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1 The biological sequence ofevents in the development of mesothelioma in rodents also appears to have a series ofprogressive steps (Boorman et a!., 1990). In inhalation studies, the first event that is observed is fibrosis in the pleura immediately subjacent to the mesothelial lining. This is multifocal in nature, possibly occurring more frequently in the interlobular pleura. In the few studies where the parietal pleura has been investigated (McConnell, et ai., 1999), the initial change was found in the noomuscular portion of the diaphragm and over the ribs (as compared to intercostal). The first indication of mesothelial change is found in these areas of pleural fibrosis. The mesothelial cells become cuboidal (as compared to a normal squamous morphology) and progress to focal hyperplasia of one to three cell layers thickness. The next step is the formation of papillary forms of growth and overgrowth of adjacent pleura. It is at this stage that mesothelioma is diagnosed. Pseudovacuolated tumor cells may be noted at this stage. Finally, the tumor evolves into the classical forms noted above. The course of events is somewhat different for instillation and injection studies. The initial response in the latter studies is inflammation, followed by a fibrogranulomatous reaction (assumed to be an attempt to wall off the fibers). A similar sequence ofprogression is assumed but results in a higher proportion of sarcomatous types of mesothelioma. Pulmonary interstitial fibrosis (see below for description) is invariably found in studies where. either asbestos or SVFs have caused either lung cancer or mesothelioma (Greim et al., 2001). However, there have been fiber studies where pulmonary fibrosis was observed without the development of fiber related neoplasms (McConnell, et al., 1994). In vitro studies may not be of high value for predicting the carcinogenic potential of a given type of fiber, although they can give some incite into the difference between the carcinogenicity of long and short fibers. There are several reasons for why they may not as useful for predicting the carcinogenic activity ofa given type. First, the fiber used is not subjected to physiological processes such as clearance and dissolution that are found in the lung Also, the in vitro test systems use "fresh" fibers so do not typically take into account pathology attenuating changes in fibers that occur over time in the lung. Finally, the in vitro "dose" may have no relevance to the lung fiber burden. However, not withstanding this, in vitro methods are highly powerful tools for understanding fiber/cell interactions and mechanisms of toxicity/carcinogenicity (see Mossman for details). Non-cancer effects: Animal models have also demonstrated many ofthe.same pathological responses that are.found in humans exposed to particulates (IARC, various volumes), the major noncancer endpoints that have been described in animals m experimental studies are phagocytosis, inflammation and pulmonary fibrosis. In regard to these endpoints, the rodent lung (and presumably.other species) reacts to asbestos and SVFs as. it would to any inhaled nonorganic foreign body that is not chemically toxic, e.g. beryllium. The lung can only react to such materials in a limited number of ways. In animals, if the particulate were deposited in the upper respiratory tract, one would assume that it would be possible for it to cause local irritation. However, this has not been observed in inhalation studies, even at high exposure levels. It is assumed that the resident time for such particles is brief, not allowing for a pathologic response. E-19 HWBUI0009736 The mucous layer in these tissues is relatively thick compared to the size of the particulate and the methods ofremoval are quite efficient. The same is true for the major airways. In experimental animals the airways are intact and have not been compromised by other toxicants as in humans, e.g. smoking. Therefore, particulates deposited on these surfaces are again efficiently removed via the mucociliary escalator and arc either swallowed or expectorated. In either case, the resident time in the body is relatively brief. For a particulate to cause pathology in experimental animals after inhalation, it must reach the alveolar region of the lung. Particulate size dictates whether this happens or not If the particle reaches terminal bronchiole it causes a foreign body reaction which is dictated by dose, particle (fiber) size and to some extent physical chemistry. The lungs' initial response is an attempt to remove the offending substance. This is accomplished by resident macrophages. If the particle is ofa size that the macrophage can engulf(phagocytize), it will be "captured and removed from the lung either by translocation to the airways or draining lymphatics. As the dose (number of particulates) increases, more macrophages are recruited. However, ifthe dose is too large for the number of available macrophages to remove, an "overload" situation develops which results in other pathologic events. Such events have been documented in animals both by histopathology and physiological tests (see Oberdorster for details). If the fiber is too large to be phagocytized and removed, i.e. longer than the size ofthe macrophage [~l 3 um diameter in rats and hamsters, monkeys ~15 um, and humans -21 um diameter (Krombach eta!., 1997)], die fiber cannot be removed unless it is broken into shorter lengths or dissolves (Maxim and McConnell, 2001). Both of the latter two phenomena have been observed with several SVFs (see below). If the dose overwhelms the physiological pulmonary defenses or the fiber is too large to be removed, the initial series ofevents in animals occur at the junction of the terminal bronchioles and proximal alveolar duct (this is where most of the fibers are initially deposited - It should be noted that rodents do not have a respiratory bronchiole, as do humans). In addition to a stimulating the local macrophages, ah influx ofadditional macrophages is recruited to the area. At this point, the local type D alveolar cells (in the proximal alveoli) undergo metaplasia to a cuboidal appearance and become hyperplastic. The resulting lesion has been termed "bronchiolization" because the change mimics the appearance ofthe jerminal airways. Increased amounts of mucous production and sometimes inspissation ofthe material often accompany this. Coincident to the bronchiolization, microgranulomas are observed. These appear to form from a coalition of macrophages and fibroblasts. At this time tbe 'micrdgrariulonias are restricted to the proximal portion ofthe alveolardiict, particularly along the alveolar duct ridge. With time and continued insult the process proceeds peripherally anrfbecomes more apparent: If the Offending fiber persists, collagen is laid down in the adjacent interstitium (presumably by direct invasion of the fiber into the epithelium jirid interstitium). At this time the lesion P referred to as interstitial fibrosis. In rodent studies, thefibrotic areas are initially focal and widely disseminated. But, if the insult persists or the dose is bightniough. fibrosis becomes more widespread. Various schemes have been developed to describe these events and grade them as to their severity for comparative purposes (McConnell et af, 1984: 2002). There is one notable difference between the qualitative appearance of the lesions produced by asbestos and SVFs in animals. Neutrophils E-20 HWBUI0009737 are often a prominent part of the inflammatory reaction with asbestos, especially with amphibotes, while they are rarely found in studies of SVFs, even at doses that produce fibrosis. The inflammatory reaction can also be documented and quantified by using the results of pulmonary lavage studies (see Oberdorster). Stop studies (where exposure is stopped and the animals are observed during a nonexposed recovery period) have proved useful for determining the reversibility of the above lesions. Such studies have clearly shown that the initial changes (macrophage response and bronchiolization) are totally reversible with most SVFs and to some degree with asbestos. Microgranulomas become less apparent and early fibrosis is also, to some degree, resolvable, at least with SVFs. In rodents, studies have demonstrated that fibrosis, even with asbestos, is not particularly progressive, once the exposure ceases. While there is no exact correlate for pleural plaques in animals, localized acellular fibrotic changes reminiscent of this lesion in humans have been observed, albeit on a much smaller scale. The qualitative changes in the pleura are somewhat different than in the lung. Macrophages and inflammatory cells are almost totally absent in the pleural response. Lavage studies have not been conducted with pleural instillation or peritoneal injection studies so it is not known if the same events occur with these routes of exposure of exposure. Animal inhalation studies also suggest that fibers need to be present in the pleura for pathologic events to occur. In vitro studies ofmesotheiial cells have been conducted using both human and animal cells. These have been primarily designed to study the mechanisms of carcinogenicity (see Mossman). Irritant effects: While there is evidence of dermal and ocular irritation ofhumans as a response to exposure to asbestos and SVFs, no such evidence has been observed in animals. Histopathological studies of the nasal cavity in rodents exposed via inhalation have not shown any evidence of pathology, although an increased mucous response could be missed with standard histopathology techniques. Similarly, ingestion studies in rats and hamsters of asbestos did not reveal any irritation of the alimentary tract (ATSDR, in press). In vitro studies on the irritant effects of cither asbestos or SVFs in animals have not been reported. . Association between fiber length and fiber-like toxicity: There are numerous animal studies that demonstrate the influence of fiber length and pathogenicity/carcinogenicity. The early. studies by using intrapleural implantation/instillation (Stanton et al., 1981) and intraperitonea? injection (Pott et al., .1976) in rats clearly show a dirccfrelationship between fiber size and carcinogenic activity.. The longer the fiber, the more carcinogenic it was in these studies. These same studies provided the basis for the hypothesis that short fibers, i.e. shorter than 8 urn in length may not represent a significant carcinogenic risk. However, the same investigations, particularly the intraperitoneal studies also demonstrated that if the dose was high enough even so-called "innocuous" particulates, e.g. titanium dioxide, caused the induction of peritoneal R-21 HWBUI0009738 mesotheliomas, albeit at a lower incidence than long fibers. Additionally, the latter studies also demonstrated that if even long fibers, e.g. woilastonite and some SVFs, were not carcinogenic if they were not biopersistent in the peritoneal cavity. There have been a few inhalation studies have been conducted to study the influence of the fiber length on the pathology of asbestos, and all have been persuasive for showing that short fibers are not carcinogenic. This has been demonstrated for chxysotile (Davis and Jones, 1988; fllgren, 1998; Wagner et al., 1980), amosite (Davis et'al., 1987; 1986) and crocidolite (Davis ef al., 1978; Wagner et al., 1984). Other circumstantial evidence for considering fiber length as being critical to the carcinogenic potential of fibers is provided by the observation that amorphous silica has been shown to be noncarcinogenic in several inhalation studies in rats, while some types of glass fibers of similar chemistry have shown to have carcinogenic activity (IARC, 1987). In fact, amorphous silica has been used as a "negative control" in rodent inhalation studies. A final piece of evidence for the importance of fiber length for the carcinogenic ofasbestos and SVFs is found in the hilar lymph nodes that drain the'lungs of animals exposed via inhalation to both asbestos and SVFs. These lymph nodes are literally filled with macrophages containing short fibers and fiber fragments with no evidence of pathology or neoplastic change in either the lymph nodes or adjacent tissues. To summarize studies in animals of short fibers and noiifibrous particulates have shown that both are potentially carcinogenic if they are introduced into a confined cavity, e.g. pleural or peritoneal, at sufficiently high doses. But the same studies clearly show that the carcinogenic potential is definitely less with fibers of the same type that are longer. Inhalation studies have clearly shown that short fibers have not caused cancer in animals. The other part of the equation that needs to be considered is the influence of pulmonary clearance and biopersistence on the carcinogenic potential of particulates. As noted above, even long fibers are not carcinogenic in animals unless they are biopersistent in the animal. There are only a few in vitro studies that address this subject but those that have clearly show a relationship between fiber length and genetic damage. For example, in a study of Chinese hamster ovary cells (CHO) short amosite failed did not cause chromosomal aberrations while long fiber amosite did (Donaldson and Golyasnya, 1995). See Mossman and others for other studies. 'fi ' " Thresholds of toxic action: There have been very few inhalation studies in animals ofeither asbestos or SVFs to assess a carcinogenic dose rcsppriie. ' It needs to be remembered that to assess a carcinogenic dose response, one must have a multidose study that shows a carcinogenic response. Mostasbestosand SVF studies were designed to address the carcinogenic potential of the fiber, not dose response. The only multi-dose inhalation studyof asbestos used amosite in hamsters (SdcCorinell et a!,, 1995). In that study, there was a definite dose-related response with regard to'both norinepplastic (macrophage response, pulmonary fibrosis, etc.) and carcinogenic activity (mesothelioma). Unfortunately, the potential lung cancer response could not be assessed because hamsters do not develop pulmonary tumors with particulates. There are a few inhalation studies of SVFs that address dose response. The only one that was positive for cancer involved E-22 i '/ HWBUI0009739 refractory ceramic fibers in rats (Mast et a!., 1995). In that study there was a clear dose response for both cancer and noncancer endpoints and a no-effect level. There are a few other multidose studies in rats using various types ofSVFs, but since none showed carcinogenic activity, one can only evaluate the dose response for noncancer endpoints (Hesterberg et al., 1996). Again* there was evidence in these studies of a dose-related change in the endpoints showing recognizable change. The "stop-studies" in many of these inhalation studies (both asbestos and SVFs) provide evidence for a dose response for noncancer endpoints. However, the number ofanimals evaluated in the "stop studies" is too small to address a cancer dose response. The only study in primates that addresses a potential threshold ofaction was with chrysotile asbestos (Patek et al., 1985). In this study, monkeys were exposed to chrysotile asbestos at an exposure level of I mg/nO (0.8 free >5 um length) for 18 months. Ten months following the last exposure, lung biopsies were taken and evaluated for fiber burden and histopalhology. There was no evidence of pathology although a few asbestos bodies were observed in the lung. The monkeys were then held unexposed for an additional-l 1 years at which time they were subjected to necropsy examination and the lungs for histopalhology examination. Again, there was no evidence of pulmonary pathology and the number of asbestos bodies had decreased (not reported - personal observation). In summary, the totality of available data suggests that there is a dose-response for both neoplastic and nonneoplastic endpoints in animals and there is a no effect level for both asbestos and SVFs. One attempt at deciding if a given exposure in animals is potentially carcinogenic involves the use of noncancer endpoints. In this scheme it was assumed that a dose that caused pulmonary fibrosis could also represent an exposure that was potentially carcinogenic io animals. .A. This was because no animal study has ever produced cancer in the absence of fibrosis. The next assumption was that since no inhalation study had ever shown fibrosis in the absence of inflammation, one could assume that an exposure that didn't result in inflammation would not reasonably be expected to be carcinogenic. The endpoint chosen for assessing inflammation was the presence of inflammatory cells over background in bronchoalveolar lavage (BAL) fluid after a 90-day inhalation exposure. Therefore, if one did not find an increase in inflammatory cells in BAL fluid, one could chose this exposure as a no-effect threshold. It is reasonable to expect that in vitro studies could shed light on the dose response of both asbestos and SVFs. While these types of,studies are primarily designed to capture and elucidate specific mechanisms of toxicity and carcinogenicity*' there may be insights into dose response that could help in establishing thresholds of effect. One such study showed that short fiber amosite did not cause inflammation, while long amosite did. *The only draw backs to and in vitro approach is that these techniques do no take lung clearance phenomena into consideration and fibers that are not biopersistent in the lung might not be differentiated from biopersistent ones because of the short time frame of the in vitro studies. E-23 HWBUI0009740 References ATSDR, (in press) Toxicological Profile for Asbestos. DHHS, Agency for Toxic Substances and Disease Registry. ATSDR, (in press) Toxicological Profile for Synthetic Vitreous Fibers. DHHS, Agency for Toxic Substances and Disease Registry. Boorman et al. 1990. Pathology of the Fischer Rat Chap. 6. Peritoneum, Retroperitoneum, Mesentery, and Abdominal Cavity. Boorman et al. 1990. Pathology of the Fischer Rat. Chap. 21. Lung. Davis, J;M. et al. 1978. Mass and number of fibres in the pathogenesis of asbestos-related lung disease in rats. Br. J. Cancer. 37:673-688. Davis, J.M. et al. 1986. The pathogenicity of long versus short fibre samples ofamosite asbestos administered to rats by inhalation and intraperitoneal injection. Br. J- Exp. Pathol. 67:415-430. Davis, J.M. and Jones, A.D. 1988. Comparisons of the pathogenicity of long and short fibres of chrysolite asbestos in rats. Br. J. Exp. Pathol. 69:717-737. Donaldson, K. and Golyasnya, N. 1995. Cytogenic and pathogenic effects of tong and short amosite asbestos. J. Pathol. 177:303-307. Greira, H. et al. 2001. Toxicity of febeis and particles - Report of the workshop held in Munich, Germany, 26-27 October 2000. Inhal. Toxicol. 13:737-754. Hesterberg, T.W. et al. 1996. Use of lung toxicity and lung particle clearance to estimate the maximum tolerated dose (MTD) for a fiber glass chronic inhalation study in the rat. Fund. Appl. Toxicol. 32:31-44. IARCj 1987-. Asbestos and certain asbestos compounds. In: iARC Monographs on the Evaluation of the Carcinogenic Risk to Humans. Suppl.7. [ARC,-1987* Man-Madd Vitreous Fibers. In: IARC Monographs on the Evaluation of the. Carcinogenic Risk to Humans. Vol. 81. Ilgren, E and Chatfield, E. 1998. Coalings fibre - A short, ampbibole-free chrysolite. Part 2: Evidence for tack of tumourigenic activity. Indoor Built Environment. 7:18-31. Krombach, et al. 1997. Cell size of alveolar macrophages: An interspecies comparison. Environ. Health Persp. 105(Suppl 5):126l-l263 E-24 HWBUI0009741 b ~ / Mast, R.W., et al, 1995. A multiple dose chronic inhalation toxicity study of size-separated kaolin refractory ceramic fiber (RCF) in mate Fischer 344 rats. Inhalation Toxicol. 7:469-502. Maxim, L.D. and McConnell, E.E. 2001. Interspecies comparisons of the toxicity of asbestos and synthetic vitreous fibers: A weight-of-the-evidence approach. Reg. Toxicol. Pharmacol. 33:1 -24. McClellan, R.O., et al. 1992. Approaches to Evaluating the Toxicity and Carcinogenicity of Man-Made Fibers: Summary of a Workshop Held November 11-13,1991, Durham, North Carolina. Reg. Toxicol. Pharm., 16:321-364. McConnell, E.E., et al. 1984. A comparative study of the fibrogenic and carcinogenic effects of UICC Canadian chrysotile B asbestos and glass microfibre (JM 100). In: Biological Effects of Man-made Mineral Fibres. World Health Organization, pp. 234-252. McConnell, E.E., et al. 1994. Chronic inhalation study of size-separated rock and slag wool insulation fibers in Fischer 344/N rats. Inhalation Toxicol., 6:571-614. McConnell, E.E. 1995. Advantages and limitations of in vivo screening tests. Ann. Occup. Hyg. 39:727-735. McConnell, E.E., et al. 1995. Chronic inhalation toxicity of a kaolin based refractory ceramic fiber (RCF) in Syrian golden hamsters. Inhalation Toxicol. 7:503-532. McConnell, E.E., et al. 1999. Studies on the inhalation toxicology of two fiberglasses and amosite asbestos in the Syrian golden hamster. Part 2. Results of chronic exposure. InhaL Toxicol. 11:785-836. McConnell, E.E. and J.M.G. Davis. 2002. Quantification of fibrosis in the lungs of rats using a morphometric method. Inhalation Toxicol. 14:101-110. Platek, S.F., et al. 1985. Chronic irritation ofshort asbestos fibers. Fund. Appl. Toxicol. 8:327340. Pott, F. et al., 1976..Results ofanimal experiments concerning the carcinogenic effect of fibrous dusts and their interpretation with regard to the carcinogenesis in humans. Abl. Bakteriol. Orig. B. 162:467-505. Pott, F. et al. 1987. Carcinogenicity studies of fibres, metal compounds, and some other dusts in rats. Exp. Pathol. 82-129. Pott, F. ct al. 1994. Lung tumours in rats alter intratracheal instillation of dusts. Ann. Occup. Hyg. 38:357-363. -25 HWBUI0009742 Stanton, M.F., et al. Relation of particle dimension to carcinogenicity in amphibole asbestoses and other fibrous minerals. J. natl Cancer Inst. 67: 965-975. Wagner, J.C., et al. 1974. The effects of the inhaltion of asbestos in rats. Br. J. Cancer 29:252269. Wagner, l.C. et at. 1980. The comparative effects of three chrysotiles by injection and inhalation in rats. 1ARC Sci. Pub!. 30:363*372. Wagner, J.C. et al., 1984. The effect of fibre size on the in vivo activity of U1CC crocidolite. Br. f. Cancer 49(4):453-458 ') I` E-26 HWBUI0009743 Dr. Mossman's Post-Meeting Comments ATSDR Fibers Panel Mechanisms of Short Fiber Toxicity There appears to be a striking difference in the pathogenicity of respirable fibers directly related to fiber length, with fibers below approximately 5 microns in length being less hazardous for the development of cancers or pulmonary fibrosis. This prompts the questions: What are the observed mechanisms of long fiber toxicity? Does composition matter? Are short (<5 microns in length) fibers pathogenic? If so, what are the mechanisms of their toxicity? One hypothesis is that long fiber effects are related to increased generation of oxidants; reviewed in Kinnula, 1999; Hansen and Mossman, 1987). It has been shown that reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated by asbestos fibers spontaneously in cell-free systems, cells in culture, and lung tissue in vivo. A primary step in response to asbestos Fiber challenge to a number of cell types is superoxide anion release from cells which have attempted to phagocytize long fibers whereas short fibers are encapsulated in phagolysosomes, often without visible damage to cells. Superoxide, however, can be further dismutated to hydrogen peroxide which can generate the reactive hydroxyl radical, catalyzed by iron vs. the Fenton reaction. Alternatively, superoxide can react with nitric oxide to form peroxynitrite that is associated with inflammation and lung injury. Asbestos stimulates the release of ROS and induces oxidants intracellularly in both inflammatory cell types (Hansen and Mossman, 1987; Goodgltck and Kane, 1986; 1990) and target cells (Xu et at., 2002). Moreover, indirect evidence for oxidant stress by asbestos is indicated by elevations ofantioxidant enzymes in cells in culture and lung tissue after inhalation ofcrocidolite asbestos (Janssen et at, 1992, 1994b). In human mesothelial cells, these increases were not observed with exposures to polystyrene beads, or riebeckite, a chemically similar nonfibrous analog ofcrocidolite (Janssen et at., 1994b). The role of oxidants by crocidolite asbestos in causation of inflammation and fibrosis has been confirmed in rodent inhalation studies (Mossman ct ai., 1990), and supports the central dogma that asbestos fibers activate transcription factors and early response genes involved in proliferation and . inflammation by generating ROS via "frustrated phagocytosis"- (reviewed in Manning et a!., 2002). .. Several papers show that "frustrated phagocytosis" and oxidant production occur selectively in response to long vs. short fibers of asbestos or'glass. A study ofluciginen-depeodent chemiluminescence (CL) in human monocytes found a strong correlation between superoxide release and fiber lengths from 6.to 20 microns. All samples of fibers except wollastonite induced CL release in a dose-dependentmanner. Superoxide release was non-specific for the compositional type of fiber, arid fibers with lengths below 7 microns were only weakly active. In studies by Blake ct al. (1998), CL.induction after zymosan stimulation and LDH release, a measure of lytic cell death, were measured in Manviltc Code 100 (JM-100) fiber challenged rat alveolar macrophages. A novel feature of this study was the use of fibers carefully sized to average lengths of 33, 17, 7, 4, and 3 microns. The greatest toxicity was seen with the longer F:-27 HWBUI0009744 fibers which had multiple macrophages attached along the surface, indicating that incomplete phagocytosis was associated with toxicity. These studies reinforce the many experiments in the literature showing that long fibers are more toxic than shorter fibers in a number of cell types, i.e., Goodglick and Kane, 1990. Increased fiber length has also been linked to activation of transcription factors and cytokines. For example. Tumor Necrosis Factor-alpha (TNF) is a cytokine involved in inflammation and fibrosis. In a study by Ye et al. (1999), glass fibers with lengths of6.5 +/- 2.7 microns and 16.7+/-10.6 microns were used to challenge a mouse macrophage cell line. Glass fibers stimulated TNF production and caused Nuclear Factor-kB (NF-kB) activation, a process involving ROS. Long fibers were more potent than short fibers which were effectively engulfed by macrophages. Short fiber-induced TNF and TNF gene promoter activation was on the order of one-third to one-half of long fibers. In another study (Cheng et al., 1999), crocidolite asbestos caused parallel increases in TNF production in macrophages in a dose-dependent manner;. without cytotoxicity at the optimum stimulating condition. Titanium oxide dust was without effect TNF production may also be linked to inflammation by asbestos, and it has been shown that injection of long vs. short amosite fibers intraperitoneally results in inflammation and macrophage activation related to the proportion of long fibers (Donaldson et al., 1989). Another pathway leading to activation of protooncogenes {fos/jun) that comprise the Activator Protein- i transcription factor is the Mitogen Activated Protein Kinase (MAPK) cascades, consisting of'c-jun-N-terminal amino kinases (INKs), Extracellular Signal Regulated Kinases (ERKs) and p38 kinases. In studies by Ye et al. (2001) using macrophages, long glass fibers were more potent than short fibers in activating MAPK .which led to activation ofc-Jun and the TNF promoter. Studies by Zanella et al. (1996) explored the stimulation of ERKs in mesothelial cells. and found increases with crocidolite and chrysotile asbestos, but not with the non fibrous analogs, riebeckite or antigorite. Similarly, elevations in c-fos and c-jun expression were seen with asbestos fibers and erionite in mesothelial cells, but were not induced by,a variety of particulates, MMVF-10 or RCF-l fibers at comparable concentrations.(Janssen el al., 1994a). Long fibers of crocidolite (> 60 microns) were selectively associated with phosphorylation of the Epidermal Growth Factor receptor in human mesothelial cells (Pache et al., 1997), an event not occurring with MMVF-10 or particles. In general, pathogenic dusts such as asbestos or silica.. produce a variety of cytokines from cells and activate a number of transcription factors through ROS or RNS (Mossman and Churg, 1998; Churg ct al., 2000). Another ramification of transcription factor activation is cell proliferation. Mechanistic studies using target cells in culture or tracheal cxplants have shown that long fibers are more toxic and more apt to cause cell proliferation than short fibers (Brown et al., 1986; Wright et al., 1986; Marsh and Mossman, 1988; Sesko and Mossman. 1989; Woodworth et al:, 1983). These events may be coupled, as compensatory hyperplasia may result from initial epithelial cell injury. In studies by Woodworth et al. (1983), epithelial proliferation and squamous metaplasia were ; observed with various types of fibers including glass and attapulgite, but not with nonfibrous analogs of asbestos, i.e. riebeckite and antigorite and other particles. E-28 o . / HWBUI0009745 An intratracheal model in rats using long {>2.5 microns) and short crocidolite asbestos after intratracheal instillation has yielded some mechanistic information on the differential effects of long vs. short fibers (Adamson and Bowden 1987a, b; 1990). These studies suggest that the increased fibrogenic response to long fibers may be due to selective increases in cell proliferation, in addition, both long and short asbestos fibers cause alveolar macrophages to secrete fibrogenic cytokines, but interstitial fibroblasts exposed to short asbestos fibers do not respond to these cytokines. Surfactant adsorption may be a mechanism whereby reactive particles or fibers are rendered inactive or nonpathogenic. To determine the effect of surfactant adsorption on chrysotile genotoxicity using an assay for micronucleus induction in Chinese hamster lung cells (V79) (Lu et al., 1994), two lengths ofchrysotile fibers were used with and without pretreatment with DPPC, i.e. NEEHS intermediate (65%> 10 microns) and short (98% < 10 micron) fibers. The longer fibers were most active, and DPPC treatment diminished the activity approximately 15%. The maximum activity of the short fiber sample was 70% of the activity of the non-treated intermediate, and the DPPC-treated short fibers expressed about 45% of the activity of the untreated. That is, DPPC did not fully suppress the activity of the fibers, but had a much more pronounced effect on the short Fibers. One possibility is that the partial suppression of genotoxicity reflects suppression ofa component of toxicity by surfactant on the mineral surface. Thus, short fiber genotoxicity, as reported here, may reflect a combination of mineral surface functional groups which direct membranolytic activity and can be modulated by interactions with components of the pulmonary surfactant system as well as phagocytosis-associated ROS. In conclusion, studies summarized above show decreased or no effects of short fibers and nonfibrous analogs ofasbestos in a number of bioassays. The effects of long glass and asbestos fibers may be comparable in some studies. However, the duration of these short-term assays may be too short to reflect important solubility changes occurring in lung over time. E-29 HWBUI0009746 3 References Adamson IYR, DH Bowden. (1987a) Response of mouse lung to crocidotite asbestos, t. Minimal ftbrotic reaction to short fibers. Journal of Pathology 152:99-107. Adamson IYR, DH Bowden. (1987b) Response of mouse lung to crociddlite asbestos. 