Draft 16 March 2011 Chrysotile Health Risk Revisited David Bernstein Jacques Dunnigan Ken Donaldson Thomas Hesterberg Robert Brown John Hoskins Raúl Barrera Rodríguez Allen Gibbs ……………….. Table of Contents 1 Summary:....................................................... 2 2 Introduction:.................................................. 2 2.1 World Health Organization evaluations and governmental regulatory evaluations of chrysotile:............................2 2.2 The differences in serpentine and amphibole asbestos:.......2 2.3 Use and exposures in the past and today.....................2 3 WHAT WAS KNOWN THEN............................................ 2 3.1 Epidemiology studies:.......................................2 3.2 Toxicology Studies in experimental animals:.................2 4 WHAT WE KNOW NOW............................................... 2 4.1 Recent epidemiological evaluations:.........................2 4.1.1 Liddell et al. (1997):...................................2 4.1.2 McDonald et al. (1997):..................................2 4.1.3 Hodgson & Darnton (2000):................................2 4.1.4 Paustenbach et al. (2004)................................2 1
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Chrysotile Health Risk RevisitedDavid Bernstein Jacques DunniganKen Donaldson Thomas HesterbergRobert BrownJohn Hoskins Raúl Barrera Rodríguez Allen Gibbs
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Table of Contents1 Summary:......................................................................................................................................2
2.1 World Health Organization evaluations and governmental regulatory evaluations of chrysotile:..........................................................................................................................................2
2.2 The differences in serpentine and amphibole asbestos:........................................................2
2.3 Use and exposures in the past and today..............................................................................2
3 WHAT WAS KNOWN THEN............................................................................................................2
4.2.6 Aguilar-Madrid et al. (2010):..........................................................................................2
4.2.7 Schneider et al., (2010):.................................................................................................2
4.2.8 Donaldson et al., (2010):..................................................Error! Bookmark not defined.
4.3 Other studies not included in these analyses also indicate that chrysotile produces little if any effect...........................................................................................................................................2
4.3.1 Rees et al. (1999, 2001):................................................................................................2
4.3.2 Camus et al. (1998):.......................................................................................................2
4.4 Toxicology Studies in experimental animals:.........................................................................2
4.4.1 The use of sub-chronic inhalation toxicology studies in the evaluation of fiber toxicity:2
4.4.2 The role of biopersistence and fiber length in chronic carcinogenicity:.........................2
4.4.3 Fiber translocation to the pleural cavity:.......................................................................2
5 The Hit & Run theory:....................................................................................................................2
A. Asbestos is a generic term which refers to two distinct fibrous mineral types: chrysotile and amphibole asbestos. Chrysotile and amphibole asbestos have very different physical and chemical characteristics which are reflected in the way they act in the lung.
B. While the association of 'asbestos' exposure with disease dates from the turn of the 19th century, nearly all epidemiological studies published through the mid 1990's on which this association is based did not base exposure estimates on workplace measurements that were capable of distinguishing fiber type as such measurements were not readily available at the time.
C. Regulatory decisions to ban chrysotile asbestos rely heavily upon these epidemiological studies in which an assessment of the actual exposure to chrysotile versus amphibole is impossible.
D. Beginning in the late 1990s and extending into the present, numerous cohorts were evaluated in epidemiological studies all of which, when fiber type was determined, clearly indicate that exposure to chrysotile (without amphibole asbestos) results in to detectable mesothelioma.
E. Experimental toxicology studies of asbestos also can be differentiated in a similar fashion. Prior to the mid-1990s nearly all inhalation toxicology studies of chrysotile asbestos were performed at enormous exposure concentrations often exceeding 1 million fibers per cubic centimeter. At these enormous concentrations, most of which were composed of short fibers and particles, lung overload was found to occur making the studies inappropriate for fiber hazard evaluation.
F. More recent quantitative inhalation toxicity studies as well as fiber biopersistence studies, have clearly demonstrated that chrysotile is rapidly removed from the lung following inhalation and that it does not induce any inflammatory response in the lung at concentrations up to 5000 times the TLV. In addition, recent studies employing non-invasive techniques to assess fiber translocation from the lung to the pleural cavity have shown that chrysotile is not translocated to the pleural cavity and does not induce any inflammatory response in the pleural cavity.
G. Similar studies have shown that amphibole asbestos, even following a short five day exposure, leads to pulmonary interstitial fibrosis within 28 days. In addition, amphibole asbestos has been shown following a five-day exposure to quickly translocate to the pleural cavity (within seven days) and to initiate a marked inflammatory response in the pleural cavity.
H. With a full understanding of the older studies and integration of newer, more quantitative studies the consensus of the data available today clearly shows that chrysotile can be used safely.
I. Comparison of these results with the limited epidemiological and toxicological data available for proposed substitutes to chrysotile indicate that many of the substitutes have a much greater potential for producing a toxic effect than chrysotile.
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2 Introduction:
The health risk from chrysotile asbestos as used today in high density cement products is often viewed with controversy. While many studies in the past have associated carcinogenic effects with chrysotile exposure, more recent studies have often indicated the opposite. Key to understanding this is the differentiation of exposure, dose and response of the serpentine mineral chrysotile in comparison to the amphibole asbestos fibers such as crocidolite, tremolite and amosite. This paper reviews the full range of scientific studies and discusses how the epidemiological and toxicological data provide today a convergence in the understanding of the risk from chrysotile.
The association of asbestos exposure with disease dates from the turn of the 19th century (McDonald & McDonald (1996). The report by Wagner et al. 1960, reporting on 33 cases of mesothelioma primarily from the crocidolite mining area in the North West Cape Province of South Africa was instrumental in establishing a relationship to asbestos exposure. While the relationship Wagner described concerned individuals working primarily in crocidolite mining, there was virtually no quantification of exposure at this time. The use of the generic term "asbestos" to describe both minerals, the serpentine chrysotile and the amphibole family (amosite, crocidolite, and tremolite anthophyllite, actinolite, of which only the first two were industrially important) further compounded any differentiation in association of disease to mineral type. In addition, because of the common use of the name asbestos with the two mineral types, and the scientific basis for differentiating fiber types then current, it was conceivable to imagine that all asbestos types could have similar potency. In essence, because the same name was used for these two very different minerals, the impetus was to equate the two rather than differentiate them.
As a result of the lack of distinction in nomenclature and the limitations in analysis and identification, most studies through the late 1990s provided little quantitative scientific basis for distinguishing between the effects of chrysotile as compared to those of amphibole asbestos.
2.1 World Health Organization evaluations and governmental regulatory evaluations of chrysotile:
The WHO IPCS, US EPA and European commission have all relied on chrysotile studies published prior to the late 1990s. IARC convened a working group (2009) to re-examine all types of asbestos. The IARC classification process is hazard-based classification which implies according to their monograph criteria that if a substance is suspected of causing cancer in humans under any conditions it should be classified as a human carcinogen, even if the conditions do not exist today. No distinction is made as to time frame, exposure concentration, or in the case of asbestos the differential potency of chrysotile versus amphibole asbestos. In addition, and perhaps most importantly, since the year 2000, IARC specifically excludes any scientist who ever worked with industry from participating in the working groups. As a result, no scientists were present in the IARC working group on the re-evaluation of asbestos that had any direct experience with the last 10 years of research.
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In the following review, the epidemiological and toxicological data prior to 1998 which was used in these assessments is critically reviewed in terms of precision, applicability and reliability in differentiating chrysotile from amphibole asbestos. Following this we present a summary of the numerous epidemiological and toxicological studies that have been published to clearly differentiate chrysotile from amphibole asbestos.
2.2 The differences in serpentine and amphibole asbestos:
That chrysotile and amphibole asbestos could have different toxicological profiles is not unexpected. While the term asbestos historically has been used to describe both mineral families, chrysotile and amphibole asbestos are in fact two distinct minerals with different physical and chemical characteristics.
Chrysotile is a cylindrical fibrous silicate, which is formed as a very thin rolled sheet. The sheet, which is composed of a sandwich of magnesium and silica, is about 8 angstroms (0.8 nanometers) thick and the magnesium is on the outside of the roll. Magnesium is an essential element in the body (the adult human body contains approximately 20-28 g of magnesium, WHO, 2002) and the magnesium layer is soluble in biological systems. As illustrated in Figure 1, in the lung, the magnesium dissociates and the crystalline structure of the silicate sheet is readily attacked by acid, such as occurs inside the macrophage (pH 4 - 4.5), whose evolved function is to engulf foreign particles that deposit in the lungs. This process causes the rolled sheet of the chrysotile fiber to break apart and decompose into small pieces. These pieces can then be readily cleared from the lung by macrophages through muco-cilliary and lymphatic clearance. Fibres cleared on the muco-cilary escalator are cleared to the gut where they are attacked by the even stronger acid environment (hydrochloric acid, pH 2) of the stomach.
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Figure 1
This is in contrast to the amphibole asbestos class of fibers, which are formed as solid rods/fibers. The structure of an amphibole is a double chain of tetrahedral silicate which makes it very strong and durable. The external surface of the crystal structures of the amphiboles is quartz-like, and has the chemical resistance of quartz. The basic strutureal matix of amphibole fibers therefore has negligible solubility at any pH that might be encountered in an organism although some associated surface contaminating metals such as iron can become ionised and can then be released from the fibre.
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2.3 Use and exposures in the past and today.
In the past, as was the case for many industries, there was little control of dust levels and little use of personal protection equipment in the asbestos industry. This resulted in excessively high exposure concentrations. In addition, because knowledge of the differential potency of chrysotile versus amphibole asbestos was sparse at best, the two minerals were often used interchangeably in industrial applications. While in some situations one was preferential to the other in terms of process, often cost and availability were the overriding factor in determining which mineral was used. In addition, industrial associations were often instrumental in determining which fiber was used. As an example in the UK, many of the mining operations in South Africa were either owned or associated with a UK company and as such the UK became the largest importer of amphibole asbestos in the world.
Dust levels were not well controlled in the mines, and applications for which the minerals were used such as open spraying, also resulted in very high exposure concentrations. Similarly with textile production which again was very dusty.
Today the situation is remarkably different. Firstly and perhaps most important is the fact that with very few exceptions today only chrysotile is mined and used. Further, while in the past occasional chrysotile mines were contaminated with tremolite veins, today, the tremolite veins, which are easily differentiated from chrysotile because they are of a different colour, can be identified and avoided in those few mines that have such veins. It should be noted that the large majority of chrysotile mines throughout the world are tremolite free and contrary to some perceptions the majority of chrysotile sources are not contaminated with traces of tremolite. In the past even when no effort was made to avoid mining the tremolite veins, the percentage of tremolite was very small and measurements in one study showed it never amounted to more than 0.24% found in 1 out of 8 chrysotile samples analyzed, while the other 7 samples contained no tremolite (detection limit of 0.002 - <0.0002% using scanning electron microscopy (SEM), the most sensitive of the analytical methods used) (Addison and Davies, 1990).
