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43. Neoplasms of the Pleura 579 Asbestos Fiber Types and Dose, and IVlesothelioma Risk and Induction lips it is well known that there exists a dose-response causal dationship between asbestos exposure and MM, for any lit fiber type or mixture39 (Table 43.8).288 In addition, the ||| amphibole varieties of asbestos are substantially more |H potent for MM induction than chrysotile42'288 (Table |g| 43.9),289 and an extensive review by Hodgson and J||' Darnton93 on the dose-response relationships between !H asbestos and mesothelioma risk estimated that the relaIH tive potencies for crocidolite, amosite, and chrysotile for jf mesothelioma induction are roughly 500:100:1, respec- jjf lively. However, in a subsequent analysis from Australia, U! based on lung tissue amphibole fiber concentrations |H allowing for clearance half-lives, Leigh and Robinson43 jjj calculated the potency ratios to be 26:14:1. respectively, id another set of potency ratios cited in the literature is jjf 30:15:1, respectively.42 |j. The factors that determine these differential potencies jH are sometimes summarized as the three D's: dose, dimen sions, and durability (i.e., biopersistence in tissue).42 Because of their wavy characteristics, chrysotile fibers appear to be trapped more readily within the upper airways and central bronchi than amphibole fibers (Figs. 43.2 and 43.3).290 In the circumstances of air flow through tubular airways, fibers tend to be concentrated in the central regions of the airway lumen where flow is laminar, with the long axes of fibers parallel to the direction of flow, and fractional deposition of fibers is determined by straight versus curly fiber characteristics and by the diam eter of the fibers, rather than their length.290 Accordingly, Middleton et al.291 found that the fraction of chrysotile deposited in rats was in the range of 17% to 36% of cro cidolite at varying inhaled concentrations, and the depos ited fraction of amosite was 65% of crocidolite. Other studies did not detect such differences, but there appears to be general agreement that for exposures in experimen tal animals lasting for 6 weeks or longer, the relative retention of amphibole fibers is greater than for chryso tile.290 Fibers and particles most likely to be deposited are those with an aerodynamic equivalent diameter in the range of about 1 to 5 pm, and the sites of greatest deposi tion are the bifurcations of terminal bronchioles.290 Table 43.8. Mesothelioma rates in groups exposed occupationally to asbestos, according to fiber types and duration Fiber type Industry Duration (years since first employed) Rale per 106 person-years Mixed fiber exposure: crocidolite. amosite. and chrysotile Textile manufacture and insulation Mixed fiber exposure: mainlv amosite Insulation workers Mixed fiber exposure: crocidolite and chrysotile Chrysotile. some crocidolite Fibrous cement manufacture Textile manufacture Amosite Mixed fiber exposure Insulation manufacture Dockyards Crocidolite Mining and milling 20-24 25-30 31 + 20-24 25-29 30-34 35-39 40-44 45+ 20-24 25-29 30-34 20-24 25-29 30-34 35-39 40+ 20-24 25-29 30-34 35+ 20-24 25-29 30-34 35-40 40-44 45-49 20-24 25-29 30-34 35-39 1520 1710 3180 290 1550 2760 6300 6330 8110 2700 6300 9600 108 143 1156 493 1774 744 2623 5078 1842 120 410 220 370 1240 1510 900 2200 3000 7000 Source: Modified from de Klerk NH. Armstrong BK. The epidemiology of asbestos and mesothelioma. In: Henderson DW, Shilkin KB, Langlois SL, Whitaker D, eds. Malignant mesothelioma, pp. 223-250. Copyright 1992 by Hemisphere. Reproduced with permission of Informa Healthcare Books via Copyright Clearance Center. (See same reference for detailed reference listing.) 580 S.P. Hammar et ai. Table 43.9. Different mineral fibers, their properties, and MM risks Fiber MM risk Aspect ratio3 Biopersistence Erionite (E) Amphiboie asbestos Crocidolite (C) Amosite (A) Tremoiite (T) Anthophyiiite High High High but less than C, E Probably high, ?