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General observations on induction of mesothelioma by asbestos, especially the amphibole varieties of asbestos such as crocidolite and amosite
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- The dose-response relationship between the amphiboles and mixtures of asbestos types is linear at high exposures [15]
- Properties of asbestos fibres that determine carcinogenicity
General observations on induction of mesothelioma by asbestos, especially the amphibole varieties of asbestos such as crocidolite and amositeThe linkage between the amphibole varieties of asbestos, and commercial chrysotile, and the subsequent development of malignant mesothelioma is well established and is not in dispute.This link is generally accepted as causal; in this respect, asbestos fulfils all The Bradford Hill Criteria for the establishment of causality [44]. There is a dose-response relationship between cumulative exposure to asbestos and the subsequent incidence of mesothelioma in asbestos-exposed cohorts or populations; the incidence is also related to time since exposure, so that early exposures are more significant for mesothelioma induction than later exposures, other factors being equal.This relationship is expressed by the Peto model and its various modifications: I = K*F*(Tp – [T – D]p) where I = incidence; K depends on fibre type, mix, size and other site-specific variables; F = intensity of exposure in f/ml; and D = years of exposure. For the purposes of modelling, T can be replaced by (T – 10) to build in a minimum 10-year lag-time, and the cubic power of time (T3) is often used, so that: I = K*F*([T – 10]3 – [T – 10 – D]3) An important aspect of this model is that early exposures are more significant for mesothelioma induction than later equivalent doses. Of the variables D, F and K, it is D that is the most accurately measurable, whereas the values for K and F are often unknown, though some estimates of F can be made from the type of work activity. When there are multiple periods of employment for which the type of work is similar for each, one can assume that the value for each of F1, F2, F3 ... Fn remains constant, which also applies to K1, K2, K3 ... Kn, so that: I ([T – 10]3 – [T – 10 – D]3) In practice, a simpler equation can be used: I = ctk where the constant c is dependent on exposure, usually taken as proportional to the intensity of exposure multiplied by its duration (i.e. cumulative exposure), with weightings for different fibre types; the power k remains about 3.5, or 3 for short periods of exposure. As de Klerk and Armstrong [135] state: "The model predicts that risk is increased after each increment of exposure by an amount proportional to the level of exposure and the cube of time after that. In terms of the multistage model of cancer, it implies that asbestos acts at the first stage of a 4-stage process. ... The model predicts that incidence is much more dependent on early or low levels of exposure and increases less rapidly as exposure continues to increase, depending mainly on time since first exposed." [p 232]. When one is faced with multiple exposures to asbestos, the following points emerge, specifically for mesothelioma induction, provided that the characteristics and time for each exposure are appropriate for a biological effect: (i) it is not valid to point to one exposure among the others and incriminate it as the sole cause of a mesothelioma, with exoneration of the other exposures; (ii) it is not valid to point to one exposure among the others and exonerate it from a causative role in the development of a mesothelioma, and to incriminate all the others; (iii) when there are multiple episodes of exposure as a background to a mesothelioma, it is often the case that each exposure in isolation would be sufficient for attribution of the mesothelioma to asbestos, with the provisos mentioned above (characteristics and times of exposures). When each exposure among others is appropriate for mesothelioma induction if the particular exposure occurred alone, it is not logical to state that this exposure — which could have a biological effect in isolation — has no effect when in combination. In such circumstances, it is not the presence or absence of an effect that is in question, but the magnitude of each effect in proportion to the others. A dose-response relationship has been observed with both estimates of airborne exposure to asbestos [136], and quantitative and qualitative fibre burden analysis of the asbestos content in human lung tissue of mesothelioma patients [3, 25, 137, 138]: e.g. see Rogers et al. [3], and, more recently, Williams et al. [138], who noted in 1997 that: "It was shown there that while the relative risk of all three diseases [i.e. asbestosis, mesothelioma and lung cancer] increased with increasing exposure, the relative risk of malignant mesothelioma is greater at low levels of exposure when compared with the risk of asbestosis but is lower at very high levels of exposure." [p. 39]. In their study on the relationship between lung asbestos fibre type and the lung tissue concentration of asbestos versus the relative risk of mesothelioma, Rogers et al. [3] made the following comment: "Fiber content in the lung depends on both the amount of fiber deposited and the amount cleared. The amount deposited depends on duration and intensity of exposure in the occupational or general environment. Clearance rate is thought to be dependent on the amount deposited at any point in time, i.e, clearance is exponential. Thus, the same fiber content in the lung at death or time of resection may be achieved from a high