Such trivial levels would seem to be unimportant since the induction of mesothelioma by tremolite requires very high exposure levels of long fibers over many years. Fortunately, tremolite when associated with chrysotile ore has a short length and low aspect ratio and appears to be a very low-potency mesothelial carcinogen ; extremely high exposures over many years, such as encountered by chrysotile miners and millers in the past, were required to produce an appreciable incidence of tumours. As a practical matter, the data indicate that chrysotile will not produce mesotheliomas in those exposed to any current or recently regulated number of fibers, and certainly not in those exposed at environmental levels » (Churg 1988).
In the mines, the use of water control spraying technology to limit dust levels and closed-circuit systems greatly reduce the dust levels to which the workers are exposed.
Today, the vast majority of chrysotile is used in high density cement products. In these products, chrysotile is bound in the cement matrix with little opportunity for release. The industry also has instituted extensive training and educational programs on how to limit dust levels to assure personal
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protection, not only in the mining sectors, but also in use (installation, maintenance, repair, and disposal) in the construction trades.
3 WHAT WAS KNOWN THEN (prior to the late 1990s)
3.1 Epidemiology studies:
The early case-control studies of mesothelioma provided relationships of occupational exposure to asbestos (Elmes 1965, Newhouse 1965, Mcewen 1970, Mcdonald 1970, Rubino 1972, Ashcroft 1973, Hain 1974 & Zielhuis 1975). However, due to the state of occupational hygiene measurements at the time, none of the studies was able to use exposure measurements which included fiber number or fiber type. The associations to disease were attributed to the fiber most used without consideration of the criteria that have been understood more recently which determine fiber potency: biopersistence and fiber length.
In an analysis of available epidemiological data on the different asbestos types, Berman and Crump (2003) summarised the various limitations that likely influence the epidemiological evaluations and that had to be addressed. These included:• limitations in air measurements and other data available for characterizing historical exposures;• limitations in the manner that the character of exposure (i.e., the mineralogical types of fibers and
the range and distribution of fiber dimensions) was delineated;• limitations in the accuracy of mortality determinations or incompleteness in the extent of tracing
of cohort members;• limitations in the adequacy of the match between cohort subjects and the selected control
population; and• inadequate characterization of confounding factors, such as smoking histories for individual
workers.
In addition, the authors reviewed the capabilities and limitations of the analytical techniques used for determining the asbestos exposure measurements in these epidemiological studies (Table 1). Midget impinger (MI) and phase contrast microscopy (PCM) were the two analytical techniques used to derive exposure estimates in the majority of epidemiology studies from which the existing risk factors were derived. However, the manner in which asbestos was quantified in the available epidemiology studies (i.e., MI and PCM) may not have adequately reflected the characteristics of the inhaled aerosol that relate to biological activity.
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Table 1 (reproduced from Berman & Crump, 2003)
With few exceptions little or no quantitative sampling was conducted prior to the 1960s when exposure concentrations were generally considered to be higher than those monitored more recently, due to lack of use of dust control equipment at the time and procedures to reduce dust levels that were introduced only later. For most studies, therefore, early exposures had to be estimated by extrapolation from later measurements.
In particular, as a result of the measurement techniques there was often little quantitative mineralogical exposure information on the types of fibers to which workers were exposed. The nature of the industrial process may have suggested the type of fiber used. However, in the past there was little attempt to differentiate serpentine from amphibole asbestos, and as a result amphibole was often substituted or mixed with serpentine without detailed documentation. The use of amphibole in place of serpentine resulted from such factors as availability, cost, and effectiveness in the process. In addition, work histories of employees were not always as well documented as might occur today. While all uncertainty factors are important in assessing the difference between chrysotile and amphiboles, the differentiation of the fiber type in the exposure atmosphere is obviously critical in determining possible effects associated with each type of fiber.
The residual inconsistency in both the lung cancer and mesothelioma potency values is primarily driven by those calculated from Quebec chrysotile miners and from South Carolina chrysotile textile workers. Dement et al., 1982 & 1983, in the original publication of the South Carolina cohort stated that based upon inquiry with the management that chrysotile is the only type of asbestos ever processed at this plant as a raw fiber. Dement et al., 1983 stated that:
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"A small amount of crocidolite yarn was woven into a tape or made into a braided packing beginning in the 1950s until approximately 1975. Crocidolite was never carded, spun, or twisted. The total quantity of crocidolite ever processed was extremely small (less than 2000 pounds), and all weaving of crocidolite tapes was done wet on a single loom; thus exposures were low. According to company personnel, an average of approximately 6-8 million pounds of chrysotile were processed annually at this point. Chrysotile was received from Quebec, British Columbia, and Rhodesia."
However, Dreesen et al. (1938) in a report predating this publication states that "Approximately 90 percent of the asbestos used in these plants is obtained from Canada. The remaining 10 percent comes from Arizona or South Africa, and, infrequently, from Russia and Australia." South Africa and Australia were the largest suppliers of the blue and brown amphibole asbestos, crocidolite and amosite. In addition, the building which housed the textile plant was located directly across the street from the Charleston Naval Shipyard which used large quantities of amphibole asbestos in navy shipbuilding. Subsequent analyses of occasional samples of lung and air filters from the South Carolina plant confirm the presence of amphibole fibers (refs). Sebastien et al., (1989) reporting on the analysis of a small number of lung biopsy samples from the Charleston plant and from the Thetford mine in Canada reported that "Non-trivial concentrations ( > 0.1 f/µg) of amosite and crocidolite were measured in 32% of specimens from Charleston and 9% from Thetford."
So the question remains of whether a few percent use of amphibole used in the South Carolina textile plant can explain the results. The answer to this lies in the studies by McDonald et al. (refs) on the Canadian chrysotile miners and in the recent quantitative comparisons of chrysotile and amphibole in inhalation toxicology studies. McDonald attributed the cancer incidence to the small amount of tremolite present in the mine. Analyses have shown that the tremolite was present in quantities of less than 1 %. With up to 10 % use of amphibole in the South Carolina cohort, the carcinogenic effects observed are easily explained by the presence of amphibole asbestos. As discussed below, the recent work by Bernstein et al. (2010) has shown that amphibole is much more potent than chrysotile and that with such a differential in response, the findings reported in the South Carolina cohort can be fully understood from the exposure to amphibole asbestos present. It is clear that the South Carolina cohort was not a pure chrysotile cohort as originally postulated.
Even more important however, in the light of chrysotile use today, is the fact that large-scale production of asbestos textiles no longer occurs.
3.2 Toxicology Studies in experimental animals:
The early toxicology studies were just as difficult to interpret as the early epidemiological studies. Concentration was determined using gravimetric techniques without consideration of fiber number or fiber length and diameter and little consideration was given to the length and diameter distribution of the fibers to which the animals were exposed.
In early studies, such as those reported by Vorwald et al. (1951), the fiber dust concentrations were produced using a rotating paddle in a dust hopper. Concentrations were reported based upon light
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microscopy in the range of 30 to 50 million particles and fibers per cubic foot. This corresponds to approximately 500,000 particles and fibers/cm3 if it were measured by TEM (Breysse et al., 1989). Subsequent studies such as those by Gross et al. (1967) based exposure in gravimetric concentration and reported a mean gravimetric concentration of 86 mg per cubic meter (range 42 to 146 mg cubic meter). Following this Wagner et al. (1974) reported on studies of UICC Canadian and Rhodesian chrysotile performed at a nominal concentration of 10 mg/m3. This gravimetric concentration of 10 mg/m3 became a semi-de facto concentration for subsequent studies by Wagner and other investigators through the 1980s with some investigators still reporting on studies at this exposure concentration more recently (eg Morris et al., 2004).
In a recent review by Bernstein et al. (2010), the available chronic inhalation studies with chrysotile have been evaluated in terms of the extrapolated exposure concentration if the exposure atmosphere had been evaluated using transmission electron microscopy. They reported that the TEM measurement of the 10 mg/m3 exposure to chrysotile would likely correspond to more than 1,000,000 fibers/cm3. Also, there are few quantitative data presented in past publications on nonfibrous particle content of test fiber preparations. The gravimetric exposure concentrations that were reported in the chronic inhalation studies with chrysotile that were performed through the 1980s ranged from 2 to 86 mg/m3, which based upon the extrapolation mentioned above corresponds to between 200,000 and 8,600,000 f/cm3. In a chronic inhalation study using NIEHS chrysotile (Mast et at, 1995; Hesterberg et al. 1993), in which total fiber aerosol exposure was reported by SEM as 100,000 f/cm3 and which by TEM would have been more than 1,000,000 f/cm3, the total chrysotile lung burden following 24 months of exposure was by SEM observed to be 5.5 X 1010 fibers/lung (Bernstein, 2007). However, with extrapolation to that which would have been observed by TEM (Breysse et al., 1989) the lung burden in this study would be 9.4 X 10 11 f/lung. This would correspond to an average of 2,300 fibers per alveoli (assuming 10 % deposition). An asbestos exposure concentration of 10 mg/m3 corresponds to more than 18 million times the American Conference of Industrial Hygienists (ACGIH) Threshold Limit Value (TLV) of 0.1 f/cm3 for asbestos fibers. At an exposure level 18 million times the TLV, it would be reasonable to expect that the lung would be overloaded and have difficulty clearing the fibers deposited there. These overload conditions would be sufficient to severely reduce the normal clearance of the chrysotile fibers from the lung and initiate a nonspecific inflammatory and proliferative response which has been shown to lead to fibrosis and cancer.
4 WHAT WE KNOW NOW
4.1 Recent epidemiological evaluations:
More recently epidemiological analyses have been performed which were designed to try to re-evaluate the older studies with the aim of differentiating effect by asbestos fiber type. It should be pointed out that these studies did not re-analyze or find new data in these older studies, but applied more sophisticated statistical techniques to differentiate effects.
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4.1.1 Wagner et al. (1982)Several epidemiological studies have been conducted of workers at an asbestos factory in the north of England. The predominant exposure was stated to be chrysotile but also a small amount of crocidolite was used which was considered to be unimportant in relation to the asbestos related diseases associated with the factory. Indeed mesotheliomas occurred in workers from the factory which were attributed to chrysotile. However, when asbestos content of the lung tissues of 24 former employees of the factory was determined by electron microscopy substantial amounts of crocidolite were identified in addition to chrysotile in mesothelioma cases as well as in those who had died from other causes (Wagner et al., 1982). The mesotheliomas could therefore not be attributed solely to chrysotile exposure.