2. Pulmonary fibrosis after long fibers. Journal of Pathology 142:109-117. Adamson IYR, DH Bowden. (1990) Pulmonary reaction to long and short asbestos fibers is independent of fibroblast growth factor production by alveolar macrophages. American Journal of Pathology 137:523-529. Blake T, V Casttaaova, D Schwegler-Berry, P Baron, GJ Deye, C Li, W Jones. (1998) Effect of fiber length on glass microfiber cytotoxicity. Journal ofToxicology and Environmental Health 54:243-259. t Brown GM, H Cdwie, JMG Davis, K. Donaldson. (1986) In vitro assays for detecting carcinogenic mineral fibres: A comparison oftwo assays and the role of fibre size. Carcinogenesis 7( 12): 1971-1974. Cheng N, X Shi, J Ye, V Castranova, F Chen, SS Leonard, V Vallyathan, Y Rojanasakul. (1999) Role of transcription factor NF-kappaB in asbestos-induced TNFalpha response from macrophages. Experimental and Molecular Pathology 66(3):201-210. Churg A, J Wright, B Gilks, J Dai. (2000) Pathogenesis of fibrosis produced by asbestos and man-made mineral fibers: what makes a fiber fibrogenic? Inhalation Toxicology 12(Suppt 3): 15-26. Donaldson K, GM Brown, DM Brown, RE Bolton, JMG Davis. (1989) Inflammation generating potential of long and short fibre amosite asbestos samples. British Journal of Industrial Medicine 46:271-276. Goodglick LA, AB Kane (1986) Role of reactive oxygen metabolites in crocidolite asbestos toxicity to mouse macrophages. Cancer Research 46:5558-5566. Goodglick LA, AB Kane. (1990) Cytotoxicity of long and short croctdolite.asbestos fibers in vitro and in vivo. Cancer Research 50:5153-5163. Hansen K BT Mossman. (1987) Generation of superoxide from alveolar macrophages exposed to asbestiform and nonftbrous particles. Cancer Research 47:1681-1686. Janssen YMW, JP Marsh, MP Absher, D Hcmenway, PM Vacek, KO Leslie, PJA Borm, BT Mossman. (1992) Expression of antioxidant enzymes in rat lungs after inhalation of asbestos or silica. Journal of Biological Chemistry 267:10625-10630. E-30 HWBUI0009747 Janssen YMW, NH Heintz, JP Marsh, PJA Bonn, BT Mossman- (1994a) Induction of c-fos and c-juo proto-oncogenes in target celts of the Sung and pleura by carcinogenic fibers. Am. J. Respiratory Cell and Molecular Biology 11:522-530. Janssen YMW, JP Marsh, MP Absher, E Gabrielson, PJA Borm, K Driscoll, BT Mossman. (1994b) Oxidant stress responses in human pleural mesotheliai cells exposed to asbestos. American Journal of Respiratory and Critical Care Medicine 149:795-802. Kinnula VL. (1999) Oxidant and antioxidant mechanisms of lung disease caused by asbestos fibres. European Respiratory Journal 14:706-716. Lu J, MJ Keane, T Ong, and WE Wallace. (1994) In vitro genotoxicity studies ofchrysotile asbestos fibers dispersed in simulated pulmonary surfactant. Mutation Research 320(4):253-259. Manning CB, V Vallyathan, BT Mossman (2002) Diseases caused by asbestos: mechanisms of injury and disease development In: JE Talmadge and T Hugli, eds. Int. Immunopharmacologv: (MI Luster and MH Karol, guest eds); Vol. 2, pp. 191-200. Marsh JP, BT Mossman. (1988) Mechanisms of induction of ornithine decarboxylase activity in tracheal epithelial cells by asbestiform minerals. Cancer Research 48:709-714. Mossman BT, JP Marsh, A Sesko, S Hill, MA Shatos, J Doherty, J Petruska, KB Adler, D Hemenway, R Mickey, P Vacek, E Kagan (1990) Inhibition of lung injury, inflammation and interstitial pulmonary fibrosis by polyethylene glycol-conjugated catalase in a rapid inhalation model ofasbestosis. American Review of Respiratory Diseases 141:1266-1271, Mossman BT, A Churg. (1998) State-of-the-Art. Mechanisms in the pathogenesis of asbestosis and silicosis. American Journal of Respiratory and Critical Care Medicine 157:1666-1680 Pache JC, YMW Janssen, ES Walsh, TR Quinlan, CL Zanella, RB Low, DJ Taatjes, BT Mossman. (1998) Increased epidermal growth factor-receptor protein in a human mesotheliai cell line in response to long asbestos fibers. American Journal of Pathology 152:333-340. Sesko A, BT Mossman. (1989) Sensitivity of hamster tracheal epithelial cells to asbestiform minerals is modulated by serum and by transforming growth faetdrf beta 1. Cancer Research 49:2743-2749. Woodworth CD, BT Mossman, JE Craighead. (1983) Induction of squamous metaplasia in organ cultures of hamster trachea by naturally occurring and synthetic fibers. Cancer Research 43:49064912. Wright A, H Cowie, IP Gormley, JMG Davis. (1986) The in vitro cytotoxicity of asbestos fibers, i. P388D1 cells. American Journal of Industrial Medicine 9(4):37l-384. E-31 HWBUI0009748 Xu A, H Zhou, D Zengliaag Yu, TK Hei. (2002) Mechanisms of the genotoxicity of crocidolite in mammalian cells: implication from mutation patterns induced by reactive oxygen species. Environmental Health Perspectives 110:1003-1008. Ye J, X Shi, W Jones, Y Rojanasakul, N Cheng, D Schwegler-Berry, P Baron, GJ Deye, C Li, V Castranova. (1999) Critical role of glass fiber length in TNF-alpha production and transcription factor activation in macrophages. American Journal of Physiology 276(3 Ft 1):L426-L434. Ye J, P Zeidler, SH Young, A Martinez, VA Robinson, W Jones, P Baron, X Shi, and V Castranova. (2001) Activation ofmitogen-activated protein kinase p38 and extracellular signalregulated kinase is involved in glass fiber-induced tumor necrosis factor-alpha production in macrophages. Journal of Biological Chemistry 276:5360-5367. Zanella CL, J Posada, TR Tritton, BT Mossman. (1996) Asbestos causes stimulation of the extracellular signal-regulated kinase 1 mitogen-activated protein kinase cascade after phosphorylation of the epidermal growth factorreceptor. Cancer Research 56:5334-5338. J E-32 y HWBUI0009749 Dr. Oberddrster's Post-Meeting Comments When responding to the charge questions in Topic Area 1 (physiological fate ofasbestos and SVF fibers less than 5 micrometers in length). Dr. Oberdorster gave a brief presentation to the panel. He asked that a copy of the overheads from this presentation be included in this appendix of the report. A copy of the overheads Dr. Oberdorster prepared for the meeting follow, including some overheads that were not shown at the meeting due to time constraints. Dr. Oberdorster also provided an additional comment not mentioned at the expert panel meeting. He noted that the panelists overlooked an important concept of short fiber toxicity which involves an increased retention in the lung of short fibers in people (e.g., smokers) who have disturbed alveolar macrophage mediated lung.clearance. These people, he noted, can experience a marked increase in short fiber retention and thereby increase the potential for fiber toxicity significantly. Long fibers are reportedly not affected to the same degree as short fibers, as was described in a paper by Churg ("Effects of cigarette smoke on the clearance ofshort asbestos fibres from the.Iung and a comparison with the clearance of long asbestos fibres," International Journal of Experimental Pathology 73(3): 2B7-297, 1992). n-33 HWBUI0009750 Airborne Fibers and Host Interactions Human activities/ Susceptibility Mechanisms mO ess fi E OS O ft. <c3 (2- o09 *.mQ4 Ofi aa ci .+2* /--4). c. 0U$ .2* WJ / / ao el> *2 03 *E " <5 Sf 1i a^ s g(Si .s3 e<o3sJ>s oa `3a ve cuw S s: CO I- ^5 5 0> V* ca O ft X &' / V00*1*1i op oo Vi 13 2*-2- Og 1-VOGt .O2J >> JS -Si 01 Cu ou E 9* Ka* ^3 "3 t5SL g. SO.a.. o '5 on a. On GS o aEa?S oC O HWBUI0009751 HWBUI0009752 a *" HWBUI0009753 Mouth-breathing Nose-breathing HWBUI0009754 Effective filtra tio n o f long fibers by nose 0 HWBUI0009755 Asgharian and Yu, 1989 Correlation between Geometric and Aerodynamic Diameter Fiber Diameter (fJ-m) Q, O' HWBUI0009756 Long fibers are poorly respirable in rats HWBUI0009757 13 U P 4> o. U 2 8S3 P s < a> Gofl Q 13 4> m ft .O **** 5A O pQ ii !i Together, these mechanisms define the Biopersistence o f a Fiber o C o <au, Sft a* a> G ?*> w *0 V X5S" Wa>5 .C5 oo S& S "3 a o g .22 <y 4> 43 O- U c| .oy Us CA <SS > 5 jT HWBUI0009758 For non-cancer --------- all fibers (but: also im pact fo r tum ors!) <3J iN4 m 43 +- m 42 E 4> m 0 43 ft O u u 03 a 0U *0s3 .13 o POSN3 jS(^U aW>D ^^ O * 43 0$ . ft *2 43 H ss oHri o cs d a# TS o S3 0 a> 0 fj u 0 03 03 U 03 o. JM 13 d o sa .<M <3 *3 t533 ai X* a, as s l, o cd >i *; Os Os '--i Os Os <3 fc^i v Oc^ <4) SS O 3) 55 ~ss o v> o Os <3 <1 '--t *Q <ONs Os s *"i a -4 tf *^ o *"n Si 90 -JS Os -i <1 "T3 IS 1 bp o * Sf -c> 3k. o CQ /---- i =L e k4 ffi' SL 3 M *4 "i: f4i B T) '. a o# < vs> ft *8*4 * c a a a * B <3* 09*311 s 32 > S O c* c C3 43 u, 0J CJ S3 OS U Sw* O ft 1 HWBUI0009759 (Oberdorster et a l, 1988) m O + m Xi c -'M mi 5o O S c s 4 4 .<3J ^T3 , : - PU a> P >:' N C/) >> X -d > ml m XI cm O O T3 +* XS a Em >> g. fse:ii S s =1. 3. v ' os $ B =t d. in m o *33 xj 3 u i*! S3 Q u X X! U S uw 1H. > J . m 4* *5fl X* 045 . T3 Si * "3 2 C0 < -5S so "3S . S* s' 3 " vs a, HWBUI0009760 93 O XS Q O O m<mm<OsUU*> P* XI Ph *o s; 4*o215| o*** *5 S' tSi .5 *-%is<0d1u* So Vo c 1 c 2 x. >5 c: J"S o N~ o fiq S i*p. hr y CN K<S*x>. fsgj Ss <3 * XS Pn s; ! I r* S3 m4 *.* S3 <3J 15o"X Ko sf j2o 5 o Q ai|^ *Sg *? V.* 3 =3 P O 5 %5Si *WIU| a. o St 2 <2>:. o 3 **u2u 8< - Biopersistence = Biodurability + Physiological Clearance 'l HWBUI0009761 Fiber length (jim) (s/tep) 3J||-Jieq o CM O O CO oo in -r- o o c 3 c3 cc _o o SfucTM a> o CO >* u J= U Oi a G as *ca <D 0 'i \y i HWBUI0009762 Inhaled Particles V, 1982 Fig. 8. Bivariate distribution of fibres in Pankiula bagging section. ti HWBUI0009763 rell, Inhaled Particles V, 1982 Fin. 10. Uiviriate presentation of.tibre retention. HWBUI0009764 twflWSiwi 6uil)iuSuai SutfNfrwi U1 ncra 83 Sunij.iflStm CO \ j HWBUI0009765 FIBER DOSIMETRY FOLLOWING RCF-i EXPOSURE G e lz ld c h te r t d l, 1996 % I i f )FIG. Ri'lantc mic diarilHtmm f libcn uoUled from (A) anawl, IB) Day S limy, Huy M lung, (R) Day 0 pleura, (E) Day Spleura, uml (F) Day K' pleura lutfut* tterr tabulated hated no histogram analysis of the ueiutul cloud and fiber twnlen data (average of six (an). Median bin vuluer. are damn nn (he < and t au> Pulrtunury anj pleural fiber burden* were normalized lo Day 5 data with arean under the curve equal to I0U on Day S. J m fi'i T i ;--i--i----i---------n--i . m--i----- 1 o- jrt -- *n 3dOos sisoaau From: Timbrell et ah, Inhaled Particles VI, Fig. 5. Relationships when the parameter o f fibre quantity is number. 111 i i > -- ion o HWBUI0009766 3 3Moos sisoaarj j'i HWBUI0009767 From : TimbrelI et al., Inhaled Particles VI, JQ M F ig . 3. Relationships when the parameter o f fib re quantity is mass. Linked data points relate to tissue 11 specimens fro m the same subject. Fig. 4. Relationships when the parameter o f fibre quantity is surface area. (i \ S -Q S <3 K O, ~cj 5o Oo Oos \ <zu i r i rr o in ill tZo> to ,oo> MK o in a. 'O h~ o OX a - 2g o o. .in " 3 3 ce g a to ae Ct 111 g ,o-1 tn tsi cc . GO .c r ~-T,'n-n--i--i-------r - in 3M03S sisoijau t i r i" 11 m a Ui >J HWBUI0009768 eui0l(9({)0S0lU i|)|M SJBJ % Peritoneal mesothelioma A fte r LP. Injection o f Long-and Short Ghrysotile i.p. Dose, mg HWBUI0009769 ) > HWBUI0009770 oo uofifsodao (ouo|6a|j % HWBUI0009771 Diameter Jim) = Alveolar; TB = Tracheobronchial; NPL = Nasal, Pharyngeal, Laryngeal a sa ? M<O-o ^ <3 5dS' ^ <** -g .a *- jQ 3 ft 6 W<aa *o3 > 6 AS S t IV -1 j0 W MA3 iof 3 $1 o 6 p< % 00 m6 1C I"* m S3 s "3 o, 2B i o 3 ft ft *3 *20C3 a 43j a Ca '*3 O C M3 <29 e0) &* *? a 1 4> =5 B 2? *-3 <t> o 42 *3 S O2s a ix -Q5, To3 O r; O .5 o *a? , g 1 o s HWBUI0009772 M e c h a n is m s o f F ib e r C a rc in o g e n e s is 1 tvo, Ow . 2 tKo -2 'o' 0 1 ws * s, o < **-d *s5 Z Q 2 - o . fi? o 4>4 t 1 B so* to ->ov g & a Ies fed O>3 *3 I S && 808 to d'ods 13 ess* p 5 * 2 ~o sr <3 8 S * ,<o*> xs ) ~ la * 2: %fi ? *.' U. * s{5 '<$> o :;. - > i . JS ' s: < a 2>os* 01 c OJ .2 J3 O *3 2 : o *. > <5, s: s&0 Vs)* 3 o o $> CJ -S2 ** 1 *<43 8 o 3 id Oud 4d ew* tUo Xi 1=1 2s *s?: ^2- po i.I Ill I, 0c 1 *H3.' I V. s o a-w CD i.U OS g oc>, *KOoK>* ~i S0? 1 o82 o <cj s; ?3 Sr B cg .2 -2 -5? g *. i-is | -g 3*- o O. 53 v. - 2 ;s 2 b^ 3 2 s: .*C5* oSo oJg3 M<*5 its 2^ 1 ! o id M * S OS m% 4* CS o 4d > o oo JK f : gSS 4 aj cKQ^J,. ^g o ;:,sbs <u OIt o. -:5g.^; a C#5 * ^ u <u :;3 c X3 o "S otdn es to C O60 .2 u es a *08 5^. s JS v S0 1 3 eOra j *o 9t*S S -CS 3 2.*U2C 9Ut i-< o M c 3 "saa; 4 So os: ts as 0 2 j .*2o V. ^ es s; 5 1 o oo to -O4} 6 es M *5 03 tuo X3 2 5V^j 5*-: II r* ro m 3 j HWBUI0009773 Dr. Wallace's Post-Meeting Comments Health Effects of Asbestos and Synthetic Vitreous Fibers: The Influence of Fiber Length [ participated in the Agency for Toxic Substances and Disease Registry (ATSDR) expert panel on "Health Effects of Asbestos and Synthetic Vitreous Fibers: The Influence ofFiber Length", held in New York City on October 29-30,2002. I limited my comments to one of the topics which ATSDR requested that the panel consider: "Topic #2: Health Effects of Asbestos and Vitreous Fibers less than 5 micrometers in length." My research background has involved some studies ofthe surface properties and associated toxicides of respirable silica and silicate particulate dusts, which may have some indirect relevance to one of the questions asked of the panel under Topic #2, specifically: "Do the mechanisms ofaction ofother materials (e.g., larger asbestos fibers, silicates, mineral dusts, amorphous silica) with potentially similar compositions aid in understanding small-fiber mechanisms of action?" Dr. Ralph Zumwalde ofNIOSH, who has an extensive background in the epidemiology of fiberassociated diseases, attended the proceedings as an observer and contributed information and recommendations concerning the availability of data and the analyses of epidemiology studies of occupational exposures to fibers. In this review and revision of my comments on the panel, 1 also comment on the question: "Is there indirect evidence for less-than-5 micron fiber induced adverse health effects?" because of its association with the question of mechanism and because of some reports of inverse correlations of fiber length with fibrosis seen in asbestos workers' lungs. As discussed in the following review, my evaluation of information presented and commentary made by and to the panel is that there is a need for focused and short-term research oh short fiber hazard; and that there are new opportunities for the design of that research. Question: Do the mechanisms of action of other materials (e.g., larger asbestos fibers, silicates, mineral dusts, amorphous silica) with potentially similar compositions aid in understanding small-fiber mechanisms of action? A. TSonie lessons from non-fibrous' particulate studies /. Non-fibrous crystalline silica is cytotoxic, ftbragenic and carcinogenic. Respirable crystalline silica particles, which arc non-fibrous by any definition, are strongly pathogenic for fibrotic lung disease, and 1ARC. the US EPA, and others have recently evaluated quartz and cristobalite, two crystalline silica polymorphs, to be carcinogenic (1). E-57 HWBUI0009774 Q Exposure to these crystalline silica dusts can directly damage cells. Research suggests that consequent to this damage, there can be intrarcellular generation of reactive oxygen species and a cascade ofevents similar to the those evoked by asbestos fiber (2,3). As depicted by Dr. Mossman and others, that sequence may lead to the synthesis and release of TNF-alpha or other cytokines which stimulate near-by fibroblasts to proliferate and to up-regulate their synthesis and secretion of procollagen into the extracellular space of the pulmonary interstitium. There the procotlagen matures into one or several forms of collagen fibers causing simple or progressive lung fibrosis. The initial damage by quartz dust and by cristobalite dust to cells in vitro has been shown to be associated with the presence of sitanois. hydroxyl groups on the crystalline silica surface. Bolasitis et al. (4,5) showed that calcining, e.g., heating, quartz resulted in the loss of surface silanols and a parallel loss ofdirect membranolytic cell damaging activity.. As the dust aged in normal humidity air, the silanols re-formed on the surface over a period ofdays, and toxicity was restored parallel to that restoration. Saffiotti et al. (6) observed similar behavior with cristobalite. In some circumstances, e.g., sand-blasting occupational exposures, highly reactive free radical species are formed on the freshly broken crystalline silica surface; these exhibit heightened toxicity to cells in vitro in the absence of materials which can react to quench that activity, and may provide a additional mechanism of heightened toxicity (7). 2. Mineral-specificfibrogenicity: Short-term in vitro bioassaysfor mineralparticles do not work Some silicate dusts are cytotoxic in vitro but are not strongly pathogenic in vivo. Clays, layered alumino-silicates, are not associated with strong fibrogenic activity in human workplace exposures or in animal model exposure studies (8). In particular, respirable-sized kaolin clay dust, perhaps the structurally simplest alumino-silicate clay, is comparable to respirable-sized quartz dust for in vitro cytotoxicity (9) as measured by short term assays ofcell damage, e.g., membranolysis, cytosolic or lysosomal enzyme release, or dye-exclusion measures of cell viability. Therefore, direct short-term in vitro cellular assays do not distinguish the distinct in vivo fibrogenic potentials ofquartz versus kaolin clay dusts. Because of this, the general prevalence ofclays in many mixed dust exposures prevents the use of short-term in vitro cytotoxicity systems to predidtdust hazard. - 3. Thefirst events in'particle' hrfiber interaction with the deep lung surface: ' An important but generally ignored component for physiologically-representative in vitro bioassays: a. The environmental interface of the deep lung is surfactant-coated Particles or fibers depositing in the deep lung respiratory bronchioles or pulmonary alveoli will., first contact the aqueous "hypophase" lining on the terminal airway and airsac surfaces. This thin layer is coated at the air-liquid interface with surfactant which acts to reduce the surface tension and physically stabilize the airspaces (10). The hypophasc layer is also rich with micellar E-58 HWBUI0009775 dispersion of surfactant. The surfactant is comprised principally of lipids and lipoproteins. The major constituents are phospholipids: diacyl phosphatidylcholines. Dipalmitoy! phosphatidyl choline (DPPC) dispersed in physiological saline provides perhaps the simplest model of lung surfactant, representing the major surfactant constituent and generally reproducing the surface tension-lowering characteristics of full lung surfactant. b. toxic particles adsorb surfactant and are promptly neutralized Both quartz and kaolin clay dust particles promptly adsorb DPPC surfactant from dispersion in physiological saline; this immediately coats the particle surfaces and prophylactically extinguishes their short-term cytotoxicity (12). The amounts ofsurfactant in the alveolar hypophase compared to the surface areas of respirable mineral dusts and their adsorption isotherms for DPPC suggest that there is adequate surfactant in the lung to coat and neutralize depositing particles even in most high dust exposures (13). c. Restoration of particle toxicity and a possible basis for mineral-specific fibrogenicity Subsequent to the suppression by pulmonary surfactant ofotherwise prompt cytotoxic activity, the surfactant-coated particles can be phagocytized by macrophages and subjected to phagolysosomai enzymatic digestion (14). Cell-free experiments have correlated the digestive removal of DPPC from quartz and kaolin particle surfaces by phospholipase A2 enzyme with, the restoration of membranolytic activity. In cell-free tests using pH -neutral acting phospholipase A2 and in limited in vitro/in vivo tests, quartz is stripped ofsurfactant significantly more rapidly that kaolin(lS). Cellular in vitro studies have found that macrophage-like cells in vitro digest quartz- and kaolin-adsorbed DPPC at comparable rates over a period ofabout 7 to 10 days with initial partial restoration starting at 3 to 5 days (16). It has not been demonstrated that this detoxification/re-toxification process is the mechanism distinguishing quartz and alumina-silicate expression of toxicity in vivo. 4. Site ofparticulate-inducedfibrogenic activity Churg et al. (17) briefly discuss the principal site of asbestos activity, noting the alveolar macrophage is commonly regarded as the crucial effector cell. This is the background assumption also for most experiments on the cytotoxic and fibrosis-associated activity of crystallihe silica dusts. However, Adamson, referenced by Churg et al. in a different context, has 'published a suite of studies which make a case that it is interactions ofsilica particles with interstitial cells which control the stimulation of exacerbated collagen synthesis by pulmonary fibroblasts, and that the macrophage is responsible for only an inflammatory response evoking neutrophil influx to the alveolus but not tied to explicit fibrosis(!8). While the mechanism of initial cell damage or stimulation may differ between silica or silicates and fibers, e.g,, ROSTrom a "frustrated" phagocytosis mechanism for asbestos and surface silanol hydroxyl membranolysis by quartz or clay, a parallel analysis to Adamson's silica study findings might be considered in researching the site of asbestos action for fibrosis. E-59 HWBUI0009776 5. Possible interferences in short-term bioassays OberdSrster and others (19) have found that the conventional protocol for extended-term in vitro cellular assays may inadvertently cause a non-physiologic surface conditioning of mineral particles which significantly affects assay results. The use of fetal bovine serum can confer a prophylaxis on silica and perhaps on kaolin (20), probably due to the mineral surface adsorption of lipo-proteins from the FBS. That may not represent a physiological situation in the intact lung in vivo and may interfere with attempts to model the condition of particle surfaces upon deposition in the lung and resultant effects on their expression of toxicity in vivo. For purposes of in vitro investigation of Fiber or particle toxicity, this interference might be circumvented, e.g., by excluding serum from the medium during a short-term period for particle or fiber challenge. 6. Environmental conditioning ofparticle surfaces can affect their in vivo pathogenic activity Even animal model in vivo tests can fail to be predictive in the case ofa cytotoxic and fibrogenic mineral in mixed composition dusts, e:g., quartz particles in workplace dusts: conventional mineralogical and cytotoxicity assays may not correlate with short-or intermediate-term in vivo fibrogenic response. Alumino-silicate surface contamination of quartz particle surfaces can delay for months of perhaps years the expression of fibrogenic activity. Aluminosilicate or other mineral occlusion of the underlying host particle can alter the expression of toxicity in vivo during the bio^persistence of the surface contamination. This has been seen worldwide in anomalies in the fibrogenicity of coal mine dust exposures (21). This was clearly demonstrated by LeBouffant et al. (22) by in vitro and in vivo studies of the fibrogenicity ofsilica in coal mine dusts and in natural lightly contaminated sands. More recently, new spectroscopic surface analysis methods have demonstrated natural clay occlusion of quartz dusts from some workplace where epidemiology studies had detailed anomalies in disease risk correlation with conventional measures ofdust exposure (23). B. Fibrous mineral and crystalline silica particle differences and similarities 1. Mechanisms oftoxicityforfibrous and non-Jibrous materials a. Conventional assays do not clarify the bases ofasbestos or silica particle toxicity Churg et al: (17) review highlights and caveats; to the general models of asbestos activity. Some fibers can evoke the responses from ROS generation through the cascade to increased expression of TNF-alpha, but have not been shown to induce fibrosis. And asbestos produces fibrosis in some systems without increasing TNF-alpha expression. Chrysbtile contains little iron but is . fibrogenic; albeit not a potent as amphiboly . Churg et aL suggest, a comparison of asbestos and silica-induced fibrosis data. Their paper compares the generation of.ROS, RMS, and activation of NF-kB and AP-1, and increased production of TNF-alpha and other factors and find the dusts to be indistinguishable. In the face of this, asbestosis and silicosis differ in histopathological appearance: asbestosis is a diffuse fibrosis and silicosis is in localized nodules. Their conclusion E-60 HWBUI0009777 is that the tabulated responses fail to explain comprehensively how asbestosis or silicosis develop. b. Surfactant does not fully suppress all asbestos fiber in vitro cytotoxicity Asbsetos fiber as well as particulate silicate can adsorb the DPPC and components ofpulmonary surfactant (24). We have briefly researched the effect of surfactant adsorption on chrysotile in vitro genotoxicity, using an assay for micronucleus induction in cultured Chinese hamster lung cells (V79 cells) (25): in our test of two chrysotile asbestos fiber samples, pre-treatment with DPPC in physiological saline surrogate lung surfactant did not fully suppress a short-term toxic activity to cells in vitro. NDEHS intermediate length chrysotile asbestos fiber (average 101 micrometer length, 65% > 10 micron) and NDEHS short chrysotile asbestos fiber (average 11.6 micron, 98% < 10 micron) were tested for micronucieus induction in V79 macrophage-derived cells for 72 hour challenge 47- DPPC surfactant pre-treatment of the fibers. For the longer fiber sample, DPPC did not significantly affect the activity, a numerical reduction ofabout 20% in the activity was observed but was not statistically significant. However, DPPC treatment reduced the shorter-length fiber sample activity significantly, to about half that ofthe untreated shorter fiber sample. Similar effects were seen for multi-nuclei induction and for dye-exclusion viability measure for cell toxicity. No activity was seen for either sample in a sister chromatid exchange assay. c. A surface modification which did not affect long asbestos fiber toxicity in vitro 'v / We also attempted to see ifa significant surface modification of chrysotile without a significant modification of fiber size would affect in vitro geaotoxic activity (26). The NEEHS intermediate length chrysotile asbestos fiber used above was mildly acid leached to remove near-surface magnesium, but to retain fiber length. The treatment resulted in a 20% reduction in fiber length in each of three length categories: <3 micron, 3-10 micron, > 10 micron. Spectroscopic surface analysis and zeta-potential measurements showed significant reduction in surface-associated magnesium and in its influence on surface chemistry. However there was no significant change in measured activity for micronucieus induction between the treated and non-treated fibers. d. Is there more than one mechanism of fiber cytotoxicity? Do short fibers also act as particles? One interpretation of these two experiments is this: at least two mechanisms are involved in the initial damage or interaction of fibrous particles with the lung: a component which is at least transiently suppressed by surfactant conditioning which significantly contributes to shorter fiber activity, and a component which is not suppressed by surfactant conditioning, and which is not affected by one significant modification of surface composition and chemistry, and which is the principal mechanism for longer fibers. That is. a mode! which suggests itself is the combination of the frequently discussed "frustrated phagocytosis" mechanism for longer fibers, e.g., those which are too long to be fully phagocytizcd and internalized by the cell target, and a surface E-61 HWBUI0009778 property-mediated toxicity mechanism for internalized particles or short fibers, i.e., fibers which are internalized and subjected to conventional phagoiysosoma! processes. One possible consequence of "frustrated phagocytosis" of longer fibers is that the partially invaginated fiber stimulates the cell to release superoxide in a manner related to the respiratory burst upon normal phagocytosis, or that superoxide is produced by the cell in response to an autolytic effect ofenzymes or other lysosomal or cytosolic agents released into the annular invagination of the fiber. The superoxide is then in close approximation with reactive iron species on the fiber surface in or extending beyond the partially invaginated fiber to create hydroxyl radical for strongly toxic effects at the cell or neighboring cells. The paper by M Ohyama et al. (27) provided to the panel presents a difficult argument against frustrated phagocytosis: The study used luciginen-dependent chemiluminescence (CL) induced in vitro over a short (2 hour) period, and found a strong correlation ofresponse indicative ofsuperoxide release with fiber length 6 to 20 um. All samples except wollastonite induced CL response in a dose-dependent manner. Superoxide release was non-specific for compositional type of fiber. The four fibers with lengths below 7 um werfe only weakly active. Longer fiber activity correlated with length. Research on the surfactant suppression and subsequent lysosomal enzymatic restoration of mineral particle cytotoxicity within a cell, suggests that short fibers which are fully taken into the cell in a phagosome may express, in part, a cytotoxicity within the cell after removal ofadsorbed prophylactic surfactant. That is, some part of short fiber toxicity may be related to the mineral surface-specific mechanism ofnon-fibrous particulate toxicity. Those do not exhaust the possible mechanisms for long or short fiber damage to cells. Asbestos fiber penetrating the cell or cell nucleus maiy exercise modes of direct genetic or epigenetic damage. In our above study of surfactant effects on chrysotile genotoxicity in vitro, a limited investigation using immunofluorescent kinetochore staining indicated that both clastogenic and aneuploidogenic effects were associated in similar proportion with the observed micronucleus induction. That is, fibers may directly or indirectly interact with the spindle mechanism involved in chromosomal separation during cell division. During mitosis, the nuclear membrane disintegrates, possibly providing intracellular fibers access to the genetic material or kinetochores and spindle apparatus. 2. Intracellular response tofiber challenge a. Long fiber challenge Whatever the mechanisms ofdirect fiber damage or stimulation of the cell surface, some components of the consequent intracellular response have been well-defined. Mossman and others have detailed the cascade of events following fiber challenge to pulmonary macrophages or perhaps to other cells. A recent review (3) explicates the central dogma that damage to or stimulation of the cell by fibers is followed by an increase in intracellular reactive oxygen species which trigger a cascade of transcription factor activation leading to the up-regulated production F.-62 HWBUI0009779 and release ofTNF-alpha or other cytokines. This also was recently the subject of a NIOSH study by Cheng et al. (28) in which crocidolite with a median fiber length of 11.5 um challenged lavaged rat AM in FBS-containing medium for l to 24 h.. Crocidolite caused parallel increases in TNF-alpha production andNF-kB activation.in a dose-dependent manner. A titanium oxide control dust had no stimulatory effect on TNF-a secretion. The report by V Kinnula which was provided to the panel (29) reviews the possible roles of reactive oxygen species (ROS) and reactive nitrogen species (RNS) generated by asbestos fiber in cell-free and cellular and tissue systems. A primary step in response to asbestos "long" fiber challenge of cells is agreed to be superoxide anion release in cells which have attempted to phagocytize fibers. This superoxide can further be dismutated to hydrogen peroxide, which can generate hydroxyl radical, catalyzed by iron via the Fenton reaction. That hydroxyl radical is extremely toxic and reactive, but therefore short-lived. There is some contention that fibers stimulate the release of ROS from inflammatory cells and not target cells. However, asbestos fiber can generate ROS spontaneously in cell-free systems. This fiber-prompted production and release ofTNF-alpha can stimulate nearby pulmonary fibroblasts to proliferate and increase pro-collagen synthesis, which is released extra-cellularly to mature into collagen scarring. b. Intracellular response to challenge by well-classified shorter fibers and particles Dr. Baron of NIOSH has been developing a fiber size classifier (separator) which can permit in vitro or perhaps limited in vivo experiments with sets of fibers of fairly well-defined length (30). A dielectrophoretic classifier can separate fibers from an airstream producing about 1 mg/day of a size cut These classes of JM-100 glass fibers were recently produced for in vitro toxicology study: cut l: Length = 32.7 micrometer +/- 23.5 SD; Width = 0.75 micrometer +/- 0.50 micrometer cut 2: L = 16.7 u +/- (0.6 u; W = 0.49 u +/- 0.27 u cut 3: L = 6.5 u +/- 2.7 u; W = 0.44 u +/- 0.22 u cut 4: L = 4.3 u +/- 1:0 u; W = 0.40 +/- 0.15 u cut 5: L = 3.0 u +/- | .0 u; W = 0.35 u +/- 0.14 u In recent NIOSH studies by Dr. Castranova and colleagues,-these samples were used in a comparisdnof"long";and "short''fiber cytotoxicity and of induction of the cytokine cascade in vitro:. Blake et al. (31) used 18 hbur challenge of rat alveolar macrophages in vitro and the lactate dehydrogenase (LDH) release assay, the 17 micrometer,sample expressed about 2 X the activity of the shorter samples (and also 2X the activity of the 33 micrometer longer sample) on a mass basis. However, all samples were active well above-control levels. The 7 micrometer fiber set had about 8 X more fibers per gram than the 17 micrometer set, or about 3 X the linear surface area. Thus, the 17 micrometer long fibers were on the order of 6 or 7 X more cytotoxic than the shorter 7 micrometer fibers on a linear surface basis. Similar effects were seen with an assay using chemiluminescent response to zymosan challenge. And multiple macrophages were seen attached along<the length of the long fibers, suggesting "frustrated" or incomplete phagocytosis was occurring for longer fibers. : : E-63 HWBUI0009780 S Ye et af.