initial deposition, followed by absence of deposition and absence of clearance over a long period of time, or by a continuous deposition at a lower level, with or without clearance. Since detailed mechanisms of mesothelioma initiation and progression are not known, 'dose' as estimated by final lung fiber content may not relate to the 'dose' required to produce mesothelioma. It is thus possible that a high lung fiber content in a mesothelioma case may represent continuing accumulation of fibers after a lower level of fibers had produced malignant change. It is more likely, however, that the malignant change did not occur until the fiber content reached a sufficiently high level." [p 1913]. The dose-response relationship between the amphiboles and mixtures of asbestos types is linear at high exposures [15]For example, please see EHC 203 and Table 4. This dose-response relationship between asbestos exposure and the risk of mesothelioma has also been detected at low levels of exposure, which overlap with environmental exposures.table 4: incidence of mesothelioma in occupationally exposed groups by fibre type and time since first employed
A recent case-control study [136] from France on the dose-response relationship between low levels of asbestos exposure and the odds ratio (OR) for mesothelioma showed a clear dose-response relationship between estimated cumulative asbestos exposure and the OR for pleural mesothelioma. In the final paragraph of the article, the authors stated: "We found a clear dose-response relation between cumulative exposure to asbestos and pleural mesothelioma in a population-based control study, with retrospective assessment of exposure. A significant excess of mesothelioma was observed for levels of cumulative exposure that were probably far below the limits adopted in many industrial countries during the 1980s." [last sentence of abstract]. Although some concerns have been expressed about this type of investigation [139], it is my opinion that these points were addressed in the original paper [136], and they are common and intrinsic to epidemiological studies of this type — e.g. see Camus et al. [140, 141]. This study [136] found an OR for mesothelioma of 4.2 [95 per cent CI 2.0-8.8] at estimated cumulative exposures of 0.5-0.99 fibre-year,17 with elevation of the OR at about 0.5 fibre-year. In a fibre burden study on mesothelioma patients, Rödelsperger [137] observed that: "A significantly increased OR [for mesothelioma] is obtained even within the very low concentration range of 0.1-0.2 F/µg [i.e. concentrations in the range of 100,000-200,000 fibres per gram dry lung tissue], which may be expected for about 5% of the population." [p lll] (which also corresponds to an estimated cumulative exposure in the range of about 1-2 fibre-years). In a more recent study on mesothelioma cases (N = 66) and controls (N = 66), Rödelsperger et al. [25] found an OR for mesothelioma of 4.5 at fibre concentrations of 100,000 to < 200,000 per gram dry lung tissue (for fibres > 5 µm in length; 95 per cent CI 1.1-17.9). These authors also recorded an OR = 2.4 at concentrations of 50,000 to < 100,000 fibres per gram dry lung tissue (95 per cent CI 0.8-7.6). The controls for this study — surgical lung resections mainly for lung cancer — would be expected to bias the OR towards 1.0 (i.e. underestimate the effect) [25], and hence the OR of 2.4 probably represents a genuine doubling of risk or more at these low fibre concentrations. "Even within the concentration interval of 0.1-0.2 f/µg dry weight [i.e. 100,000 to 200,000 fibres per gram dry weight], a significantly increased odds ratio of 4.5 was obtained. Previously, the same method of tissue analysis was used to estimate a 95 percentile of the amphibole fibre concentration of 0.1 f/µg dry weight for persons without detectable exposure to asbestos at the workplace. Therefore, within the range of the normal background level [up to 300,000 fibres per gram dry lung in Germany], a positive dose response is observed." [p 191]. This study did not detect an increase in the OR for chrysotile or for other mineral fibres. The risk detected by Rödelsperger et al. [25] appears to correlate reasonably well with the French case-control study reported by Iwatsubo et al. [136], which found an OR for mesothelioma of 4.2 at estimated cumulative exposures of 0.5-0.99 fibre-year, with elevation of the OR at about 0.5 fibre-year. No lower threshold (minimum) level of asbestos exposure has been delineated, below which there is demonstrably no increase in the risk of mesothelioma.This observation is expressed by Hillerdal [20] in the following terms: "There is no proof of a threshold value — that is, a minimal lower limit below which asbestos fibres cannot cause the tumour [i.e. mesothelioma] — and thus it is plausible that even such low exposure can cause mesothelioma (even if the risk is extremely low). Patients with mesothelioma whose lungs show fibre concentrations within the normal range cannot be dismissed as background cases, — that is, not due to asbestos. ... The only way to prove such a hypothesis would be to compare the incidence of mesothelioma in a group with such background exposure with the incidence in a truly non-exposed group. This is not possible, as no such group can be found." [i.e. the lung tissue of virtually all mammals contains some asbestos fibres derived from natural, environmental or occupational sources] [p 510]. Points worth emphasis in Hillerdal's review [20] include reports of mesothelioma among school teachers (9/487 patients with mesothelioma in one reference), in jewellers, and in individuals exposed to asbestos insulation at home (6/262 patients with mesothelioma according to one reference). Hillerdal [20] also makes the point that low-level asbestos exposure "more often than not contains peak concentrations which can be very high for short periods" (e.g. airborne asbestos fibre concentrations of up to 78 f/ml from sweeping asbestos from the floor [New Caledonia]). The dose-response relationship for commercial Canadian chrysotile and mesothelioma incidence is also linear at high levels of exposure.For example, among the Quebec chrysotile miners and millers it has been noted that: "All the observed 38 cases were pleural with the exception of one of low diagnostic probability, which was pleuro-peritoneal. None occurred in workers exposed for less than two years. There was a clear dose-response relationship, with crude rates of mesotheliomas (cases/thousand person-years) ranging from 0.15 with cumulative exposure < 3530 million particles per m3 (mpcm)-years (< 100 million particles per cubic foot (mpcf)-years) to 0.97 for those with exposures of more than 10 590 mpcm-years (> 300 mpcf-years)." [EHC 203, p 8]. So far as I am aware, there are no observational data on dose-response relationships between chrysotile only at low exposure levels and mesothelioma incidence; in this respect, estimates are based on extrapolation of a linear dose-response line from high exposures down to low exposures."Overall, the available toxicological data provide clear evidence that chrysotile fibres can cause fibrogenic and carcinogenic hazard to humans. The data, however, are not adequate for providing quantitative estimates of the risk to humans. This is because there are inadequate exposure-response data from inhalation studies, and there are uncertainties concerning the sensitivities of the animal studies for predicting human risk." [EHC 203, p 7]. Because of the lack of such data, no definite threshold for chrysotile in relation to mesothelioma and lung cancer has been delineated: According to EHC 203 (p 144): "(a) Exposure to chrysotile asbestos poses increased risks for asbestosis, lung cancer and mesothelioma in a dose-dependent manner. No threshold has been identified for carcinogenic risks." In summary: table 5: asbestos-related dose-response relationships for mesothelioma
To the best of my knowledge, there are no observational data on the interactive effect of low (or for that matter, high) concentrations of inhaled chrysotile fibres only, when these are superimposed later and separately upon a pre-existing amphibole ± chrysotile burden within lung tissue (?superimpositional additive or multiplicative effect).For example, it has been estimated that up to 15-20 per cent of men in industrialized societies may have sustained occupational exposure to asbestos (chrysotile/amphiboles). Rödelsperger et al. [137] indicate that fibre concentrations of 100,000-200,000 amphibole fibres per gram dry weight lung tissue may be expected for about 5 per cent of the population in Germany. We do not know what the effect of subsequent chrysotile fibre inhalation on top of this type of amphibole burden might be. "Data were analysed on a case-referent basis, to relate relative risks of mesothelioma to dose of fibre, as measured both by lung content and estimated airborne exposure. Multivariate analysis of cases found a dose response relationship for lung fibre content of crocidolite, amosite and chrysotile and the development of mesothelioma. Either a multiplicative or additive model could be used to fit the relative risk/dose coefficients for the various asbestos types. A progressive increase in relative risk with increasing fibre content was reported for all fibres ... . Tests for trend were highly significant in all cases." [NICNAS 99, p 61]. There is a long lag-time between asbestos exposure and the subsequent diagnosis of mesothelioma (10 years as a minimum; usually in the range of 20-40 years). It follows that the mesotheliomas encountered in the 1990s and the incidence of mesothelioma in various nations are a consequence of exposures, especially occupational exposures, sustained from the 1940s through to the 1970s and even beyond.Exposures from the 1940s through to the 1980s usually involved one or more of the amphibole varieties of asbestos. For example, asbestos-cement building products used in Australia usually contained one or more of the amphibole varieties of asbestos, namely crocidolite or amosite, or both, at different times; in this respect, the use of crocidolite in the products was discontinued in 1966, and amosite in 1984. Peto et al. [24] make this point in the following terms: "The extraordinarily high mesothelioma incidence throughout Western Europe in men born around 1945-50 reflects the extent of asbestos use in the 1960s and 1970s at the beginning of their working lives. Annual raw asbestos imports to European Union countries peaked in the early to mid 1970s and remained above 800 000 tonnes per year until 1980, falling to about 100 000 tonnes by 1993 (European Commission, 1996). Increasingly stringent exposure limits were enforced in the manufacture of asbestos-containing products over this period, but exposure to users of such materials, particularly in the building industry, remained virtually uncontrolled in many countries. Chrysotile asbestos products are still widely used in several European countries, and maintenance or demolition work on older buildings may result in substantial exposure to amphiboles as well as to chrysotile. We have not included men born after 1955 in our projections, but the effects of asbestos exposure during the 1980s and 1990s, although not yet apparent, may prove considerable." [p 670]. Properties