4.1.2 Green et al. (1997)Green et al. (1997) examined the fibre content of lung tissues from 39 former asbestos workers and 31 referents. The asbestos workers had been employed at the Charleston, South Carolina textile plant, the subject of several previous epidemiological studies. The plant had used predominantly chrysotile asbestos but in addition some crocidolite yarn was woven into a tape or made into a braided packing from the 1950’s to 1975. The referents were obtained from the local population. It was found that both cumulative exposure and asbestos fibre levels were strongly correlated with severity of lung fibrosis. The concentration of tremolite fibres in the lung provided a better estimate of lung fibrosis than did the concentration of chrysotile. Interestingly significant quantities of commercial amphibole fibres were found in 52.4% of the cases and 35.5% of the referents. The study indicated that a substantial proportion of the workers had been exposed to commercial amphibole asbestos as well as chrysotile and tremolite.
4.1.3 Liddell et al. (1997):Liddell et al., reported on the mortality experienced by chrysotile workers in mines of the Eastern Townships region of Quebec by following observations on a birth cohort of almost 11,000 men which they followed from first employment (the earliest in 1904) to 1992.
At exposures below 300 (million particles per cubic foot) x years, (mpcf.y), equivalent to roughly 1000 fibres/ml x years - or, for example: 10 years of exposure at the highest concentration in the 1940s of 100 (fibres/ml) - findings were as follows. There were no discernible associations of degree of exposure and Standard Mortality Ratios (SMR: observed vs expected) whether for all causes of death or for all the specific cancer sites examined. The average Standard Mortality Ratios were 1.07 (all causes), and 1.16, 0.93, 1.03 and 1.21, respectively, for gastric, other abdominal, laryngeal and lung cancer.
Higher exposures have, however, led to excess mortality from all causes, increasing with degree of exposure, and from lung and stomach cancer. However, such exposures, of at least 300 mpcf.y, are several orders of magnitude greater than any those seen in recent years. The effects of cigarette smoking were much more deleterious than those of dust exposure, not only for lung cancer (the Standard Mortality Ratios for smokers of 20 + cigarettes a day being 4.6 times higher than that for
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non-smokers), but also for stomach cancer (2.0 times higher), laryngeal cancer (2.9 times higher), and-most importantly-for all causes (1.6 times higher).
The authors concluded that "Thus it is concluded from the point of view of mortality that exposure in this industry to less than 300 mpcf.years has been essentially innocuous".
4.1.4 McDonald et al. (1997):In a further analysis of the same cohort as reported in the Liddell et al. (1997) study, McDonald et al. (1997) reported on the epidemiology and aetiology of the mesothelioma in the Québec chrysotile miners and millers. The authors reported that "Within Thetford Mines, case-referent analyses showed a substantially increased risk associated with years of employment in a circumscribed group of five mines (Area A), but not in a peripherally distributed group of ten mines (Area B); nor was the risk related to years employed at Asbestos, either at the mine and mill or at the factory." In addition, "Lung tissue analyses showed that the concentration of tremolite fibres was much higher in Area A than in Area B, a finding compatible with geological knowledge of the region". Within Thetford Mines, there is clear evidence from case-referent analyses that the risk arising from employment in the localised area of central mines in the main complex (Area A) was much higher than in the peripherally located mines (Area B), where it was extremely low.
The authors concluded that: "At present-day levels of dust controls, whether or not contaminated with tremolite, the mesothelioma risk must be vanishingly small".
4.1.5 Hodgson & Darnton (2000):Hodgson & Darnton (2000) reviewed 17 epidemiology studies that were referenced in reports by Peto et al. (1985), HEI (1991) and INSERM (1996) with the goal of differentiating risk by asbestos fibre type. The authors state that “Not only are there the inevitable problems of extrapolating earlier exposures on the basis of more recent measurements; there are also problems of converting the most usual historic measurements (in terms of particle counts) to the more relevant measure of fibre counts. Direct fibre counting only became generally used in the 1970s”.
For the Carolina cohort they stated that “Very small amounts of crocidolite yarn were used, but raw crocidolite fibre was not processed. The quantity of crocidolite used was about 0.002% of the total.” However, no reference was cited as to where this was derived and no mention is made of the use and presence of amphibole as described above. Even so, Hodgson & Darnton (2000) did differentiate chrysotile from amphibole asbestos. It is interesting to note that 37% of the total fiber count in the lungs of the Carolina cohort were amphibole asbestos (Sebastien et al. 1989). The authors reported that: ‘….. At exposure levels seen in occupational cohorts it is concluded that the exposure specific risk of mesothelioma from the three principal commercial asbestos types is broadly in the ratio 1:100:500 for chrysotile, amosite and crocidolite respectively…’
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4.1.6 Paustenbach et al. (2004)Paustenbach et al. reviewed more than 25 epidemiological studies that were conducted from 1975 to 2002 examining the risks of asbestos-related diseases in brake mechanics. The exposure concentrations as determined by the National Institute of Occupational Safety and Health in the United States were between 0.004 and 0.28 fibers per cubic centimeter. The asbestos used in friction products was nearly exclusively chrysotile asbestos. Only UK railroad engine brake linings reported the use of a small amount of amphibole asbestos. The authors reported that the studies clearly indicated that brake mechanics were not at increased risk of adverse health effects due to asbestos exposure. There was no increased risk found of mesothelioma or asbestosis in brake mechanics and in addition there was no evidence that lung cancer in this occupational exposure group could be attributed to asbestos.
The authors also reviewed 20 studies published during the same time period which evaluated asbestos exposure or asbestos-related health effects in friction product manufacturing workers. These studies indicated that these workers were historically exposed to concentrations of chrysotile fibers perhaps 10 to 50 times greater than those of brake mechanics, but the risk of asbestosis, mesothelioma, and lung cancer, if any, was not apparent, except for those workers who had some degree of exposure to amphibole asbestos during their careers.
4.1.7 Hodgson et al. (2005):In a more recent analysis, Hodgson et al. (2005) modelled the expected burden of mesothelioma mortality in Great Britain, male mesothelioma deaths from 1968 to 2001 as a function of the rise and fall of asbestos exposure during the 20th century taking account of the difference between fibre types. Two models were fit to the data and the predicted exposure patterns compared with the actual exposure patterns based on imports of amosite and crocidolite. The authors state that chrysotile had zero weight in both (sic) models. Thus, the mesothelioma occurring in Great Britain since 1920 was explained by a combination of amosite and crocidolite reversing the earlier explanation of this as due to chrysotile (Peto et al., 1999). It is interesting to note that Peto who was first author on the 1999 publication is also a co-author of the Hodgson et al. (2005) publication which reverses the conclusion of the 1999 paper. Weill et al. (2004) have recently examined the temporal pattern and change in trend of mesothelioma incidence in the United States since 1973. They concluded that mesothelioma risk was prominently influenced by exposure to amphibole asbestos (crocidolite and amosite) which reached its peak usage in the 1960s and thereafter declined.
4.2 Recent epidemiological reviews and cohort studies
4.2.1 Yarborough (2006):Yarborough (2006) reviewed all available epidemiological studies to determine if chrysotile was a cause of mesothelioma. This review was prompted by the long-standing debate over the potential contribution of chrysotile to mesothelioma risk. Yarborough undertook an extensive review of the epidemiological cohort studies in order to evaluate the extent of the evidence related to free
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chrysotile fibers, with particular attention to confounding by other fiber types, job exposure concentrations, and consistency of findings. A total of 71 asbestos cohorts exposed to free asbestos fibers were reviewed. The authors concluded that the studiy “does not support the hypothesis that chrysotile, uncontaminated by amphibolic substances, cause mesothelioma”.
4.2.2 Carel et al., (2006):Carel et al., (2006) in a study led by the International Agency for Research on Cancer (IARC) the risk of lung cancer was examined following occupational exposure to asbestos and man-made vitreous fibers in a multi-center case-control study in Europe. Two regions were studied in this program, six Central and Eastern European countries and the UK, during the period 1998-2002. Comprehensive occupational and socio-demographic information was collected from 2205 newly diagnosed male lung cancer cases and 2305 frequency matched controls. Adjustment was made in the odds ratios (OR: The odds ratio is a way of comparing whether the probability of a certain event is the same for two groups; an OR of 1 or less indicates no effect. Even if the OR is greater than 1, if the lower bound of the 95 % confidence interval (CI) is 1 or less then the OR is not different statistically from 1 ).An OR of 1 or less indicates no effect. Even if the OR is greater than 1, if the lower bound of the 95 % confidence interval (CI) is 1 or less then the OR is not different statistically from 1. ) to take into account other relevant occupational exposures and tobacco smoking. The OR for asbestos exposure was 0.92 (95% confidence interval (CI) 0.73-1.15) in Central and Eastern Europe and 1.85 (95%CI 1.07-3.21) in the UK. Similar ORs were found for exposure to amphibole asbestos. The OR for MMVF exposure was 1.23 (95%CI 0.88- 1.71) with no evidence of heterogeneity by country. The Central and Eastern European asbestos industry had been reliant upon Russia for supplying asbestos in the 30 to 50 years prior, when exposure would have been important for determining this outcome. Russia, then as now, uses chrysotile asbestos commercially. While not discussed directly in this publication, the differences in the ORs are readily understood, in terms of the by the fact that the UK was the largest importer and users of amphibole per capita in the world. In comparison, in Central and Eastern Europe chrysotile alone was used. The Carel et al., (2006) study clearly demonstrates that when chrysotile alone was used as in Central and Eastern Europe, there is no measurable lung cancer risk.
4.2.3 White et al. (2008):South Africa, like Australia, represents a very particular situation in the history of the use of asbestos. Both these countries have been historically the major sources of amphiboles (crocodolite and amosite (in South Africa), and have used these varieties of asbestos locally along with chrysotile, which was also mined in both South Africa and Australia.
In both these countries, the number of mesothelioma cases have been much higher than anywhere else in the world. White et al. (2008) have indicated that 23% of cases in South Africa were found in persons never employed in mining, but were found associated with living in neighborhoods close to amphibole mining facilities, predominately one area with crocidolite mines, thus associated with « environmental » exposure. The authors conclude: "No cases [of mesothelioma] were associated with South African chrysotile. Consequently, in the vast majority of cases of mesothelioma, environmental exposure to asbestos
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occurred in the Northern Cape province, in proximity to mines, mills and dumps where crocidolite was processed. Crocidolite appears more mesotheliomagenic than amosite, and chrysotile has not been implicated in the disease. This is true for both occupationally and environmentally exposed individuals".