(32) challenged a mouse macrophage cell line with the 7 and with the 17 urn glass fiber cuts, for 3, 6, and 16 h. Glass fibers stimulated TNF-alpha production, activation of TNF-alpha gene promoter activity, and activation of DNA binding activity of nuclear factor (NF)-kB. Reactive oxygen species (ROS) were involved in the activation and production. Dose was set at 5 fibers per cell; by that metric the longer fibers were more potent than short fibers by a factor of about 3. However, on a basis of length of fiber exposed to the cell or surface area, the activities were about equal for the long and short fibers. As seen in photomicrographs, short fibers but not long fibers were effectively engulfed by macrophages. In a subsequent study by Ye et al. (33) it was found that the long fibers were more potent than short fibers at the same dose of 5 fibers/cell in activating MAP kinases which activate transcription factor c-Jun which acts on the TNF-a gene promoter through the cyclic AMP response element and the AJP-1 binding site. Again, the activities were comparable for long and short fibers on the basis of exposed fiber length or surface area. Question: Is there indirect evidence for less-than-5 micron fiber induced adverse health effects? A. Human studies 1. Churg et al. (34) found the grade of interstitial fibrosis asbestosis in the lungs of a group of chrysotile miners and millers to be directly proportional to tremolite or chiysotile fiber concentrations, but inversely proportional to mean fiber length and length-related parameters. Churg et al., (35) graded fibrosis in the lungs of some shipyard and insulation workers, finding fibrosis grade to be strongly positively correlated with araosite concentration and negatively correlated with mean fiber size parameters including fiber length; they suggested "...these observations again raise the possibility that short fibers may be more important than is commonly believed in the genesis of fibrosis in man." In a study of chiysotile miners and millers, Churg, et at., found pleural plaques were strongly associated with mean tremolite fiber aspect ratio, but no differences in mean fiber size, including length, were seen for any other disease studied (mesothelioma, airway fibrosis, asbestosis. or carcinoma) (36). One member brought to the panel's attention a recent publication (37) analyzing fibers in lung tissue from two groups of former chrysotile miners and millers: the study concluded that "...fiber dimension does not seem to be a factor that accounts for the difference in incidence of respiratory disease between the two groups", it has been generally speculated that shorter fibers in lung tissue may be the residue of fibers which were longer when deposited, and disease initiation was due to the originally long fibers, which were subjected to subsequent in vivo'dissolution or degradation into the observed short fibers (17). This appears to be one plausible explanation of the inverse correlations reported between fibrosis and fiber length in human lungs. But this does not limit the research opportunity or imperative, provided by the seemingly anomalous or "counter-intuitive" results, to address possible short fiber-associated disease mechanisms. 2. A possible "short fiber" exposure cohort. Dr. Zumwalde ofNIOSH suggested to the panel that a past NIOSH study of2,302 workers at an attapulgitc mining and milling facility (38) may have E-64 \ HWBUI0009781 . |\ y; involved exposures, in part, to short mineral fibers. A significant deficit of mortality (SMR = 43, 90% Cl 23-76) from nonmalignant respiratory disease (NMRD) was observed for the cohort; but a statistically significant excess of mortality from lung cancer was observed among whites (SMR = 193,90% Cl 121-293), but a deficit occurred among nonwhites (SMR = 53,90% Cl 21-112). This may present an opportunity for review and re-analysis and a source for collection of materials for study. NIOSH also is re-analyzing archived materials available from a past study of asbestos workers in South Carolina. Question: Are short fibers pathogenic? What should we do? I. Review ofin vitro toxicology For non-fibrous particles: - Non-fibrous mineral particles can be cytotoxic, fibrogenic, and carcinogenic. - That pathogenicity is mineral-specific. - Surface characteristics may delay expression of that pathogenic activity in vivo. - That pathogenicity is not necessarily reflected in short-term in vitro cytotoxicity assays. - The first interaction of particles depositing in the deep lung, namely, adsorption of the lung lining surfactant, strongly affects mineral particle prompt toxicity. - The bio-persistence ofthat surfactant prophylaxis may be a critical factor in the timing and severity of mineral particle expression of toxicity. - After expression of the primary toxic event in particle challenge to cells, the intracellular response may be much similar to the cascade induced by asbestos or fiber challenge: leading to the induction of pathogenic, e.g., fibrogenic activity by nearby cells. For fibrous particles: - Many studies have found an association of pulmonary fibrosis, cancer, and mesothelioma with occupational exposures to long fibers, e.g., fibers with length greater than the dimensions of the target cells. - Long fibers clearly are cytotoxic in vitro. r Long fiber cytotoxicity and the initiation of pathogenic processes are generally considered to be resultant from a "frustrated phagocytosis'* mechanism. - Some studies of fiber burden and disease in tissue from asbestos workers have shown an .itvyerse^correlation .of disease with fiber length. - Those,disease-correlated shorter fibers appear in some of the cases to be mineral specific; e:g., associated with contaminant amphibole more than with seprentine asbestosu - Limited in vitro study data suggest that shorter fibers may have a component of cytotoxicity which is surface associated, perhaps independent of a "frustrated phagocytosis" mechanism involved in long fiber toxicity. - in short term in vitro assays, weli-controllcd for fiber length, shorter glass fibers can cause intracellular events comparable on a fiber or surface basis to those associated with longer fiber challenge and with asbestos fiber challenge. E-65 HWBUI0009782 2. Interprelability ofshort-term in vitro assays The ability to interpret many in vitro experiments on particle of fiber toxicity is complicated by the lack ofmodeling of initial conditioning ofparticles in the lung and the time course of expression oftoxicity in vivo. Surfactant adsorption in the lung can dramatically alter the short term in vitro toxicities of mineral particles, and may determine iftoxicity is expressed in times long or short compared to clearance. This surfactant effect and associated delay in toxicity expression does not appear to be a factor for long fiber asbestos expression of in vitro toxicity. Whether this is a factor for short fibers is unknown. That is, ifshort fibers have a component of toxicity independent of a "frustrated phagocytosis" mechanism but dependent on a surface-property mechanism then such conditioning and time delays in expression of toxicity could be critical in the design of experiments for the detection and analysis of short fiber toxicity by in vitro or short-term in vivo assay. 3. Research opportunities a. The ability to collect milligram quantities of well-classified (sized) small fibers presents the opportunity to do carefully size-controlled in vitro studies and possibly some (more limited) in vivo studies, e.g., by nose-only inhalation or tracheal instillation. b. Epidemiology study results suggest types of fibers which should be compared and contrasted in such experiments, e.g., short tremolite vs. short chrysotile. c. A review of epidemiological studies of attapulgite or other short fiber exposures may provide an identification of other short fiber asbestos and non-asbestos materials for toxicological study for which human disease epidemiology information is available for comparison. d. Preceding the initiation of new toxicology studies, a review ofpast in vitro studies might identify the controls for surface conditioning of the test fibers: were effects of lung conditioning modeled, or were non-physiologic effects of medium adsorbates possible in past studies? e. So-designed in vitro toxicology studies of classified short fibrous materials which have known positive or.negative correlations with pathology could be attempted to determine if there is a short fiber toxicity with a reasonable potential to initiate disease in vivo, and if that potential is dependent on fiber mineral type or surface property or morphology. f. A similar review of short-term in vivo studies might help the design ofmethods of challenge and time course for tests of materials selected from the in vitro study results. g. Results of the in vitro and in vivo studies would suggest ifuseful application could be made to dusts of current concern, e.g., Libby vcrmiculstc or World Trade Center disaster-associated dusts. E-66 ) HWBUI0009783 References 1. IARC Monographs on the Evaluation of Carcinogenic Risk to Humans. Vol. 68: "Silica, some silicates, coal dust, and para-aramid fibrils". ISBN 92 832 1268 1, 1997. 2. Driscoll, K. The role of interleukin-1 and tumor necrosis factor-a in the lung's response to silica. In: Silica and Silica-InducedLung Diseases, V Castranova, V Vallyathan, and W Wallace, eds., Boca Raton, FL., ppl63-184, 1996. 3. C Manning, V Vallyathan, and B Mossman: "Diseases caused by asbestos: mechanisms of injury and disease development" International Immunopharmacology 2:191 -200,2002. 4. Razzaboni BL, Bolsaitis P, Wallace WE, Keane MI. "Effect of thermal treatment on the surface characteristics and hemolytic activity of respirable size silica particles. Proc. Of the Vllth International Pneumoconioses Conference, Pittsburgh, PA, 1988. DHHS (NIOSH) Pub!. No. 90108 Part 1,215-230, 1990. 5. Pandurangi RS, Seehar MS, Razzaboni BL, Bolsaitis. "Surface and bulk infrared modes of crystalline and amorphous silica particles: a study of the relation ofsurface structure to cytotoxicity of respirable silica. Environ. Health Perspect. 86:317-336,1990. . 6. Fubini B, Zanetti G, Altilia J, Tiozzo R, Lison D, Saffiotti U. "Relationship between surface properties and cellular responses to crystalline silica: studies with heat-treated cristobalite". Chernies Toxicol 12(8): 737-745,1999. 7. Castranova V, Dalai NS, Vallyathan V. "Role of surface free radicals in the pathogenicity of silica". In: Silica and Silica-Induced Lung Diseases, V Castranova, V Vallyathan, and W Wallace, eds., Boca Raton, FL., pp91-l05, 1996. 8. Gamble J. "Silicate pneumoconioses" in "Occupational Respiratory Diseases",'ed. JA Merchant.pp. 243-284 . DHHS, (NIOSH) Publication No. 86-102., .1986. 9. Vallyathan, V, D.Schwegler, M Reasor, L Stcttler, FHY Green (1988). Comparison of in vitro cytotoxicity and relative pathogenicity of mineral dusts. Ann. Occ. Hyg. 32,279-289. 10. King RJ, Clements JA. "Surface active materials from dog lungJ. Method of isolation." Am J Physiol. 223:707-726, 1972. 11. Wallace, WE, V. Vallyathan, MJ Keane. V. Robinson (1985). In vitro biologic toxicity of native and surface-modified quartz and kaolin. I. Tox. Env. Health 16:415-424. 13. Wallace WE, Headley LC, Weber KC. "Dipalmitoyl lecithin surfactant adsorption by kaolin dust in vitro." J Colloidal Interface Sci 51:535, 1975. E-67 HWBUI0009784 14. Allison AC. "Lysosomes and the toxicity of particulate pollutants". Arch. Intern. Med. 128: 131,1971. 15. Wallace, W, M Keane, P Mike, C Hill, V Vallyathan, and E Regad (1992). Contrasting respirable quartz and kaolin retention oflecithin surfactant and expression of membranolytic activity following phospholipase Az digestion. J Tox. Environ. Health 37:391-409. 16. Hill, C, W Wallace, M Keane, and P Mike (1995). The enzymatic removal of a surfactant coating from quartz and kaolin by P388D, cells. Cell Biol. Tox. 11:119-128. 17. Churg et al. "Pathogenesis of fibrosis produced by asbestos and man-made mineral fibers: what makes a fiber fibrogenic?". Inhalation Toxicology 12(S3): 15-26,2000, 18. Bowden DH; Hedgecock C; Adamson IY(1989). Silica-induced pulmonary fibrosis involves the reaction ofparticles with interstitial rather than alveolar macrophages. J Pathol 58:73-80. 19. Barrett EG, Johnston C, Oberdorster G, Finkelstein JN. "Surum binds serum proteins resulting in a shift of the dose-response for silica-induced chetnokine expression in an alveolar type II celt line." Toxicol. Appl. Pharmacol. 161: 111-122,1999. 20. Gao N, Keane MJ, Ong T, Ye J, Miller WE, Wallace WE. "Effects of phospholipid surfactant on apoptosis induction by respirable quartz and kaolin in NR8383 rat pulmonary macrophages". Toxicol. Appl. Pharmacol. 175:217-225,2001. 21. Robock K, Klosterkotter W. "Investigations into the specific toxicity ofdifferent Si02 and silica dusts. Staub Reinhart Luft 33:3360-3363, 1973. 22. LeBouffant L, Daniel H, Martin J.C, Bruyere S; "Effect of impurities and associated minerals on quartz toxicity. Ann. Occup. Htg. 26: 625-634,1982. 23. Harrison J, Brower PS, Attfield MD. Doak CB, Keane MJ, Grayson RL, Wallace WE. "Surface composition of respirable silica particles in a set of US anthracite and bituminous coal mine dusts". J Aerosol Sci. 28:689-696, 1997: 24. Jaurarid MC, Reiner A, Bignon J. "The adsorption of phospholipids and red blood cell membranes on chrysotile fibers". In "In Vitro Effects ofMineral Dusts''. Ed. RC Brown. Academic Press, London 1980: 125-130. ' - 25. Liu J "In vitro genotoxicity studies ofchrysotile asbestos fibers dispersed in simulated pulmonary surfactant" Mutation Res 320: 253-259, 1994. 26. Keane ah "A study of the effect of chrysotile fiber surface composition on genotoxicity in vitro". J Tox & Environm Hllh:57:529-541. 1999. E-68 27. M Ohyacna, T Otake, and K Morinaga, "Effect of size of man-made and natural mineral fibers on chemiluminescent response in human monocyte-derived macrophages." Environ Hlth Perspec 109:1033-1039,2001. 28. Cheng et al. "Role of transcription factro NF-kB in asbestos-induced TNF-alpha response from Macrophages" ExpL And Mol Pathology 66:201-210, 1999. 29. V Kinnula which was provided to the panel, "Oxidant and antioxidant mechanisms of lung disease caused by asbestos fibers" European Respiratory Journal I4(3):706-716,1999 30. Baron et al. "Length separation of fibers". Aerosol Sci. Tech. 21:179-192, 1994. 31. Blake et al. "Effects of fiber length on glass microfiber toxicity" J Toxicol Environ Hlth 54: 243-259,1998. 32. J Ye et al. "Critical role of glass fiber length in TNF-alpha production and transcription factor activation in macrophages." Am J Physiol276 (Lung Cell Mol Physiol 20):L426-L434, 1999. 33. Ye et al. "Activation of mitogen-activated protein kinase p38 and extracellular signalregulated kinase is involved in glass fiber-induced tumor necrosis factor-alpha production in macrophages" J Biological Chem 276:5360-5367,2001. 34. Churg et al. ''Mineralogical correlates of fibrosis in chrysotile miners and millers". Am Rev Resp Dis 139:891-896, 1990. 35. Churg et al. "Mineralogical parameters related to amosite asbestos-induced fibrosis in humans" Am Rev Resp Dis 142: 1331-1336, 1990. 36. Churg et al. "Fiber burdens and patterns of asbestos-related diseases in workers with heavy mixed amosite and chrysotile exposures". Am J Resp Crit Care Med 150:663-669,1994. 37. Nayebzadeh A, Dufrense A, Case B, el al. "Lung mineral fibers of former miners and millers from Thetford-Mines and asbestos regions: a comparative study of fiber concentration and dimension." Arch Environ Health 56{ 1 ):65-76, 2001. 38. Waxweiler RJ, Zumwalde RD, Ness GO, Brown DP. "A retrospective cohort mortality study of males mining and milling attapulgitc clay". Am J Ind Med 13(3): 305-315,1988. F.-69 J HWBUI0009786 Appendix Panelists' Comments Submitted After the Meeting Note: The expert panelists were asked to provide premeeting comments and to participate in the discussions at the expert panel review meeting. In addition, several panelists chose to submit additional written comments after the expert panel review meeting. Some panelists submitted updated versions of their premeeting comments (see Appendix B), while others wrote summaries of the discussions they led at the expert panel review meeting. All post meeting comments are presented here, regardless of their content Panelists were not required to submit post-meeting comments. This section presents the post-meeting comments exactly as they were submitted to ERG, with only minor changes to format and references. The expert panel was not asked to comment on the content of these post-meeting comments. Contents: Dr. Lippmann's Post-Meeting Comments ................................................................. - E-l - Dr. Lockey's Post-Meeting Comments........ ................................................................ E-7 ; Dr. McConnell's Post-Meeting Comments............................................................... - E-l7 Dr. Mossman's Post-Meeting Comments................................................................... E-27 Dr. Oberdorster's Post-Meeting Comments.................................... .......................... E-33 Dr. Wallace's Post-Meeting Comments............................................................. .. E-57 Note: Dr. Case submitted post-meeting comments as a list of suggested revisions to an earlier draft of this report. Dr. Case's comments have been incorporated directly into the text of this report and are not replicated here. HWBUI0009787 Dr. Lippmann's Post-Meeting Comments ATSDR Fiber Panel Review Topic # 1. Physiological Fate of Asbestos and Vitreous Fibers less than 5 Microns in Length. Discuss/review current knowledge about die physiological fate of small fibers when they enter the body. A. What is the expectedphysiological depositional patternfor less-than-5-micronfibers in the lung? This is well established in terms ofthe depositional mechanisms of impaction, sedimentation. Brownian motion and (for fibers) interception. Fibers with aspect ratios >10 behave aerodynamically like unit density spheres with diameters three times their fiber width (Stober et al., 1970; Timbrel!, 1972). The only exception, in terms of being influential in deposition in lung airways isfor fibers longer than about 10 pm, where the mechanism of interception becomes influential (Sussman et al, 1991). This also accounts for the fact that longer fibers have proportionately more deposition in the airways as opposed to peripheral alveoli. The fact that lung retention also increases more markedly with fibers greater than 10 microns is supported by theoreticalcalculations (Yu etal., 1990), analysis of lung dust content in humans (Timbrell, 1982; Chuxg and Wiggs, 1987; Pooley and Wagner* 1998) and studies using experimental animals (Morgan 1979, 1995). Thus, for fibers <5 pm in length, deposition patterns and efficiencies will be determined almost entirely according to the fiber width, which for fibers <5 pm long will be less than about 1.6 pm. For fiber widths between about 0.1 and 1.6 mm, total lung deposition in healthy people will be between 10 and 20%, with almost all of it in the deep lung. For fibers thinner than 0.1 pm, deposition will increase with decreasing width, and there will be a somewhat greater proportion of the deposition in the more proximal airways. Particles that are not deposited remain suspended in the tidal air and are exhaled. There are significant differences between humans and rats with respect to deposition efficiencies of long as well as short fibers; respirability is very different and the deposition fractions are significantly different as well between the two species: B. What is known about clearancelbiopersistente ofles-than-5-micronfibers once deposited in the lungs? For these short fibers, which can be fully engulfed by lung cells and do not dissolve in airway fluids in less than a few weeks, their clearance will be similar to other mineral and vitreous particles. Those depositing in lung conductive airways will be largely removed to the G.I. tract by mucociliary clearance within about one day. Most of those depositing in the gas-exchange region will be phagocytized by alveolar macrophages and cleared to and through the mucociliary escalator within a few weeks. Other particles may be engulfed by epithelial cells, primarily in the E-l J HWBUI0009788 ^ vicinity of the bronchial-alveolar duct junctions, and retained for much longer periods, with gradual removal to lymph nodes. The relatively rapid clearance of short fibers and compact particles from the lung has been demonstrated in a number of studies (reviewed in Health Effects Institute-Asbestos Research, 1991; Davis, 1994; OberdSrster et al., 1990; Morgan, 1995). Such particles can be: 1) readily transported through tracheobronchial and other lymph nodes to more distal lymphatics, the pleura, or other organs; 2) cleared via the mucociliary escalator and alveolar macrophages; and 3) effectively phagocytized by a number of cell types in the lung including epithelial cells (Churg et al., 2000). Once within a phagolysosome or in general in lung fluids, shorter fibers of chiysotile asbestos (Hume and Rimstidt, 1992) or glass (reviewed in Lippmann, 1990) are more prone to dissolution and fragmentation than longer fibers and amphibole types of asbestos. Absent abnormalities in phagocyte function ofthese particles should be removed even ifthey are chemically resistant if: (a) the dose is not too great to overwhelm these normal mechanisms; and (b) the mechanisms themselves are intact. There are medical conditions which affect these mechanisms, however, so there are likely to be vulnerable populations (such as those with primary ciliary disorders; these tend to be genetic and very rare such as primary ciliary dyskinesia (incidence 1:20,000 to 1:60,000)). Of greater frequency is the lesser effect on mucociliary clearance in asthma. In addition environmental influences, including smoking and nitrogen dioxide (Case et al., .1982), can affect these normal mechanisms through direct ciliary damage or disrupted function. Some common pharmaceuticals slow mucociliary transport (for example, some general anaesthetics and atropine), while others accelerate it (for example, theophyllines and sympathomimetics). Bronchial secretion is also an important contributor to clearance or impaired clearance, as can be seen most dramatically in cystic fibrosis. Overall, then, there are a number of possible factors that may interfere with particle clearance, but none have been associated with "fiber length" parameters with the possible exception of smoking (Takahashi et al., 1994). The most important physiological clearance mechanism in alveolar region is clearance by alveolar macrophages (AM). Of importance is fiber length with respect to phagocytosis and removal by alveolar macrophages. Short fibere are easily phagocytized, fibers longer than 20 pm are not; There are species differences in AM size. Thiis, clearance for long fibers is prolonged, as is that for short fibers when high lung burdens are reached (particle overload). Also, intrinsic toxicity, which iiPSiuences clearance, has to be considered. Inflammatory conditions in the lung (for example, smokers) also contribute to impairment ofalveolar macrophage-mediated mechanical clearance and need to be considered. Biopersistence is the sum of physiological clearance processes and physicochemical processes, which together, account for the retention halftime of the fibrous or non-fibrous material in the lung. Physicochemical processes include dissolution, leaching, breaking and splitting, depending on the fibrous material, thht can occur intra- as well as extra-cellularly, and differences in pH in both locations are of importance here. Clearance rates of fibers of different length categories have been determined from short- and long-term inhalation studies (Davis et al., 1986,1987; E-2 HWBUI0009789 Wagner, 1990). Generally, short fibers are cleared rapidly if biosoluble (pH differs intracellularly vs. extracellularly), or at rates similar to nonfibrous particles. Breakage oflong fibers will give input into short fiber category. The hazards associated with man-made vitreous fiber (MMVF) appear to be most strongly associated with the ability to persist within lung tissue. This is, in part, dependent upon chemical composition of the MMVF, in that increased concentrations of stabilizers such as aluminum impact a greater degree of chemical durability. In vitro tests to measure fiber solubility should be performed to reflect an acid pH of 4.5 to 5.0 such as found in phagolysomes within alveolar macrophages as well as pH of 7.4 reflecting extra-cellular fluid. Short fibers that are ingested by macrophages will encounter the lower pH that overall could affect their biopersistence. In general, solubility tests identified the following rank order from lowest to greatest solubility of MMVF in comparison to asbestos fibers: crocidoiite <amosite <RCF <special purpose glass fibers crock wool <slag wool cconventional glass fibers (NRC, 2000). In rodent exposure to mixed dust resulted in an increased transport of fibers across the visceral pleura and increase production of lung tumors and mesothelioma (IARC# 140,1996). C. What type(s) ofmigration are expected within the bodyfor less-than-5-micronfibers? Fibers with diameters less than ~0.1 pm, which could be a significant fraction of fibers <5 pm in length, can penetrate through the respiratory epithelia and be transported through lymph channels to hilar and peripheral (mesothelial) lymph nodes and through blood to more distant body organs. Gelzleichter et al. (1996) exposed rats to nose only inhalation of kaolin-based refractory ceramic fiber. It was identified that fibers rapidly translocate to the pleural tissue with a difference between those in the pleural tissue arid the parenchymal tissue. Within the pleural tissue the geometric mean length 1.5 pm (GSD,w2.0) and geometric mean diameter 0.09 pm (GSD --1.5). For comparison parenthymal tissue GML = 5.0 pm (GSD -2.3) and GMD 0.3 pm (GSD -1.9.) This would indicate the short thin fibers are capable of translocating to the pleural tissue. This maybe an important subject, at least for the parietal pleura, ifit is necessary for fibers to reach the pleura to cause lesions (plaques and mesothelioma). It remains possible that fibers still within the.peripheral lung may be capable ofcontributing to the mechanisms of these diseases. Mechanisms remain speculative, but long amphiboie. fibers may tend to localize toward the lung periphery, and it remains possible (but unproven and indeed untested) that chemical mediators may Cross the visceral pleura into the pleural space. Chiirg and Wiggs (1987), among others, have observed that "accumulation of lorig fibers' immediately under the upper lobe pleura may be important in the genesis of mesothelioma." ' Two recent studies are informative (Boutin et al., 1996; Dumortier et al., 2002). They found that "the distribution of asbestos fibers in the pleura was heterogeneous and that they might concentrate in:. .'Mack spots' of the parietal pleura." Using thoracoscopy in living patients from "normal areas.ofthe parietal pleura" rather than plaques and tumor, and using controls, they showed that, "amphiboies outnumbered chiysotile in all samples" and that of all fibers 22.5% were in fact greater than or equal to 5 pm in length; a proportion at least as great as that usually seen in lung tissue. The means of hranslocation remains unknown, although these findings E-3 HWBUI0009790 o, strongly suggest lymphatic drainage paths. The pathogenic significance also remains unknown, although the authors emphasized their hypothesis that these fibers might contribute to plaque and mesothelioma genesis. Other papers that have been published (in relation to human disease) have been for the most part based on static "fiber burdens" that purport to be in "the pleura" but which on careful reading are in fact in mesotheliomatous tissues and/or pleural plaques; the false assumptions are then made that "short fibers" - usually very short chrysotile fibers, averaging less than 0.2 pm in length have "translocated" to the "pleura" from &e lung. In feet the "pleura" was not studied, tumor and plaque, which by definition could not contain fibers except via specimen contamination or incorporation, most likely.from adjacent lung. Both Rogers et al. (1994) and Case et al. (1994) have also reported contamination by short crocidolite fibers ofNuclepore filter materials and in uncontrolled studies of this nature any material from air, fluids, and paraffin in the pathology laboratory from which the specimens originally were referred to specimen preparation materials are suspect. References Boutin, C., P. Dumortier, F. Rey, J.R. Viallat, and P. De Vuyst. 1996. Black spots concentrate oncogenic asbestos fibers in the parietal pleura. Thoracoscopic and mineralogic study. Am. J. Respir. Crit. Care Med. 153:444-449. Case, B.W., RE. Gordon, and 1. Kleinerman. 1982. Acute bronchiolar injury following nitrogen dioxide exposure: A freeze fracture study. Environ. Res. 29:399-413. Case, B.W.K., M. Hanigan, and A. Dufresne. 1994. Lung fibre content of American children aged 8-15 years. Ann. Occup. Hyg. 38:639-645. Churg, A. and B. Wiggs. 1987. Accumulation of long asbestos fibers in the peripheral upper = lobe in cases of malignant mesothelioma. Am. J. Ind. Med. 11:563-569. Churg, A., J. Wright, B. Gilks, and J Dai. 2000. Pathogenesis of fibrosis produced by asbestos and man-made mineral fibers: What makes a fiber fibrogenic? Inhal. Toxicol. 12:15-26. Davis, l'M.G. 1987-: Experimental dataxelating to the importance of fibre type, size, deposition, dissolution and migration. In: Proceedings of 1987 Mineral Fiber Symposium. Lyons:. International Agency for Research on Cancer. Davis, J.M.G. 1994. The role of clearance and dissolution in determining the durability of biopersistence of mineral fibers. Environ. Health Perspect. 102:113-117. Davis, J.M.G., J. Addison, RE. Bolton, K. Donaldson, A.D. Jones, and T. Smith. 1986. The pathogenicity of long versus short fiber samples of amosite asbestos administered to rats by inhalation and intraperitoneal injection. Br. J. Exp, Pathol. 67:415-430. -: E-4 HWBUI0009791 o Dumortier, P., F. Rey, J.R. Viallat, I. Broucke, C. Boutin, P. De Vuyst. 2002. Chiysotile and tremolite asbestos fibres in the lungs and parietal pleura of Corsican goats. Occup. Environ. Med. 59:643-646. Gelzleichter T.R., E. Bermudez, J.B. Mangum, B.A. Wong, J.I. Everitt, and O.R. Moss. 1996. Pulmonary and pleural responses in Fischer 344 rats following short-term inhalation of a synthetic vitreous fiber. I. Quantitation of lung and pleural fiber burdens. H. Pathobiologic responses. Fundam. Appl. Toxicol. 30:31-46. HEI-AR Asbestos Literature Review Panel. 1991. Asbestos in public and commercial buildings: A literature review and synthesis of current knowledge. Cambridge, MA: Health Effects ' Institute - Asbestos Research. Hume, L.A. and J.D. Rimstidt 1992. The biodurability ofchiysotile asbestos. Am. Mineral 77:1125-1128. IARC. 1996. Mechanisms of Fibre Carcinogenesis. In: IARC Scientific Publications No. 140, eds. A.B. Kane, P. Bofetta, R. Saracci, and J.D. Wilboum. Lyon: Intemational Agency for Research on Cancer. Lippmann, M. 1990. Effects of fiber characteristics on lung deposition, retention, and disease. Environ. Health Perspect. 