<C Low High Persistent High High but less than C As for A Fairly low Persistent Persistent Persistent Persistent Chrysotile Fiberglass Ceramic/MMMF Low, not zero (disputed) Zero Not documented in humans Low Low High to low Poor; less than ail above Probably poor Probably as for amphiboles Human exposure Environmental and residential (Turkey) Occupational, nonoccupationai Occupational, nonoccupationai Environmental, some occupational Environmental, formerly restricted occupational (Finland) Occupational, nonoccupationai Occupational Experimental aLength: diameter ratio. MMMF, man-made mineral fibers. Source: Modified from Hammar.289 Once deposited, amphiboie fibers are more persistent in tissues than chrysotile. The clearance half-life in lung tissue has been estimated at 5 to 10 years for crocidolite292'293 (clearance rate is about 10% to 15% per year) and up to 20 years for amosite fibers,279 in comparison to 90 to 110 days for chrysotile (although one study294 recorded a longer clearance half-life of about 8 years for long chrysotile fibers among chrysotile miners/millers in Quebec). Clearance appears to be more effective for short than long fibers--although de Klerk et al.293 could find no difference between the clearance rates for long and short crocidolite fibers--so that the length of retained fibers increases with time after exposure.290 Clearance for chrysotile appears to involve both longitudinal and trans verse splitting and solubilization of fibers, so that such cleavage can increase the number of fibers per unit weight of lung even after cessation of exposure, before further clearance of fibers accompanied by a diminution in their numbers.38-295 To induce MM, deposited asbestos fibers presumably must first translocate to the pleura from the lung where they are deposited initially, but we know of no data on the precise mechanisms and rates at which translocation occurs in humans. However, Boutin et al.240 demonstrated that asbestos fibers are concentrated in parietal pleural "black spots" located near stomata on the parietal pleura. Amphiboles outnumbered chrysotile in all samples, and 22.5 % of fibers in black spots were >5 ,um in length, which might explain in part why the parietal pleura seems to be the target site for both MM and plaques, and why chryso tile is less potent than the amphiboles (whereas chrysotile appears to be no less potent than the amphiboles when fibers are implanted directly into the pleural cavity of experimental animals). Other studies have demonstrated the presence or even a predominance of chrysotile fibers in human pleural tissue (e.g., see the World Health Orga nization monograph Environmental Health Criteria 203: Chrysotile Asbestos,92 pp. 64-65). Translocation may take place by either migration of naked amphiboie fibers, or by ingestion of the fibers by macrophages followed by subsequent transport along lymphatic vessels to the subpleural lymphatic channels.290 Nonetheless, it seems worth emphasizing that studies on the persistence and clearance of fibers discussed above have focused on lung tissue, obviously not the site where MMs develop, and there appear to be no systematic data for humans on the clearance rates for fibers translocated to the pleura. The relationship between asbestos inhalation and the subsequent risk of mesothelioma can be expressed by the Peto model and its various modifications28836: where I is the incidence; k depends on fiber type, mix, size, and other site-specific variables; / is the intensity of exposure in fibers/mL; t is the time in years following exposure; and d is the exposure in years. For the purposes of modeling, variations of the basic equation have been proposed to account for latency period, multiple periods of exposure, weightings for different fiber types in the exposure history, and clearance rates.297 From the Peto model and its modifications, the following deductions can be inferred: Early exposures to asbestos are more significant for MM induction than later exposures, other factors being equal. When there are multiple episodes of exposure, each increment of exposure within an acceptable latency interval produces a corresponding increment in the risk/incidence of MM, dependent on the time of the exposure, its magnitude, and the types of asbestos fiber involved. This issue was discussed at some length in the World Trade Organization (WTO) report on asbestos (specifically chrysotile),42 and the dose-response rela tionship between asbestos and mesothelioma was illus- . . . 4: 1 i 1 \ * , ` ' 43. Neoplasms of the Pleura 581 trated in tabular form by de Klerk and Armstrong in 19922S8 (Tabie 43^ Is a Threshold or Minimal Level of Asbestos Exposure/Inhalation Required for Mesothelioma Induction? No minimum threshold dose of inhaled asbestos has been delineated below which there is no increase in the risk of mesothelioma.92-93,176-389,212,217 In a study on time trends and occupational risk factors for pleural mesothelioma in Sweden, based on the Swedish Family-Cancer Database, Hemminki and Li212 found an increasing age-adjusted incidence of pleural mesothelioma over the period 1961-- 1998, not only for occupations expected to be associated with asbestos exposure (manual and blue-collar workers), but also in professional groups and even farmers. In relation to the no-threshold model for mesotheli oma