4.2.4 Berman and Crump, (2008).
The EPA models assume that there is no difference in the potencies of different types of asbestos (chrysotile or different varieties of amphibole asbestos) in causing lung cancer or mesothelioma and that risk can be predicted from exposures quantified using phase-contrast microscopy (The PCM counts only of fibers longer than 5 μm and thicker than approximately 0.25 μm). However, there is increasing evidence that neither assumptions of EPA models are valid, which could account for the disparate estimates of potency obtained in different environments (Berman and Crump, 2003).
Berman and Crump (2008) provide a parallel analysis that incorporates data from studies published since the EPA 1986 and update the EPA health assessment document for asbestos (Nicholson 1986). The EPA lung cancer model assumes that the relative risk varies linearly with cumulative exposure lagged 10 years. This implies that the relative risk remains constant after 10 years from last exposure. The EPA mesothelioma model predicts that the mortality rate from mesothelioma increases linearly with the intensity of exposure and, for a given intensity, increases indefinitely after exposure ceases, approximately as the square of time since first exposure lagged 10 years.
Using the EPA models, lung cancer potency factors (KL’s) and Mesothelioma potency factors (KM’s) were estimated from the three sets of raw data and also from published data covering a broader range of environments than those originally addressed in the EPA 1986 update. Uncertainty in these estimates was quantified using “uncertainty bounds” that reflect both statistical and nonstatistical uncertainties. KL’s were developed from 20 studies from 18 locations, compared to 13 locations covered in the EPA 1986 update. KM’s were developed for 12 locations compared to four locations in the EPA 1986 update. Although the 4 locations used to calculate KM in the EPA 1986 update include one location with exposures to amosite and three with exposures to mixed fiber types, the 14 KM’s derived in the present analysis also include 6 locations in which exposures were predominantly to chrysotile and 1 where exposures were only to crocidolite.
The KM’s showed evidence of a trend, with lowest KM’s obtained from cohorts exposed predominantly to chrysotile and highest KM’s from cohorts exposed only to amphibole asbestos, with KM’s from cohorts exposed to mixed fiber types being intermediate between the KM’s obtained from chrysotile and amphibole environments. Despite the considerable uncertainty in the KM estimates, the KM from the Quebec mines and mills was clearly smaller than those from several cohorts exposed to amphibole asbestos or a mixture of amphibole asbestos and chrysotile. Questions concerning the affect of fiber size and type were investigated more systematically in Berman & Crump 2008.
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4.2.5 Sichletidis et al., (2009):Sichletidis et al., (2009) reported on an investigation into the mortality rate among workers exposed to relatively pure chrysotile in an asbestos cement factory. The asbestos cement plant was opened in 1968 and the investigation covered all 317 workers. The plant used annually 2000 tons of chrysotile. Regular asbestos fiber measurements were made and the day and cause of death recorded among active and retired workers. Asbestos fiber concentrations were always below permissible levels. Fifty-two workers died during the study. The cause was cancer in 28 subjects; lung cancer was diagnosed in 16 of them. No case of mesothelioma was reported. Death was attributed to cardiovascular diseases in 23 subjects and to liver cirrhosis in 1. Overall mortality rate was significantly lower than that of the Greek general population, standardized mortality ratio (SMR) was 0.71 (95% CI 0.53–0.93). Mortality due to cancer was increased (SMR: 1.15, 95% CI 0.77–1.67), mainly due to lung cancer mortality (SMR: 1.71, 95% CI 0.98–2.78), but not significantly. The authors concluded that occupational exposure to relatively pure chrysotile within permissible levels was not associated with a significant increase in lung cancer or with mesothelioma. Decreased overall mortality of workers indicates a healthy worker effect, which – together with the relatively small cohort size – could have prevented the detection of small risks.
4.2.6 Paoletti & Bruni (2009):Paoletti & Bruni (2009) reported on the size distribution of amphibole fibers from lung and pleural tissue samples of mesothelioma cases due to environmental exposure. This study was initiated in order to evaluate the hypothesis that fibers less than 5 µm long could enter the pulmonary pleural barrier and reach the parietal pleural thus inducing mesothelioma. The size of amphibole fibers from healthy lung tissue was compared with those from pleural tissue samples from subject whose death cause was mesothelioma. We note that this hypothesisis is flawed in that recent research emphasises failure of long fibres that reach the pleural space to clear through the parietal pleural stomata, that is the initiating event retaining fibre dose at the parietal mesothelium (see later). Four cases of mesothelioma due to environmental exposure were studied with the fibers from pleural tissue characterized by SEM with the chemical composition confirmed by x-ray microanalysis. The authors reported that the average length of fibers from the lung and pleural tissues taken from the same subject did not differ by more than 10 - 12%. Ninety-five percent of fibers found in the lung tissue had a length greater than 5 µm and 98% of the fibers found in the pleural tissues had a length greater than 5 µm. In addition the authors reported that the average diameter of fibers found in pleural tissue was 70% of the diameter of the fibers found in the lung tissues. The authors concluded that the experimental data obtained in this study confirmed the correlation between malignant mesothelioma and the presence in the lung and pleural tissues of fibers with a length greater, even much greater, than 4 - 5 µm, and that the hypothesis that the chief factors inducing mesothelioma are ‘ultrashort’ ‘ultrathin’ fibers appears rather weak.
4.2.7 Aguilar-Madrid et al. (2010):Aguilar-Madrid et al. (2010) reported on a study in which they carried out a case-control study of malignant pleural mesothelioma in 472 workers insured by the Mexican Institute of Social Security, all Valley of Mexico residents, with 119 incident cases and 353 controls. Unfortunately in the study
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there was no measure of exposure in any work environment in which asbestos was used. The authors "estimated" exposure in four categories based upon comparison with other studies. As a result there was no knowledge available of which fibers were used in the work environments.
Unfortunately for "asbestos" workers, the use of amphibole types (especially crocidolite, or mixtures containing amphiboles) was widespread in Mexico up to the 90s, in particular in the manufacture of fibro-cement pipes. As it is well known that clinical diagnosis of mesothelioma can be some 40-45 years after onset of exposure, mesothelioma cases that are diagnosed in 2010 may well relate to exposure conditions prevailing back in the 70s. For this reason, it is almost certain that more new cases will be diagnosed in the near future.
Because there was no measure of which fibers were used and their concentrations, it is impossible in this study to distinguish effects from chrysotile versus those from amphibole asbestos. In addition the recent confirmation of mesothelioma cases following exposure to naturally occurring erionite which outcrops over an area of central Mexico will produce difficulties in attributing cause to occupational cases (Ilgren et al., 2008a & 2008b).
4.2.8 Schneider et al., (2010):Schneider et al., (2010) reported on the measurement of asbestos fiber content of the lungs as it was associated with diffuse interstitial fibrosis (DPF). The asbestos fiber burden was determined in patients with diffuse pulmonary fibrosis who had a history of asbestos exposure in which their biopsies did not meet established criteria for asbestosis. This was compared to the fiber burden and confirmed asbestosis cases. The fiber burden analysis was performed using scanning electron microscopy and energy-dispersive x-ray analysis of lung parenchyma from 86 patients with DPF and 163 patients with asbestosis. The correlation of the number of asbestos fibers found for a quantitative degree of fibrosis was reported. Schneider et al., (2010) reported that the fibrosis scores of the asbestosis cases correlated best with the number of uncoated commercial amphibole fibers.
4.2.9
[[Churg/Boutin - Almost all of the fibres found in the pleural spots were amphiboles and 22.5% of the fibres were longer than 5 µm.]]
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4.3 Other studies not included in these analyses also indicate that chrysotile produces little if any effect.
4.3.1 Boutin et al. (1996) & Müller et al. (2002)
Boutin et al. (1996) collected thoracoscopic biopsy samples from these black spots and from normal areas of the parietal pleura and lung from 14 subjects (eight with and six without asbestos exposure). Asbestos content was determined by transmission electron microscopy. In exposed subjects, mean fiber concentrations were 12.4 ± 9.8 x 106 fibers/g of dry tissue in lung, 4.1 ± 1.9 in black spots, and 0.5 ± 0.2 in normal pleura. In unexposed subjects, concentrations were 0, 0.3 ± 0.1, and 0, respectively. Amphiboles outnumbered chrysotile in all samples and a total of 22.5% of fibers were ≥ 5 µm in length in black spots. The authors concluded “that the distribution of asbestos fibers is heterogeneous in the parietal pleura. Indeed, the fibers concentrate in black spots, where they can reach high concentrations. These findings could explain why the parietal pleura is the target organ for mesothelioma and plaques.”
Müller et al. (2002) examined the morphology of black spots in order to understand their formal pathogenesis and their role in the development of malignant mesotheliomas. They analysed morphologically and by energy dispersive X-ray analysis 12 black spots (4 surgical and 8 autopsy specimens) located in the parietal pleura. The pleural black spots were found to develop in close correlation to lymphatic channels and blood vessels and were associated with a mild fibrosis and an inflammatory reaction to the foreign particles with the formation of hyaline granulomas. Aluminum, silicone and sometimes fibres were found.
4.3.2 Rees et al. (1999, 2001):Rees et al. (1999, 2001) reported that while South Africa is noted for amphibole mining it has also mined about 100,000 tons of chrysotile per year. Cases of mesothelioma have not been found in the South African chrysotile miners and millers despite decades of production. The authors suggest one possible explanation for the scarcity or absence of the cancer may be the relative lack of fibrous tremolite, an amphibole that occurs in some chrysotile ores deposits.
4.3.3 Camus et al. (1998):Non-occupational studies such as that reported by Camus et al. (1998) examined the effect of chrysotile on non-occupationally exposed women in two mining areas in the province of Quebec. Mean ambient exposure concentrations were estimated to have peaked around 1945 at approximately 1 – 1.4 f/cm3. Average total cumulative life-time exposure was estimated as 25 fiber-ml/year. The authors reported that there was no measurable excess risk of death due to lung cancer among women in two chrysotile-asbestos–mining regions.
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4.4 Toxicology Studies in experimental animals:
As discussed above, the early toxicology studies were just as difficult to interpret as the early epidemiological studies. Concentration was determined using gravimetric techniques without consideration of fiber number or fiber length and diameter and little consideration was given to the dose, and the length and diameter distribution of the fibers to which the animals were exposed.