88:311-317. - Morgan, A. 1995. Deposition of inhaled asbestos and man-made mineral fibres in the respiratory tract Ann. Occup. Hyg. 39:747-758. NRC. 2000. Review of the U.S. Navy's Exposure Standard for Manufactured Vitreous Fibers. Washington, DC: National Academy Press. OberdSrster, G., J. Ferin, J. Finkelstein, S. Soderholm, and R. Gelein. 1990. Mechanistic studies on particle-induced acute and chronic lung injury. In: Aerosols: Science, Industry, Health and Environment, Vol. 2, eds. S. Masuda and K. Takahashi, pp. 1229-1233. New York; NY: Pergamon Press. Rogers A.L, J. Berry, et al. 1994. Dose-response relationship between airborne and lung asbestos fibre type,'length, and concentration, and the relative risk of mesothelioma. Ann. Occup. Hyg: 38:631-638. Stober, W., H. Flachsbart, and D. Hochrainer. 1970. Der aerbdynamische Durchmesser von ~ Latexaggregaten and Asbestfasem. Staub-Reinhalt Luft. 30:277-285. =. Sussman, R.G., B.S. Cohen, and M. Lippmann 1991a. Asbestos fiber deposition in a human trachebbrOhchial cast. I. Experimental. Inhal. Toxicol. 3:145-160. Sussman, R.G., B.S. Cohen, and M. Lippmann 1991b. Asbestos fiber deposition in a human tracheobronchial cast. IL Empirical model. Inhal. Toxicol. 3:161-179. E-5 HWBUI0009792 Takahashi, KL, B.W. Case, A. Dufresne, R, Fraser, T. Higashi, and J. Siemiatycki. 1994Relation between lung asbestos fibre burden and exposure indices based on job history. Occup. Environ. Med. 51:461-469. Timbrel!, V. 1972. An aerosol spectrometer and its applications. In: Assessment of Airborne Particles, eds. T.T. Mercer, P.E. Morrow, and W. Stober, pp. 290-330. Springfield, IL: Charles . C. Thomas. Timbrel!, V. 1982. Deposition and retention of fibres in the human lung. Ann. Occup. Hyg. 26:347-369. Wagner, J.C. 1990. Biological effects of short fibers. In: Proceedings of the VII International Pneumoconiosis Conference (Pittsburgh, PA, August 1988). NIOSH 90-108, Vol. 2, pp. 835840. Washington, DC: National Institute of Occupational Safety and Health. E-6 HWBUI0009793 Dr. Lockey's Post-Meeting Comments What do human/epidemiological data tell us about small fibers? Discussion Leaders: Dr. Lockey and Dr. Case Cancer Effects Short natural occurring fibers. A study by Higgins, etal. [1] in 1983 reviewed the mortality of workers employed at the Reserve Mining Company at Babbit, Minnesota. These workers were involved with mining taconite, which is a dense hard rock composed of silica, silicates and iron. Taconite mined in the eastern tip of the Mesabi range contained amphiboles in the cummingtonite-grunerite series. These fibers are short in length with reportedly the vast majority being <10 pm and are related to amosite asbestos. Of the 9,065 men employed by the company as of July 1,1976, 5,751 had worked one year or more. The investigators established the vital status of96% of those who worked for five years or longer and 75% of former workers who worked one to four years. The total respirable dust ranged from 0.02 mg/m3 to 2.52 mg/m3 and as high as 2.75 mg/m3 with the modal range from 0.2 mg/m3 to 0.6 mg/m3. There were relatively few measurements of fibers and those that were available demonstrated concentrations usually low with a few at or above 0.5 fibers/ml in the crushing department. Reportedly none approached the OSHA threshold limit value which at that time was 2 fibers/ml. Results of the study indicated that there was no excess death in this population including those men with cumulative exposure of 1,000 to 3,000 total dust years or 500 to 1,000 silica dust years. The conclusions of the study indicated the death rates for all causes were significantly below expectations including selected respiratory disease and death from malignant disease was marginally below that expected for the State of Minnesota. There was no relationship between lifetime dust exposure and increased mortality, nor was there any indication that malignant neoplasm was increased after 15 to 20 years latency. The authors identified a weakness of the study in that the average latency ofthe cohort was 14.7 years with a maximum of 24.6 years, or a relatively short latency for development of cancer. A study by McDonald, et al. [2] regarding the mortality from long-term exposure to cummingtonite-grunerite from a gold extraction process at the Homestake Mine, Lead, South Dakota was reviewed. Those workers who had worked 21 years or longer were traced and of 660 men who had died, the cause of death was ascertained for 657. Results of the study indicated pneumoconiosis, which was mainly silicosis along with tuberculosis, and heart disease were causes of excess death. There was a dust exposure relationship for both pneumoconiosis and respiratory tuberculosis, but reportedly no convincing increase in respiratory cancer. It was noted that more than 75% of the 660 men who had died started to work before 1925. The interval between first employment and death and the 76 fatalities from tuberculosis or pneumoconiosis ranged from 22 to 61 years with a median of 35 years. Average silica dust concentrations ranged from 11.0 to 24.6 mppcfbefore 1952. A study by Dement, et al. [3] reported that 80% to 90% of fibers in the mine had an amphibole diffraction pattern by transmission/scanning electron microscope equipped with an energy-dispersive X-ray spectrometer. The mean total fiber concentration was 4.82 0.68 free (range 0.66-11.79) with 0.36 + 0.08 free (range 0.07-1.29) greater than 5 pm in length. There was one potential mediastinal mesothelioma which could not be confirmed in the 17 respiratory malignancies (16.5 expected based on South Dakota rates). E-7 HWBUI0009794 The results of the study were in conflict with an earlier study by Gillam, et al of the same mine of 440 males who worked at least five years underground by 1960. Reportedly there were 10 deaths from neoplasm of the respiratory system between I960 and 1973 where as 2.7 were expected based on the male population of South Dakota [4]. Conclusions There is no data regarding human exposure to asbestos fiber uniformity less than 5 pm in length. Studies of workers exposed to cummingtonite-grunerite, a type ofamphibole related to amosite, demonstrated no consistent increase in overall mortality, mortality related to selected respiratory disease, or respiratory cancer. The vast majority of airborne fibers were reported to be less than 10 pm in length. Studies of workers of a gold mine in Lead, South Dakota exposed to cummingtonitegrunerite initially demonstrated an increased mortality from malignant respiratory disease. A subsequent study did not confirm the initial finding but demonstrated an increase in silicosis and tuberculosis. Mean total fiber concentration was 4.82 free with 0.36 free greater than 5 pm in length. Consideration should be given for performing a feasibility study regarding an updated mortality analysis of these two cohorts. MMVF Mortality Studies. Mortality studies of glass fiber and mineral wool production workers have been ongoing in the U.S. most recently under the direction of Marsh, et al at the University of Pittsburgh, and within the European Union under the direction of the International Agency for Research on Cancer (IARC). The most recent follow up study by Marsh, et al. [5,6,7] of 10 U.S. glass fiber manufacturing plants demonstrate no excess mortality from all causes, all cancers combined, or non-malignant respiratory disease. For respiratory system cancer, there was an observed 6% excess that was statistically significant for the total cohort but not found in workers who had five or more years of employment. An association was seen with calendar time and time since first employment, but no relationship was found with duration of employment, or increase in exposure to respirable glass fiber. A case-control study, of respiratory system cancer did not identify increased risk with duration of exposure, cumulative exposure, or time since first employment. An association with non-baseline levels of average intensity of exposure to respiratory fibers was not present when adjusted for smoking. A previous case-control study of a glass fiber manufacturing facility included in the U.S. glass fiber study demonstrated that differences in local versus national smoking rates may have been a contributing factor in the excess respiratory cancer seen in that manufacturing facility. [8] The potential confounding impact of cigarette smoking in the U.S. glass fiber and rock/slag wool studies was further explored by Buchanich, et al. [9] and Marsh, et al. [10] and identified as the potential unaccounted for factor regarding the small excess respiratory system cancer not related to exposure indices. Previous analysis of five rock and slag wool plants in the U.S. demonstrated increased lung E-8 HWBUI0009795 cancer mortality using U.S. but not local rates, and this was confined to short-term workers or those workers with less than five years duration ofemployment. There was no association with measures of respirable fiber exposure. [II] Within the U.S. a case-control study of 9 slag wool plants demonstrated an association with smoking but not MMVF exposure. [12] Most recent analysis of the U.S. rock and slag wool workers as well as glass fiber production workers identified ten death certificates that mentioned the term mesothelioma. [13] Of the ten cases of mesothelioma, two on pathology review were definitely not felt to be mesotheliomas, one had a 50% chance of mesothelioma, and two others had less than 50% chance of mesothelioma. Medical records or pathology specimens were not available on the remaining five. Using a timeframe when specific malignant mesothelioma coding rubrics were available, the expected mesothelioma rate (local county comparison) was 2.19 versus 1 observed. Overall the authors felt there was no increased risk from the malignant mesothelioma in the U.S. MMVF cohort. The IARC have followed the mortality ofworkers among 13 MMVF manufacturing facilities in Europe. [14] The most recent update demonstrated a significant increase in lung cancer mortality in rock and slag wool workers as well as glass wool workers, using national mortality rates which disappeared for the glass wool workers when using local adjustment factors to the national mortality rates. In addition, there was no association in the glass wool workers with time since initial employment or duration of employment, and with removal of glass wool workers with less than one-year employment no excess lung cancer was noted. Within the rock and slag wool cohort there was an increase in lung cancer risk but the authors felt there was no clear information to indicate that the increased cancer risk was specifically related to fiber exposure. [14] A subsequent cohort study demonstrated similar results. [15] A case-control study nested in this latter cohort indicated no relationship between cumulative rock or slag wool exposure and lung cancer. [16,17] Within the IARC study there were five cases of mesothelioma, two which occurred in workers with less than one-year employment and two in workers with most likely prior asbestos exposure. [14] Preliminary results of a mortality study of U.S. RCF manufacturing workers demonstrate no significant increase in malignant or non-malignant respiratory mortality and no malignant mesothelioma: The power ofthetudy was limited as the cohort was relatively young and small in number. [18] n Conclusions !. There are no data regarding human exposure to MMVF uniformityless than 5 pm in length. . ': There is no persuasive evidence that exposure to glass fiber, rock wool, slag wool, or refractory ceramic fiber has been associated with increased lung cancer risks based oh ongoing U.S. andEuropean mortality studies. : There is no indication of an increased risk for mesothelioma. u HWBUI0009796 Non-Cancer Effects MMVF Morbidity and Mortality Studies. Non-malignant respiratory effects: Studies of five fiberglass and two mineral wool manufacturing facilities identified small opacities in 1.6 % of the population studied that were predominantly irregular in shape. [19] These workers were involved with working in facility manufacturing fibers over 3 jxm in diameter and fibers averaging 1 pm to 3 pm in diameter. The overall rate of chest X-ray changes was no different in comparison to a non-MMVF exposed comparison group, and any relationship between exposure indices was seen at profusion level 1/0 but not 1/1. There was no increase in upper or lower respiratory tract symptoms. Similar results were seen in a study in Australia of glass and rock wool production workers with no findings of asthma, pulmonary fibrosis or pleural disease. [20] A similar study of rock wool workers also did not demonstrate increased respiratory symptoms or abnormalities with DLCO or DL/Va. A potential additive or synergistic effect, however, was seen regarding the FEV1/FVC ratio, fiber exposure, and those with greater than 40-pack year history of cigarette smoking. [21] The IARC [22] study demonstrated no increased mortality from asthma, bronchitis or emphysema, which is similar to the most recent analysis of the glass fiber workers in the United States which did not identify increased mortality from non-malignant respiratory disease. [5] Of interest in the IARC study was the suggestion of an increased risk from non-malignant renal disease (SMR 0.97,95% Cl 0.36 to 2.11) in regard to duration of employment or employment at an early phase within the rock and slag wool industry. Within the U.S. mineral wool study a similar trend was noted (p < .05) with a SMR of204 (observed 12) in regard to nephritis and nephrosis. [11] Similar type patterns have not been demonstrated in relationship to nephritis and nephrosis deaths in U.S. glass wool manufacturing facilities. [23] There are very limited studies on end users of man-made vitreous fibers. One study identified increased prevalence of chest radiograph evidence of irregular opacities in workers using rotary spun fiberglass, but there was a question of airborne asbestos fibers within the plant site. [24,25] In insulators a decrease in FEV1 was identified in comparison to a non-exposed control group after adjusting for smoking habits and self-assessed former asbestos exposure. [26] On-going morbidity studies of workers involved with refractory ceramic fiber (RCF) manufacturing have identified a relationship between pleural plaques and time from initial employment, duration of employment, and cumulative refractory ceramic fiber exposure. Pleural changes were seen 2.7%. or 27 workers out of 1,008 of which 22 were pleural plaques. Of those with greater than 20 years latency from initial production job.or 20 years duration in a production job, 16 workers or 8.0% and 5 workers or 8.1% had pleural changes, respectively. Interstitial changes were noted in 1.0% at profusion category >1/0', similar to other non-specified dust exposed worker populations and showed a non-significant elevated OR in regard to cumulative fiber exposure of 4.7 (95% Cl, 0.97 to 23.5). In regard to cumulative fiber exposure, 5.4% (8 of 148) with greater than 45 to 135 fiber-month/cc exposure had pleural changes (OR 5.6,95% Cl, 1.5 - 28.1). For those with >135 fiber-months/cc exposure, 9.8% (6 of 61) had pleural changes (OR 6.0, Cl 1.4 -31.0). [27] European studies concurred that there was some evidence of a relationship between RCF latency and pleural changes including pleural plaques but not duration or intensity of RCF exposure, but it was difficult to separate the effects asbestos and RCF exposure and any relationship between RCF exposure and small opacities was at best ambiguous. [28] E-10 HWBUI0009797 Previous studies of the RCF workers demonstrated a relationship between 10 years of employment in production job tasks prior to 1987 and small decrements in FVC for current (165.4 m!) and past (155.5 ml) male smokers, but not never-smokers, and small decrements in FEV1 for current male smokers only (134.9 ml). For never-smoker women there was also a decrement in FVC (350.3 ml) per 10-years employment in production job tasks. [29] A longitudinal analysis in those male workers able to provide five tests or more did not demonstrate any further decrement of the FEV1 or FVC between initial and final tests. [30] Conclusions Regading Non-Cancer Effects of MMVF There are no available morbidity studies of workers exposed to MMVF uniformly less than 5 pm in length. No increased mortality from non-malignant respiratory disease. No indication ofchest radiograph interstitial or pleural changes in regard to glass and mineral wool production workers but data is limited. . Refractory ceramic fiber (RCF) exposure appears to be associated with the occurrence of pleural plaques that most likely are related to increased exposure levels in the RCF manufacturing facilities prior to 1985. Potential additive or synergistic effect with MMVF exposure and small decrement in FVC and/or FEV1 involving current or former smokers. Within mineral wool cohort, question ofpotential increased mortality from non-malignant renal disease such as nephritis and nephrosis. End user studies of MMVF users are limited and are confounded by potential previous asbestos exposure. : Irritant Effects MMVF can cause skin irritation particularly-in an area where-clothing comes in close contact to the skin Such as around the neck or forearms. Essentially this occurs in 5% of new workers involved with MMVF production. [31] Residential coritaminationof man-made vitreous fibers in high concentration can also cause irritation to the upper as well as lower respiratory tract. [32] Glass fibers with diameters greater than 5.3 pm have been reported to be more likely to cause skin irritation than the smaller diameter fibers, mainly due to mechanical irritation. [33,34] There has been documentation of eye irritation associated with MMVF as well as nasal and pharyngeal irritation with unusual MMVF dust exposure situations. [35,36] Conclusions Skin irritation appears to be related to the mechanical effects of fiber ~5 pm in diameter and appears to be worse in hot, humid weather. J HWBUI0009798 Accidental exposure to increased concentrations of MMVF can result in upper and lower respiratory tract irritation as well as eye irritation. Association Between Fiber Length and Fiber-like Toxicity There have been no published studies that address whether asbestos fibers uniformly <5 pm in length have been associated with pleural or parenchymal disease in human. Any potential risk associated with fiber exposure <5 pm in length most likely would be related to an increased risk for pulmonary asbestosis, and most likely would occur at a substantially higher dose in comparison to exposures to asbestiform fibers (long fibers with high aspect ratios). [37] There is some indication that fibers with diameters with <0.1 pm to 0.4 pm and lengths <10 pm may have a propensity for inducing pleural plaques. [38] Methodologies used to analyze pleural and/or parenchymal tissue for the presence of fibers and association of pleural changes differ markedly between investigators, however. Human studies of individual exposed to asbestos fibers are difficult to interpret in regard to toxicity solely related to fibers <5 pm in length because exposure situations almost.uniformly contain a broad distribution of fiber diameters and length. Preliminary results of residents of Libby, Montana that were exposed to asbestiform tremolite indicate a high propensity for pleural changes in comparison to interstitial changes. [39] There is some indication that exposure to tremolite fibers with relatively low aspect ratios in comparison to the asbestiform type tremolite may be capable of causing pleural plaques. [40] Pleural plaques can occur with minimal exposure to asbestos and can occur within a wide range of tissue burdens of asbestos fibers which overlap with control populations. [41] Conclusions Even though there are no human studies solely of MMVF <5 pm in length, the available morbidity and mortality studies ofMMVF production workers indicate limited overall toxicity from MMVF exposure. There are no human studies regarding exposures solely to asbestos fiber <5 pm in length but there has been some speculation that durable fibers <10 pm in length and <0.1 to 0.4 pm in diameter may be associated with pleural plaques in relatively low concentration, in , particular the amphibole tremolite. For asbestos fibers <5 pm in length, it would appear that very high doses may have the propensity to cause interstitial fibrosis, particularly if the fibers are durable within intracellular fluids. Thresholds for Toxic Action For asbestos and MMVF less than 5 pm in length, thresholds for toxic action in humans have not been established but most likely is substantially higher than the thresholds for long durable Fibers with increased aspect ratios of respirable size. E-12 HWBUI0009799 Asbestos Versus MMVF Based on animal and human studies, natural occurring asbestos fibers that are of respiratory size, long and thin with high aspect ratios, and durable within physiologic fluids represent the highest risk for malignant (lung cancer and mesothelioma) and non-malignant (interstitial fibers) respiratory disease. These abnormalities have not been demonstrated in MMVF manufacturing workers. References 1) Higgins ITT, Glassman JH, Oh MS, Cornell RG. Mortality of reserve mining company employees in relation to taconite dust exposure. Am JEpidemiol 1983;118(5);710-719. 2) McDonald JC, Gibbs GW, Liddell FDK, McDonald AD. Mortality after long exposure to cummingtonite-grunerite. Am Rev RespirDis 1978;118:271-277. 3) Gillam JD, Dement JD, Lemen JM, Wagoner JK, Archer VE, Blejer HP. Mortality patterns among hard rock gold miners exposed to an asbestiform mineral. NYAcadSci 1976:271-336. 4) Dement JM, Zumwalde RD, Wallingford KM. Discussion paper: Asbestos fiber exposure in a hard rock gold mine. Ann NYAcad Sci. 1976:271-345. 5) Marsh GM, Youk AG, Stone RA, Buchanich JM, Gula MJ, Smith TJ, Quinn MM. Historical cohort study ofUS man-made vitreous fiberproductionworkers: 1.1992 fiberglass cohort follow-up: Initial finding. JOFM2001 ;43(9):741-756. 6) Youk, AO, Marsh GM, Stone RA, Buchanich JM, Smith TJ. Historical cohort study of U.S. man-made vitreous fiber production workers: HI. Analysis of exposure-weighted measures of respirable fibers and formaldehyde in the nested case-control study of respiratory system cancer. JGM2001;43(9):767-778. 7) Stone RA, Youk AO, Marsh GM, Buchanich JM, McHenry MB, Smith TJ. Historical cohort study of U.S. man-made quantitative exposure-response analysis of the nested case-control study of respiratory system cancer. JrQEM2001;43(9).:779-792. 8) Chiazze L, Watkins DK, Fryan C. A case-control study of malignant and noil-malignant respiratory disease among employees of a fiberglass manufacturing facility. BrJInd Med 1992;49:326-331. ~' 9) Buchanich JM, Marsh GM, Youk AO. Historical cohort of U.S. man-made vitreous fiber production workers: V. Tobacco-smoking habits. JOEM 2001 ;43(9):793-802. 10) Marsh GM, Buchanich JM, Youk AO. Historical cohort study of U.S. man-made vitreous fiber production workers: VI. Respiratory system cancer standardized mortality ratios adjusted for the confounding effects of cigarette smoking. JOEM2001 ;43(9):803-808. 11) Marsh G, Stone R, Youk A, et al. Mortality among United States rock wool and slag wool workers: 1989 update. J Occup Health Safety-Anst NZ 1996; 12:297-312. E-13 o HWBUI0009800 12) Wong O, Foliart D, Trent LS. A case-control study of lung cancer in a cohort of workers potentially exposed to slag wool fibres. BrJIndMed 1991;48:818-824. 13) Marsh GM, Gula MF, Youk AO, Buchanich JM, Churg A, Colby TV. Historical cohort study ofU.S.' man-made vitreous fiber production workers: II. Mortality from mesothelioma. JOEM2001;43(9):757-766. 14) BofFetta P, Saracci R, Andersen A, et al. Cancer mortality among man-made vitreous fiber production workers. Epidemiology 1997;8:259-268. 15) Boffetta P, Anderson A, Hansen J, et al. Cancer incidence among European man-made vitreous fiber production workers. Scan J Work Environ Healthl999;25:222-226. 16) Kjaerheim K, Boffetta P, Hansen J, Ghenie J, Chang-Claude J, Eilber U, Ferro G, Guldner K, Olsen JH, Plato N, Proud L, Saracci R, Westerholm P, Andersen A. Lung cancer among rock and slag wool production workers. Epidemiology 2002 Jul; 13(4):445-453. 17) IARC monographs on the evaluation ofcarcinogenic risks to humans. Volume 81, Man made Vitreous Fibres 2002. 18) Lemasters G. Lockey J, Levin L, Yiin J, Reutman S, Papes D, Rice C. A longitudinal study of chest radiographic changes and mortality of workers in the refractory ceramic fiber industry. 2001 Congress of Epidemiology Abstracts Am JEpidemiology 2001; 153(11 ):S264. 19) Hughes JM, Jones RN, Glindmeyer HW, et al. Follow up study of workers exposed to man made mineral fibres. BrJInd Med 1993;50:658-666. 20) Woodcock AJ Mellis CM. Respiratory health of workers in the Australian giasswool and rockwool manufacturing industry. Final report prepared for Insulation Wools Research Advisory Board by Institute of Respiratory Medicine. Royal Prince Alfred Hospitals. Sydney, Australia. 1994. 21) Hansen EF, Rasmussen FV. Hardt F, Kamstrup O. Lung function and respiratory health of long-term fiber-exposed stonewool factory workers. Am JRespir Crit Care Med 1999;160:466472. J. 22) Sali D, Boffetta P, Anderson A, et al. Non-neoplastic mortality of European workers who produce inan made vitreous fibres. Occup Environ Med 1999;56:612-617. 23) Chiazze L, Watkins DK, Fryan C. Fayerweathcr W, Bender JR, Chiazze M. Mortality from nephritis and nephrosis in the fiberglass manufacturing industry. Occup Environ Med 1999;56:164-166. 24) Kilbum KHy Powers D, Warshaw RH. Pulmonary effects of exposure to fine fiberglass: Irregular opacities and small airways obstruction. BrJInd Med 1992;49:714-720. E-I4 HWBUI0009801 25) Bender JR. Pulmonary effects of exposure to fine fiberglass: Irregular opacities and small airways obstruction. BrJIndMed 1993;50:381-382. 26) Clausen J, Netterstrom B, Wolff C. Lung function in insulation workers. BrJInd Med 1993;50:252-256. 27) Lockey JE, LeMasters GK, Levin L, Rice C, Yiin J, Reutman S, Papes D. A longitudinal study of chest radiographic changes of workers in the refractory ceramic fiber industry. Chest 2002;121:2044-2051. 28) Cowie HA, Wild P, Beck J, Auburtin G, Piekarski C, Massin N, Cherrie JW, Hurley JF, Miller BG, Groat S, Soutar CA. An epidemiological study of the respiratory health ofworkers in the European refractory ceramic fibre industry. Occup Environ Med2001;58:800-810. 29) Lemasters G, Lockey J, Rice C, et al. Radiographic changes among workers manufacturing refractory ceramic fibre and products. Ann Occup Hyg 1994;38(1 ):745-751. 30) Lockey JE, Levin LS, Lemasters GK, et al. Longitudinal estimates of pulmonary function in refractory ceramic fiber manufacturing workers. JRespir Crit Care Med 1998; 157:12261233. 31) Bjomberg A. Glass fiber dermatitis. Am JInd Med 1985;8:395-400. 32) Newhali HH, Brahim SA. Respiratory response to domestic fibrous glass exposure. Environ Res 1976;12:201-207. 33) Fossick PA, Gellin GA, Key MM. Fibrous glass dermatitis. Am IndHyg Assoc J 1970;31:12-15. 34) Heisel EB, Mitchell JH. Cutaneous reaction to fiberglass. Ind Med Surg 1957;26:547-550. 35) Stokholm J, Norn M, Schneider T. Ophthalmologic effects of man made mineral fibers. ScandJ Work Environ Health 1982;8:185-190. 36) Milby TH, Wolf CR. Respiratory tract irritation from fibrous glass inhalation. J Occup Med 1969;11:409-410. 37) Iiippmann M. Asbestos exposure indices. Environ Res 46:86-108,1988. 38) Lentz TJ, Rice CH, Lockey JE, SuccopPA, Lemasters GK. Potential significance of airborne fiber dimensions measured in the U.S. refractory ceramic fiber manufacturing industry. Am JInd Med 1999;36:286-298. 39) Year 2000 Medical testing of individuals potentially exposed to asbestofoim minerals associated with vermiculite in Libby, Montana. A report to the community. August 23, 2001. ATSDR. E-15 ) HWBUI0009802 40) American Thoracic Society. Medical Section of the American Lung Association. Health effects of tremolite. Am RevRespir Dis 1990; 142:1453-1458. 41) Hilierdal G. Pleural plaques: incidence and epidemiology, exposed workers and the general population; a review. Indoor Built Environ 1997;6:86-95. E-I6 HWBUI0009803 Dr. McConnell's Post-Meeting Comments How Do Animal/Experimenta! Data Augment Our Understanding of Human Health Effects Background: There have been numerous studies of the effects of various types of asbestos (ATSDR, in press) and SVFs (ATSDR, in press) in animals. Both fibrous and nonfibrous particulates have been used. Most studies have been conducted in rats and hamsters, but others, including nonhuman primates have been used. Routes of exposure have included inhalation (whole-body and nose-only), intratracheal instillation, intrapleural implantation/injection, intraperitoneal injection and ingestion. All of the routes of administration have their strengths and weaknesses (advantages, disadvantages and limitations) for use for assessing potential health effects in humans (McConnell, 1995). However, the inhalation route appears to produce the most relevant data because it is the only route that duplicates all aspects of human fiber exposure and disease (inflammation, fibrosis, lung cancer and mesothelioma) resulting from the exposure (McClellan et at, 1992). Also, the neoplastic changes typically occur late in the rodents' life, similar to what occurs in humans exposed to asbestos. Other routes of exposure are also useful for comparing the toxic potential of various types of fibers and understanding the mode of action and many of the mechanisms of fiber toxicity and carcinogenicity. Additionally, the oral route (ingestion) appears to be the most appropriate route of exposure for studying the potential hazard of ingested asbestos. Cancer effects: Rats and hamsters are the most frequently used species for assessing the potential carcinogenic effects as asbestos (IARC, 1987) and SVFs (IARC, 2002) and have been used with various routes of exposure. Of the two species, the rat appears to be the most appropriate one because it exhibits both lung cancer and mesothelioma in response to inhalation of known human carcinogenic fibers, e.g. asbestos. The hamster can be a useful model if one is only interested in the inflammatory, fibrogenic and mesotheliogenic effects of particulates. However, the hamster does not develop lung cancer after exposure to high levels of either chtysotile (McConnell et a!., 1995) or amosite asbestos (McConnell et al., 1999). Other species have been used but have significant limitations that preclude their general use for carcinogenic bioassays. For example;, the mouse is not as useful as the rat or hamster because its terminal airways are smaller and therefore, particulates of a mean mass aerodynamic diameter (MMAD) of greater than >0.5 um cannot reach the deep lung (alveolar region) which is the site ofprimary disease. Non-human primates would be an ideal animal model but are precluded because of their long life-span (would require at least 20-30 years to demonstrate a noncarcinogenic effect), availability (a cancer bioassay requires >200 animals/sex), and expense (such a study would cost >$20 million. Most chronic rodent inhalation bioassays of asbestos have been conducted in rats, have not shown significant strain differences and males and females are equally sensitive to its carcinogenic effects (ATSDR, in press). The only large series of studies of various types of E-17 "\ y) HWBUI0009804 1 asbestos showed that if there is a gender difference, males might be slightly more responsive (Wagner, et ah, 1974). Therefore, either sex is appropriate with males slightly more preferable. Just as importantly, both sexes are probably not necessary. However, these same studies have shown that while life-time exposure to asbestos may not be necessary, it is important to observe the animals for most of their life-span (see below). The types of cancer induced by asbestos and SVFs in rodents are comparable to those observed in humans, although the preponderance of a given type and its biologic behavior appears to be species specific. In inhalation studies in rats the preponderant form of lung cancer is bronchoalveolar in origin, arising from type II alveolar cells. They occur late in the animal's life, usually after 21 months of age. This is why lifetime studies may be necessary to fully exonerate a fiber from being considered carcinogenic. The tumors are slow growing and only occasionally are the cause ofdeath. The biological sequence of growth is typically from bronchoalveolar hyperplasia to bronchoalveolar adenoma to bronchoalveolar carcinoma, although all aspects of the sequence of progression may not be found in a given lesion (Boorman and Eustis, 1990). Squamous cell metaplasia is not unusual and typically is found as part of the morphology of larger tumors. Squamous cell carcinoma may predominate in a small percentage of rodent tumors, but has rarely been observed to occur de novo. Squamous cell types may be more common with intratracheal instillation of the fibers (Pott et al., 1994). The malignant tumors are locally invasive and can metastasize but it is an unusual event for them to do so. When this occurs it is usually within the lung, but distant metastases have been observed. The presence of mitotic figures is in direct relation to the degree of malignant transformation. Tumors of the upper respiratory tract and airways have not been observed in response to inhalation exposure of asbestos or SVFs in rodents (IARC, 1987; 2002). Mesothelioma has also been found in rodent carcinogenic bioassays of asbestos and SVFs (IARC, 1987; 2002. In inhalation studies in rats they are usually found at a lower incidence than lung cancer. Again, there does not appear to be a gender predisposition and the mesotheliomas in rodents typically occur late in life (after 21 months of age). They rarely are the cause of death. They grow by expansion, growing over the pleural surface. They typically do not invade the lung or other adjacent structures, although this has been observed. They usually.present as. multiple lesions on both sides of the lung and involve both the visceral and parietal pleura. Rarely, distant metastases have been observed. In inhalation studies, all of the major morphological types(tubulqpapillary, sarcomatous and mixed) have been observed, although the tubulopapillary response is the predominate-fbrm. There is one exception todhis and that is found in the . inhalation study of erionite, where the sarcomatous type predominated, was highly invasive and the tumors were exceptionally lethal causing death-in most of the rats by 15 months (Wagner et al., 1988).. In contrast to inhalation, direct instillation into the pleural .