Commercial Chrysotile and Mesothelioma Induction

Commercial Chrysotile and Mesothelioma Induction

1. There is general agreement that commercial chrysotile has the capacity to induce mesothelioma in experimental animals and humans

   1. 
      There is dispute, however, over which fibres in commercial chrysotile are implicated (i.e. the predominant chrysotile or the trace quantities of fibrous tremolite).
      

2. Canadian chrysotile contains trace amounts of tremolite, including fibrous tremolite, as a contaminant [2, 10, 13, 14, 145-148]

   1. 
      The amount of tremolite appears to vary from one sample to another, but is generally < 1 per cent (please see EHC 203).
      

3. It has been argued that the occurrence of mesotheliomas among the Quebec chrysotile miners and millers is a consequence — not of the chrysotile per se — but of the coexistent trace quantities of tremolite (a non-commercial amphibole).

   1. 
      Analysis of the asbestos fibre content of lung tissue from this cohort demonstrates disproportionately high concentrations of tremolite in comparison to chrysotile; this appears to represent a bio-accumulation phenomenon whereby chrysotile is cleared from lung tissue more rapidly than the tremolite, so that the tremolite not only persists but increases in proportional concentration. In this respect, the tremolite content of the lung tissue can be used as an index on the past chrysotile exposure and some claim that the incidence of mesotheliomas in the same cohort can be related directly to the tremolite content [13, 14].
      

4. It is known that fibrous tremolite has the capacity for mesothelioma induction

   1. 
      Mesotheliomas related to the use of tremolite in whitewash or stucco have been reported in Turkey, Greece, Cyprus and Corsica [149-152] (for additional references, see Hillerdal [20]).
      

2. 
   Tremolite has also been implicated in lung cancer and mesothelioma induction in a group of vermiculite miners in Montana [2, 16, 153, 154]. It appears that these miners were exposed only to tremolite-actinolite fibres. The group was shown to have a:
   

3. 
   Case [2] has extensively reviewed the biohazards of tremolite, including epidemiological investigations in humans and experimental data on animal models. In his review, he emphasized the pathogenicity of the tremolite found in Quebec chrysotile samples, especially at Asbestos and in the Thetford mine:
   

4. 
   He also favoured the expression "chrysotile/tremolite" for Quebec chrysotile:
   

5. 
   Case [2] also states:
   

5. Clearance of chrysotile from lung tissue

   1. 
      It is well known that chrysotile fibres are cleared more rapidly than amphiboles, especially in long-term studies [145]. Clearance of amphibole fibres does occur and the clearance mechanisms appear to be more effective for short fibres (for both chrysotile and the amphiboles) so that the mean length of retained fibres increases over time. Churg and Vedal [155] calculated a half-life in lung tissue of about 20 years for amosite. Estimates of the tissue half-life for crocidolite fibres have been somewhat shorter (in the order of 5-10 years) [156-158], and de Klerk et al. [158] could find no difference between the clearance rates for long and short fibres. Oberdörster [159] estimates human clearance half-times to be about 90-110 days for chrysotile and 200-1500 days for crocidolite fibres > 16 µm in length, based on extrapolated rat and primate inhalation data.
      
   2. 
      It has been claimed that chrysotile is cleared from lung tissue within 28-48 hours of inhalation. This claim seems extraordinary and begs the question: why, if chrysotile is cleared from lung tissue so rapidly, is it still demonstrable in human lung tissue many years or decades after cessation of inhalation of commercial chrysotile (or mixtures of asbestos types)? For example, in one of my recent referral cases — an elderly man with lung cancer who sustained exposure from mixing loose asbestos and sweeping up dried insulation materials — an asbestos fibre analysis carried out on lung tissue resected 16 years after his exposure stopped showed a total asbestos fibre count of 8,440,000 fibres/gram dry lung (> 1 µm in length; aspect ratio ≥ 3:1), made up by 6,250,000 chrysotile fibres + 940,000 tremolite fibres + 940,000 anthophyllite fibres + 310,000 crocidolite fibres (the 24 year lag-time is enough for a carcinogenic effect).
      

6. The Quebec chrysotile cohort

   1. 
      In an analysis of mesotheliomas among the Quebec chrysotile miners and millers, up to 1997, McDonald et al. [13, 14] reported 38 mesotheliomas, and most of these occurred after prolonged and heavy exposure, especially at the mine where the greatest concentrations of trace tremolite occurred (Thetford). For example, these authors [13] recorded the breakdown of the mesotheliomas shown in Table 6 (below).
      