While well-designed chronic inhalation toxicology studies of synthetic vitreous fibers (SVFs) have been performed, few chronic inhalation toxicology studies of asbestos have been performed with similar high standard. McConnell, et al. (1999) reported on perhaps the only well designed multiple-dose study of any asbestos where amosite particle and fiber number and length were chosen to be comparable to the SVF exposure groups. In this hamster inhalation toxicology study the amosite aerosol concentration ranged from 10 to 69 long fibers (> 20 µm)/cm3 with exposure levels selected based upon a previous, multi-dose 90-day subchronic inhalation study (Hesterberg et al., 1999). In the chronic study, the high dose amphibole amosite asbestos exposure resulted in 19.5 % mesotheliomas.
In a well-designed short-term exposure study in the rat (6 hours/day, 5 days) with the amphibole tremolite asbestos at an exposure concentration of 100 long fibers (> 20 µm)/cm 3, interstitial fibrosis developed within 28 days after cessation of the 5 day exposure (Bernstein et al., 2005). This 90-day sub-chronic inhalation study has been performed using similar fiber selection techniques and without exceeding lung overdose, in contrast with earlier studies as reported above (3.2).
4.4.1 The use of sub-chronic inhalation toxicology studies in the evaluation of fiber toxicity:
The 90-day sub chronic toxicity study has been used extensively in regulatory evaluation. The use of this and other shorter term studies for the evaluation of the toxicity and potential carcinogenicity of fibers was reviewed by an ILSI Risk Science Institute Working Group (ILSI, 2005). This working group was sponsored by the ILSI Risk Science Institute and the U.S. Environmental Protection Agency Office of Pollution Prevention and Toxics.
The objectives of the working group were:1. To summarize the current state of the science on short-term assay systems for assessing potential fiber toxicity and carcinogenicity of natural and synthetic fibrous materials. 2. To offer insights and perspectives on the strengths and limitations of the various methods and approaches. 3. To consider how the available methods might be combined in a testing strategy to assess the likelihood that particular fibers may present a hazard and therefore may be candidates for further (e.g., long-term) testing.
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Current testing methods were reviewed and testing strategies were recommended for prioritizing fibers for chronic testing. The working group reiterated the importance of dose, dimensions, biopersistence in the lung, and in some cases surface reactivity of the fibers as critical parameters related to adverse health effects (ILSI, 2005).
The working group stated that current short-term testing methods, defined as 3 months or less in exposure duration, evaluate a number of endpoints that are considered relevant for lung diseases induced by fibers such as asbestos. Subchronic studies to assess biomarkers of lung injury (e.g., persistent inflammation, cell proliferation, and fibrosis) are considered to be more predictive of carcinogenic potential than in vitro measures of cellular toxicity. Of particular importance in the evaluation of fiber toxicity using the 90 day sub chronic inhalation toxicity study is the finding that:
“All fibers that have caused cancer in animals via inhalation have also caused fibrosis by 3 mo. However, there have been fibers that have caused fibrosis but not cancer. Therefore, in vivo studies that involve short-term exposure of rat lungs to fibers and subsequent assessment of relevant endpoints, notably fibrosis, are probably adequately conservative for predicting long-term pathology— that is, will identify fibers that have a fibrogenic or carcinogenic potential.”
The working group also recommended that specific parameters should be measured in 90 day fiber inhalation studies, which have been noted in the U.S. EPA Guideline for Combined ChronicToxicity/CarcinogenicityTesting of Respirable Fibrous Particles (U.S. EPA, 2001). These parameters should include lung weight, fiber lung burden and clearance, cell proliferation, inflammatory response markers, and histopathology. The European Commission guideline for subchronic inhalation toxicity testing of synthetic mineral fibers in rats (European Commission, 1999b) specifies similar parameters.
Bellmann et al. (2003) reported on a calibration study to evaluate a number of endpoints in a 90-day subchronic inhalation toxicity study, which compared the toxicity of a number of SVFs having a range of biopersistences with that of the very biodurable amosite asbestos. One of the SVFs tested was a calcium-magnesium-silicate (CMS) fiber, a relatively biosoluble fiber, for which the stock preparation had a large concentration of non-fibrous particles in addition to the fibers. In this study, due to the method of preparation, the aerosol exposure concentration for the CMS fiber was 286 fibers/cm3
length < 5µm, 990 fibers/cm3 length > 5µm, and 1793 particles/cm3, a distribution which is not observed in manufacturing. The total CMS exposure concentration was 3,069 particles/fibers /cm 3. The authors pointed out that “The particle fraction of CMS that had the same chemical composition as the fibrous fraction seemed to cause significant effects.” For the CMS fiber, the authors reported that the number of polymorphonuclear leukocytes (PMN) in the bronchoalveolar lavage fluid (BALF) was higher and interstitial fibrosis was more pronounced than had been expected on the basis of biopersistence data. In addition, the interstitial fibrosis persisted through 14 weeks after cessation of the 90-day exposure. This effect was attributed to the large number of non-fibrous particles in the exposure aerosol--50% of the aerosol was composed of non-fibrous particles and short fibers.
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By comparison, after chronic inhalation exposure of rats to another CMS fiber, X607 fiber, which had considerably fewer non-fibrous particles present, no lung tumours or fibrosis was detected (Hesterberg et al., 1998b). This provides support for the argument that it was the large non-fibrous component of the CMS used in the Bellmann study and the resulting lung overload that caused the pathogenicity observed with this relatively biosoluble fiber. A similar overload mechanism might explain the results of earlier chrysotile inhalation studies, in which animals were exposed to much higher levels of non-fibrous particles and short (< 5 µm) fibers.
Bernstein et al. (2006) reported on the toxicological response of a commercial Brazilian chrysotile following exposure in a multi-dose sub chronic 90 day inhalation toxicity study, which was performed according to the protocols mentioned above as specified by the U.S. EPA (2001) and the European Commission (1999b).
In this study, male Wistar rats were exposed to two chrysotile levels at mean fiber aerosol concentrations of 76 fibers L>20 μm/cm3 (3,413 total fiber/cm3; 536 WHO fiber/cm3) or 207 fibres L>20 μm/cm3 (8,941 total fiber/cm3; 1,429 WHO fiber/cm3). The animals were exposed using a flow past, nose only exposure system for five days per week, 6 h/d, during 13 consecutive weeks followed by a subsequent non-exposure period of 92 days. Animals were sacrificed after cessation of exposure and after 50 and 92 days of non-exposure recovery. At each sacrifice, the following analyses were performed on sub-groups of rats: lung burden; histopathological changes; cell proliferation; inflammatory cells in the broncho-alveolar lavage ; clinical biochemistry; and confocal microscopic analysis.
Exposure to chrysotile for 90 days and 92 days of recovery, at a mean exposure of 76 fibres L>20 μm/cm3 (3,413 total fiber/cm3) resulted in no fibrosis (Wagner score 1.8 to 2.6) at any time point. The long chrysotile fibers were observed to break apart into small particles and smaller fibers. At an exposure concentration of 207 fibres L>20 μm/cm3 (8,941 total fiber/cm3) slight fibrosis was observed. In comparison with other studies, the lower dose of chrysotile produced less inflammatory response than the biosoluble synthetic vitreous CMS fiber referred to above and considerably less than amosite asbestos (Bellmann et al. 2003).
In contrast, tremolite (amphibole asbestos) exposure for five days (6 h/d) at an aerosol concentration of 100 fibers L> 20 µm/cm3 (2,016 total fiber/cm3) resulted in extensive inflammatory response with interstitial fibrosis observed within 28 days after cessation of exposure (Bernstein et al. 2005).
4.4.2 The role of biopersistence and fiber length in chronic carcinogenicity:
In an analysis that provided the basis for the European Commission’s Directive on synthetic mineral fibers, Bernstein et al. (2001a & 2001b) reported on the correlation between the biopersistence of fibers longer than 20 µm and the pathological effects following either chronic inhalation or chronic intra-peritoneal injection studies.
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This analysis showed that it was possible, using the clearance half-time of SVFs longer than 20 µm, which was determined from the inhalation biopersistence studies, to predict:
1) the number of fibers longer than 20 µm remaining in the lung following a 24 month chronic inhalation exposure;
2) the early fibrotic response (collagen deposition) observed after 24 months of exposure in the chronic inhalation toxicology studies; and
3) the number of tumours and fiber dose in the chronic intraperitoneal injection studies.
For SVFs, the clearance half-time of fibers longer than 20 µm ranged from a few days to less than 100 days.
Biopersistence studies were performed on serpentine (chrysotile) and amphibole asbestos using the same protocol. In these studies, chrysotile asbestos (with a clearance half-time for fibers longer than 20 µm of 0.3-11.4 days) was much more biosoluble than the amphibole asbestos types (clearance half-time for fibers longer than 20 µm of 500 days)—in fact chrysotile was even more biosoluble than most of the SVFs.
For synthetic vitreous fibers, the European Commission has established a Directive, which states that, if the inhalation biopersistence clearance half-time of a fiber is less than 10 days, then it is not classified as a carcinogen.
4.4.3 Fiber translocation to the pleural cavity:
Bernstein et al. (2010):In a recent study by Bernstein et al. (2010), the pathological response and translocation of a commercial chrysotile product similar to that which was used through the mid-1970s in a joint compound intended for sealing the interface between adjacent wall boards was evaluated in comparison to amosite-asbestos. This study was unique in that it presented a combined real-world exposure and was the first study to investigate whether there were differences between chrysotile and amosite asbestos fibers in time course, size distribution, and pathological response in the pleural cavity. Rats were exposed by inhalation 6 h/day for 5 days to either sanded joint compound consisting of both chrysotile fibers and sanded joint compound particles (CSP) or amosite-asbestos.
The mean number was 295 fibers/cm3 for chrysotile and 201 fibers/cm3 for amosite. The mean number of WHO fibers (defined as fibers > 5 μm long, < 3 μm wide, and with length:width ratios > 3:1; WHO, 1985) in the CSP atmosphere was 1496 fibers/cm3, which was more than 10,000 times the OSHA occupational exposure limit of 0.1 fibers/cm3. The amosite-exposure atmosphere had fewer shorter fibers, resulting in a mean of 584 WHO fibers/cm3.