{Stanton et al., 1981) or peritoneal cavities (Pott et al., 1987) results in a preponderance, of sarcomatous neoplasms, and in fact, it may be difficult to find mesothelial cells in many of the tumors, particularly after peritoneal injection. However, even in these studies, the mesotheliomas seldom invade local tissues or metastasize to other areas of thp body. E-I8 HWBUI0009805 % The biological sequence of events in the development of mesothelioma in rodents also appears to have a series of progressive steps (Boorman et at, 1990). In inhalation studies, the first event that is observed is fibrosis in the pleura immediately subjacent to the mesothelial lining. This is multifocal in nature, possibly occurring more frequently in the interlobular pleura. In the few studies where the parietal pleura has been investigated (McConnell, et al., 1999), the initial change was found in the nonmuscular portion of the diaphragm and over the ribs (as compared to intercostal). The first indication of mesothelial change is found in these areas of pleural fibrosis. The mesothelial cells become cuboidal (as compared to a normal squamous morphology) and progress to focal hyperplasia of one to three cell layers thickness. The next step is the formation ofpapillary forms of growth and overgrowth of adjacent pleura. It is at this stage that mesothelioma is diagnosed. Pseudovacuolated tumor cells may be noted at this stage. Finally, the tumor evolves into the classical forms noted above. The course ofevents is somewhat different for instillation and injection studies. The initial response in the latter studies is inflammation, followed by a fibrogranulomatous reaction (assumed to be an attempt to wall off the fibers). A similar sequence of progression is assumed but results in a higher proportion of sarcomatous types of mesothelioma. Pulmonary interstitial fibrosis (see below for description) is invariably found in studies where either asbestos or SVFs have caused either lung cancer or mesothelioma (Greim et al., 2001). However, there have been fiber studies where pulmonary fibrosis was observed without the development of fiber related neoplasms (McConnell, et al., 1994). In vitro studies may not be of high value for predicting the carcinogenic potential of a given type of fiber, although they can give some incite into the difference between the carcinogenicity of long and short fibers. There are several reasons for why they may not as useful for predicting the carcinogenic activity of a given type. First, the fiber used is not subjected to physiological processes such as clearance and dissolution that are found in the lung. Also, the in vitro test systems use "fresh" fibers so do not typically take into account pathology attenuating changes in fibers that occur over time in the lung. Finally, the in vitro "dose" may have no relevance to the lung fiber burden. However, not withstanding this, in vitro methods are highly powerful tools for understanding fiber/cell interactions and mechanisms of toxicity/carcinogenicity (see Mossrnan for details). :V Non-cancer effects: Anitiial models have also demonstrated many of the same pathological responses that are found in humans exposed to particulars (IARC, various volumes). The major noncancer endpoints that have been described in animals in experimental studies are ! phagocytosis, inflammation and pulmonary fibrosis. In regard to these endpoints, the rodent lung (and presumably other species) reacts to asbestos and SVFs as it would to any inhaled nonorganic foreign body that is not chemically toxic, e.g. beryllium. The lung can only react to such materials in a limited number of ways. In animals, if the particulate were deposited in the tipper respiratory tract, one would assume that it would be possible for it to cause local irritation. However, this has not been observed in inhalation studies, even'at high exposure levels. It is assumed that the resident time for such particles is brief, not allowing for a pathologic response. E-19 -\ ) HWBUI0009806 The mucous layer in these tissues is relatively thick compared to the size of the particulate and the methods ofremoval are quite efficient. The same is true for the major airways. In experimental animals the airways are intact and have not been compromised by other toxicants as in humans, e.g. smoking. Therefore, particulates deposited on these surfaces are again efficiently removed via the mucociliary escalator and are either swallowed or expectorated. In either case, the resident time in the body is relatively brief. For a particulate to cause pathology in experimental animals after inhalation, it must reach the alveolar region of the lung. Particulate size dictates whether this happens or not If the particle reaches terminal bronchiole it causes a foreign body reaction which is dictated by dose, particle (fiber) size and to some extent physical chemistry. The lungs' initial response is an attempt to remove the offending substance. This is accomplished by resident macrophages. If the particle is of a size that the macrophage can engulf(phagocytize), it will be "captured and removed from the lung either by translocation to the airways or draining lymphatics. As the dose (number of particulates) increases, more macrophages are recruited. However, if the dose is too large for the number ofavailable macrophages to remove, an "overload" situation develops which results in other pathologic events. Such events have been documented in animals both by histopathology and physiological tests (see Oberdorster for details). If the fiber is too large to be phagocytized and removed, Le. longer than the size of the macrophage [~I3 urn diameter in rats and hamsters, monkeys ~15 um, and humans ~21 urn diameter (Krombach et al., 1997)], the fiber cannot be removed unless it is broken into shorter lengths or dissolves (Maxim and McConnell, 2001). Both of the latter two phenomena have been observed with several SVFs (see below). If the dose overwhelms the physiological pulmonary defenses or the fiber is too large to be removed, the initial series of events in animals occur at the junction of the terminal bronchioles and proximal alveolar duct (this is where most of the fibers are initially deposited - It should be noted that rodents do not have a respiratory bronchiole, as do humans). In addition to a stimulating the local macrophages, an influx of additional macrophages is recruited to. the area. At this point, the local type II alveolar cells (in the proximal alveoli) undergo metaplasia to a cuboidal appearance and become hyperplastic. The resulting lesion has been termed "bronchiolization" because the change mimics the appearance of the terminal airways. Increased amounts ofmucous,production and sometimes inspiss.ation of the material often accompany this. Coincident to-the bronchiolization, microgranulomas are observed. These appear to form from a coalition ofmacrophages and fibroblasts. At this time the microgranulomas are restricted to the proximal portion of the.alveolar duct, particularly along the alveolar duct ridge. With time and continued insult the process proceeds peripherally and becomes more apparent. If the offending fiber persists, collagen is laid down in the adjacent interstitium (presumably by direct invasion of the fiber, into the epithelium and interstitium). At this time the lesion is referred.to as interstitial fibrosis. In rodent studies, the fibrotic areas are initially focal and widely disseminated. But, if the insult persists or the dose is high enough, fibrosis becomes more widespread. Various schemes have been developed to describe these events and grade them as to their severity for comparative purposes (McConnell et al., 1984: 2002). There is one notable difference between the qualitative appearance of the lesions produced by asbestos and SVFs in animals. Neutrophils E-20 HWBUI0009807 are often a prominent part ofthe inflammatory reaction with asbestos, especially with amphiboles, while they are rarely found in studies of SVFs, even at doses that produce fibrosis The inflammatory reaction can also be documented and quantified by using the results of pulmonary lavage studies (see Oberdorster). Stop studies (where exposure is stopped and the animals are observed during a nonexposed recovery period) have proved useful for determining the reversibility of the above lesions. Such studies have clearly shown that the initial changes (macrophage response and bronchiolization) arc totally reversible with most SVFs and to some degree with asbestos. Microgranulomas become less apparent and early fibrosis is also, to some degree, resolvable, at least with SVFs. In rodents, studies have demonstrated that fibrosis, even with asbestos, is not particularly progressive, once the exposure ceases. While there is no exact correlate for pleural plaques in animals, localized acellular fibrotic changes reminiscent of this lesion in humans have been observed, albeit on a much smaller scale. The qualitative changes in the pleura are somewhat different than in the lung. Macrophages and inflammatory cells are almost totally absent in the pleural response. Lavage studies have not been conducted with pleural instillation or peritoneal injection studies so it is not known if the same events occur with these routes of exposure of exposure. Animal inhalation studies also ' suggest that fibers need to be present in the pleura for pathologic events to occur. In vitro studies ofmesotheiial cells have been conducted using both human and animal cells. These have been primarily designed to study the mechanisms of carcinogenicity (see Mossman). Irritant effects: While there is evidence ofdermal and ocular irritation of humans as a response to exposure to asbestos and SVFs, no such evidence has been observed in animals. Histopathological studies of the nasal cavity in rodents exposed via inhalation have not shown any evidence ofpathology, although an increased mucous response could be missed with standard histopathology techniques. Similarly, ingestion studies in rats and hamsters of asbestos did not reveal any irritation ofthe alimentary tract (ATSDR, in press). In vitro studies on the irritant effects of either asbestos or SVFs in animals have not been reported. Association between fiber length and fiber-like toxicity: There are numerous animal studies that demonstrate the influence of fiber length and pathogenicity/carcinogenicity! The early studies by using intrapleural impiantation/instillatioh (Stanton et al., 1981) and intraperitoneal injection (Pott et al., 1976) in rats clearly show a direct relationship between fiber size and carcinogenic activity. The longer the fiber, the more carcinogenic if was in these studies. Thfese same studies provided the basis for the hypothesis that short fibers, i.e. shorter than 8 urn in length may not represent a significant carcinogenic risk. However, the same investigations, particularly the intraperitoneal studies also demonstrated that ifthe dose was high enough even so-called "innocuous" particulates, e.g. titanium dioxide, caused the induction of peritoneal E-21 HWBUI0009808 mesotheliomas, albeit at a lower incidence than long fibers. Additionally, the latter studies also demonstrated that if even long fibers, e.g. wollastonite and some SVFs, were not carcinogenic if they were not biopersistent in the peritoneal cavity. There have been a few inhalation studies have been conducted to study the influence of the fiber length on the pathology of asbestos, and all have been persuasive for showing that short fibers are not carcinogenic. This has been demonstrated for chrysotile (Davis and Jones, 1988; Itgren, 1998; Wagner et al., 1980), amosite (Davis et al., 1987; 1986) and crocidolite (Davis et al., 1978; Wagner et al., 1984). Other circumstantial evidence for considering fiber length as being critical to the carcinogenic potential of fibers is provided by the observation that amorphous silica has been shown to be noncarcinogenic in several inhalation studies in rats, while some types of glass fibers ofsimilar chemistry have shown to have carcinogenic activity (IARC, 1987). In fact, amorphous silica has been used as a "negative control" in rodent inhalation studies. A final piece of evidence for the importance of fiber length for the carcinogenic of asbestos and SVFs is found in the hilar lymph nodes that drain the lungs ofanimals exposed via inhalation to both asbestos and SVFs. These lymph nodes are literally filled with macrophages containing short fibers and fiber fragments with no evidence ofpathology or neoplastic change in either the lymph nodes or adjacent tissues. To summarize studies in animals of short fibers and nonfibrous particulates have shown that both are potentially carcinogenic if they are introduced into a confined cavity, e.g. pleural or peritoneal, at sufficiently high doses. But the same studies clearly show that the carcinogenic potential is definitely less with fibers of the same type that are longer. Inhalation studies have clearly shown that short fibers have not caused cancer in animals. The other part of the equation that needs to be considered is the influence ofpulmonary clearance and biopersistence on the carcinogenic potential of particulates. As noted above, even long fibers are not carcinogenic in animals unless they are biopersistent in the animal. There are only a few in vitro studies that address this subject but those that have clearly show a relationship between fiber length and genetic damage. For example, in a study of Chinese hamster ovary cells (CHO) short amosite failed did not cause chromosomal aberrations while long fiber amosite did (Donaldson and Golyasnya, 1995). See Mossman and others for other studies..: ... Thresholds of toxic action: There have been very few inhalation studies in animals of either asbestos 0r SVFs to assess a carcinogenic dose response. It needs to be remembered that to . assess .a carcinogenic dose response, one must have a multidose study that shows a carcinogenic response. Most asbestos and SVF studies were designed to address the carcinogenic potential of the fiber, not dose response. The only multi-dose inhalation study of asbestos used amosite in hamsters (McConnell et al., 1995). In that study, there was a definite dose-related response with regard to both nonneoplastic (macrophage response, pulmonary fibrosis, etc.) and carcinogenic activity (mesothelioma). Unfortunately, the potential lung cancer response could not be assessed because hamsters do not develop pulmonary tumors with particulates. There are a few inhalation studies of SVFs that address dose response. The only one that was positive for cancer involved E-22 HWBUI0009809 refractory ceramic fibers in rats (Mast et al., 1995). In that study there was a clear dose response for both cancer and noncancer endpoints and a no-effect level. There are a few other multidose studies in rats using various types of SVFs, but since none showed carcinogenic activity, one can only evaluate the dose response for noncancer endpoints (Hesterberg et al., 1996). Again, there was evidence in these studies of a dose-related change in the endpoints showing recognizable change. The "stop-studies" in many of these inhalation studies (both asbestos and SVFs) provide evidence for a dose response for noncancer endpoints. However, the number of animals evaluated in the "stop studies" is too small to address a cancer dose response. The only study in primates that addresses a potential threshold of action was with chrysotile asbestos (Patek et al., 1985). In this study, monkeys were exposed to chrysotile asbestos at an exposure level of 1 mg/m3 (0.8 ffcc >5 um length) for 18 months. Ten months following the last exposure, lung biopsies were taken and evaluated for fiber burden and histopathology. There was no evidence ofpathology although a few asbestos bodies were observed in the lung. The monkeys were then held unexposed for an additional ~11 years at which time they were subjected to necropsy' examination and the lungs for histopathology examination. Again, there was no evidence of pulmonary pathology and the number of asbestos bodies had decreased (not reported - personal observation). In summary, the totality ofavailable data suggests that there is a dose-response for both neoplastic and nonneoplastic endpoints in animals and there is a no effect level for both asbestos and SVFs. One attempt at deciding if a given exposure in animals is potentially carcinogenic involves the use of noncancer endpoints. In this scheme it was assumed that a dose that caused pulmonary fibrosis could also represent art exposure that was potentially carcinogenic in animals. This was because no animal study has ever produced cancer in the absence of fibrosis. The next assumption was that since no inhalation study had ever shown fibrosis in the absence of inflammation, one could assume that an exposure that didn't result in inflammation would not reasonably be expected to be carcinogenic. The endpoint chosen for assessing inflammation was the presence of inflammatory cells over background in bronchoalveolar lavage (BAL) fluid after a 90-day inhalation exposure. Therefore, if one did not find an increase, in inflammatory cells in BAL fluid, one could chose this exposure as a no-effect threshold. It is reasonable to expect that in vitro studies could shed light on the dose response of both ;= asbestos and SVFs. While these types of studies are primarily designed to capture and elucidate specific mechanisms of toxicity and carcinogenicity, there maybe insights into dose response that could help in establishing thresholds of effect. One such study showed that short fiber amosite did not cause inflammation, while long amosite did. The only draw backs to and in vitro approach is that these techniques do no take lung clearance phenomena into consideration and fibers that are not biopersistent in the lung might not be differentiated from biopersistent ones because of the short time frame of the in vitro studies. E-23 HWBUI0009810 % References ATSDR, (in press) Toxicological Profile for Asbestos. DHHS, Agency for Toxic Substances and Disease Registry. ATSDR, (in press) Toxicological Profile for Synthetic Vitreous Fibers. DHHS, Agency for Toxic Substances and Disease Registry. Boorman etal. 1990. Pathology of the Fischer Rat. Chap. 6. Peritoneum, Retroperitoneum, Mesentery, and Abdominal Cavity. Boorman et al. 1990. Pathology of the Fischer Rat. Chap. 21. Lung. Davis, J.M. et al. 1978. Mass and number of fibres in the pathogenesis ofasbestos-related lung disease in rats. Br. J. Cancer. 37:673-688. Davis, J.M. et al. 1986. The pathogenicity of long versus short fibre samples of amosite asbestos administered to rats by inhalation and intraperitoneal injection. Br. J. Exp. Pathol. 67:415-430. Davis, J.M. and Jones, A.D. 1988. Comparisons of the pathogenicity of long and short fibres of chrysotile asbestos in rats. Br. J. Exp. Pathol. 69:717-737. Donaldson, K. and Golyasnya, N. 1995. Cytogenic and pathogenic effects of long and short amosite asbestos. J. Pathol. 177:303-307. . Greim, H. et al. 2001. Toxicity of febers and particles - Report of the workshop held in Munich, Germany, 26-27 October 2000. Inhat. Toxicol. 13:737-754. Hesterberg, T.W. et al. 1996. Use of lung toxicity and lung particle clearance to estimate the maximum tolerated dose (MTD) for a fiber glass chronic inhalation study in the rat. Fund. Appt. Toxicol. 32:31-44. IARC, 1987. Asbestos and certain asbestos compounds. In: IARC Monographs on the Evaluation of the Carcinogenic Risk to Humans.; Suppl. 7. . IARC, 1987. Man-Made Vitreous Fibers. In: IARC Monographs on the Evaluation of the Carcinogenic Risk to Humans. Vol. 81. Itgren, E and Chatfield, E. 1998. Coalinga fibre -- A short, amphibole-free chrysotile. Part 2: Evidence for lack of tumourigenic activity. Indoor Built Environment. 7:18-31. Krombach, et al. 1997. Cell size of alveolar macrophages: An interspecies comparison. Environ. Health Persp. I05(Suppl 5): 1261-1263 E-24 HWBUI0009811 o *) Mast, R.W., et al. 1995. A multiple dose chronic inhalation toxicity study ofsize-separated kaolin refractory ceramic fiber (RCF) in male Fischer 344 rats. Inhalation Toxicol. 7:469-502. Maxim, L.D. and McConnell, E.E. 2001. Interspecies comparisons of the toxicity ofasbestos and synthetic vitreous fibers: A weight-of-the-evidence approach. Reg. Toxicol. Pharmacol. 33:1-24. McClellan, R.O., et al. 1992. Approaches to Evaluating the Toxicity and Carcinogenicity of Man-Made Fibers: Summary of a Workshop Held November 11-13,1991, Durham, North Carolina. Reg. Toxicol. Pfaarm., 16:321-364. McConnell, E.E., et al. 1984. A comparative study of the fibrogenic and carcinogenic effects of UICC Canadian chrysotile B asbestos and glass microfibre (JM 100). In: Biological Effects,,of Man-made Mineral Fibres. World Health Organization, pp. 234-252. McConnell, E.E., et al. 1994. Chronic inhalation study ofsize-separated rock and slag wool insulation fibers in Fischer 344/N rats. Inhalation ToxicoL, 6:571-614. McConnell, E.E. 1995. Advantages and limitations of in vivo screening tests. Ann. Occup. Hyg. 39:727-735. McConnell, E.E., et al. 1995. Chronic inhalation toxicity of a kaolin based refractory ceramic fiber (RCF) in Syrian golden hamsters. Inhalation Toxicol. 7:503-532. McConnell, E.E., et al. 1999. Studies on the inhalation toxicology of two fiberglasses and amosite asbestos in the Syrian golden hamster. Part 2. Results of chronic exposure. Inhal. Toxicol. 11:785-836. McConnell, E.E. and J.M.G. Davis. 2002. Quantification of fibrosis in the lungs of rats using a morphometric method. Inhalation Toxicol. 14:101-110. Platek, S.F., et al. 1985. Chronic irritation of short asbestos fibers. Fund. Appl. Toxicol. 8:327- 340. ... iV Pott; F. et al., 1976. Results of animal experiments concerning the carcinogenic effect of fibrous dusts and their interpretation with regard to the carcinogenesis in humans. Abl. Bakteriol. Orig. B. 162:467-505. : Pott, F. et al. 1987. Carcinogenicity studies of fibres, metal compounds, and some other dusts in rats. Exp. Pathol. 82429. Pott, F. et al. 1994. Lung tumours in rats after intratracheal instillation of dusts. Ann. Occup. Hyg. 38:357-363. E-25 ' HWBUI0009812 Stanton, M.F., et al. Relation of particle dimension to carcinogenicity in amphibole asbestoses and other fibrous minerals. J. natl Cancer Inst. 67: 965-975. Wagner, J.C., et al. 1974. The effects of the inhaltion of asbestos in rats. Br. J. Cancer 29:252269. Wagner, J.C. et al. 1980. The comparative effects of three chrysotiles by injection and inhalation in rats. IARC Sci. Publ. 30:363-372. Wagner, J.C. et al., 1984. The effect of fibre size on the in vivo activity of UICC crocidolite. Br. J. Cancer 49(4):453-458 ) E-26 HWBUI0009813 Dr. Mossman's Post-Meeting Comments ATSDR Fibers Panel Mechanisms of Short Fiber Toxicity There appears to be a striking difference in the pathogenicity ofrespirable fibers directly related to fiber length, with fibers below approximately 5 microns in length being less hazardous for the development of cancers or pulmonary fibrosis. This prompts the questions: What are the observed mechanisms of long fiber toxicity? Does composition matter? Are short (<5 microns in length) fibers pathogenic? If so, what are the mechanisms of their toxicity? One hypothesis is that long fiber effects are related to increased generation of oxidants; reviewed in Kinnula, 1999; Hansen and Mossman, 1987). It has been shown that reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated by asbestos fibers spontaneously in cell-free systems, cells in culture, and lung tissue in vivo. A primary step in response to asbestos fiber challenge to a number of cell types is superoxide anion release from cells which have attempted to phagocytize long fibers whereas short fibers are encapsulated in phagolysosomes, often without visible damage to cells. Superoxide, however, can be further dismutated to hydrogen peroxide which can generate the reactive hydroxyl radical, catalyzed by iron vs. the Fenton reaction. Alternatively, superoxide can react with nitric oxide to form peroxynitrite that is associated with inflammation and lung injury. Asbestos stimulates the release of ROS and induces oxidants intracelluiarly in both inflammatory cell types (Hansen and Mossman, 1987; Goodglick and Kane, 1986; 1990) and target cells (Xu et al., 2002). Moreover, indirect evidence for oxidant stress by asbestos is indicated by elevations ofantioxidant enzymes in cells in culture and lung tissue after inhalation of crocidolite asbestos (Janssen et al, 1992, 1994b). In human mesothelial cells, these increases were not observed with exposures to polystyrene beads, or riebeckite, a chemically similar nonfibrous analog of crocidolite (Janssen et al., 1994b). The role of oxidants by crocidolite asbestos in causation of inflammation and fibrosis has been confirmed in rodent inhalation studies (Mossman et al., 1990), and supports the central dogma that asbestos fibers activate transcription factors and early response genes involved in proliferation and inflammation by generating ROS via "frustrated phagocytosis" (reviewed in Manning et al., 2002). i Several papers show that "frustrated phagocytosis" and oxidant production occur selectively in response to long vs. short fibers of asbestos or glass. A study of luciginen-dependent chemiluminescence (CL) in human monocytes found a strong correlation between superoxide release and fiber lengths from 6 to 20 microns. All samples of fibers except wollastonite induced CL release in a dose-dependent manner. Superoxide release was non-specific for the compositional type of fiber, and fibers with lengths below 7 microns were only weakly active. In studies by Blake et al. (1998), CL induction after zymosan stimulation and LDH release, a measure of lytic celt death, were measured in Manville Code 100 (JM-100) fiber challenged rat alveolar macrophages. A novel feature of this study was the use of fibers carefully sized to average lengths of 33, 17, 7,4, and 3 microns. The greatest toxicity was seen with the longer E-27 HWBUI0009814 fibers which had multiple macrophages attached along the surface, indicating that incomplete phagocytosis was associated with toxicity. These studies reinforce the many experiments in the literature showing that long fibers are more toxic than shorter fibers in a number of cell types, i.e., Goodglick and Kane, 1990. Increased fiber length has also been linked to activation of transcription factors and cytokines. For example. Tumor Necrosis Factor-alpha (TNF) is a cytokine involved in inflammation and fibrosis. In a study by Ye et al. (1999), glass fibers with lengths of 6.5 +/- 2.7 microns and 16.7+/-10.6 microns were used to challenge a mouse macrophage cell line. Glass fibers stimulated TNF production and caused Nuclear Factor-kB (NF-kB) activation, a process involving ROS. Long fibers were more potent than short fibers which, were effectively engulfed by macrophages. Short fiber-induced TNF and TNF gene promoter activation was on the order of one-third to one-halfof long fibers. In another study (Cheng et al., 1999), crocidolite asbestos caused parallel increases in TNF production in macrophages in a dose-dependent manner, without cytotoxicity at the optimum stimulating condition. Titanium oxide dust was without effect TNF production may also be linked to inflammation by asbestos, and it has been shown that injection of long vs. short araosite fibers intraperitoneally results in inflammation and macrophage activation related to the proportion of long fibers (Donaldson et al., 1989). Another pathway leading to activation of protooncogenes (fos/jun) that comprise the Activator Protein-1 -transcription factor is the Mitogen Activated Protein Kinase (MAPK) cascades, consisting.ofc-jun-N-terminal amino kinases (JNKs), Extracellular Signal Regulated Kinases (ERKs) and p38 kinases. In studies by Ye et al. (2001) using macrophages, long glass fibers were more potent than short fibers in activating MAPK which led to activation ofc-Jun and the TNF promoter. Studies by Zanella et al. (1996) explored the stimulation of ERKs in mesothelial cells, and found increases with crocidolite and chiysotile asbestos , but not with the nonfibrous analogs, riebeckite or antigorite. Similarly, elevations in c-fos and c-jun expression were seen with asbestos fibers and erionite in mesothelial cells, but were not induced by a variety of particulates, MMVF-10 or RCF-1 fibers at comparable concentrations (Janssen et al., 1994a). Long fibers of crocidolite (> 60 microns) were selectively associated with phosphorylation of the Epidermal Growth Factor receptor in human mesothelial cells (Pache et al., 1997), an event not occurring with MMVF-10 or particles. In general, pathogenic dusts such as asbestos or silica, produce a variety of cytokines from cells and activate a number of transcription factors through ROS or RNS (Mossman and Churg, 1998; Churg et al., 2000). Another ramification of transcription factor activation is cell proliferation. Mechanistic studies using target cells in culture or tracheal explants have shown that long fibers are more toxic and more apt to cause cell proliferation than short fibers (Brown et al., 1986; Wright et al., 1986; Marsh and Mossman, 1988; Sesko and Mossman, 1989; Woodworth et al., 1983). These events may be coupled, as compensatory hyperplasia may result from initial epithelial cell injury. In studies by Woodworth et al. (1983), epithelial proliferation and squamous metaplasia were observed with various types of fibers including glass and attapulgite, but not with nonfibrous analogs of asbestos, i.e. riebeckite and antigorite and other particles. E-28 HWBUI0009815 An intratracheal mode! in rats using long (>2.5 microns) and short crocidolite asbestos after intratracheal instillation has yielded some mechanistic information on the differential effects of long vs. short fibers (Adamson and Bowden 1987a, b; 1990). These studies suggest that the increased fibrogenic response to long fibers may be due to selective increases in cell proliferation. In addition, both long and short asbestos fibers cause alveolar macrophages to secrete fibrogenic cytokines, but interstitial fibroblasts exposed to short asbestos fibers do not respond to these cytokines. Surfactant adsorption may be a mechanism whereby reactive particles or fibers are rendered inactive or nonpathogenic. To determine the effect of surfactant adsorption on chiysotile genotoxicity using an assay for micronucleus induction in Chinese hamster lung cells (V79) (Lu et al., 1994), two lengths of chrysotile fibers were used with and without pretreatment with DPPC, i.e. NEEHS intermediate (65%> 10 microns) and short (98% < 10 micron) fibers. The longer fibers were most active, and DPPC-treatment diminished the activity approximately 15%. The maximum activity of the short fiber sample was 70% of the activity of the non-treated intermediate, and the DPPC-treated short fibers expressed about 45% of the activity of the untreated. That is, DPPC did hot fully suppress the activity of the fibers, but had a much more pronounced effect on the short fibers. One possibility is that the partial suppression of genotoxicity reflects suppression of a component of toxicity by surfactant on the mineral surface. Thus, short fiber genotoxicity, as reported here, may reflect a combination of mineral surface functional groups which direct membranolytic activity and ean be modulated by interactions with components of the pulmonary surfactant system as well as phagocytosis-associated ROS. In conclusion, studies summarized above show decreased or no effects of short fibers and nonfibrous analogs ofasbestos in a number of bioassays. The effects of long glass and asbestos fibers may be.comparable in some studies. However, the duration of these short-term assays may be too short to reflect important solubility changes occurring in lung over time. 1 / E-29 ) HWBUI0009816 References Adamson IYR, DH Bowden. (1987a) Response of mouse lung to crocidolite asbestos. 