of asbestos fibres that determine carcinogenicityAs indicated in the documents submitted to the WTO Panel, the properties of asbestos fibres implicated for mesothelioma induction (and, possibly, lung cancer and other disorders), can be summarized as the three Ds: Dose: this issue is covered in the preceding sections [(e)(ii)to (vi)]. Dimensions: according to The Stanton Hypothesis, the carcinogenicity of asbestos fibres appears to reside primarily in long thin fibres (length > 5 µm and especially > 8 µm, and in the range of 10-20 µm, and diameters < 0.25 µm) — e.g. see Pott [142]. On the other hand, shorter fibres appear to be less carcinogenic, although data indicate that tremolite fibres > 4 µm in length and < 1.5 µm in diameter produce malignant mesenchymal tumours when implanted into the pleural cavities of rats [2]. On the other hand, very short-length fibres appear to have little carcinogenic activity, although Churg [143] comments on fibre dimensions in the following terms: "There has been extensive investigation of the relation of mesothelioma induction and fiber size in experimental models. Using intrapleural inoculation of different types of fibers with different size distributions, Stanton et al. concluded that long, thin (i.e., high aspect ratio) fibres were much more powerful mesothelial carcinogens than were short, thick fibers and that fiber type was less important. The exact size of fiber that qualifies as long and thin is unclear: fibers ... longer than 8 µm and widths narrower than 1.5 µm are usually cited from Stanton's work, but the same experiments show that fibers with lengths greater 4 µm and widths less than 0.25 µm were also effective carcinogens. The Stanton hypothesis has been supported by animal inhalation experiments using size-separated fibers: few mesotheliomas were found with either amosite or chrysotile prepared to contain few fibers longer than 5 µm. Human data on the question of fiber length and mesothelioma are equivocal. The tremolite found as a natural constituent of chrysotile ore is a relatively short, thick fiber compared with commercial amosite or crocidolite, and if one attributes 'chrysotile-induced' mesotheliomas in man to the tremolite component, the differences in mesothelioma do correlate with fiber size. However, attempts to prove this proposition directly have produced equivocal results ... McDonald et al. concluded that the number of fibers longer than 8 µm explained most mesotheliomas and that chrysotile played no role. However, Rogers et al. found that fibers both longer and shorter than 10 µm, including chrysotile fibers, played a role, although long fibers were generally more important. The problem with both of these studies is that most patients with mesothelioma have had occupational asbestos exposure, and fibers in lungs from those with occupational exposure are always longer than fibers in the general population; thus the same result would have been obtained if the test group were exposed but had no disease or some disease other than mesothelioma. My colleagues and I have attempted to circumvent this problem by comparing fiber sizes in a chrysotile mining and milling cohort and a cohort with heavy amosite exposure, using exposed workers with no disease as the control group. In neither cohort could we show that fibers in mesothelioma cases were significantly longer and thinner than those in the other disease categories or even in the disease-free workers." [p 353]. In other words, it is possibly the bio-persistence of amphibole fibres that is important for mesothelioma induction, rather than precise fibre dimensions. Durability (bio-persistence): the greater mesotheliomagenic (mesothelioma-producing) potency of the amphiboles in comparison to chrysotile is widely ascribed to greater persistence of the amphiboles in tissues, with significantly longer half-lives than chrysotile (please see later discussion, Section (f)(v)). On the other hand, it is conceivable that the same effect might be achieved by sustained inhalation of chrysotile over a prolonged time interval or, possibly, shorter, but more intense exposures so that the chrysotile fibres persist despite shorter half-lives than the amphiboles. There is general though not universal agreement of a differential potency between the amphiboles versus chrysotile for mesothelioma inductionIn this respect, the amphiboles are substantially more potent, with estimates ranging from 2‑4X, to 10X, to 12X on a fibre-for-fibre basis, to 30X, to a 30-60X greater potency, or more (e.g. please see EHC 203). A minority view that the amphiboles in chrysotile have roughly equal mesotheliomagenicity is not supported by the prevailing evidence for humans. Although acknowledging the greater potency of the amphiboles for mesothelioma induction, some argue that chrysotile is of equal or greater importance overall, because chrysotile accounts for > 95 per cent of world asbestos production. According to this perspective, commercial chrysotile is a weaker carcinogen on a fibre-for-fibre basis, but this lesser potency is multiplied across a much greater tonnage, leading to an overall equivalent or greater effect [144]. Tobacco smoke plays no role in the development of mesothelioma at any anatomical site — unlike the synergy between asbestos and tobacco smoke for the causation of asbestos-related lung cancer (see section (h)(i) below).Directory: english -> tratop e -> dispu e dispu e -> Annex g list of exhibits submitted by the parties dispu e -> World Trade Organization dispu e -> World Trade Organization Download 1.28 Mb. Share with your friends:
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