   2. 
      McDonald et al. [13] identify two main reasons for the low mesothelioma rate from the five smallest mines (1 case only among 6010 person-years, equivalent to 166 cases per million person-years): firstly, workers within this sub-group were younger than the remainder of the cohort; secondly, these mines had been opened recently so that "there were inadequate periods of latency". A single additional mesothelioma shortly after completion of the study would erase the difference in incidence rates between the five smallest mines and the main complex. McDonald et al. [13] go on to indicate that the other rates are "reasonably comparable". In comparison to the Thetford main complex, there were relatively few mesotheliomas among workers at the asbestos mine and mill (23 versus 8), despite nearly equivalent person-years of observation; in addition, asbestos fibre analysis on lung tissue demonstrated crocidolite and amosite in five out of the eight cases from the mine and mill at Asbestos and in two out of the five mesotheliomas from the Asbestos factory (Table 7, below). In focussing on the Thetford mines group, it was noted that most of the mesotheliomas came from the five central mines (Area A; Group C) as opposed to the 10 peripheral mines (Area B; Group P), so that the odds ratio for mesothelioma for Group C plus employees who had jobs in both Area A and Area B (Group M) was 2.50 (based on net service; 20 adjusted years), in comparison to an odds ratio of 0.80 for Group P.
      

3. 
   The clear implication of this complex and sophisticated study is that the risk of mesothelioma was related strongly to years of service in the central area at Thetford where geological factors "in Area A would probably result in tremolite, some in fibrous form, being mined with the ore". In addition, the mesothelioma rate for miners and millers was > 2.5 times higher at Thetford mines (excluding the smallest mines) than at Asbestos, and this difference was also attributed to differences in the amount of fibrous tremolite in the ores. Despite these differences within the cohort for the distribution of mesothelioma related to chrysotile and tremolite (and also to crocidolite and amosite at the Asbestos factory and the Asbestos mine and mill), the results indicate that Quebec chrysotile — on average contaminated by fibrous tremolite in small amounts — is capable of mesothelioma induction: the Abstract describes 25 mesotheliomas from the Thetford mines, representing a mesothelioma rate of 337 per million person-years, which is substantially (almost 20X) higher than the mesothelioma incidence rate of about 17 per million per person-years for men in British Colombia and the USA in 1982 and 1973-1984 respectively, and well above the background rate for spontaneous mesotheliomas of 1-2 per million person-years.
   

cases among quebec chrysotile miners and millers

4. 
   In the final two paragraphs of the paper, McDonald et al. [13] comment as follows:
   

At present-day levels of dust control the mesothelioma risk must be vanishingly small. Even so, it remains desirable to minimise, perhaps by screening, the contamination of commercial chrysotile by amphibole fibres, however difficult this may be." [p 718].

1. 
   Despite the importance of this study by McDonald et al. [13], the following comments can also be made:
   

• 
  The number of mesotheliomas in all groups except for the Thetford main complex was small (1, 8 and 5 mesotheliomas respectively; please see Table 6 above). In this respect, misdiagnosis or misclassification of the mesotheliomas according to the places worked could significantly affect the results, although there is no evidence that this happened; however, the probability for the diagnosis of mesothelioma also varied, with a high probability in 19 cases, moderate probability in 14, and a low probability (though considered more likely than not) in five; of these 38 cases, only 18 had been coded on the death certificate to ICD 163, and the rest to a variety of other diagnostic codes. Furthermore, in analysing the mesotheliomas according to Area A versus Area B at the Thetford mines (groups C, M and P), the numbers were 104 for group C, 69 for group P and 35 for group M; McDonald et al. noted that the odds ratio for group P was unstable as shown by the "very wide confidence intervals, and as the point estimate is well below unity it is quite unrealistic ".
  
• 
  The low incidence of mesotheliomas in the Quebec chrysotile cohort appears to parallel similar low incidence rates for asbestosis and lung cancer for the same cohort
  

6. 
   For these reasons and because of the different rates of various asbestos diseases (asbestosis, lung cancer and mesothelioma) between the Quebec cohort and other groups of workers, I would be reluctant to recommend national policies from the findings in this cohort in isolation, and I would look for coherence of the evidence across different cohorts and studies.
   
7. 
   In relation to the Quebec cohort, there is an important error in the Canadian reply to Question 4 (see Annex II) from the European Communities, where the following statement is made:
   

1. 
   The statement that "most of the cases were related to short-term exposure to commercial amphiboles" is incorrect and misleading. As demonstrated in the study by McDonald et al. [13], most of the mesotheliomas occurred among chrysotile miners who worked at the Thetford main complex, without exposure to commercial amphiboles such as crocidolite or amosite. This is clearly shown in Table 7 (above), slightly modified from the paper by McDonald et al. [13] where fibre burden analysis on lung tissue from 14 mesothelioma cases from the Thetford mines showed both chrysotile and a high concentration of tremolite, with a zero count for the commercial amphiboles crocidolite and amosite. The point to be emphasized is that the mesotheliomas from the Thetford mines were not related to commercial amphiboles such as crocidolite or amosite, but to chrysotile with its content of fibrous tremolite.
   

1. As discussed earlier, a dose-response relationship between the incidence of mesothelioma and cumulative asbestos exposure has been demonstrated for commercial chrysotile.

   1. 
      Mesotheliomas have also been produced in experimental animals by implantation and inhalation of chrysotile (presumably also containing trace amounts of tremolite). Mesotheliomas can also be induced in rats by intraperitoneal injection of chrysotile, with evidence of a dose-response effect [1] (see also bibliography for EHC 203).
      

1. Chrysotile is also known to be toxic to a variety of cell lines in vitro, with induction of a variety of chromosomal alterations (e.g. please see EHC 203, pp 69-102).

1. 
   
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