1. Minimal fibrotic reaction to short fibers. Journal of Pathology 152:99-107. Adamson IYR, DH Bowden. (1987b) Response of mouse lung to crocidolite asbestos. 2. Pulmonary fibrosis after long fibers. Journal of Pathology 142:109-117. Adamson IYR, DH Bowden. (1990) Pulmonary reaction to long and short asbestos fibers is independent of fibroblast growth factor production by alveolar macrophages. American Journal of Pathology 137:523-529. Blake T, V Castranova, D Schwegler-Berry, P Baron, GJ Deye, C Li, W Jones. (1998) Effect of fiber length on glass microfiber cytotoxicity. Journal ofToxicology and Environmental Health 54:243-259. Brown GM, H Cowie, JMG Davis, K Donaldson. (1986) In vitro assays for detecting carcinogenic mineral fibres: A comparison of two assays and the role of fibre.size. Carcinogenesis 7(12):1971-1974. Cheng N, X Shi, J Ye, V Castranova, F Chen, SS Leonard, V Vallyathan, Y Rojanasakul. (1999) Role of transcription factor NF-kappaB in asbestos-induced TNFalpha response from macrophages. Experimental and Molecular Pathology 66(3):201-210. Churg A, J Wright, B Gilks, J Dai. (2000) Pathogenesis of fibrosis produced by asbestos and man-made mineral fibers: what makes a fiber fibrogenic? Inhalation Toxicology 12(Suppl 3): 15-26. Donaldson K, GM Brown, DM Brown, RE Bolton, JMG Davis. (1989) Inflammation generating potential of long and short fibre amosite asbestos samples. British Journal of Industrial Medicine 46:271-276; Goodglick LA/AB Kane (1986) Role ofreactive oxygen metabolites in crocidolite-asbestos toxicity to mouse macrophages. Cancer Research 46:5558-5566. Goodglick LA, AB Kane. (199.0) Cytotoxicity of long and short crocidolite asbestos fibers in vitro and in vivo. Cancer Research 50:5153-5163. Hansen K, BT Mossman. (1987) Generation of superoxide from alveolar macrophages exposed to asbestiform and nonfibrous particles. Cancer Research 47:1681-1686. .: Janssen YMW, JP Marsh, MP Absher, D Hemenway, PM Vacek, KO Leslie, PJA Borm, BT Mossman. (1992). Expression of antioxidant enzymes in rat lungs after inhalation of asbestos or silica. Journal of Biological Chemistry 267:10625-10630. E-30 / HWBUI0009817 Janssen YMW, NH Heintz, JP Marsh, PJA Bonn, BT Mossman. (1994a) Induction of c-fos and c-jun proto-oncogenes in target cells of the lung and pleura by carcinogenic fibers. Am. J. Respiratory Cell and Molecular Biology 11:522-530. Janssen YMW, JP Marsh, MP Absher, E Gabrielson, PJA Bonn, K Driscoll, BT Mossman. (1994b) Oxidant stress responses in human pleural mesothelial cells exposed to asbestos. American Journal of Respiratory and Critical Care Medicine 149:795-802. Kinnula VL. (1999) Oxidant and antioxidant mechanisms of lung disease caused by asbestos fibres. European Respiratory Journal 14:706-716. Lu J, MJ Keane, T Ong, and WE Wallace. (1994) In vitro genotoxicity studies of chrysotile asbestos fibers dispersed in simulated pulmonary surfactant. Mutation Research 320(4):253-259. Manning CB, V Vallyathan, BT Mossman (2002) Diseases caused by asbestos: mechanisms of injury and disease development In: JE Talmadge and T Hugh, eds. Int. Immunophaimacology; (MI Luster and MH Kafol, guest eds); Vol. 2, pp. 191-200. Marsh JP, BT Mossman. (1988) Mechanisms of induction of ornithine decarboxylase activity in tracheal epithelial cells by asbestifoim minerals. Cancer Research 48:709-714. Mossman BT, JP Marsh, A Sesko, S Hill, MA Shatos, J Doherty, J Petruska, KB Adler, D Hemenway, R Mickey, P Vacek, E Kagan (1990) Inhibition of lung injury, inflammation and interstitial pulmonary fibrosis by polyethylene glycol-conjugated catalase in a rapid inhalation model of asbestosis. American Review of Respiratory Diseases 141:1266-1271, Mossman BT, A Churg. (1998) State-of-the-Art. Mechanisms in the pathogenesis ofasbestosis and silicosis. American Journal of Respiratory and Critical Care Medicine 157:1666-1680 Pache JC, YMW Janssen, ES Walsh, TR Quinlan, CL Zanella, RB Low, DJ Taatjes, BT Mossman. (1998) Increased epidermal growth factor-receptor protein in a human mesothelial cell line in response to long asbestos fibers. American Journal of Pathology 152:333-340. Sesko A, BT Mossman. (1989) Sensitivity ofhamster tracheal epithelial cells to asbestiform minerals is modulated by serum and by transforming growth factor, beta 1. Cancer Research 49:2743-2749. Woodworth CD, BT Mossman, JE Craighead. (1983) Induction of squamous metaplasia in organ cultures ofhamster trachea by naturally occurring and synthetic fibers. Cancer Research 43:49064912. Wright A, H Cowie, IP Gormley, JMG Davis. (1986) The in vitro cytotoxicity of asbestos fibers. I. P388D1 cells. American Journal of Industrial Medicine 9(4):371-384. E-31 HWBUI0009818 Xu A, H Zhou, D Zengliang Yu, TK Hei. (2002) Mechanisms of the genotoxicity of crocidolite in mammalian cells: implication from mutation patterns induced by reactive oxygen species. Environmental Health Perspectives 110:1003-1008. Ye J, X Shi, W Jones, Y Rojanasakul, N Cheng, D Schwegler-Beriy, P Baron, GJ Deye, C Li, V Castranova. (1999) Critical role of glass fiber length in TNF-alpha production and transcription factor activation in macrophages. American Journal of Physiology 276(3 Pt 1):L426-L434. Ye J, P Zeidler, SH Young, A Martinez, VA Robinson, W Jones, P Baron, X Shi, and V Castranova. (2001) Activation ofmitogen-activated protein kinase p38 and extracellular signalregulated kinase is involved in glass fiber-induced tumor necrosis factor-alpha production in macrophages. Journal of Biological Chemistry 276:5360-5367. Zanella CL, J Posada, TR Tritton, BT Mossman. (1996) Asbestos causes stimulation of the extracellular signal-regulated kinase 1 mitogen-activated protein kinase cascade after phosphorylation of the epidermal growth factor receptor. Cancer. Research 56:5334-5338. J. E-32 HWBUI0009819 Dr. Oberdorster's Post-Meeting Comments When responding to the charge questions in Topic Area 1 (physiological fate of asbestos and SVF fibers less than 5 micrometers in length). Dr. Oberdorster gave a briefpresentation to the panel. He asked that a copy of the overheads from this presentation be included in this appendix of the report. A copy ofthe overheads Dr. Oberdorster prepared for the meeting follow, including some overheads that were not shown at the meeting due to time constraints. Dr. Oberdorster also provided an additional comment not mentioned at the expert panel meeting. He noted that the panelists overlooked an important concept ofshort fiber toxicity which involves an increased retention in the lung ofshort fibers in people (e.g., smokers) who have disturbed alveolar macrophage mediated lung clearance. These people, he noted, can experience a marked increase in short fiber retention and thereby increase the potential for fiber toxicity significantly. Long fibers are reportedly not affected to the same degree as short fibers, as was described in a paper by Churg ("Effects of cigarette smoke on the clearance of short asbestos fibres from the lung and a comparison with the clearance of long asbestos fibres," International Journal of Experimental Pathology 73(3): 287-297,1992). E-33 HWBUI0009820 Airborne Fibers and Host Interactions Human activities/ Susceptibility Mechanisms m a O A m a $ 'S' SB 'S <*> K .SS i" 13m Gt OGD o <CC&A3> S f4aocs->u O S3 aa> o> oa S 53 Ow d> ss cc a k W <CoO u Jm S3 00 CA S3 O 'ss 43 .2 au. .13 .2 B s C3 * 43 a> uoS o >> -C -4 a tsH 4Ca*As * 43 Ph 3m o. wo P4 So u u c 3 cum o I (3 *43 cs (3 a> a B rw\ HWBUI0009821 1 ') HWBUI0009822 h/ I i .ffc <S. etx *o? *a 3 -a3 Q C2> ; vf : 3" (3 O e* HWBUI0009823 Predicted deposition of fibers in human extrathoracic airways (after Yu, 1990) Effectivefiltration o f longfibers by HWBUI0009824 / HWBUI0009825 Asgharian and Yu, 1989 Fig. 4. Tracheobronchial deposition via trachea at a lung volume of 10.78 cm3, a tidal volume of L68 on3, ^ breathingTxequency o f 98 cydesnthC1and p=3.37 gem-3. Fiber Diameter (Mm) to cC CO CM O HWBUI0009826 uoipRij uoiiisodeq Long fibers are poorly respirable in rats HWBUI0009827 Retained Dose = Deposited Dose - Amount Cleared * norm al AM -m ediated clearance: Tm rat ~70 days Ko to !k. S'***-* m Qhi 'd s<D pOi--t -si o K fc <d o <D 0GO o 01 CD n . * ** to &a OO GO .s; dGO *3 CD 03 3 >eA <d <D S a fc* S3 eg *0**3$ o53 eg CD tJ 0' oeg 3 obi GO 43 Ph 2 J Vo0 eg GO Seg3 S. -3. `V3 m U CD aaC> A GO 1-4 <d p>1> 43 ns a> S3 i-i 3 u CD -M <d n3 GO p-4 CD d eg u eg CD U CO GO GO CD a o u a .... s eg e S3 <D 43 o P-4 GO 43 On g> S<3 es a Sa>3 w (GMO GO U COD; :<pnD< to <> t GO s .Co o*ss cd C ta I <s> g I HWBUI0009828 Pathogenicity and Fiber Length: 14 For non-cancer --------- all fibers (but: also impact fo r tumors!) V3 <N Os Os Os Os cs to 01 <3 T3 C O to 01 a ~S2 CS o <3 w Oo -c> s Os S a u '--I o ft. a<x> 'a 0 to 01 Os C a> Os O s tf IS 01 a> o K Oo Os 01 '"t ^1 a o <3 01 tkO o *l!Ko4 WS -O u <a co SIS | o' CM a? P4i ffl W Si m CS o ?-< HWBUI0009829 ) (Oberdorster et a!., 1988) C!i -i-_> 0. a V . ss ^ m m m -g fiQ c. s K cO s? S ^8 O St 'M s ^ <> S ^q a> a P _Q m H M Pm 2 o* *?* -Si J ta *c> <y o p? cs Ml 0$ a> U_ xtx <w m*1 5c j?2 Op, m >> 43 A s; o '-G <y -3 s;} 53 <n p a 15"M 5-Ja Is K O <W "*3 <Qo> O Q .Sa S IS e 53 S! qq 2 >5 ** ** 5j EX, HWBUI0009831 (sAep) 9J!l-||Bq DO r- cm O O OO o co in r- a Clearance of Chrysotile from Rat Lung Fiber length (|im) ( Aep) a*ej aouejeap ) HWBUI0009832 r HWBUI0009833 Fig. 8. Bivariate distribution of fibres in Pnakkila bagging section. # N0IJ.N3i.3il 3AIJVT3U rell. Inhaled Particles V, 1982 F ig. 10. Bivariate presentation of fibre retention. HWBUI0009834 Y-' ,/ 'o o0v\ <3 Jk, -.so; -ia Cl) e> iUJrt) qiSuai --I--TT t--r r :-s (mil) ihAmi 3 .3o 3o (an)) iflOutr) US (tint) tii&iiri m (ufrtjqieuai 9 sre vz zi uo zro 9?0 no woo soo KOO mo (un1)qjSusi o Dl#mator (pm) DlamtHef (pm) HWBUI0009835 FIG-, 2. Relative size distribution o f fibers isolated from (A) aerosol, (B) Day 5 lung, (C.) Day 32 lung, (D) Day 0 pleura, (E) Day S pleura, and (F) Day 32 pleura, isobars wise calculated based on histogram analysis o f the aerosol cloud and liber burden data (average o f si* rats). Median bin values are shown on the x- tutd y-axes. Pulmonary and pleural liber burdens were normalized to Day 5 data with areas under the curve equal to 100 on .Day 5, From: Timbrell et a l, Tnknled PnrticleS VI, 1988 F ig . 5. Relationships when the parameter o f fib re quantity is number. HWBUI0009836 From: Timbrell et a l, Inhaled Particles VI, 10f i x HWBUI0009837 From: Timbrell et al 'd Particles VI, 1988 HWBUI0009838 emofpiposaui ipiAi sjej o/o HWBUI0009839 Peritoneal mesothelioma A fte r I.P. Injection . ' o f Long and Short Chrysotile i.p. Dose, St <3 s rfi -Cl <3 EX, ST o Co g J^53 ^Q3j co <3 O .*? bO R a -43 o a Ru o <S HWBUI0009840 (predicted lung burden o f.Ti02 in "overload" range, ~10 mg/lung) = no mesothelioma with chrysotile alone - greater effect o f added quartz than o f added T i0 2 uofiisodea puo|6ay % o o 0.0001 0.001 0.01 0.1 1 Diameter (jxm) 10 100 ii < HWBUI0009841 Alveolar; TB = Tracheobronchial; NPL = Nasal, Pharyngeal, Laryngeal ) I IH 15 o id am* m mcs 0 *aa-s Js 4) f 1 JtvsOjS.'. ' . 4> :n 'S g s <m* "?S J aa i| 111 HWBUI0009842 Fibers act as co-carcinogeris or carriers of chemical carcinogens to target cells -- synergism between cigarette smoke and asbestos exposure -- interaction betweenfibrosis and non-fibrous dusts 00 ''O Os -uof-t u Os 5*-t *--c b> K * o u Csfi m pH m fl 2 n E5 -o 8 bo a o * mr -*-> >SL 03 43 2 CO sO ^u "a ''a a a <S-2^ CD ois SQ ,,4> T3 at 5Jm Ii4s- +<Dv CS Jh ao 'a aaCD oakKi " 55 o 5 (U a c &l tx> a. 0 CSD? -CisD .cCaDj "S <> a C<3D COJ 0 5bso a ce m a -532 -5a & jS 01 ^1 5-1 <s *50; - "^A; . >>. -a u :XS a, e- 0> u 11&4-t u 2 <tf 4*2H ss Cc< a ' 5 a S" ' <QC4>lT x-> J=3 m u S o 2^ 6, ,, <s ff 1 a^ a `-S3 t a. ,4-<fwo--u4tj ua, <3 `aoa <a3 &* j) to a <3 : 2 Ct. CCDD faj, CD bOoao'o 2 O a A -52 PO 5S** S CJ <o ^ <w3> OS oa '5> S Ss PS> sn VS >-l 42 a C"aOD *-*aoA P*<-3Jk *5, oSCDT ^ -USS CaD "Q a .CD 03 a o>* om . -a . O03D. 93 <I--a<0a>-UI> TS is CsDs .a CCDD <X. CCoaCaDD3 e 93 ^a - C >oM* r 2 (3 S Oa -o <c, a' o a C5 c oa' e fup 4 * a o u Atj o a. \CasD ^5 6r3 a> o Ao s: s- ll a, wIU> A**H gs? ' >o 4-a* -a I1 ri co m /i HWBUI0009843 Dr. Wallace's Post-Meeting Comments Health Effects of Asbestos and Synthetic Vitreous Fibers: The Influence of Fiber Length 1 participated in the Agency for Toxic Substances and Disease Registry (ATSDR) expert panel on "Health Effects of Asbestos and Synthetic Vitreous Fibers: The Influence of Fiber Length", held in New York City on October 29-30,2002. I limited my comments to one of the topics which ATSDR requested that the panel consider: "Topic #2: Health Effects ofAsbestos and Vitreous Fibers less than 5 micrometers in length." My research background has involved some studies of the surface properties and associated toxicides of respirable silica and silicate particulate dusts, which may have some indirect relevance to one ofthe questions asked of the panel under Topic #2, specifically: "Do the mechanisms of action of other materials (e.g., larger asbestos fibers, silicates, mineral dusts, amorphous silica) with potentially similar compositions aid in understanding small-fiber mechanisms of action?" Dr. Ralph Zumwalde ofNIOSH, who has an extensive background in the epidemiology of fiberassociated diseases, attended the proceedings as an observer and contributed information and recommendations concerning the availability of data and the analyses of epidemiology studies of occupational exposures to fibers. In this review and revision ofmy comments on the panel, I also comment on the question: "Is there indirect evidence for less-than-5 micron fiber induced adverse health effects?" because of its association with the question of mechanism and because of some reports of inverse correlations of fiber length with fibrosis seen in asbestos workers' lungs. As discussed in the following review, my evaluation of information presented and commentary made by and to the panel is that there is a need for focused and short-term research on short fiber hazard; and that there are new opportunities for the design of that research. : Question: Do the mechanisms of action of other materials (e.g., larger asbestos fibers, silicates, idineraldusts, amorphous silica) with potentially similar compositions aid in understanding small-fiber mechanisms of action? ' A. Some lessons from nori-fibrous particulate studies 1. Non-fibrous crystalline silica is cytotoxic, fibrogenic and carcinogenic. ` Respirable crystalline silica particles, which are non-fibrous by any definition, are strongly pathogenic for fibrotic lung disease, and IARC, the US EPA, and others have recently evaluated quartz and cristobalite, two crystalline silica polymorphs, to be carcinogenic (1). E-57 \ J HWBUI0009844 Exposure to these crystalline silica dusts can directly damage cells. Research suggests that consequent to this damage, there can be intercellular generation of reactive oxygen species and a cascade of events similar to the those evoked by asbestos fiber (2,3). As depicted by Dr. Mossman and others, that sequence may lead to the synthesis and release of TNF-alpha or other cytokines which stimulate near-by fibroblasts to proliferate and to up-regulate their synthesis and secretion of procollagen into the extracellular space of the pulmonary interstitium. There the procollagen matures into one or several forms ofcollagen fibers causing simple or progressive lung fibrosis. The initial damage by quartz dust and by cristobalite dust to cells in vitro has been shown to be associated with the presence of silanols, hydroxyl groups on the crystalline silica surface. Bolasitis et al. (4,5) showed that calcining, e.g., heating, quartz resulted in the loss of surface silanols and a parallel loss of direct membranolytic cell damaging activity. As the dust aged in normal humidity air, the silanols re-formed on the surface over a period of days, and toxicity was restored parallel to that restoration. Saffiotti et al. (6) observed similar behavior with cristobalite. In some circumstances, e.g., sand-blasting occupational exposures, highly reactive free radical species are formed on the freshly broken crystalline silica surface; these exhibit heightened toxicity to cells in vitro in the absence of materials which can react to quench that activity, and may provide a additional mechanism ofheightened toxicity (7). 2. Mineral-specificfibrogenicity: Short-term in vitro bioassaysfor mineral particles do not work Some silicate dusts are cytotoxic in vitro but are not strongly pathogenic in vivo. Clays, layered alumino-silicates, are not associated with strong fibrogenic activity in human workplace exposures or in animal model exposure studies (8). In particular, respirable-sized kaolin clay dust, perhaps the structurally simplest alumino-silicate clay, is comparable to respirable-sized quartz dust for in vitro cytotoxicity (9) as measured by short term assays of cell damage, e.g., membranolysis, cytosolic or lysosomal enzyme release, or dye-exclusion measures of cell viability. Therefore, direct short-term in vitro cellular assays do not distinguish the distinct in vivo fibrogenic potentials of quartz versus kaolin clay dusts. Because of this, the general prevalence of clays in many mixed dust exposures prevents the use of short-term in vitro cytotoxicity systems to predict dust hazards -- 3. Thefirst events in.particle orfiber interaction with the deep lung surface: An important but generally ignored component for physiologically-representative in vitro bioassays: - ...... a. The environmental interface of the deep lung is surfactant-coated Particles or fibers depositing in the deep lung respiratory bronchioles or pulmonary alveoli will first contact the aqueous "hypophase" lining on the terminal airway and airsac surfaces. This thin layer is coated at the air-liquid interface with surfactant which acts to reduce the surface tension and physically stabilize the airspaces (10). The hypophase layer is also rich with micellar E-58 HWBUI0009845 dispersion ofsurfactant The surfactant is comprised principally of lipids and lipoproteins. The major constituents are phospholipids: diacyl phosphatidylcholines. Dipalmitoyl phosphatidyl choline (DPPC) dispersed in physiological saline provides perhaps the simplest model of lung surfactant, representing the major surfactant constituent and generally reproducing the surface tension-lowering characteristics of lull lung surfactant. b. toxic particles adsorb surfactant and are promptly neutralized Both quartz and kaolin clay dust particles promptly adsorb DPPC surfactant from dispersion in physiological saline; this immediately coats the particle surfaces and prophylactically extinguishes their short-term cytotoxicity (12). The amounts of surfactant in the alveolar hypophase compared to the surface areas of respirable mineral dusts and their adsorption isotherms for DPPC suggest that there is adequate surfactant in the lung to coat and neutralize depositing particles even in most high dust exposures (13). c. Restoration of particle toxicity and a possible basis for mineral-specific fibrogenicity Subsequent to the suppression by pulmonary surfactant of otherwise prompt cytotoxic activity, the surfactant-coated particles can be phagocytized by macrophages and subjected to phagolysosomal enzymatic digestion (14). Cell-free experiments have correlated the digestive removal of DPPC from quartz and kaolin particle surfaces by phospholipase A2 enzyme with the restoration of membranolytic activity. In cell-free tests using pH -neutral acting phospholipase A2 and in limited in vitro/in vivo tests, quartz is stripped of surfactant significantly more rapidly that kaolin(15). Cellular in vitro studies have found that macrophage-like cells in vitro digest quartz- and kaolin-adsorbed DPPC at comparable rates over a period of about 7 to 10 days with initial partial restoration starting at 3 to 5 days (16). It has not been demonstrated that this detoxification/re-toxification process is the mechanism distinguishing quartz and alumino-silicate expression of toxicity in vivo. 4. Site ofparticulate-inducedfibrogenic activity Churg et al. (17) briefly discuss the principal site of asbestos activity, noting the alveolar macrophage is commonly regarded as the crucial effector cell. This is the background assumption also for most experiments on the cytotoxic and fibrosis-associated activity of crystalline silica dusts:. However, Adamson, referenced by Churg et at. in a different context, has published a suite of studies which make a case that it is interactions of silica particles with interstitial cells which control the stimulation of exacerbated collagen synthesis by pulmonary fibroblasts, and that the macrophage is responsible for only an inflammatory response evoking neutrophil influx to the alveolus but not tied to explicit fibrosis(18). While the mechanism of initial cell damage or stimulation may differ between silica or silicates and fibers, e.g., ROS from a "frustrated" phagocytosis mechanism for asbestos and surface silanol hydroxyl membranolysis by quartz or clay, a parallel analysis to Adamson's silica study; findings might be considered in researching the site of asbestos action for fibrosis. E-59 /} HWBUI0009846 5. Possible interferences in short-term bioassays Oberdorster and others (19) have found that the conventional protocol for extended-term in vitro cellular assays may inadvertently cause a non-physiologic surface conditioning of mineral particles which significantly affects assay results. The use of fetal bovine serum can confer a prophylaxis on silica and perhaps on kaolin (20), probably due to the mineral surface adsorption of lipo-proteins from, the FBS. That may not represent a physiological situation in the intact lung in vivo and may interfere with attempts to model the condition of particle surfaces upon deposition in the lung and resultant effects on their expression of toxicity in vivo. For purposes of in vitro investigation of fiber or particle toxicity, this interference might be circumvented, e.g., by excluding serum from the medium during a short-term period for particle or fiber challenge. 6. Environmental conditioning ofparticle surfaces can affect their in vivo pathogenic activity Even animal model in vivo tests can fail to be predictive.in the case of a cytotoxic and fibrogenic mineral in mixed composition dusts, e.g., quartz particles in workplace dusts: conventional mineralogical and cytotoxicity assays may not correlate with short-or intermediate-term in vivo fibrogenic response. Alumino-silicate surface contamination of quartz particle surfaces can delay for months or perhaps years the expression of fibrogenic activity. Aluminosilicate or other mineral occlusion of the underlying host particle can alter the expression of toxicity in vivo during the bio-persistence ofthe surface contamination. This has been seen worldwide in anomalies in the fibrogenicity ofcoal mine dust exposures (21). This was clearly demonstrated by LeBouffant et al. (22) by in vitro and in vivo studies of the fibrogenicity of silica in coal mine dusts and in natural lightly contaminated sands. More recently, new spectroscopic surface analysis methods have demonstrated natural clay occlusion of quartz dusts from some workplace where epidemiology studies had detailed anomalies in disease risk correlation with conventional measures of dust exposure (23). B. Fibrous mineral and crystalline silica particle differences and similarities I. Mechanisms oftoxicityforfibrous and non-fibrous materials a. Conventional assays do not clarify the bases of asbestos or silica particle toxicity Churg et al. {17) review highlights and caveats to the general models of asbestos activity. Some fibers can evoke the responses from RO$ generation through the cascade to increased expression of TNF-alpha, but have not been shown to induce fibrosis.. And asbestos produces fibrosis in some systems without increasing TNF-alpha expression, Chrysotile contains little iron but is fibrogenic, albeit not a potent as amphibole. Churg et ai. suggest a comparison of asbestos and silica-induced fibrosis data. Their paper compares the generation of ROS, RNS, and activation of NF-kB and AP-fyand increased production of TNF-alpha and other factors and find the dusts to be indistinguishable. In the face of this, asbestosis and silicosis differ in histopathological appearance: asbestosis is a diffuse fibrosis and silicosis is in localized nodules. Their conclusion E-60 HWBUI0009847 is that the tabulated responses fail to explain comprehensively how asbestosis or silicosis develop. b. Surfactant does not folly suppress all asbestos fiber in vitro cytotoxicity Asbsetos fiber as well as particulate silicate can adsorb the DPPC and components of pulmonary surfactant (24). We have briefly researched the effect of surfactant adsorption on chrysotile in vitro genotoxicity, using an assay for micronucleus induction in cultured Chinese hamster lung cells (V79 cells) (25): in our test of two chrysotile asbestos fiber samples, pre-treatment with DPPC in physiological saline surrogate lung surfactant did not fully suppress a short-term toxic activity to cells in vitro. NIEHS intermediate length chrysotile asbestos fiber (average 101 micrometer length, 65% > 10 micron) and NIEHS short chrysotile asbestos fiber (average 11.6 micron, 98% <10 micron) were tested for micronucleus induction in V79 macrophage-derived cells for 72 hour challenge +/- DPPC surfactant pre-treatment of the fibers. For the longer fiber sample, DPPC did not significantly affect the activity, a numerical reduction of about 20% in the activity was observed but was not statistically significant. However, DPPC treatment reduced: the shorter-length fiber sample activity significantly, to about half that of the untreated shorter fiber sample. Similar effects were seen for multi-nuclei induction and for dye-exclusion viability measure for cell toxicity. No activity was seen for either sample in a sister chromatid exchange assay. c. A surface modification which did not affect long asbestos fiber toxicity in vitro We also attempted to see if a significant surface modification of chrysotile without a significant modification offiber size would affect in vitro genotoxic activity (26). The NIEHS intermediate length chrysotile asbestos fiber used above was mildly acid leached to remove near-surface magnesium, but to retain fiber length. The treatment resulted in a 20% reduction in fiber length in each of three length categories: <3 micron, 3-10 micron, >10 micron. Spectroscopic surface analysis and zeta-potential measurements showed significant reduction in surface-associated magnesium and in its influence on surface chemistry. However there was no significant change in measured activity for micronucleus induction between the treated and non-treated fibers. d. Is there more than one mechanism of fiber cytotoxicity? Do short fibers also act as particles? One interpretation of these two experiments is this: at least two mechanisms are involved in the initial damage or interaction of fibrous particles with the lung: a component which is at least transiently suppressed by surfactant conditioning which significantly contributes to shorter fiber activity, and a component which is not suppressed by surfactant conditioning, and which is not affected by one significant modification of surface composition arid chemistry* and which is the principal mechanism for longer fibers. That is, a model which suggests itselfis the combination of the frequently discussed "frustrated phagocytosis'5 mechanism for longer fibers, e.g., those which are too long to be folly phagocytized and internalized by the cell target, and a surface E-61 HWBUI0009848 property-mediated toxicity mechanism for internalized particles or short fibers, i.e., fibers which are internalized and subjected to conventional phagolysosomal processes. One possible consequence of "frustrated phagocytosis" of longer fibers is that the partially invaginated fiber stimulates the cell to release superoxide in a manner related to the respiratory burst upon normal phagocytosis, or that superoxide is produced by the cell in response to an autolytic effect'of enzymes or other lysosomal or cytosolic agents released into the annular invagination of the fiber. The superoxide is then in close approximation with reactive iron species on the fiber surface in or extending beyond the partially invaginated fiber to create hydroxyl radical for strongly toxic effects at the cell or neighboring cells. The paper by M Ohyama et al. (27) provided to the panel presents a difficult argument against frustrated phagocytosis: The study used luciginen-dependent chemiluminescence (CL) induced in vitro over a short (2 hour) period, and found a strong correlation of response indicative of superoxide release with fiber length 6 to 20 um. All samples except wollastonite induced CL response in a dose-dependent manner. Superoxide release was non-specific for compositional type of fiber. The four fibers with lengths below 7 um were only weakly active. Longer fiber activity correlated with length. Research on the surfactant suppression and subsequent lysosomal enzymatic restoration of mineral particle cytotoxicity within a cell, suggests that short fibers which are fully taken into the cell in a phagosome may express, in part, a cytotoxicity within the cell after removal of adsorbed prophylactic surfactant. That is, some part of short fiber toxicity may be related to the mineral surface-specific mechanism of non-fibrous particulate toxicity. Those do not exhaust the possible mechanisms for long or short fiber damage to cells. Asbestos fiber penetrating the cell or cell nucleus may exercise modes of direct genetic or epigenetic damage. In our above study of surfactant effects on chrysotile genotoxicity in vitro, a limited investigation using immunofluorescent kinetochore staining indicated that both clastogenic and aneuploidogenic effects were associated in similar proportion with the observed micronucleus induction. That is, fibers may directly or indirectly interact with the spindle mechanism involved in chromosomal separation during cell division. During mitosis, the nuclear membrane disintegrates, possibly, providing intracellular fibers access to the genetic material or kinetochores and spindle apparatus, 2. Intracellular response tofiber challenge. . - =. -i a. i Long fiber challenge Whatever the mechanisms of direct fiber damage or stimulation of the cell surface, some components of the consequent intracellular response have been well-defined. Mossman and others have detailed the cascade of events following fiber challenge to pulmonary macrophages or perhaps to other cells. A recent review (3) explicates the central dogma that damage to or stimulation of the cell by fibers is followed by an increase in intracellular reactive oxygen species which trigger a cascade of transcription factor activation leading to the up-regulated production E-62 HWBUI0009849 and release of TNF-alpha or other cytokines. This also was recently the subject of a NIOSH study by Cheng et at. (28) in which crocidolite with a median fiber length of 11.5 um challenged lavaged rat AM in FBS-containing medium for 1 to 24 h.. Crocidolite caused parallel increases in TNF-alpha production and NF-kB activatiomin a dose-dependent manner. A titanium oxide control dust had no stimulatory effect on TNF-a secretion. The report by V Kinnula which was provided to the panel (29) reviews die possible roles of reactive oxygen species (ROS) and reactive nitrogen species (RNS) generated by asbestos fiber in cell-free and cellular and tissue systems. A primary step in response to asbestos "long" fiber challenge ofcells is agreed to be superoxide anion release in cells which have attempted to phagocytize fibers. This superoxide can further be dismutated to hydrogen peroxide, which can generate hydroxyl radical, catalyzed by iron via the Fenton reaction. That hydroxyl radical is extremely toxic and reactive, but therefore short-lived. There is some contention that fibers stimulate the release of ROS from inflammatory cells and not target cells. However, asbestos fiber can generate ROS spontaneously in cell-free systems. This fiber-prompted production and release ofTNF-alpha can stimulate nearby pulmonary fibroblasts to proliferate and increase pro-collagen synthesis, which is released extra-cellularly to mature into collagen scarring. b. Intracellular response to challenge by well-classified shorter fibers and particles Dr. Baron ofNIOSH has been developing a fiber size classifier (separator) which can permit in vitro or perhaps limited in vivo experiments with sets of fibers of fairly well-defined length (30). A dielectrophoretic classifier, can separate fibers from an airstream producing about 1 mg/day of a size cut. These classes ofJM-100 glass fibers were recently produced for in vitro toxicology study; cut 1: Length = 32.7 micrometer +/- 23.5 SD; Width = 0.75 micrometer+/- 0.50 micrometer cut 2: L = 16.7 u +/- 10.6 u; W = 0.49 u +/- 0.27 u cut 3: L = 6.5 u +/- 2.7 u; W = 0.44 u +/- 0.22 u cut 4: L = 4.3 u +/- l.Ou; W = 0.40 +/- 0.15 u cut 5:L = 3 0 u +/- 1.0 u; W = 0.35 u +/- 0.14 u In recent NIOSH studies by Dr. Castranova and colleagues, these samples were used in a comparison of "long" and "short" fiber cytotoxicity and of induction of the cytokine cascade in vitro: Blake et al. (31) used 18 hour challenge of rat alveolar macrophages in vitro and the lactate dehydrogenase (LDH) release assay, the 17 micrometer sample expressed about 2. X the activity of the shorter samples (and also 2X the activity of the 33 micrometer longer sample) on a mass basis. However, all samples were active well above control levels. The 7 micrometer fiber set had about 8 X more fibers per gram than the 17 micrometer set, or about 3 X the linear surface area. Thus, the 17 micrometer long fibers were on the order of 6 or 7 X more cytotoxic than the shorter 7 micrometer fibers oh a linear surface basis. Similar effects were seen with an assay using chemiluminescent response to zymosan challenge. And multiple macrophages were seen attached along the length of the long fibers, suggesting "frustrated" or incomplete phagocytosis was occurring for longer fibers. E-63 * ) HWBUI0009850 J Ye et al.