An important part of the Bernstein et al. (2010) study was to design procedures for evaluation of the pleural space while limiting procedural artefacts. These methods included examination of the diaphragm as a parietal pleural tissue and the in situ examination of the lungs and pleural space
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obtained from freeze-substituted tissue in deep frozen rats. The diaphragm was chosen as a representative parietal pleural tissue because at necropsy it could be removed within minutes of sacrifice with minimal alteration of the visceral lung surface. The area of the diaphragm chosen for examination included an important lymphatic drainage site (stomata) on the diaphragmatic surface. The use of both confocal microscopy and (SEM) enabled the identification of fibers as well as examination for possible inflammatory response. The examination of the pleural space in situ including the lung, visceral pleura, and parietal pleura in rats deep frozen immediately after termination provided a non-invasive method for determining fiber location and inflammatory response.
No pathological response was observed at any time point in the CSP-exposure group. The long chrysotile fibers (L > 20 μm) cleared rapidly (T1/2 of 4.5 days) and were not observed in the pleural cavity. In contrast, a rapid inflammatory response occurred in the lung following exposure to amosite resulting in Wagner grade 4 interstitial fibrosis within 28 days. Long amosite fibers had a T 1/2
> 1000 days in the lung and were observed in the pleural cavity within 7 days post exposure. By 90 days the long amosite fibers were associated with a marked inflammatory response on the parietal pleural. This study provides support that exposure to chrysotile fibers and joint compound particles following inhalation would not initiate an inflammatory response in the lung, and that the chrysotile fibers present do not migrate to, or cause an inflammatory response in the pleural cavity, the site of mesothelioma formation.
Donaldson et al., (2010):Donaldson et al., (2010) reviewed the hypothesis regarding the role of long fibre retention in the parietal pleura, inflammation and mesothelioma for the amphibole asbestos amosite, and for carbon nanotubes. This review synthesises new data with multi-walled carbon nanotubes (CNT) with the hypothesis developed for amphibole asbestos for the behaviour of long fibres in the lung and their retention in the parietal pleura leading to the initiation of inflammation and pleural pathology such as mesothelioma. The authors describe evidence that a fraction of all deposited particles reach the pleura and that a mechanism of particle clearance from the pleura exits, through stomata in the parietal pleura. They suggest that these stomata are the site of retention of long fibres which cannot negotiate them, leading to inflammation and pleural pathology including mesothelioma. Long fiber retention in the stomata, as a consequence of length-restricted clearance through the normal stomatal clearance system, initiates inflammation and pleural pathology including mesothelioma.
The authors conclude that this general hypothesis on the key role of fibre length restricted clearance from the pleural space as a mechanism for delivering a high, focussed, effective dose of long fibres to the mesothelial cells around the parietal pleural stomata, has important implications. These lie in future research into the mesothelioma hazard from HARN (High Aspect Ratio Nanoparticles) but also for our current view of the origins of asbestos-initiated pleural mesothelioma and the use of lung parenchymal fibre burden as a correlate of this tumour, which arises in the parietal pleura, not the lung parenchyma or visceral pleura.
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5 The Hit & Run theory:
As scientific studies began to demonstrate that chrysotile was rapidly removed from the lung following inhalation and that it is not biopersistent in the lung, those who thought that chrysotile was equally potent as the amphibole fibers were at a loss as to how to explain how this could happen. As further studies were published showing that a variety of chrysotiles from different sources all had very low biopersistence in the lung, those who still thought that chrysotile had high potency had to invent a concept to support such an idea. This concept that was invented was the hit-and-run theory. However, its designers had failed to take into account was that the hit-and-run theory is not supported by either toxicology studies, or the current concepts on human cancer etiology.
What the hit-and-run theory proposes is that when a chrysotile fiber briefly comes in contact with a cell, some event occurs which alters the cell without creating any inflammatory response. This single alteration is then maintained for hundreds if not thousands of cell generations until 30 or more years later when it eventually expresses itself as cancer. In other words, they propose that chrysotile, unlike every other fiber, produces no histological features in the lung or pleural cavity over the individual’s lifetime until the moment when cancer occurs.
A working group comprised of the leading experts in fiber toxicology was convened by ILSI/EPA to assess toxicology studies for the evaluation of fiber toxicity. In the subsequent publication (ILSI, 2005) the working group stated that in all studies with fibers which produced a carcinogenic outcome in experimental animals, these fibers also produced interstitial fibrosis by 90 days. These fibrotic lesions which are observed histologically, result from an intense inflammatory response in the lung that is initiated when the macrophages fail to remove longer fibers which are biopersistent.
Kagan (1988) reported that the histologic features of asbestosis can be detected in humans within months after the initial contact with asbestos. However, in contrast, the signs of asbestos-related disease usually are not radiologically detectable, even by the most sensitive imaging techniques, until after a latency period of at least a decade, and often considerably longer. There is, therefore, a long diagnostic delay between the time when asbestosis is histologically detectable and when it is radiographically detectable.
Inflammation has long been associated with the development of cancer (Rakoff-Nahoum 2006). The mechanisms responsible for asbestos carcinogenicity are being elucidated and linked to the secretion of tumor necrosis factor-α (TNF-α) by mesothelial cells and macrophages exposed to asbestos that in turn leads to nuclear factor kappa B (NF-B) activation. The activation of the NF-B pathway in mesothelial cells allows these cells to survive the toxic insult and the genetic damage caused by asbestos, and these damaged cells may proliferate into a mesothelioma (Pass, et al., 2008).
Oddly, biopersistence is proposed as a determinant of fibre toxicity among substitute fibres but not among natural mineral fibres, in contradiction with prevailing concepts today.
Recently published evidence should put to rest the “hit-and-run phenomenon” used by some authors to implicate chrysotile in causing mesothelioma. The “hit-and-run" view and the universally recognized importance of biopersistence are completely contradictory. The former is unsupported
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speculation, the latter is based on solid toxicological evidence and is in line with epidemiological observations.
6 Threshold:
As reviewed above, recent updates of epidemiological studies are consistent with a practical threshold level of exposure to chrysotile below which no adverse effects are detectable.
The use of earlier epidemiological studies to evaluate threshold is impossible for two important reasons. Firstly, as already described in section 3.1, there was no quantitative assessment of either what fiber was used (that is chrysotile or amphibole asbestos) nor were the dimensions of the fibers determined. Secondly, these early epidemiological studies assessed exposures at very high concentrations usually without any controls to limit exposure in the workplace. Thus, the studies did not have the ability to assess the effect that might occur with the use of chrysotile alone at controlled use exposure levels. As many of the studies involved mixed exposure of amphibole asbestos and chrysotile, even small quantities of amphibole asbestos as has been seen in the inhalation toxicology studies, can significantly change the dose response relationship. Even with these shortcomings analysis of the earlier epidemiological studies by Hodgson & Darnton (2000) demonstrated a large difference in potency between chrysotile and amphibole asbestos.
The recent inhalation toxicology studies reviewed in section 4.4 have shown that chrysotile is rapidly removed from the lung and that in a sub-chronic 90-day inhalation toxicology study did not produce any pathological response at an exposure concentration of 5000 times current TLVs. In contrast, the amphibole asbestos amosite, following just a five-day inhalation exposure, produced an intense inflammatory response leading to interstitial fibrosis within 28 days.
These results have been confirmed in recent epidemiological studies reviewed in section 4.1 of workers in Canada, Eastern Europe, Greece, the United States, and Australia which have demonstrated that low exposure to chrysotile is not associated with a carcinogenic response.
7 Proposed Substitutes for chrysotile:
When the inclusion of chrysotile asbestos was discussed at the tenth meeting of the Intergovernmental Negotiating Committee of the Rotterdam convention, a number of delegates were concerned about the lack of information on the health effects of alternative to chrysotile. Information on such alternatives was necessarily limited to that which the notifying countries had considered, and may not be complete.
The Committee (RC) requested the International Programme on Chemical Safety (WHO) to undertake, as soon as possible, an evaluation of chrysotile and its alternatives. The representative of the World Health Organization (WHO) advised the Committee that IPCS had conducted an assessment of chrysotile in 1998 and conveyed the willingness of the WHO to work on only the health assessment of alternatives to chrysotile. The WHO refused to consider the large body of
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scientific literature published since 1998 (Report presented at the Observers meeting at the IARC Substitutes Workshop (see below) by Shelia Logan, secretary to the Rotterdam Convention on Prior Informed Consent Procedure for Certain hazardous chemicals and pesticides in international trade). The Committee agreed that the Interim Chemical Review Committee should identify appropriate alternatives for IPCS to review. At its fifth session, the Interim Chemical Review Committee reviewed a list of alternatives to chrysotile asbestos submitted by governments, and submitted this list to the World Health Organization. The list prioritized substances which were identified by a number of governments, and, where possible, on the importance of the uses identified. The WHO delegated the International Agency for Research on Cancer (IARC) to perform the review on only the substitutes to chrysotile.
The WHO Workshop on Mechanisms of Fibre Carcinogenesis and of Assessment of Chrysotile Asbestos Substitutes took place in Lyon, France on 9-12 November 2005.
As stated in the WHO Guidance on the scope of workshop discussions:Prepared by the Secretariat in response to questions received from participants: “The workshop comprised general discussions on the mechanisms of fibre carcinogenesis (Part 1) and an assessment of some chrysotile substitutes (Part 2).” “An assessment of chrysotile per se was not within the workshop scope.” In addition, the WHO clearly stated that this was a hazard evaluation, not a risk assessment.
Fourteen substances (fiber types) were evaluated and included: Aramid and para-aramid, Attapulgite, Carbon fibres, Cellulose fibres, Graphite whiskers, Magnesium sulfate whiskers, Polyethylene fibres, Polypropylene fibres, Polyvinyl alcohol fibres, Polyvinyl chloride fibres, Potassium octatitanate fibres, Synthetic vitreous fibres, Wollastonite, and Xonotlite.
The report from this meeting was issued 3 years later on 9 October 2008 and was entitled: Report of the World Health Organization workshop on mechanisms of fibre carcinogenesis and assessment of chrysotile asbestos substitutes (IARC, 2008). It was published by the Rotterdam Convention on the Prior Informed Consent Procedure for Certain Hazardous Chemicals and Pesticides in International Trade Conference of the Parties Fourth meeting Rome, 27–31 October 2008, document UNEP/FAO/RC/COP.4/INF/16.
The results from this evaluation are summarized below. For each fiber type three main areas were evaluated: epidemiology, toxicology and biopersistence.
7.1 Epidemiology of Substitutes: Of the 14 fiber types evaluated, only one fiber type had epidemiological data available, synthetic vitreous fibers. For all other fiber types there was no data. In the IARC monograph volume 82 on synthetic vitreous fibers, the working group considered that the epidemiological data available was insufficient in making a classification.
7.2 Toxicology of Substitutes:Of the 14 fibers evaluated, seven fiber types had no toxicological data available. These are:
Carbon fibres No data are available
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Graphite whiskers No data are available.