induction by asbestos, reviews and several casecontrol studies from Europe are of particular relevance and include the following: A review by Hillerdal363 on mesothelioma related to nonoccupational asbestos exposure was published in 1999. It is of particular interest in relation to mesothe liomas as a consequence of low-level exposures to asbestos. A review and meta-analysis by Bourdes et al.29S of the risk of pleural mesothelioma from environmental exposure to asbestos was published in 2000. These authors identified eight relevant studies on the risk of pleural mesothelioma from household or neighbor hood exposures to asbestos. These studies did not include the case-control studies outlined below. These authors found that the RRs of pleural mesothelioma for household exposure ranged between 4.0 and 23.7, with a summary risk estimate of 8.1 (95% Cl, 5.3-12). For neighborhood exposures, the RRs ranged between 5.1 and 9.3 with a summary estimate of 7.0 (95% Cl, 4.7-11). This analysis appears to be in reasonable agreement with the studies by Magnani et al.299,300 and Rodeisperger et al.3ui (see below). Bourdes et al.298 commented that their data were insufficient to esti mate the magnitude of excess risk at the levels of envi ronmental exposure commonly experienced by the general population in industrial countries (in other words, from the general environment). In a case-referent study reported from France by Iwatsubo et al.,91 it was found that the odds ratio for meso thelioma (ORMm) was 4.2 with low-dose exposures in the range of 0.5 to 0.99 fibers/mL-years (fiber-years). In this study, there was a clear dose-response trend from no exposure, through levels of 0.001 to 0.49 fiberyears, 0.5 to 0.99 fiber-years, 1.0 to 9.9 fiber-years, and >10 fiber-years with age and socioeconomic, class- adjusted ORs (RRs) of 1.0 (for no exposure), 1.2, 4.2, 5.2, and 6.7, respectively. Although the ORMm of 1.2 at 0.001 to 0.49 fiber-years did not achieve statistical sig nificance, further calculations show a highly significant trend. Furthermore, it has been suggested that this study lacked statistical power because the number of subjects was too small to detect an ORMm = 1-2 at the usual scientific level of significance. Accordingly, this study91 is not inconsistent with a no-threshold model. In a case-referent study reported from Germany by Rodeisperger et al.,301 the ORMm was >4.5 with lung tissue asbestos fiber concentrations in the range of 100,000 to 200,000 fibers longer than 5 pm per gram of dry lung tissue, and an ORMm of about 2 or more was recorded for lower lung tissue asbestos fiber concentra tions, in the range of 50,000 to 100,000 fibers longer than 5 pm per gram dry lung. In a meticulous case-referent analysis published in 2001 using individualized estimates of exposures, Rodeisperger et al.94 found that the ORMM was 7.9 with low exposures in the range of anything more than 0 to 0.15 fibers/mL-years (>0-0.15 fiber-years). Similar find ings were reported by Magnani et al.299 In a population-based study on the distribution of mesothelioma in California, after attempted allowance for occupational exposures, Pan et al.302 reported an apparent direct correlation between the odds of meso thelioma and proximity of residence according to the distribution of ultramafic rocks in the general envi ronment (serpentinite/ultramafic rocks in California contain mainly chrysotile, with some other forms of asbestos in some areas, such as tremolite). These authors found about a 6% reduction in the odds of mesotheli oma for residence for every 10 km further away from the ultramafic rocks. As set forth in their review on dose-response relation ships between asbestos and mesothelioma, Hodgson and Darnton93 estimated that a cumulative exposure of 1.0 fiber/mL-year for crocidolite yields a lifetime risk '`best" estimate of about 650 mesothelioma deaths/100,000 (range - 250-1500), 90/100,000 for amosite (range - 15-300), and 5/100,000 for chrysotile (range = 1-20). For a cumulative exposure of 0.1 fibers/ mL-years, these authors set forth a best estimate of about 100 deaths per 100,000 exposed for crocidolite, with a highest arguable estimate of 350 and a lowest of 25; for amosite, the corresponding figures were 15 deaths per 100,000, with a highest arguable estimate of 80 and lowest of 2; at this level of exposure, the risk for chrysotile was "probably insignificant," with a highest arguable estimate of four deaths per 100,000. For a cumulative exposure of 0.01 fibers/mL-years, the best estimate was about 20 deaths per 100,000 exposed for crocidolite, with a highest arguable estimate of 100 and a lowest of two; for amosite, the corresponding figures