(32) challenged a mouse macrophage cell line with the 7 and with the 17 um glass fiber cuts, for 3,6, and 16 h. Glass fibers stimulated TNF-alpha production, activation of TNF-alpha gene promoter activity, and activation of DNA binding activity ofnuclear factor (NF)-fcB. Reactive oxygen species (ROS) were involved in the activation and production. Dose was set at 5 fibers per cell; by that metric the longer fibers were more potent than short fibers by a factor of about 3. However, on a basis of length of fiber exposed to the cell or surface area, the activities were about equal for the long and short fibers. As seen in photomicrographs, short fibers but not long fibers were effectively engulfed by macrophages. In a subsequent study by Ye et al. (33) it was found that the long fibers were more potent than short fibers at the same dose of 5 fibers/cell in activating MAP kinases which activate transcription factor c-Jun which acts on the TNF-a gene promoter through the cyclic AMP response element and the AP-1 binding site. Again, the activities were comparable for long and short fibers on the basis ofexposed fiber length or surface area. Question: Is there indirect evidence for less-than-5 micron fiber induced adverse health effects? A. Human studies 1. Cburg et al. (34) found the grade of interstitial fibrosis asbestosis in the lungs of a group of chrysotile miners and millers to be directly proportional to tremolite or chiysotile fiber concentrations, but inversely proportional to mean fiber length and length-related parameters. Churg et al., (35) graded fibrosis in the lungs of some shipyard and insulation workers, finding fibrosis grade to be strongly positively correlated with amosite concentration and negatively correlated with mean fiber size parameters including fiber length; they suggested "...these observations again raise the possibility that short fibers may be more important than is commonly believed in the genesis of fibrosis in man." In a study of chrysotile miners and millers, Churg, et al., found pleural plaques were strongly associated with mean tremolite fiber aspect.ratio, but no differences in mean fiber size, including length, were seen for any other disease studied (mesothelioma, airway fibrosis, asbestosis, or carcinoma) (36). One member brought to the panel's attention a recent publication (37) analyzing fibers in lung tissue from two groups of former chrysotile miners and millers: the study concluded that "...fiber dimension does not seem to be a factor that accounts for the difference in incidence of respiratory disease between the two groups". It has been generally speculated that shorter fibers in lung tissue may be the residue of fibers which were longer when deposited, and disease initiation was due to the originally long fibers, which were subjected to subsequent in vivo dissolution or degradation into the observed : short fibers (17). This appears to be one plausible explanation of the inverse correlations reported between fibrosis and fiber length in human lungs. But this does not limit the research opportunity or imperative, provided by the seemingly anomalous or "counter-intuitive" results, to address possible short fiber-associated disease mechanisms. 2. A possible "short fiber" exposure cohort. Dr. Zumwalde of NIOSH suggested to the panel that a past NIOSH study of 2,302 workers at an attapulgite mining and milling facility (38) may have E-64 HWBUI0009851 % involved exposures, in part, to short mineral fibers. A significant deficit of mortality (SMR -- 43, 90% Cl 23-76) from nonmalignant respiratory disease (NMRD) was observed for the cohort; but a statistically significant excess ofmortality from lung cancer was observed among whites (SMR = 193,90% Cl 121-293), but a deficit occurred among nonwhites (SMR = 53,90% Cl 21-112). This may present an opportunity for review and re-analysis and a source for collection of materials for study. NIOSH also is re-analyzing archived materials available from a past study of asbestos workers in South Carolina. Question: Are short fibers pathogenic? What should we do? /. Review ofin vitro toxicology For non-fibrous particles: - Non-fibrous mineral particles can be cytotoxic, fibrogenic, and carcinogenic. - That pathogenicity is mineral-specific. - Surface characteristics may delay expression of that pathogenic activity in vivo. - That pathogenicity is not necessarily reflected in short-term in vitro cytotoxicity assays. - The first interaction ofparticles depositing in the deep lung, namely, adsorption of the Sung lining surfactant, strongly affects mineral particle prompt toxicity. - The bio-persistence ofthat surfactant prophylaxis may be a critical factor in the timing and severity of mineral particle expression of toxicity. - After expression of the primary toxic event in particle challenge to cells, the intracellular response may be much similar to the cascade induced by asbestos or fiber challenge: leading to the induction of pathogenic, e.g., fibrogenic activity by nearby cells. For fibrous particles: - Many studies have found an association of pulmonary fibrosis, cancer, and mesothelioma with occupational exposures to long fibers, e.g., fibers with length greater than the dimensions of the target cells; - - Long fibers clearly are cytotoxic in vitro. - Long fiber cytotoxicity and the. initiation ofpathogenic processes are generally considered to be resultant from a "frustrated phagocytosis" itnechanism. . Some studies of fiber burden and diseasein tissue from asbestos workers have shown an inverse correlation ofdisease with fiber lfehgth. - Those disease-correlated shorter fibers appear in some of the cases to be mineral specific, e.g.; associated with contaminant amphibole more than with seprentine asbestos; - Limited in vitro study data suggest that shorter fibers may have a component of cytotoxicity which is surface associated, perhaps independent of a "frustrated phagocytosis" mechanism involved in long fiber toxicity. ' = - In short term in vitro assays, well-controlled for fiber length, shorter glass fibers can cause intracellular events comparable on a fiber or surface basis to those associated with longer fiber challenge and with asbestos fiber challenge. E-65 ) HWBUI0009852 2. Interpretability ofshort-term in vitro assays The ability to interpret many in vitro experiments on particle of fiber toxicity is complicated by the lack of modeling of initial conditioning ofparticles in the lung and the time course of expression of toxicity in vivo. Surfactant adsorption in the lung can dramatically alter the short term in vitro toxicities of mineral particles, and may determine if toxicity is expressed in times long or short compared to clearance. This surfactant effect and associated delay in toxicity expression does not appear to be a factor for long fiber asbestos expression of in vitro toxicity. Whether this is a factor for short fibers is unknown. That is, ifshort fibers have a component of toxicity independent of a "frustrated phagocytosis" mechanism but dependent on a surface-property mechanism then such conditioning and time delays in expression of toxicity could be critical in the design of experiments for the detection and analysis of short fiber toxicity by in vitro or short-term in vivo assay. 3. Research opportunities a. The ability to collect milligram quantities of well-classified (sized) small fibers presents the opportunity to do carefully size-controlled in vitro studies and possibly some (more limited) in vivo studies, e.g., by nose-only inhalation or tracheal instillation. b. Epidemiology study results suggest types of fibers which should be compared and contrasted in such experiments, e.g., short tremolite vs. short chrysotile. c. A review of epidemiological studies of attapulgite or other short fiber exposures may provide an identification of other short fiber asbestos and non-asbestos materials for toxicological study for which human disease epidemiology information is available for comparison. d. Preceding the initiation of new toxicology studies, a review of past in vitro studies might identify the controls for surface conditioning of the test fibers: .were effects of lung conditioning modeled, or were non-physiologic effects of medium adsorbates possible in past studies? e' So-designed in vitro toxicology studies of classified short fibrous materials which have known positive or negative correlations with pathology could be attempted to determine if there is a i short fiber toxicity with a reasonable potential to initiate disease, in vivo, and if that potential is dependent on fiber mineral type or surface property or morphology. f. A similar review of short-term in vivo studies might help the design.of methods of challenge and time course for tests of materials selected from the in vitro study results. g. Results of the in vitro and in vivo studies would suggest if useful application could be made to dusts of current concern, e.g., Libby vermiculite or World Trade Center disaster-associated dusts. E-66 HWBUI0009853 References 1. IARC Monographs on the Evaluation of Carcinogenic Risk to Humans. Vol. 68: "Silica, some silicates, coal dust, and para-aramid fibrils". ISBN 92 832 1268 1,1997. 2. Driscoll, K. The role of interleukin-1 and tumor necrosis factor-a in the lung's response to silica. In: Silica and Silica-InducedLung Diseases, V Castranova, V Vallyathan, and W Wallace, eds., Boca Raton, FL., ppl63-184,1996. 3. C Manning, V Vallyathan, and B Mossman: "Diseases caused by asbestos: mechanisms of injury and disease development" International Immunopharmacology 2:191-200,2002. 4. Razzaboni BL, Bolsaitis P, Wallace WE, Keane MI. "Effect of thermal treatment on the surface characteristics and hemolytic activity of respirable size silica particles. Proc. Of the Vllth International Pneumoconioses Conference, Pittsburgh, PA, 1988. DHHS (NIOSH) Publ. No. 90108 Part 1,215-230, 1990. 5. Pandurangi RS, Seehar MS, Razzaboni BL, Bolsaitis. "Surface and bulk infrared modes of crystalline and amorphous silica particles: a study of the relation of surface structure, to cytotoxicity ofrespirable silica. Environ. Health Perspect. 86:317-336, 1990. 6. Fubini B, Zanetti G, Altilia J, Tiozzo R, Lison D, Saffiotti U. "Relationship between surface properties and cellular responses to crystalline silica: studies with heat-treated cristobalite". Chem res Toxicol 12(8): 737-745,1999. 7. Castranova V, Dalai NS, Vallyathan V. "Role of surface free radicals in the pathogenicity of silica". In: Silica and Silica-InducedLung Diseases, V Castranova, V Vallyathan, and W Wallace, eds., Boca Raton, FL., pp91-105,1996. 8. Gamble J. "Silicate pneumoconioses" in "Occupational Respiratory Diseases", ed. JA Merchantpp. 243-284. DHHS, (NIOSH) Publication No. 86-102., 1986. -r 9. Vallyathan, V, D.Schwegler, M Reasor, L Stettler, FHY Green (1988). Comparison of in vitro cytotoxicity and relative pathogenicity of mineral dusts. Aim! Occ. Hyg. 32,279-289. 10. King RJ, Clements JA. "Surface active materials from dog lung.I. Method of isolation." Am J Physiol. 223:707-726, 1972. . ; 11. Wallace, WE, V. Vallyathan, MJ Keane, V: Robinson (1985). In vitro biologic toxicity of native and surface-modified quartz and kaolin. J. Tox! Env. Health 16:415-424. 13. Wallace WE, Headley LC, Weber KC. "Dipalmitoyl lecithin surfactant adsorption by kaolin dust in vitro." J Colloidal Interface Sci 51:535, 1975. E-67 } ) HWBUI0009854 14. Allison AC. "Lysosomes and the toxicity of particulate pollutants". Arch. Intern. Med. 128: 131,1971. 15. Wallace, W, M Keane, P Mike, C Hill, V Vallyathan, and E Regad (1992). Contrasting respirable quartz and kaolin retention of lecithin surfactant and expression of rnembranolytic activity following phospholipase A2 digestion. J Tox. Environ. Health 37:391-409. 16. Hill, C, W Wallace, M Keane, and P Mike (1995). The enzymatic removal of a surfactant coating from quartz and kaolin by P388D, cells. Cell Biol. Tox. 11:119-128. 17. Churg et al. "Pathogenesis of fibrosis produced by asbestos and man-made mineral fibers: what makes a fiber fibrogenic?". Inhalation Toxicology 12(S3): 15-26, 2000, 18. Bowden DH; Hedgecock C; Adamson IY(1989). Silica-induced pulmonary fibrosis involves the reaction ofparticles with interstitial rather than alveolar macrophages. J Pathol 58:73-80. 19. Barrett EG, Johnston C, Oberdorster G, Finkelstein JN. "Surum binds serum proteins resulting in a shift ofthe dose-response for silica-induced chemokine expression in an alveolar type II cell line." Toxicol. Appl. Pharmacol. 161: 111-122,1999. 20. Gao N, Keane MJ, Ong T, Ye J, Miller WE, Wallace WE. "Effects of phospholipid . surfactant on apoptosis induction by respirable quartz and kaolin in NR8383 rat pulmonary macrophages". Toxicol. Appl. Pharmacol. 175: 217-225,2001. 21. Robock K, Klosterkotter W. "Investigations into the specific toxicity of different Si02 and silica dusts. Staub Reinhart Luft 33:3360-3363, 1973. 22. LeBouffant L, Daniel H, Martin J,C, Bruyere S. "Effect of impurities and associated minerals on quartz toxicity. Ann. Occup. Htg. 26: 625-634, 1982. 23. Harrison J, Brower P;S, Attfield MD,. Dpak CB, Keane MJ, Grayson RL, Wallace WE. "Surface composition ofrespirable silica particles in a set of US anthracite and bituminous coal mine dusts". J Aerosol Sci. 28:689-69.6,1997. - 24. Jaurand MC; Reiner A, Bignon J. "The adsorption ofphospholipids and red blood cell membranes on cbrysotiie fibers". In "In Vitro Effects of Mineral Dusts". Ed. RC Brown. Academic Press, Londonl980: 125-130. ' 25. Liu J "In vitro genotoxicity studies of chrysotile asbestos fibers dispersed in simulated pulmonary surfactant" Mutation Res 320:253-259,1994. 26. Keane al. "A study of the effect of chrysotile fiber surface composition on genotoxicity in vitro". J Tox & Environm Hlth;57:529-54I, 1999. ^ E-68 HWBUI0009855 27. M Ohyama, T Otake, and K Morinaga, "Effect of size of man-made and natural mineral fibers on chemiluminescent response in human monocyte-derived macrophages." Environ Hlth Perspec 109:1033-1039,2001. 28. Cheng et al. "Role of transcription factro NF-kB in asbestos-induced TNF-alpha response from Macrophages" Expt. And Mol Pathology 66:201-210,1999. 29. V Kinnula which was provided to the panel, "Oxidant and antioxidant mechanisms of lung disease caused by asbestos fibers" European Respiratory Journal 14(3):706-716,1999 30. Baron etal. "Length separation of fibers". Aerosol Sci. Tech. 21:179-192, 1994. 31. Blake et al. "Effects of fiber length on glass microfiber toxicity" J Toxicol Environ Hlth 54: 243-259, 1998. 32. J Ye et al. "Critical role of glass fiber length in TNF-alpha production and transcription factor activation in macrophages." Am J Physiol276 (Lung Cell Mol Physiol 20):L426-L434, 1999. 33. Ye et al. "Activation ofmitogen-activated protein kinase p38 and extracellular signalregulated kinase is involved in glass fiber-induced tumor necrosis factor-alpha production in macrophages"J Biological Chem 276:5360-5367,2001. . 34. Churg et al. ''Mineralogical correlates of fibrosis in chrysotile miners and millers". Am Rev Resp Dis 139: 891-896,1990. 35. Churg et al. "Mineralogical parameters related to amosite asbestos-induced fibrosis in humans" Am Rev Resp Dis 142: 1331-1336,1990. 36. Churg et al. "Fiber burdens and patterns of asbestos-related diseases in workers with heavy mixed amosite arid chrysotile exposures". Am J Resp Grit Care Med 150:663-669,1994. 37. Nayebzadeh A, Dufrense A, Case B, et al. "Lung mineral fibers of former miners and millers from Thetford-Mines and asbestos regions: a comparative study of fiber concentration and dimension." Arch Environ Health 56(l):65-76, 2001. 38. Waxweiler RJ, Zumwalde RD, Ness GO, Brown DP. "A retrospective cohort mortality study of males mining and milling attapulgite clay". Am J Ind Med 13(3): 305-315,1988. :) E-69 HWBUI0009856 Reporton thePeer Consultation Workshop to Discuss, a Proposed Protocol to Assess Asbestos-Related Risk )) Preparedfor: U.S. Environmental Protection Agency Office of Solid Waste and Emergency Response Washington, DC 20460 EPA Contract No. 68-C-98-148 Work Assignment 2003-05 Prepared by: Eastern Research Group, Inc. 110 Hartwell Avenue Lexington, MA 0242! FINAL REPORT May 30, 2003 HWBUI0009857 NOTE This report was prepared by Eastern Research Group, Inc. (ERG), an EPA contractor, as a general record ofdiscussion fehifaepejer coiiSuitatibni work^liop oil3a pfdpdsfedprotodol ter tiaras asbestosrelated risk. llus.RpQit:captjir^^ie iiK^poiinls.pjEsfiiedulrf presentations,highlights'discussions among the panelists, and documents the public comments provided at the meeting. This report does not contain a verbatim transcript ofall issues discussed, and it does not embellish, interpret, or enlarge upon mates that were incomplete or unclear. EPA will use the information presented during the peer consultation workshop to determine whether foe proposed risk assessment methodology can be used to support decisions at asbestos-contaminated sites. Except as specifically noted, no statements in this report represent analyses by or positions of EPA or ERG. /i j i HWBUI0009858 CONTENTS List of Abbreviations ..................... ......---------- ......................................................................... 5 Executive Summary .................................................................................................................. v 1. Introduction .............................................................................................................. 1-1 LI Background ...................................... .... . . . . vi ; ^ . . . r. . .i 1-1 ;>-> 1.2 Scope of the Peer Consultation Workshop u .. .d ................. 1-2 1.2.1 Activities Prior to the Peer Consultation Workshop ........................... 1-2 1.2.2 Activities at the Peer,Goostitation-Wodshop i.. 1-3' 1.2.3 Activities Following the Peer Consultation Workshop.......................... 1-4 1.3 Report Organization.........................i.;v. * -.:u . - i - ------- ------- 1-5 ... * - v.;'; 2i Background on the Proposed Protocol to Assess Asbestos-Related Risk............. 2-1 i -' .... 'J '."it y * ft ' . . i 3.; ' Comments on Topic Area 1: Interpretations of the Epidemiology ' and Toxicology literature ............................................................................................. 3-1 : '.?l* i -r . r:v r\. 3.1 Lung Cancer ........................................................................................................ 3-1 3.1.1 Lung Cancer and Fiber Type; Inferences from th&Epidemiology Literatufe-1 3.1.2 TUingiCaneerand Fiber Type-;Meren(^fiom Animal Toxicology and Mechanistic Studies ...................................................................... 3-6 3.1.3 Lung Cancer and Fiber Dimension; Inferences from the a ... J Epidemiology Literature........................................................................ 3-7 3.1.4 Lung Cancer and Fiber Dimension; Inferences from Animal Toxicology and Mechanistic Studies.............................................-..;- sir? ? 3.1.5 Other Issues Related to Lung Cancer ................................................. 3-10 3.2 Mesothelioma..................................................... .v 3-12-:' 3.2.1, > Meso&elioma and Fiber Tyj: .Inferencesifom the :Epidemiology;Litpialulfi: 3.2.2 Mesothelioma and Fiber Type; Inferences fan Animal -jgr,:., ^ToxicoIogyandMechanisticShidies-iv.'j...;.:;. . .....^.3-14.'' 3.2.3 Mesothelioma and Fiber Dimension; Inferences from the . ;' r, . ;. '.r'EpidemiblegyLiterature . . . ; .':0-3tfl6.' 3.2.4 Mesothelioma and Fiber Dimension; Inferences from Animal Toxicology and,. Mechanistic Studies.................................... ........................................ 3-17 3.3 Exposure Estimates in the Epidemiology Literature .......................................... 3-18 CONTENTS (Continued) 4. Comments on Topic Area 2: The Proposed Exposure Index................... '............... 4-1 t . 4.1 4.2 43 Responses to Charge Question 4........................................................................ Responses to Charge Question 5..................................................................... ;. Responses to Charge Question 6 -v.. ------i-'. 5. - . Comments on Topic Area 3: General Questions.- . v :tJ.... 1. .................. 5-1 5.1 Responses to Charge Question 7 ....... 5-1 5.2 Responses to Charge Question 8........................................................................ 5-2 53 Req>onses.to'ChaigeQuestion-.9 ;.... 4..... ... ,in5-3 5.4 Responses to Charge Question 10...................................................................... 5-4 5.5 Responses to Cbaige Questidh 12-: . ii-.'Sut. v-.. .-s.-i 5-6? 6. Comments on Topic Area 4: Conclusions and Recommendations........................... 6-1 ->--6.T Responses to.Charge Question? 11 :.li------ --- >;...........;.............. 6-1 6.2 Gonchisiossanti Reteommeiidatidhs'n-a........................... 6-6 7. References r. ........................... 7-1 Appendices Appendix A List ofExpert Panelists 11 - ' Appendix B. Bremeeiirig Comments, Alphabetized by Autoor(mciudesbibs ofpanelists and the charge to'theiievietifers)..^ - Appendix C List of Registered Observers ofthe PeerConsultation Wbricshop Appendix D AgendaTor the PeepConsultation Workshop ;-v*- Appendix E Observer Comments Provided at the Peer Gonstdtatidft.Wbrfcshop Aj^ndix F'!?vObsewerPos^MeetnigComments '" ) ) ) HWBUI0009860 LIST OF ABBREVIATIONS ATSDR, . Agency forToxic Substances andJOisease Registry EPA U.S. Environmental Protection Agency ERG ; ' Eastern Research Ghroiip, Inc. IARQ m;onCancer - IRIS Integrated Risk Information System NIOSH ' 'N^ftKiaiTiiSante lwt>ccr$aiional Safety ahd'Heaiith PCM phase contrast microscopy SEM scanning electron microscopy SVF synthetic vitreous fibers 1EM transmi^ionejesctronirncroscopy.,,. . ........ pm micrometers <1 <7 / ifi HWBUI0009861 EXECUTIVE SUMMARY Eleven expert panelists participated in a peer consultation workshop to review a proposed protocol to assess asbestos-related risks. The protocol is documented in the report, `Technical Support Document for a Protocol to Assess Asbestos-Related Risk, Parts I MAW (Beririan and'Cramp 1999,2001)1 At the end of the 214-day workshop, which, was(open.to the.pubUc, the expert panelists, .drafted the; following summary oftheir finding: `v;5uo ` '' The peer consultation panel strongly endorsed the conceptual approach ofdeveloping an updated cancer risk assessment methodology that takes into account fiber type and fiber dimension. The opportunity is at hand to use substantial new information from epidemiology, experimental toxicology, and exposure characterization on what continues to be an extremely important societal issue--assessing the health risks associated with environmental and occupational exposures to asbestos. The panel recommended that EPA proceed in an expeditious manner to consider the panelists' conclusions and recommendations with a goal ofhaving an updated asbestos risk assessment methodology. It is important that EPA devote sufficient resources so that this important task can be accomplished in a timely and scientifically sound manner. The panel urges that additional analyses underpinning the document, preparation ofdocumentation, and further review be carried out in an open and transparent manner. Prior to die workshop, the participants received draft copies of the "Methodology for Conducting Risk Assessments at Asbestos Superfimd Sites Part 1: Protocol" and "Part 2: Technical Background Document" The panelists generally found that these documents did not provide a complete and transparent description ofhow the data were analyzed to support the conclusions presented. The incomplete documentation ofmethodology precluded the replication ofthe findings, in advance ofthe meeting, by several panelists. The methodology used was clarified by the comprehensive presentations that Drs, Berman and Cramp made at the workshop. However, future drafts of these documents mustv v ) i HWBUI0009862 clearly describe the methodologies and include sufficient data, perhaps in appendices, such that the findings can be replicated. ' ' " `` j "" Measurement methods. (Shiinidrigapyarices Have been made in tfe apijlii^fion ofexposure measdreibent febhr^^W include the use oftransmission tecfihiqrifes (Kg;; energy dispersive x-ray detection, or EDS) as an alternative to phase contrast microscopy (PCM), `thereby allowing the bivariate^Le^ iengtfraiid tgjpe;. Tlie proposed risk:assessment irietKodolo^iritofi>oriies^thlse'adVfmcesin thbdevelopment of ; ah eXpostrre ihdfe^ 'ffife|pijei ag^mStttTffifit this aspebf ofthe new risk assesshnint i! `'m^m^o^'lqxese^a^si^^ifp . -O'. i'njt .... ia-c ,-i: >;s.io' l`-tJ ' :1" '.:, ... : , ' 'IliJtfegratiSh ofexposureiand risk 'Assessment7 'models. Afeeyaspect' ofthe'proposed'ride aSsSsmeaii: ntediafdlbgy ts a lih^g^of^tifie'expbiiijfeoharaet&^i^ffi&fidflbld^y With e^Stfeitesponse fcoeffidlmfe' Ifital''B^ifena^SiaSiz^fh^^ydl2^e'm'lHe'iSpbsifite"i! ` ii^^e^tibn metrics iricifbfe^ccbt^iKifed'ByfcHa^^mlhe'ejqjbSiiteire^nSdi^iiblfficienfs 71ofthe rfelc assessment mi>deis:>n!us tyas'sipiasi^il'hi tfie' i^if%nd^plitil3E^^^ed this yte^-f , V:T-.:-h. { -! :;. ^n-mns ; . m; ;rucihi, >--- ' ." vjlir i-".- . ` ;..;0 fi W.h. : ' Access to additional raw data sets. The panelists strongly recommended that EPAStSke expostfe iiifomidfidh'fofM^ re-ataMy^;'Sever^p^eli^ teUe^M "that tevihwdf additional datA'Sets'offers substantial'oppoftiM^' fSfImprbwng'^^ '7 irieihdSolbgy. hithe eyerii' or ' ofiiefr&frictibife;'tHe'f^nelSfe'aj^^t^S ffiiat the authoftficbiiSidS' a&kirig &osd*'Kd6,']iave- '' aiS&ssto `'^dlfetiyfb'EPA'fbrfuiiheriro&dearationfS;';v l~' - r;v1 i: !ilbV ' /!.;: '';' .; !. Sri ' i. . Cfc.sJ Ir; > '. ti; risblts \ ' 'Fiber 'diameter. The proposed ride assbsstne'nt'mediddbld^ rises a'diaffiefer errtriffof0.5 micrometers (pm) for considering 'fif&rs.,Jfhte' repotf's&jfees' tfyi'fflifersfli? pfft'in diameter Can reach the respiratory zone ofthe lung. A few panel members indicated that the fiber diameter cul^fbbdkfbe^ihi^t :a8T.5'pm;dili^ cfeil b^d&iidig^'':ri^014- iBaoitf data, 7 btiflarger cfiahiefers would f*i expected ito-belespirabife irifturriaris. TteW wAs general ! agreement that the ifi'ainetef cutoff shoidd Bd wtw8eh'6;5'afid 115 prtil This is&te is 'deserving ' offarifiefanalysis: ' v 'so;. w " :r- yi HWBUI0009863 Fiber length. Hie Berman and Cramp analyses made a significant contribution.,by.obteining and analyzing membrane Sites from the animal inhalation studies in Edinburgh and conducting quality-assured bivariate length and distribution analyses by TEM--thereby greatly reducing the uncertainty of the exposure stdfs.offte.erqipaiie-rgsponse relationship for chronic fiber exposure in rats. Unfortunately, correspondingly detailed information on bivariate size distribution is not available for humans. This leads to the need to use the animal data, although one must always repogni^^wperfointies associated with mterspecies extrapolations,aicb as anatomic.. tfoaraefonsticsaridi^ species. future analyses may benefit fio^ijusirig. other aypil^jle.lah^ptpijsf animal sets and hurpap,data sots,,, ...... ; . ...Tfop lepgfojcfisteibiitiops fotfoe human cohort exposures, are much more upcptain. Jjipr foe Witteppom, Qqei^,pd.South Carolina cohorts, foere are li^iited^W,,ligfo thshilxilioii data analysis ftpim jbistoric membiano filter sample?, butppjy ffler. <^^^cs|qnger than 5 pmandhj^ejjd^ .were.counted..Eqr foemeas^iq^^.were limited to PCM fiber counts for all fibers greater than 5 pm in length in somejand particle counts (IQx objective), qnt ]midge dg.nq|jEr^pre; tfmiibers,, ;jio not d^crh^^^r^,tweemafoS^|uid ofogtimi^c^L arndpsqM^e.no, infojpttion on ^.cpmrfrftiqpSjpf^bei^.ipngecj%m..l.p,20lf|^.4Q>^n|, or^^-l^bqra^)ty.rariatiq?Kffo opti(^|^ltrtipn,^.cojmti^ru!^.^phe,gpggqchfo qfoj^^g,^.yaty^.pi^r^rity in . assesmg.e3q>c^.in.fct^foi^ts^^^ &|n^andG^r^^^j the.avaOa|?le ^lfopnirtion to make adjustments to foe uncertainty ranges in foe exposure-response coefficients. The ... workshop panel welcomed this initiative but suggested alternative approaches (see "Methods," V ^ i >>. ;( I ?;uf ' 'ir;.-.. : '. ~C. .. ./v.: i --iS V-.-'-.V .Some,p^epffcXejtfoat an Expo^uiprAssessment W^qifcshop9.tyifoiRa^Q'i>?tnte.haying a jtgroad raqge-pfexpe5dse,jCoufo.eyaluate foe uncertfonties m.hjstoriqj^q^^tional dafosejs' gtpsure measuremagts. IJiey?fclt such.a .workshop could result in a mpiej Conficfent ^sessrnent of andmbrtuigji, iWifomcptpqiatiqifijqf.other avaUafojgin^yle^^jqji.fibgr type, grt^^%. spoking . (foayaila]ye),.aqd,^e|ektive^umba:;pfq^9s ^un^^foq^|aqd ^e^bfopfiqnia, jf jpy,)ell be possible to gain a much clearer understanding of for these a&estos-associated cancers. In addition, foe workshop would prove valuable in further dhicussipp ofoiijnerfpgcal, gepto^cal,,,andjindustrial b$gjene,is?ijs .with regarfoto application of Iv.tr s' ' : .'S :v vji.