Magnesium sulfate whiskers No data are available.
Polyethylene fibres No data are available.
Polyvinyl alcohol fibres No data are available.
Polyvinyl chloride fibres No data are available on fibrous PVC.
Xonotlite Carcinogenicity by inhalation: No data are available.
Of the remaining seven fiber types for which there is some toxicological data, only one fiber was found not to be carcinogenic and one fiber not fibrogenic in the limited studies available. All of the other fiber types as shown below produced fibrosis or cancer in the studies evaluated, sometimes such as with para-aramid at very low fiber concentrations.
Aramid and para-aramid : Produces fibrosis at 25 fibers/cm3 in a 90 day inhalation toxicity study
Attapulgite Carcinogenic by inhalation, IT & IP
Cellulose fibres Carcinogenic by intraperitoneal injection
Polypropylene fibres No Fibrosis / Carcinogenicity: No data available
Potassium octatitanate fibres Carcinogenic by intraperitoneal injection
Wollastonite Not carcinogenic in limited studies available
7.3 Biopersistence of Substitutes:Of the 14 fibers evaluated, the following six fiber types had no data available on biopersistence:
Attapulgite No data are available
Magnesium sulfate whiskers No data are available
Polyethylene fibres No data are available
Polyvinyl alcohol fibres No data are available
Polyvinyl chloride fibres No data are available
Xonotlite No data are available
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Of the remaining eight fiber types, only Wollastonite and a subset of the synthetic vitreous fibers had low Biopersistence, all other fiber types had medium to high biopersistence. In addition, all of the fiber types for which there were Biopersistence data available displayed considerably greater biopersistence than commercial chrysotile.
Aramid and para-aramid: lung clearance half-life was approximately 30 days
Carbon fibres: High biopersistence
Cellulose fibres High biopersistence
Graphite whiskers High biopersistence
Polypropylene fibres High biopersistence
Potassium octatitanate fibres High biopersistence
Synthetic vitreous fibres Low to medium biopersistence
Wollastonite Low biopersistence
8 General conclusions:
In 1986, the International Labour Organisation’s (ILO) ”Asbestos Convention No 162” provided that national laws or regulations shall prescribe the measures to be taken for the prevention and control of health hazards due to occupational exposure to asbestos. Article 3(2) of the Convention specified that these measures ”shall be periodically reviewed in the light of technical progress and advances in scientific knowledge”.
In the following years, the epidemiological data which formed the basis for evaluations such as those by the IPCS in the 1990s still had considerable uncertainty due to the inability to accurately determine what the workers were exposed to. In addition, the toxicological data presented in these evaluations was performed at exceedingly high exposure concentrations without regard to fiber size distribution and as such has been shown to exceed lung overload concentrations negating their ability to be used in differentiatingone fiber from another.
The last review of chrysotile was published by the WHO/IPCS in 1998. It was based upon a meeting of the Task Group on Environmental Health Criteria for Chrysotile in July 1996. Since then, numerous studies have been published, which show that chrysotile is much less potent than amphibole asbestos. This was reflected as well in a subsequent WHO report (Concha-Barrientos et al, 2004, pages 1687 –1689). The current epidemiological and toxicological studies clearly differentiate chrysotile from amphibole asbestos and show that amphibole is many orders of magnitude more potent than chrysotile. The inhalation studies on commercial chrysotile show that it
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is not toxic at concentrations much higher than the current workplace limit levels, while amphiboles even after a few days of exposure have been shown to produce severe inflammation and fibrosis both in the lung and in the pleural cavity. The large data base of mineralogical studies from the 1950s to the present fully supports these results and provides explanations why chrysotile is so different from amphibole asbestos.
In fact, all these results are supported by more than 70 peer-reviewed scientific publications which have been published since the 1996 IPCS Task Group meeting. Much of the “Further Research” recommended in Chapter 11 of the IPCS WHO 203 has now been carried out. Thus, the justification for revisiting and updating the health risk associated with exposure to chrysotile at current workplace limit levels is abundantly clear and timely.
The numerous more recent epidemiological studies performed in working environments which occur with chrysotile today at mandated low exposure levels have all shown chrysotile to have little or no potential to cause disease. The more recent quantitative inhalation toxicology studies of chrysotile and amphibole asbestos, have all clearly shown that chrysotile is rapidly removed from the lung following inhalation and produces no significant inflammatory response in even very high exposure concentrations. In a recent study, chrysotile was found not to translocate to the pleural cavity following inhalation and did not produce any inflammatory response in the pleural cavity.
In contrast, amphibole asbestos such as amosite fibers have been shown to induce interstitial fibrosis in a few weeks following a short five day exposure and also have been shown to translocate quickly to the pleural cavity where they initiate a marked inflammatory response.
Regarding the substitutes, the Report of the World Health Organization “Workshop On Mechanisms Of Fibre Carcinogenesis And Assessment Of Chrysotile Asbestos Substitutes” has clearly reported that there is very little scientific basis for the evaluation of the proposed substitutes for chrysotile. For many of the fiber types, the limited data available would suggest that they should be of considerably greater concern than chrysotile.
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9 References:
Addison J and Davies LST (1990) Analysis of amphibole asbestos in chrysotile and other materials. Ann. Occup. Hyg. 34 :159-175
Aguilar-Madrid G, Robles-Pérez E, Juárez-Pérez CA, Alvarado-Cabrero I, Rico-Méndez FG, Javier KG. Case-control study of pleural mesothelioma in workers with social security in Mexico. Am J Ind Med. 2010 Mar;53(3):241-51.
Ashcroft T. 1973, Epidemiological and quantitative relationships between mesothelioma and asbestos on Tyneside. J Clin Pathol. 1973 Nov;26(11):832-40.
Bellmann B, Muhle H, Creutzenberg O, Ernst H, Müller M, Bernstein DM, Riego Sintes JM. Calibration study on subchronic inhalation toxicity of man-made vitreous fibers in rats. Inhal Toxicol. 2003 Oct;15(12):1147-77.
Berman, D.W., Crump, K.S., 2003. Draft technical support document for a protocol to assess asbestos-related risk. Washington, DC 20460: Office of Solid Waste and Emergency Response U.S. Environmental Protection Agency.
Berman DW, Crump KS. 2008. A meta-analysis of asbestos-related cancer risk that addresses fiber size and mineral type. Crit Rev Toxicol. 38 Suppl 1:49-73
Bernstein et al. (2010) recent review by Bernstein et al. (2010), the available chronic inhalation studies with chrysotile
Bernstein, D.M. 2007. Synthetic Vitreous Fibers: A review toxicology, epidemiology and regulations. Critical Reviews in Toxicology, 37:10, 839 – 886.
Bernstein, D.M., Riego Sintes, J.M., Ersboell, B.K., Kunert, J., 2001a. Biopersistence of synthetic mineral fibers as a predictor of chronic inhalation toxicity in rats. Inhal. Toxicol. 13 (10), 823–849.
Bernstein, D.M., Riego Sintes, J.M., Ersboell, B.K., Kunert, J., 2001a. Biopersistence of synthetic mineral fibers as a predictor of chronic inhalation toxicity in rats. Inhal. Toxicol. 13 (10), 823–849.
Bernstein, D.M., Rogers, R., Smith, P., 2005a. The biopersistence of Canadian chrysotile asbestos following inhalation: final results through 1 year after cessation of exposure. Inhal. Toxicol. 17 (1), 1–14.
Bernstein, D.M., Rogers, R.A., Sepulveda, R, Donaldson, K., Schuler, D., Gaering, S., Kunzendorf, P., Chevalier, J. and Holm, S. E. 2010. The pathological response and fate in the lung and pleura of chrysotile in combination with fine particles compared to amosite asbestos following short term inhalation exposure – interim results. Inhalation Toxicology 2010; 22(11): 937–962.
Bernstein, David M., Rogers, Rick, Chevalier, Jörg, Smith, Paul, 2006. The toxicological response of Brazilian chrysotile asbestos: A multidose sub-chronic 90-day inhalation toxicology study with 92 day
31
Draft 16 March 2011
recovery to assess cellular and pathological response. Inhal. Toxicol. 18 (5), 1–22.
Boutin C, Dumortier P, Rey F, Viallat JR, De Vuyst P. 1996. Black spots concentrate oncogenic asbestos fibers in the parietal pleura. Thoracoscopic and mineralogic study. Am J Respir Crit Care Med. 1996 Jan;153(1):444-9.
Breysse, P. N., Cherrie, J. W. Addison, J. and Dodgson, J. 1989 Evaluation of Airborne Asbestos Concentrations Using TEM And SEM During Residential Water Tank Removal. Ann. Occup. Hyg. Vol. 33, No. 2, pp. 243-256. 1989
Camus M, Siemiatycki J, Meek B. Nonoccupational exposure to chrysotile asbestos and the risk of lung cancer. N Engl J Med. 1998 May 28;338(22):1565-71.
Carel R, Olsson AC, Zaridze D, Szeszenia-Dabrowska N, Rudnai P, Lissowska J, Fabianova E, Cassidy A, Mates D, Bencko V, Foretova L, Janout V, Fevotte J, Fletcher T, 't Mannetje A, Brennan P, Boffetta P. Occupational exposure to asbestos and man-made vitreous fibres and risk of lung cancer: a multicentre case-control study in Europe. Occup Environ Med. 2007 Aug;64(8):502-8.
Churg A (1988). Chrysotile, tremolite and malignant mesothelioma. Chest 93 : 621-628
Dement JM, Harris RL Jr, Symons MJ, Shy C. Estimates of dose-response for respiratory cancer among chrysotile asbestos textile workers. Ann Occup Hyg. 1982;26(1-4):869-87.
Dement JM, Harris RL Jr, Symons MJ, Shy CM. Exposures and mortality among chrysotile asbestos workers. Part II: mortality. Am J Ind Med. 1983;4(3):421-33
Donaldson K, Murphy FA, Duffin R, Poland CA. Asbestos, carbon nanotubes and the pleural mesothelium: a review of the hypothesis regarding the role of long fibre retention in the parietal pleura, inflammation and mesothelioma. Part Fibre Toxicol. 2010 Mar 22;7:5.
Dreessen, W.C et al. (1938) A study of asbestosis in the asbestos textile industry. National Institute of Health, Public Health Bulletin No. 211, August 1938, pp 91-125.
