rochdale asbestos textile factory. A total of 18 mesothelioma cases in men (7 in the first
group and 11 in the third group ) were observed during the study period. Despite the small
number of deaths observed (10 occurred in the main cohort), the observed and predicted
numbers were in reasonable agreement for different times since first exposure.
Newhouse et al. studied the mortality of asbestos factory workers (asbestos textiles
and others asbestos products such as asbestos cement) in east London. The population
concerned 3000 male factory workers, 1400 laggers and 700 women factory workers. The
men were first exposed between 1933 and 1964 and the women between 1936 and 1942.
Crocidolite asbestos as well as amosite and chrysotile was used in the factory. Exposure
to asbestos was classified into 4 categories according to degree (light or moderate versus
severe) and duration (<2 years versus 􀀵 2 years). During the study period, 38 pleural
and 35 peritoneal mesotheliomas were observed in men and 14 pleural and 11 peritoneal
mesotheliomas in women. Among factory workers, the mesothelioma death rates
increased according to both duration and severity of asbestos exposure.

Environmental and neighbourhood exposure to asbestos
It seems likely that mesothelioma may arise from domestic and environmental exposures,
either natural or para-occupational. This is of concern particularly among family
members of asbestos workers but also in the general population who inhale fibres
in the vicinity of asbestos plants.
In the mesothelioma series of the London area published by Newhouse and
Thompson, there were 25 cases without evidence of any exposure to asbestos. Among
them, 11 cases used to live within 800 metres of an asbestos factory, a number significantly
greater than among a control group of patients without mesothelioma. However,
at that early time, the authors seemed to be reluctant to accept this relationship,
waiting for more evidence in the future.
Subsequently, the same kinds of observation have been made in other European
countries: in Finland, in relation with dwelling in the vicinity of an anthophyllite mine;
and in north-western Italy, where an increased incidence of histologically confirmed
mesothelioma was reported in the vicinity of a large asbestos cement factory at Casale
Monferrato, in operation from 1907 to 1985.
Endemic cases of mesothelioma have been also observed in rural areas in several
European countries, Metsovo in Greece61 and Corsica in France, and also, far from
Europe, New Caledonia, with a high incidence of mesothelioma, particularly in rural
areas. The asbestos fibres concerned are mainly of the tremolite type, except in Finland,
where anthophyllite was invoved. Those cases are related to outdoor and indoor
contamination from environmental geologic sources of asbestos dusts.
Mesothelioma cases related to indoor exposures are well known, particularly among
family members of asbestos workers coming home with contaminated clothes. This issue
might also be relevant to indoor contamination by fibres in buildings with asbestos
containing materials, fibres being eventually released at very low concentrations (0.001–
0.0001 f/mL of air). Presently, there is no sufficiently large epidemiological survey to
confirm such a relationship. We must refer with caution to the mathematical projections
published in the two documents: HEI-AR, 1991 and INSERM, 1997

Role of fibre types
Numerous epidemiological studies, discussed at length in HEI-AR, have compared
the incidence of lung cancer and mesothelioma in various situations. Moreover, the
ratio of mesothelioma/lung cancer numbers has been compared according to fibre
types. However, the observed discrepancies between cohorts may be due to the fact
that it was retrospectively difficult to know exactly what types of asbestos have been
used in these plants

What about the future?
Prediction of mortality from mesothelioma
A major concern in public health is to know the trend of the incidence rate of mesothelioma:
is it decreasing, stable or increasing? What about the evolution in the next 20 years?
Recently, three publications have provided estimates of the mortality from mesothelioma
in both sexes which can be predicted in the next few years.
In 1995, Peto et al., analysing the data from the British Mesothelioma Register,
forecast a peak of deaths in 2020.21 They estimated the total size of the 1996–2020
epidemic of deaths due to mesothelioma in males as 62 000 (which extrapolates to 166
males per million male inhabitants of Britain).
In 1997 Price, analysing current trends of mesothelioma incidence in the USA,81
concluded that the peak of mesothelioma was just going to appear (1997) and that the
projected number of future mesothelioma cases suggests a peak in the annual number
of cases at 2300 for males, before the year 2000. Then, the number of male cases will
drop during the next 50–60 years toward 500.
In 1998, from the available data in France, Gilg Soit Ilg et al. predicted that the
nationwide peak will occur between 2020 and 2060, and, for men, the total size of the
epidemic will be 20 000 over the period 1998–2020, which extrapolates to 43 per million.22
Such studies are important, because it is the death toll which predominantly
builds the perception of the risk in the general population. They are necessarily based
on the past and present mortality data.