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mesothelioma cases
Mesothelioma: cases associated with
non-occupational and low dose exposures
Gunnar HillerdalAbstract
Objectives—To estimate the importance
of low dose exposure to asbestos on the
risk of mesothelioma.
Methods—A review of the literature.
Results and conclusions—There is no evidence
of a threshold level below which
there is no risk of mesothelioma. Low level
exposure more often than not contains
peak concentrations which can be very
high for short periods. There might exist a
background level of mesothelioma occurring
in the abscence of exposure ot asbestos,
but there is no proof of this and this
“natural level” is probably much lower
than the 1–2/million/year which has been
often cited.
(Occup Environ Med 1999;56:505–513)
Keywords: low exposure; asbestos; mesothelioma
Mesothelioma is an incurable disease which is
almost exclusively due to inhalation of asbestos
fibres. Asbestos has been extensively used in
industry and construction in the 20th century,
especially during and after the second world
war, and even if the mineral is no longer used in
most rich western countries the total world
production remains high. There is a worldwide
pollution with asbestos, as indicated by the
finding of the mineral in samples of Greenland
ice1 and on the Yorkshire Moors,2 and every
citizen in the world has been exposed to some
extent. Consequently, asbestos fibres can be
found in most lungs at necropsy.3 It is thus
understandable that there is concern about the
risk of mesothelioma for the general population.
However, it should be remembered that
mesothelioma is a rare disease with incidence
in industrialised countries ranging from 1 to
5/million/year among women and values fo
men 5–10 times higher (see table 3). Even in cohorts with a very heavy exposure to asbestos most people will die from other causes. In people with certified asbestosis—that is, with a heavy exposure—up to 10% will develop mesothelioma; among insulators in the United States and Canada, also a heavily exposed group, 9.3% of the deaths have been due to this disease; and in amphibole miners in South Africa or Australia, this figure is 2–4% (table 1). Clearly, with exposure concentrations several magnitudes lower, as occurs in the general population, the risk is very small, often impossible to measure. A discussion of the risks from low exposure must include the dose-response curve; the existence or non-existence of a threshold, and thus a background concentration; and should try to define low exposure and estimate to what degree that really means a low concentration. From conflicting findings and opinions attempts must be made to make a meaningful conclusion.
The diVerent types of asbestos seem to differ considerably in their ability to cause mesotheliomas. Chrysotile is considered by many authors to be a weak carcinogen in humans,11 whereas the two amphiboles crocidolite and tremolite are much more dangerous according to many studies.12 The third of the more important amphiboles, anthophyllite, was long considered not to cause mesothelioma, but such tumours have now been reported although the risk seems to be small.13 There is, none the less, a minority opinion that chrysotile is in fact responsible for most of the pleural mesotheliomas in society14 or should at least be considered to carry the same risk.15 This discussion, however, falls outside the present review and is not important for the conclusions drawn here. Definition and diagnosis of mesothelioma Mesotheliomas are, by definition, tumours that arise from mesothelial cells and can thus arise from any body cavity: the pleura, the peritoneum, the pericardial sac, and even the tunica vaginalis testis. Pleural mesotheliomas are the most common and pathologically the best defined ones. Pleural mesotheliomas have a male to female rate of about five to one, whereas for peritoneal tumours this ratio is 1.5 to 1.16 Thus, either the aetiology is diVerent, the
diagnosis is more diYcult in women, or women exposed to asbestos are more likely to develop a peritoneal than a pleural mesothelioma. In fact, one type of mesothelioma occurring almost exclusively in women is the so called multicystic mesothelioma. This tumour has a better prognosis, is more sensitive to cytostatic drugs, and seems to have no connection with exposure to asbestos.17 The pathological diagnosis of mesotheliomas requires experience, and confusion can occur with both benign pleural lesions and with metastatic pleural diseases.18 Many countries now have “mesothelioma panels”, which has meant a great improvement in the diagnosis. In most national cancer registries, most likely both overdiagnosis and underdiagnosis occur. Suggested causes of mesothelioma other than mineral fibres Apart from mineral fibres, radiation (for example, through the contrast medium Thorotrast) has been suggested to cause human mesothelioma. However, in a large retrospective study of more than 250 000 women treated for mammary carcinoma, a quarter of them initially with radiotherapy, no association between radiation and mesothelioma could be found.22 As can be seen from table 2, other causes or contributing factors have also been suggested. Viruses can cause mesotheliomas in animals, but this has not been described in humans.
DNA sequences associated with Simian virus 40 (SV 40) transforming factors have been reported in a high proportion of mesotheliomas from some countries.32 This suggests that there is a connection between SV40, which was a contaminant of live polio vaccines in 1959–61, and later development of mesothelioma. Thus, SV 40 might be a cofactor to asbestos in some patients with mesothelioma , but the results have not been confirmed and are still disputed. In summary, then, as far as is known today, factors other than mineral fibres can only explain a very small proportion of mesotheliomas, and can for practical purposes be disregarded. Thus, a malignant mesothelioma can be regarded either as caused by asbestos or belonging to a normal background level—that is a spontaneously occurring tumour. The relative imnportance of these two factors has been debated and will be further explored in this review. Incidence of mesothelioma There is a large variation in the incidence of mesothelioma in diVerent countries and in most places a steadily rising number of cases with time. In table 3, the incidence or mortality from mesotheliomas in diVerent countries at various times can be seen. As mortality for practical puprposes is the same as the incidence for this disease, both figures have been used in the table. Some of the diVerences between the countries are probably due to diagnostic diYculties, but most of the variations can be explained by the use of asbestos in the particular society some decades earlier.
Dose-response and latency time Most researchers agree that there is a positive dose-response curve for mesothelioma—the heavier the exposure to asbestos, the greater the risk. This is found in cohort studies as well as in analyses of amphibole asbestos fibres in the lungs.45–48 It was realised early that time since first exposure was of great importance, and therefore the “cubic residence-time model” was suggested by Doll and Peto in their report in 198549: I (T) = c × F × (T4−(T−D)4 Where, I (T)=incidence at the time T after exposure; c=a constant depending on the process, F=intensity of exposure, and D=duration of exposure. This equation has been used in many studies with an acceptable fit for normal occupational exposure concentrations . F in the equation is the total exposure—a combination of fibre concentrations and exposure time—usually measured in fibre-years. (1 fibre-year = a mean of 1 fibre/ml air for 1 working year). Thus, the doseresponse curve is supposed to be linear, but the result is heavily influenced by the time factor. Unfortunately, the exact value of F is often uncertain, even in well defined highly exposed cohorts. The equation is thus rarely useful especially with low doses, in which F is usually a crude guess only. As can be seen from table 1, even with heavy exposure only up to 10% of a cohort will die from mesothelioma—so the formula is not applicable in these cases either. With very heavy exposure, most patients will die from pulmonary insuYciency due to asbestosis before there has been suYcient time to develop a mesothelioma. Even more troublesome is the time factor T, which quickly becomes very important in this equation. If the equation is correct, the risk
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