Elmes PC, McCaughey WT, Wade OL. Diffuse Mesothelioma of the Pleura and Asbestos. Br Med J. 1965 Feb 6;1(5431):350-3
EUR 18748 EN, 1999. Methods for the determination of the hazardous properties for human health of man made mineral fibers (MMMF). Bernstein, D.M., Riego-Sintes, J.M.R. Vol. EUR 18748 EN, April. 93, http://ecb.ei.jrc.it/DOCUMENTS/Testing- Methods/mmmfweb.pdf: European Commission Joint Research Centre, Institute for Health and Consumer Protection, Unit: Toxicology and Chemical Substances, European Chemicals Bureau.Green FHY, Harley R, Vallyathan V, Althouse R, Fick G, Dement J, Mitha R Pooley FD. 1997. Exposure and mineralogical correlates of pulmonary fibrosis in chrysotile asbestos workers. Occup Environ Med; 54: 549-559.
Gross P, Cralley LJ, DeTreville RT. "Asbestos" bodies: their nonspecificity. Am Ind Hyg Assoc J. 1967 Nov-Dec;28(6):541-2
Hain E, Dalquen P, Bohlig H, Dabbert A, Hinz I. [Retrospective study of 150 cases of mesothelioma in
32
Draft 16 March 2011
Hamburg area (author's transl)] Int Arch Arbeitsmed. 1974 Mar 12;33(1):15-37.
Hesterberg TW, Axten C, McConnell EE, Hart GA, Miiller W, Chevalier J, Everitt J, Thevenaz P, Oberdörster G. Studies on the inhalation toxicology of two fiberglasses and amosite asbestos in the syrian golden hamster. Part I. Results of a subchronic study and dose selection for a chronic study. Inhal Toxicol. 1999 Sep;11(9):747-84.
Hesterberg TW, Hart GA, Chevalier J, Miiller WC, Hamilton RD, Bauer J, Thevenaz P. The importance of fiber biopersistence and lung dose in determining the chronic inhalation effects of X607, RCF1, and chrysotile asbestos in rats. Toxicol Appl Pharmacol. 1998 Nov;153(1):68-82.
Hesterberg TW, Miiller WC, McConnell EE, Chevalier J, Hadley JG, Bernstein DM, Thevenaz P, Anderson R. Chronic inhalation toxicity of size-separated glass fibers in Fischer 344 rats. Fundam Appl Toxicol. 1993 May;20(4):464-76.
Hodgson JT, Darnton A. The quantitative risks of mesothelioma and lung cancer in relation to asbestos exposure. Hodgson JT, Darnton A.
Hodgson JT, McElvenny DM, Darnton AJ, Price MJ, Peto J. The expected burden of mesothelioma mortality in Great Britain from 2002 to 2050. Br J Cancer. 2005 Feb 14;92(3):587-93
IARC, 2008, Report of the World Health Organization workshop on mechanisms of fibre carcinogenesis and assessment of chrysotile asbestos substitutes. 8–12 November 2005, Lyon, France. Published by the Rotterdam Convention on the Prior Informed Consent Procedure for Certain Hazardous Chemicals and Pesticides in International Trade Conference of the Parties Fourth meeting Rome, 27–31 October 2008, document UNEP/FAO/RC/COP.4/INF/16.
Ilgren, E.B., Mariana Ortega Breña, Javier Castro Larragoitia, Gustavo Loustaunau Navarrete, Alvar Fuentes Breña, Edgar Krauss, Guillermina Fehér: A Reconnaissance Study of a Potential Emerging Mexican Mesothelioma Epidemic due to Fibrous Zeolite Exposure. Indoor Built Environ 2008a;17;6:496–515
Ilgren, E.B., F.D. Pooley, J.C. Larragoitia,,M. Talamantes, G.L. Navarrete, E. Krauss, A.F. Breña: First Confirmed Erionite Related Mesothelioma in North America. Indoor Built Environ 2008b;17;6:567–568.]]
ILSI, 2005. Bernstein D, Castranova V, Donaldson K, Fubini B, Hadley J, Hesterberg T, Kane A, Lai D, McConnell EE, Muhle H, Oberdorster G, Olin S, Warheit DB; ILSI Risk Science Institute Working Group. Testing of fibrous particles: short-term assays and strategies. Inhal Toxicol. 2005 Sep;17(10):497-537.
Kagan E. Current issues regarding the pathobiology of asbestosis: a chronologic perspective. J Thorac Imaging. 1988 Oct;3(4):1-9.
Liddell FD, McDonald AD, McDonald JC. The 1891-1920 birth cohort of Quebec chrysotile miners and millers: development from 1904 and mortality to 1992. Ann Occup Hyg. 1997 Jan;41(1):13-36.
Mast, R.W., McConnell, E.E., Anderson, R., Chevalier, J., Kotin, P., Bernstein, D.M., Thevenaz, P., Glass, L.R., Miiller, W.C., Hesterberg, T.W., 1995. Studies on the chronic toxicity (inhalation) of four
33
Draft 16 March 2011
types of refractory ceramic fiber in male Fischer 344 rats, Inhal Toxicol 7(4):425-67
McConnell EE, Axten C, Hesterberg TW, Chevalier J, Miiller WC, Everitt J, Oberdörster G, Chase GR, Thevenaz P, Kotin P. Studies on the inhalation toxicology of two fiberglasses and amosite asbestos in the Syrian golden hamster. Part II. Results of chronic exposure. Inhal Toxicol. 1999 Sep;11(9):785-835.
McDonald AD, Case BW, Churg A, Dufresne A, Gibbs GW, Sébastien P, McDonald JC. Mesothelioma in Quebec chrysotile miners and millers: epidemiology and aetiology. Ann Occup Hyg. 1997 Dec;41(6):707-19.
McDonald AD, Harper A, McDonald JC, el-Attar OA. Epidemiology of primary malignant mesothelial tumors in Canada. Cancer. 1970 Oct;26(4):914-9.
McEwen J, Finlayson A, Mair A, Gibson AA. Mesothelioma in Scotland. Br Med J. 1970 Dec 5;4(5735):575-8.
Morris GF, Notwick AR, David O, Fermin C, Brody AR, Friedman M. 2004. Development of lung tumors in mutant p53-expressing mice after inhalation exposure to asbestos. Chest. May;125(5 Suppl):85S-6S
Müller KM, Schmitz I, Konstantinidis K. 2002. Black spots of the parietal pleura: morphology and formal pathogenesis. Respiration. 2002;69(3):261-7.
Newhouse ML, Thompson H. Mesothelioma of pleura and peritoneum following exposure to asbestos in the London area. Br J Ind Med. 1965 Oct;22(4):261-9.
Nicholson, W.J. 1986. Airborne asbestos health assessment update. Report 600/884003F. Washington, DC: U.S. Environmental Protection Agency
Paoletti L, Bruni BM. [Size distribution of amphibole fibres from lung and pleural tissues sampled from mesothelioma cases due to environmental exposure] Med Lav. 2009 Jan-Feb;100(1):11-20.
Pass, H.I., Vogelzang, N.T., Hahn, S.M., Carbone, M. 2008. Benign and Malignant Mesothelioma in Chapter 46: Devita, Hellman & Rosenberg's Cancer, Principles & Practice of Oncology, Eighth Edition, 978-0-7817-7207-5,
Paustenbach DJ, Finley BL, Lu ET, Brorby GP, Sheehan PJ. Environmental and occupational health hazards associated with the presence of asbestos in brake linings and pads (1900 to present): a "state-of-the-art" review. J Toxicol Environ Health B Crit Rev. 2004 Jan-Feb;7(1):25-80
Peto J, Decarli A, La Vecchia C, Levi F, Negri E. The European mesothelioma epidemic. Br J Cancer. 1999 Feb;79(3-4):666-72.
Rakoff-Nahoum S. Why cancer and inflammation? Yale J Biol Med. 2006 Dec;79(3-4):123-30. Review.
Rees D, Myers JE, Goodman K, Fourie E, Blignaut C, Chapman R, Bachmann MO. Case-control study of mesothelioma in South Africa. Am J Ind Med. 1999 Mar;35(3):213-22.
Rees D, Phillips JI, Garton E, Pooley FD. Asbestos lung fibre concentrations in South African chrysotile
34
Draft 16 March 2011
mine workers. Ann Occup Hyg. 2001 Aug;45(6):473-7.
Rubino GF, Scansetti G, Donna A, Palestro G. Epidemiology of pleural mesothelioma in North-western Italy (Piedmont). Br J Ind Med. 1972 Oct;29(4):436-42.
Schneider F, Sporn TA, Roggli VL. Asbestos fiber content of lungs with diffuse interstitial fibrosis: An analytical scanning electron microscopic analysis of 249 cases. Arch Pathol Lab Med. 2010 Mar;134(3):457-61.
Sichletidis L, Chloros D, Spyratos D, Haidich AB, Fourkiotou I, Kakoura M, Patakas D. Mortality from occupational exposure to relatively pure chrysotile: a 39-year study. Respiration. 2009;78(1):63-8. Epub 2008 Oct 9.
U.S. EPA, 2001 - U.S. EPA Health Effects Test Guidelines OPPTS 870.8355 Guideline for Combined ChronicToxicity/CarcinogenicityTesting of Respirable Fibrous Particles. EPA 712-C-01-352, July 2001.
Vorwald AJ, Durkan TM, Pratt PC. Experimental studies of asbestosis. A M A Arch Ind Hyg Occup Med. 1951 Jan;3(1):1-43.
Wagner JC, Berry G, Skidmore JW, Timbrell V. The effects of the inhalation of asbestos in rats. Br J Cancer. 1974 Mar;29(3):252-69.
Wagner JC, Berry G, Pooley FD. 1982. Mesotheliomas and asbestos type in asbestos textile workers : a study of lung content. BMJ; 285: 603-606
Weill H, Hughes JM, Churg AM. Changing trends in US mesothelioma incidence. Occup Environ Med. 2004 May;61(5):438-41.
White N, Nelson G, Murray J. South African experience with asbestos related environmental mesothelioma: is asbestos fiber type important? Regul Toxicol Pharmacol. 2008 Oct;52(1 Suppl):S92-6. Epub 2007 Oct 5.
WHO, World Health Organization. 1985. Reference methods for measuring airborne man-made mineral fibers (MMMF). WHO/EURO MMMF Reference Scheme. Copenhagen: World Health Organization.
Yarborough CM. Chrysotile as a cause of mesothelioma: an assessment based on epidemiology. Crit Rev Toxicol. 2006 Feb;36(2):165-87.
Zielhuis RL, Versteeg JP, Planteijdt HT. Pleura mesothelioma and exposure to asbestos. A retrospective case-control study in the Netherlands. Zielhuis RL, Versteeg JP, Planteijdt HT.