` srftitakb'&r.-it *:. :/ **; * * : v.< /. .A........:..n...:.':.f..o....v..... v.V_..= -. . ... between^ and PS*??:-. arc;^gited.a.ri^:.fo^ri? pne. for^erhipfoefoh offof^riska^igped.to cancer for fibers longer foan 10 pm. However, foe panel was uncertain as to, an exact out size for length and foe magnitude of foe relative potency. The panelists also agreed that foe available HWBUI0009864 > data suggest that the risk forfifoers less than 5 pm in length is veiy low and.couldbe aero. This specific issue was addressed by an expert panel convened by the Agency. fpjcTo^ic.Substances and Disease Registry (ATSDR) in October 2002. Some panelists suggested that, for mesotheUonia, greater weight shpuldperhaps.be assigned to fibers, in.the 5 .to lQ.pm.Iengih ;..:;v range and to .thinnerfibers.... ...... ..... - . .-j : Fiberifype.|?<>r mesQiheliomq,tia& panefids stj^pgrted fine u$e ofdifferent relative eamnogenic fibers is.two onfeE? pfinagaitiijle gceater-than that for cfarysojile fibere. There was some. .... discussion about the precise,ratio expressed.dne to questions about the avaihfoifi?y;oexposure .data m.edstiqg.studies (e.g., KT|aip(^ Ihere..was recognition that tme since firpteipcsuie is an important factor in determining risk for mesothelioma and some discussion is needed on the ste r, For./trn^crH?c0^,,,ttiejpstnel%s^IjidififQingthe . relatiyejpn^cyqfch^^^eaqclanjpM^hlgfillf't?.apaphibpfe;fflers .^re 5;tim^qr.j^gpe. ppt^for lung ranpea-fharijare^cl^wtfte^fibe^Ollrer jm^Usts.di^pJt.think; tte fatM^.^mIyses ib foe .dr^tmethodolp^ drwument.gj^pgrfeJbs ,.iA%e.pqtei^andwpn4e^itf4ddMQ^imdOTspffoe.epi<^^glpgical.|htetnigtti^eiij^y .fectors p^er.t^ahher type (e.g:nm(^t0r.OTi^idej^.ti^,p^yide higher HKi^te pio^the.. mater. These other facers cantheB,}^cpiiside^ed whence risk;;assessment is gpgfiQcL ..L.,.-.' .' hi 'h'J *... 1#.: ^X6U'l'*0 - i<w Cleavage fragments. The panel knew oflittle data to directly address the questjprigs.fo., whether cleavage fragments ofequal durability and dimension as fibers would have similar or . dissimilar pptaMy.for,lung.f3nc^i.Thegeneral yieiy.;is to data ;infocate.||at;dipbili!^irmd. dim^ion^.crifit^.to.putooiiaiy pa$h.^^hesis. ."Jliejcefore* it.i?.ppdent:atfois timsto^as^iime equiyalent|}ptenry for.canqsr'infhgrahs^ncp ofQfoerijnfomiatiqE to. the cgnt^ary. C^bsi&tadbn ofggndu^jng.a .adchoess,dris sissue.:.FoE:.p^ti^h^r^it.y^vigw^d.foat t^nfibers^^ratefthan 5.p;ip',m]fen#1 are more important Cleavage fragments that do riot meeffoese criteria would no^icpnteh^te to risk ofmesothelioma. i jlXi-. *. .Other amphlholes, .Y-'icH-- *-**'`.5> the,ppteiipfjpf.OTrontly dpQtipaggkm iwoi^$|1^^3^^p^Lto ^ *.. . . ..Methods. .The p^elists.extensi^ely^^cus^d foe approach toxondncting fo,e nret^naljcsis of : lhe..Iarge nimber.qfepidenupIqi^^1^fd|^, A;nqfp!w:offoe panelists ur|ed.|hat consideration be given to using more traditional approaches that would include deyelgpnxcnt agd .appjipation of specific criteria for inclusion ofstudies into the exposure-response analysis, examination of vm HWBUI0009865 # "* heterogeneity arid sources ofthe'faeterogeneity, and the use ofsensitivity analysis to identify ` Miientiafstudies. The pririeMsfs also urged, irk the study^spedfic analysis, exploration ofalternative exposure- response models other than the lung cancer and mesothelioma risk rriodels EPA has been using since 1986. This would possibly include non-linear response models (e_g., log-linear models), exatainatioh ofseparate effects forcorkferitatiriii arid duration, time K since cessation ofdq^osri^^ptK^ily'dr^^'ttie'^ factor," and difjfererif methods for \ rrKasuimienterror. The adequacy ofchffirierii'mcxKiis'shoiildbe ejcarnmedtising goodness offit statistics acat^s all studies, llie possibility ofinfernal analyses shhuldbfe reexamined (Lfe^ it may be'^JssiWe to obtaifl p^tial riiltei,' such as di^Spedfic''person yeab data, from authors)!' !:: Ej^lokation ofnoh-lihearity:sH6uld also include shape ofthe curve iii^tiie lowexpdsine area. The panelists also urged alternative approaches!to m^^Mrily^^M prirtiailar, panelists recommended meta-regression using original (untrahsformed) exposure-response coefficients, in ' ' 'which prieiiiefef1variablestriclude the estimateclfijeroaitage fiber e^osure- iespqflse cdefficieff variances' shduld beiisri^'ili^hjimfcfioii i^ttfiiiidbto effects;idtodels-1n vriiiriti:'^i<^;irilCT-sto3^^'^mtaGoti fo' long latency afitS'ad aifiriter-siudy res&lial vaiiarice-mi^bi simple inspection of likelihtiBds to iamSi3&^tftei!iiripdftarice^ofdifferent"predictor mvawrioalbiitlfetgs'. CSe^rnicsiittiiivnittyir analj^es; scKhould be conducted in which the inclusion or exclusion ofspecific studies or groups ofstudies is evaluated: ' " ;' ; . . ;.............. i-.. - .V . .. . . -4, , .. ............................................, .. Ij . . .> Cigarette'SittoRing. Most'pmelists feltarorigdy ttiat fotore aririljses nfcbd to'jpay iriore attention to' die effects ofsrhokirigdri the inddeTaricI extrapolations' to TIk/ fftSielisfsIfoted tffifsmdlang-is die'pnimty^caMse' Si lim^ iSaSfiS^ but the lung caircef dose- *t&pbik&relatiorisfiip forsriibk^; is itori^lS'rfetd'tlie'e^^'dfmokirig'duratibrit'iri^risity, .'.'riiiffc^sa'fidri.' " !-o-f <y <?t' ' o Tot ^li^ffifespecf:ti^^tm&ti6iri;%ri^tiri^ffieffdrin'oF'tiie;piriposed nted^th^e^S'dTsmblmgimy re^nre;diffeiferilT^ aridhOnismolreb. The panelists recognized that there is limited qiidetniolpgic data to address this issue, but ` make risk pfojrictions' TofarijPftiuretebhdrt;Aefeackgrdririd t^wla^^^^TS^^i^ih'tti(:fnbdei neridsto be DC HWBUI0009866 Localized tremolite exposures* Puringfee;cpurse ofpublic comments, the panel received input from several individuals who expressed concerns about environmental exposures to tremolite asbestos from localized geologic formations in California. The individuals suggested these communities. While die panel was not in a position or charged wife fee evaluation ofthis fcufe; the panel drti'feel tfiaidusWas a |Xrfsln^^t^scacK>as'ibfaeatier'ileKarvlc^'of attention by fee : ` appropriatepublic healfeiaufeoritks.T.Evaliiation ofthese kjn,ds;p>fsituations would benefit from the use of the unproved risk assessment methodology being considered. The remainder ofthis report'suirtirianizes * reviews dife panelisfe' commehts^dh tmtijr triples n'bthsted in this executive'stanmafjr, tifid dOctanenb ' fee observer comments provided at the workshop. :. i n ` -'i ) 5 Xit QsT5pi/ '< 2-'? -y.-.i- !. : "i Us. * ft\i: S\::..V : `irl'i* ^k:H -.`3: *! */ -a; ? .:r X: HWBUI0009867 1. INTRODUCTION This rfepdrt summariises npeer Consultatioriby 11 expert panelists ofa proposed profoeollto assess asbestosrEei^^d.i^cs. Contactors Jp the U.S. Enviipj^imeotal Protection Agency (EPj propo'sed'pitbtiscoi,' wMchis dookfterited ina i?^rt:iitled; `T'eciteeS!Support Document for a Protocol to Assess Asbestos-Related Risk" (Berman, and Crump 2001). Hie purpose ofthe peer consultation workshop was to provide ERA feedback on toe spiej^p.mratjpf^theproppae^.ptotpcoL Theppep consultation workshop took place ip.a meeting open to theguMf op. Febtpaty,25-27,2003,; in San Francisco, CaUfomia. t . . , . i. This report summarizes the technical discussions among the expert panelists and documents comments provided by observers. These discussions largely focused on three topic areas: interpretations of the epidemiology and toxicology literature, the proposed exposure index, and general questions about key assumptions and inferences in the protocol The remainder ofthis introductory section presents background information on the protocol (Section 1.1), describes the scope ofthe peer consultation workshop (Section 1.2), and reviews the organization of this report (Section 1.3). 1.1 Background EPA's current assessment ofasbestos toxicity is based primarily on an asbestos review completed in - -1986(EPA 1986) and has not changed substantially since that time. The 1986 assessment considers six mineral forms of asbestos and all asbestos fiber sizes longer than 5 micrometers (pm) to be of equal carcinogenic potency. However, since 1986, asbestos measurement techniques and die understanding ofhow asbestos exposure contributes to disease have improved substantially. To incorporate the knowledge gained over the last 17 years into the agency's toxicity assessment for asbestos, EPA contacted with Aeolus, Inc., to develop a proposed methodology for conducting asbestos risk assessments. The proposed methodology distinguishes between fiber sizes and fiber types in estimating l-l ! HWBUI0009868 potential health,risks related to index:for eStmktirigcarcihSg^ciisiL new exposure As a key step in determining the scientific merit ofthe proposed risk assessment methodology, EPA decided to obtain.expgrt iqput on the draft report.through a peer consultationworkshop. The purpose ofthe workshop was to obtaij of tire proposed risk assessment me^iadol.qg55.the .workshopw^s npt an. official pefr.reyh^jw. Eastern Research Group, Inc. (ERG), contract to EPA., ;?; < X 1.2 Scope,of the Peer ConsultaHtioann WWnorrlkrschhonpn ... , . ... -Vi.5':5-'" * . s'.'-.- '* 'i.vV `Vv * The pe^r cor^ultafiorr mvplvrfmany activities befpreffie workshop (^.Section 1.2;4)s^t.the. workshop (see'Section 1'212); aridafteftheworicslVop (see Sdctiori. *1:2.3): TheTdnowmgSu6sr&tions * -1 fji -(iO" describe these.actiyities^ ... .. .,1.2.1 ActivitiesP$r to the^epr.Consiiltation )VorIhpp,t . - >! . V .. . 'J: VI.1M This sectiomdescribes the.major.activities ERG and die ejq^rtppielists. cpE&ctj^ipn to consultationworicshdp: ~':1 ^'-V^ MV;:;; Y:. U: ' t:., <. -r Y Y'-,; < *n v\w. ,.nv:; * bit ;/1' '.si,' Select expertpanelists. ERG selected the expert panelists for the peer consultation workshop. ERG sought to compile a panel ofexperts with broad experience and expertise in the following disciplines: toxicology, epiden^d^g^bipstati^icsias^cs^s CTpp^sand:^nal^ica] methods, EPA's human health risk assessment guidelines, arid asbestos-related environmental and occupational health issues. Appendix A lists the expert panelists ERG selected, and Appendix B ..tneas; ... . ;. : ^very^meM:iseither:h;smorScid3iisf,!physidan;'dr:rosearclierwithiektensive:%5^>eSeiieeiri`': the aforementioned. fields, as Remonstrated,by peer-reviewed publications, awards,, and service 1-2 /) HWBUI0009869 to relevant professional societies. To ensure die peer rtonsulfatioh offered a bMahced :: perspective, ERG intentionally selected expert panelists with a broad r^ngp o.^tilia|ipns.(e:g? academia, consulting, state and federal agencies). When searching for panelists, ERG asked all candidates to disclose real or perceived conflicts of interest Prepare a charge to the expert panelists. ERG worked with EPA to prepare written 'g|fid^ines(iBtimmririy<i^leda'^chMg^l)''-fiiflfiie:p^arbdil^lltatkM^||WMksiM|^.''Flie,cfaMgie:: *- - indu,des 12 specific questions, or^nj^.ir%4;topic.area^.J0^ussipns,d % .wrak^op largely addressed tire technical issues raked in the charge, but the expert panelists were encouraged to : discuss other relevant mattes that wwe-r&t Specifibtiif^aridress^ irt:ffie:hai^''q&^tionsV A': 1 copy ofdie charge is included in appendix E- c, Distribute review documents and other relevant information. Several weefe prior ttf the peer consultation workshop, ERG sent every panelist copies of the charge and the proposed risk assessment methodology (Berman and Crump 2001). These items formed fee basis ofthe technical discussions at die workshop. In ERG distrJbuted'several'addifihrial' publications on related topics (see Table 1, at the end ofthis section, for list of the publications). The supplemental publications were provided largely in response to panelists' requests for fiirihft badsgroraM'intoriMtidh c! select^4s^e*Tlje p^ellsfe also cai^Ailaled'piibfi&tiofkS- an^|gs|temlyes,on:g)ecific topics. .Finally-.onepflhejigreptiiig chairs noted fo%&e record,, . ID drat, upon arriving in San Francisco, he also received a memo and copies ofmany abstracts and other information from Cate Jenkins of EPA The meeting chair offered to share these materials with other panelists during the workshop. Obtain and compile thefanelists'pH'me'e'tingcommiifits. After receiving' die workshop materials, the panelists were asked to prepare their initial responses to the charge questions. Booklets containing the premeeting comments were distributed to the expert panelists before the ' workshop and^ererriade'avaiiShlqfoobsclrve^at die workshop: included in this report; without modification, as Appendix B. It should be noted )|t$.<tbe ,, :I premeeting comments are preliminary in nature. Some panelists' technical findings may have changed after die premeeting comments were submitted. ! >.i i ; ; . i 1.2.2' '"Activifees:"atiKfe PeerConsultation Workshop' ''" ,r'u:v- The I I expert panelists aria approkimaii " v .iJ :- which held atfrie Westin St. Francis Hotel in San FranciscOj California, on Febnrary. 25-^27,2003. . The wrirlahop was open to the public, arid the workshop dates and times were annotuiced in the 1-3 .) J HWBUI0009870 lists -l|ie observers 9^^s^9flEng^(|ilK^r^^Eendaoioe at title.wor^shO|>.q .. registration ideslc The workshop schedule generally, followed foe agenda, presented here as ^ppgadifc." a-... ...... . .. ; .!;h:.-. The workshop beganyyifo mtoductoiy.femadcs.fro^ peer consultation. Ms. Connery welcomed the expert panelists and observers, stated the purpose of the . workshop, identified the document being reviewed, and explained the procedure,for obseryeKjp make: comments. Mr. Richard Troast (EPA) then provided background information on the review document and EPA'S.'ongoing eflToits toiassps? asbe$fos . diffpep..betyvem/EPA's exi^g3^be^.n^r^^m^t^^O(doJ[ogy|EPA;.l?86) andjfc^- ... proposed a^e^<^olq^(^m}m:.a^tCmnip #. Science Advisory Board review before being implemented. Following these opening re^dgJ |%:.) ......,.;. Wayne Berman and Dr. Kenny Grump--the authors of the proposed methodology--presented detailed information oa;tiie review dogjment; Section 2 ofthis report sunmarizgs foekpresehtjfoqns. .... . !;. -y.fi V. -'.k'J'u. ',, .- - ..hi . . . fioikymf.:: After the backgroimdpresemtetion,I3h;:Rogw.M<^j[e!l^.and;Pr. l^siie gtayper,chaired the .techni^l; .,, . discussions that followed For the remainder offoe meeting, the panelists engaged in fee-flowing discussions when answering foe charge questions and ad4ij^ing.^^tib!^;J^icsnQt specified foe charge. Observers were given the opportunity to provide verbal comments three different times during ??:?:w.- :;'!! V:: ;'ttf:;'i.'i.; .1y'-.' . ..-/'v i/l, foe workshop; these observer comments are documented in Appendix E. %pr^fnjatiyesrfipm;gPA. and foe document authors provided clarifications on foe proposed methodology periodically throughout . foe 214-day woricshop. v.if) '-V;!; j 0;'` J f *' 1.2.3- Activities .EoUoyringjlhe-^epr- Cpnsultation.,!VVpk-kshpp u s,,: v HWBUI0009871 The prirtiaty activity folldwiig ttte'pberrairisiilthtiotfiBtoi^ report; A tedihidal \vriter fioin ERG-who atfeded the me^mg.pjiqpared ai cfeaft dfthjsfteportj which ERG1 distributed to the 11 expat panelists and asked them to verify that the draft accurately reflects the tone and substance ofdie panelists' discussions at the workshop. After incorporating the panelists' suggesfcd'revisirihstothediaft rejtort, ERG^ubiriitii'tije= final repdrt'(fe.^this'iepdit)~to EPA 1-.3 -R^rtOiipiaizafioir- ' ; *" s* : h summan&tk. Stirriari arid (CMni^'slMcKgiriuM pre^tafi<ms^Secitions 3 through'<6 ate ibooriJs-'Of the paneli^-^dSaaSiijriis^fm^itirifciririiMri'tdpIc anras^iQ&pMatwik dfthe epideiriioldgy?hrkl propSosfed exposuife'mddffSedtioiiH), generaltjtiestions (Sefctidn 5), and:ajttfelHSioj&is1andfeiiri!h^idatioris`(Sedtidfi ^':FinSUy,:'SriCtidn 7provS^ifeferehces;fef;aU documditsriital in trig text - `1 vrcM:;-:, as: - The appenlfifees totfiiS report include background iriforiftation on thep^coiKidtetioii'wortehop. This information indudes items that were on display at the workshop, and items generated since the woikshop (e:g4 afiiMIMbf&ntfeesX foHtiwrig information:- ' * LiStofffirdqjfe;i^cUstS'XAppdiaiX;A5l-';: ;-n! >af: ^ > A>` - fJTir. ' iiVi;:;- " r-'i'iJjV . I .l"- := :5\s . V:-V The panelists' premeeting comments, the charge to the reviewers, arid briefbios ofthe expert .r " -jUtt hv.'-'. v. , v!y-0 A- .,v! ' - ' ^ A,/ List ofregistered observers of the peer consultation workshop (Appendix Q. Agenda for the peer consultation workshop (Appendix D). ill : Observer post-meeting comments (Appendix F). 1-5 Superfimd Sites; Part 1: Protocol. Final Draft Prepared for U.S: Environmental Protection Agency. Februidiiyi5,'l'$99.'' ':s:` Bennki, DW&d Cnu^lC 2CWl:Teclmtal Suppdrt'D6bwnienffor a'Pro'tocoife1Assess ' Asbestos-Related. Risk- Final Dpaft Prepared.for U.S. Environmental Protection Agency. September 4,2001 ' hi.- T--'a Berman, DW, Crump, KL, Chatfield, E., Davis, J. and A. Jones. 1995. The Sizes, Shapes, and Mineralogy ofAsbestos Structures that Induce Lung Tumors or Mesothelioma in AF/HAN p-v""' Following Inhalation. Ride Analysis. 15:2,181-195. Bamar4DW:^l'99$::Eriatto:lisk-Analysis. 15:4,-'541.x w..nx":xts&v-y-f : ! arts-!-- .'Xi.- _ v- .i-'i-i-'i ;* Viifccoo-.vl'.i'.'-'u a- voi.-i/s-wx-rrtTi Comruij^P. oa.H6noqcuf|ttti.onaJr|j[^aIfti Risks 4984. EPA 1986:^Aubbm^-AsbedlB^HcSi EPA 600/8i8^003F:4l'986i i;i' - :-:vi-- ` >' r'pJJ: i: .`X'.- - .X XjXXT].. :X X; J Subconunittee.- lOSSUr 1;.ri* , ,\ - . .'.if*-. . *-/[: .vi Vi-*;; `lsrw?j> ......................'iiij X . : XX. '.x-.-X` : XX .Xho; !.>' y-: '.Mil;.' :. -V....... > xi.xixxiv j`r- a isNxxik; X ! ri-'hjo/. : .. . . ;{>:- ;. ' -> ; . V-. 'Ji . ... .1; ! .'-'"X -O-,; v '>x:;x.sc' fy.. , :: 'X .'X "'-O feOC'-i! ? 'i- ;i5. i. .' I-'V- ,.xi fj... :v iv' r.-: .. . . h " : .( -x X-x'-Xii-iOi-,; Ix ,V v-r:-; :- .-V fl; '. j i ;.l.o. :S=q . ;V ; . j-.-.'s . 1-6 HWBUI0009873 2. BACKGROUND ON THE PROPOSED PROTOCOL =' TO ASSESS ASBESTOS-RELATED RISK .: This secdoii sOhsnmz^ presentatibns given by the principal authors ofdie proposed risk assessment methodology. These presentations were given because several panelists asked ERG, prior to tfje pger , consultation workshop, ifthe authors would provide detailed,background informationon how the . ` ' * '' ' *' 1 ... - *'r ` ` ; ' ' methodolbg^^was'dbvelopbdi This section reviews thd'major presentation topics* but does not present the panelists' comments on the proposed protocol. Sections 3 through 6 document the expert panelists'^ technicalfeetfliadk.ontheprotocoL , ..... .... Motivation for developing theproposedptdtdjcoLDr.. 3 loimiy-appued sampiingiandi anaiyocaipioceaares to.measure asbestos !characte^tic^mp^.p^(^yp ofrisl^.md^e^HefAat ^A's;cprent,a?bes^.risk; assessment methodology may not be adequately protective in some upohlhecSSrat me&SdolSgy, the'aUthors'intended'tcr^velop ariskassessmentTnodelthiat v adfeqiiatoly'j>riiSfciss'c^iitiet risk ih iU enVirorUWentS and can theTfefore be apphed with : . miichgt(ter:cnfidefflce to.environmentsthat b^,not.been stadi^.&.Bemtaa'^i!tUrt^l;tito;, general approach taken to develop the proposed.protocoi, as summarized in the following bulleted items. Dr. Berman provided background information on and definitions for asbestos, other fibrous structures, asbestos morphology, and cleavage fragments. He also described the capabilities and limitations ofthe analytical techniques that have been used to characterize asbestos exposures, such as midget impingeis, phase contrast microscopy (PCM), scanning electron microscopy - (SEM), and transmission electron microscopy (TEM). Dr. Berman explained how differences in these analytical techniques must be critically evaluated when comparing results reported in all epidemiological and other types ofstudies that examine asbestos exposure. Dr. Betman also stressed that it is notjust differences in analytical techniques, but choice ofspecific methods for each analytical technique that affects results. Further information on these topics is included in Chapter 4 ofthe proposed protocol (Berman and Crump 2001). Re-analysis ofhuman epidemiological data. Dr. Crump described how the authors evaluated the human epidemiological data. He displayed a list ofthe studies that were considered, noting that he had access to raw, individual-level data for three occupational cohorts: chrysotile textile workers in South Carolina, United States; crocidolite miners in 2-1 ) HWBUI0009874 i.Wjftegqom, A^c^#.^.cbi>s(^e>iiiu^.!andn#eiS]^.|Q!ad^,.Cam^ All data sets with .exposure dafe,Wre e^itfcredinthe anaiysis?.and.critefia .were nofesfabfi^ied .^..selecting studies. Dr. Crump then presented findings for asbestQ&jgelated risks, for lung cancer; apd,, mesothelioma. f l'/- . > Forlupg caneerT;j>. CMppj,;first reviewed EPA'f^^d^gl^^can^.model.^or asbestos . eigpo^trpi(see.pguafipn,6.1 ,in the proposed protpcplj,.,which relates .t|jp relative. risk oftag ,can^r;morteUgf. liReariy.tp purajilafiyeasbestra.exposure, jyiJ^^llhyearlag Japre^Ihr.. Crump noted tjhaj the pnodelpredicts.that relative risk;for,{IeyelopiHg lung cancer remains constant after asjl?esgK! ejsppf^.peasesT^^heshowpd $ras reaspi^i^itsoiisis^nt^:wijh findings fiom epidemiological studies. Dr. Crump also disci^sed:lipw..tiie.i^ei Jesses jtoteraj^Ons between exposures to cigarette smoke and to asbestosr-aa issue the panelists revisited several times. j|ata-.m;^wpr|^ipp.(e.g,i s^e.Sectip^JJ.4^ jpis^nled a seri^pf^les|tn^^gu^.^moi^i^g..iie ad^^yj^JP^^k lupg.ran.rer ; imodeis:.fir^.usiijgBgA'|.^dgfing lung Ganc^irjodej, n^M^ v^ipn pfAepao|el | cag^re inde^drat assjggs greyer.i;...; toJon^ogfeecs-Vi,..r.^ ii: f ."I ; ^, ; :o:- ` ..*;3io?m ;*s.k: ?-. . ; r 0 ;;-,=:f f-xib :nu !jfi anti! .exposures (see eqjuptiog..^ 11 feattpes^elipiiia risks vary linearly with the average asbestos exposure and increase quadratically wittr.fi^ fiprn onset ofexposure. Dr. Crump presented several tables and graphs indicating how well EPA's existing ..oonsidterabije^CTO^s; die cohp^and.the. risk <^fficien^^fr^g^e^i^hi^er!ft>jr;.ppfofte priggply to amp^bple.i^nip^i^ to those; .e^p^djpr^w^y.tojghrysotilo fibers. . data did not supjKptj(p]midata}ipn..ofa ^ljneair:.or fteshold lifter point . :;: lint. .: :!'f .fc}i. (;! " .>!! '...- ; .:!!.! ;'i , ii ,i.V,if ' ; ;'i-j ? ' .'.;f.; n&j&i potency ofaniphibole and cniysotile fibers. First, he explained how the authors weighted the ^l^ifiSacc^t^bu^^s^|t^be.cn^L-^jg^^5ist<b9^e{i0^.'^x^c^u^r %ptpis,^5signed.tp &e individual ...studjes..^;. ,Crjmip.i^entffied .the; &pr;.pncen^fiity!.^chpjnd;(i^ri^:^|eraUy iip^y eaph fctor)y(^,^igp^;^|p^pf.un(rertoh^indug^pepr^gntetiyen^siof^ir.s^nplingd^ta, the av^abiU|y;pf.ponv^iop fetora,to.pxpress exppsip^iin^im ,ofpC^^concmtrofions, and \vhether on exposure d^tion were avaflab|,er ^. pi|r^.iiim|u^i^ited the main ... conclusions fiom the meta-analysis. For lung cancer, the meta-analysis suggested that amphibole mc^.po^itf.th^^.dhi^dle .fillets, but the difference in potency was. not stafeticaiiy ..sigiificant (i.e., |he,autors poidd. not reject die hypothesis that 2-2 HWBUI0009875 '! ,vciysWe fibeii aiiii ampWboie'fibers aie'^i^-p^^Far inesoth^biflivt^ v '`^u^i^ed tliatcliiysbtile Abets ake'6.002!fiiftes,as potent as ari^hitfele fifeis/ and the tffierence w&^tafi^rallysignifi'cabL " ; ' ; ' * ' ' ` :! '' a ' iPefivatidn:01&'k''&(p0sark iAi&Ltk. BefiAan' wiplamrf;toWrtfifr !jipbsaire indi^wiiicfe islAigctly inb&Jafiony^& by mr*trjf4trA tc4skphiiafAlvinri>^fH)>rl itcinaun Avni^cJ^ et at 195)Wfit t were rrasofiably consistent"nb&'ofttfe' cobsemstt C0nBusimstega^4ingpr0p0s^'prdi0c^f}i:^ks^'iAi^ted'iMi^6Jpmposetprotocx)l is siibsiOntiaily more consent with 9iftlk)bK'3dcd&en^^m'^'sd^^c'&t^attifb'(i^'tftat 2-3 HWBUI0009876 Further, the epidemiological studies than does EPA's existing model, and the proposed protocol appears to underestimate risks oflung cancer and mesothelioma less frequently and to a lesser degree than . ... s . . ........................ uai muuw lion. < -Jit .X:-!-. ; V.'v' assessments are conducted in a consistent fashion and their results can be readily compared from one study hi tiie tiext; ' ! S;!' . . : %' .v; ' v. U : c > ! ni- V - I."f-r, it-::- ' , . \-f -in :<; v ib vv \ .-.gp, Jfiu- . ft' : I': .. : ' ''' ' ' . b. ... ."~v- - ?i .-.h / riJr? b r-.y.fry'L:) v*r ,> *.a\ur ^.^u.:-c?q.ki^tqov; ~ ..txy-'ss : ' . s,-f=: . : j.*m} $ i- C Ufi; > :;nofe;?b.jh<\: .L AX:-' ` VsU. ^ '' '1 *V - b C `a '*! '-f. . v. v I " 'V: < Kfwciy >bn;-;: a-: .vie:. .';cc>by-/ibc' bcccc-v;; : e- >; i..-r;c . 5bi .m'; ti-:ixbbb ;: 'cH; .. . -'-v:r ax w.-vb-v -v ; .liV/cotU ' y.iii cr;- :. cis . CiKn; . :\!l\ /' : : ' V. rV titi*/ ji-ijr.v ; . .oh; . bli W-':Ohri'-f>ib:' :: v ;v tc f. :-J ;ci! -c v; >. . . ; .iiKcbbbjCrri i .;! .; t'.'-'. : . r v. 1 r`-.* - ` ' X ; ; O- h`:x: : '!'!: .. !* : : ;c /:(. Hcccb 'C .> i ,'vV . ! 2-4 HWBUI0009877 3. COMl^r^'OWTdMci4^^ '' '''`EProEMdfip^ ' '"' '*' This section summarizes the panelists* discussions op, the inleipietations of the epidemiology and ftpTiarfn^'literatiinBL'Tlie'hMieti^fini^^B^-DifKicfciellap ^fe'StafpteF^^atted the discussions on this topic area, whack focused first on lung cancer (see Section;3.1) and then qn mesothelioma (see Section 3.2). This section presents a record of discussion ofthe topics mentioned during the workshop. Several panelists referred to their premeeting comments (see Appendix B) for additional suggestions for how the review ofepidemiology and toxicology literature can be improved. 3.1 Lung Cancer Hie panelists discussed at length whether the epidemiology and toxicology literature support the proposed protocol's finding for how lung cancer potency varies with fiber type and fiber length. This section summarizes these discussions, first on fiber type (Sections 3.1.1 and 3.1.2) and then on fiber length (Sections 3.1.3 and 3.1.4). General issues regarding the lung cancer evaluation are presented in Section 3.1.5. 3.1.1 Lung Cancer and Fiber Type: Inferences from the Epidemiology Literature According to the proposed risk assessment methodology, amphibole fibers have a 5-fold greater lung cancer potency than do chrysotile fibers. The panelists had differing opinions on whether this finding is consistent with the epidemiology literature. On the one hand, some panelists indicated that the epidemiology literature is consistent with amphibole fibers being more potent for lung cancer, though the magnitude ofthis increase may not be known precisely. One panelist noted, for example, that multiple analyses (e.g., Hodgson and Damton 2000, Berman and Crump 2001, and the statistical analyses a panelist presented during this discussion) all point to a consistent increased lung cancer potency for amphibole fibers compared to chrysotile fibers, albeit a small increase. On the other hand, other panelists did not believe the .epidemiologyliterature supports:thjg cpoclusion*. forreaspns; stated below. Finally, other panelists weni not offiaviticed iiteratafe siifi^oris t$fechigfaer lung cancer potency for amphibole fibers,' but theybelieveffthe difference.in,.potenpy serais, likely based on evidence from aninial fojficbldgy studies (see Sefetifoh 3:13) ah^ fiMglfiiiddh'studids; A summary of i " .. , 'ai-'.-")!"*;-!:'---- KiSKis;... .. . -xy.-'ai-' s : theppelists'idisciissiqnon tins topicfollows:: . .-j-v-i * .s,-. .: V V:: : iiSf.!- : suit .'ir2l-.fi it- f. . ion1.: * ., C&itimmis.m specificpuMkadcps. SoYer^panpIiis:.eited s$^ific,todte to, support their .positions omtherelatiVe lung cancer-ppfengy pfchiysotik; and an5}b*tlotefl^)le^*: ^ut 4 panelists .... ..oftenbad.differing<^jnions.m;theinference.tfi^.sfMxrtd.Nd^wij.,l|epaneii^.>itnentiunedtiie following specific studio: ,V ii,...Some.j^d^.not^tkit,a:r^p|-|grapaljgi^0f l^cdbpjISidlp^gspn and Damtoh. 20Q0) indicate .fhatthe limg to 50 tiiiies v greater fom-foat fijnekysotile fibers.;.Qne pa^li^djki nQ(agree;ydtii.flM$,finding, due to .... -. ... r.rtjteiQEpde^pjpaphAearfcleiuscsifo.chapctergejXslaj^y^ppt^XK.^f^ifi^y* ^^ j.'v.k, : .. panelistnofod;foal<^inpgesae>pp,teacy was^gaJaj^:^di,y^igfoepyOTll relative rriskfor a by.the,aYerage;e^po|u^ fo^tteiei^ireicobSi^.^KK11 ^ co^lorts where the data support more sophisticated exposure-response modeling. He was. ).paiticu!ariy,i!macmed;ab0Ptfoe#ytl^qrs.Vd^isipja&9nMt,|i^Js^ort,pf:SoufoC^uPolina : f. tctil0;:WOikers fim ti n^ta-analysis- bh .;: SpufclQaiplipa.caltei'b^ngM . ,p ^.whenjKpipaiMvfo.GttseE Tbe.pape&tjnpted,, hpjyfyersffmt.fog^teig canoer risk for the South Carolina cohort is; not unuaraddy^gh|^en.<^jEpjgred,> other cohorts of tortile workers. The panelist was concerned that omitting this study might have biased / . .V .,. ... /.-i-iWiy.-A... : nohib:.- foe highest leyekof smpkjngiagdjexf^aii'ej:The . ` >. ^article. was.dlstfibptedtQ the panelists pn^the firsjday.pflifg workshppfjbsdjiifti^neliste .- .-.-ii . --.cginH^^lut^pnfoe,stiK^' '- .1, .,;-*> i.sm .*\v*:,a xiai'Mik'. . .>:-.;1.' *- One panelist noted that his review ofmultiple textile cohorts (Stayner, Dankovic, and iii .; Lemati|$S6).foiiiidTdatiydy. smalldffla!ay^-in,-^ig <aflger;ptq^.oy33^ici^h- . , ..sorae.ofthe,;Qphprt&vypre exposed.to.asbestpsff^tui^.wn'^^ .... of amphibote fibers.^;.- : 3-2 HWBUI0009879 v. ,, CWe j^elisPiridicated that further evidence on howfib^fypes relates to lung cancer . . .j; ppjtoc^^l,|}e jJ^aped finuni.epiidemiQlogical stadi^toat. were not included in the . meta-analysis due to inadequate exposure data for exposure-response "modeling. ..! ,' EjQmpIiss'toJlude^a stutty'oFndri-rkx^Motially^exposed wometrfiom two dwysotile;/' ..... as^stof waning regions (Camus et.aL 199$) and a staly ofrailroad workers employed, by shops that processed different proportions ofamphiboie fibers (Ohlson et al. 19$4). Both studies, she noted, provide evidence that arnpMbOle fibers exhibit greater lung : cancer potency. This panelist added that studies ofauto mechanics have provided no convincing evidence ofincreased lung cancer due to chrysotile exposure, though she Fin the fiber length and level ofexposure. as tX'Hi.-" . 'Oae paitefi^added'fhat a i ; -si " (Ytod'efSli:iwl);shbffld be:eoMdered in futureupdates t&thepropbied protocol; 5 : file Workeis^^ie'dbhdrfhad ihcit^sed iasfcs'fdriifeig'canedF'andwere.reportedly it'.. ; exptSsM;fo'"amplfibbl>fr'-%l%s6tile-asbiestos. Ho^O^r^fainothafiranelist cited a H-r , pubfir^iiai^6^vain^adli^001)'fiiat iMchteS tot ^iestos fibiri many Chinese -- iiuKyn.sv.. - ?,.: *- -'"'-sfcp k inoru ifonrp-: .- f ; l^ydiS^sMfefistkidb^d'tlMttliepftifids&d;prtft8o5l's nteta-fflialysiis touttda 5-fo!d ':*' ' betvreffi'atttphifelS`afid-dli^6tilbfibers. However, . V-" `offiefphii^Siaica^ihat^ereixjitoathfi^rifewliS'nWkatiSii^lfy significant :,f, . Sorfle^a.ellsfsiia[dadclitibMifeser^tions%Bdut-^eau&6t?,meta-arialysis, as . - : 'sati^gizStM-'the &Ub^gb^kitedftatis:''; "** >= : 'i 5 ;;v :i-V .r;/. - : Y): `; {Zommmi&oWtfie'metd-&Ml$isisi&ppm(ich; Several'^|iiheli^:iMfiim0ated on alternate approaches the authors could have used to conduct their meta-aMly$is ofthe epidemiology studies. One panelist noted that the lung cancer potencies reported by the various studies exhibit to identify -li^t^bf^bEajgC'XSanbe^ f^fenciBs). Tlus piMliStsu^KtSifiiM^e'me^afiafysisshdtdd'-have'^^coiisidefisd^fiier'&GWrl uraddition to ;,a?^''fibbrfy^ aMJdateSnsidii;^Mi!ih1bther fiidte)is*icblilil! 'iiiaae for the cohort, and estimated percentage ofamphiboie fibersritffiidejq^feidt^tofitetextent that data on these other factors are available. / i^^gal fiiifiier.hifet^its; one panelist !F-1 ^ ihlfial StatiMM'anid^is of the i^Meiriiblc^KQ-stiidies. This analysis used a fixed effects model and a random effects model, both inverse weighted by tte variance of the studies. His analysis examined how industry and fiber type contribute to the heterogeneity 3-3 HWBUI0009880 obsew^anaojog die cofaprts andTpiUfKi.thjjt &e ,uidusjtiy.offe cohort appears* to be a stronger predictor than fiber type. The paneli^. explaiiDjed that the purpose ofdisplaying his statistical analysis was to highlight how other approaches to conducting meteTurplysis.can pffer different insights on the epidemiological data. This panelist recommended that the authors conduct similar meta^iegie^iQnaiialyses.tp,my^gateAe.iropprtance ofvarious ^yari^l^on the lung cancer .PO-t?hPy?'.\(.\v; ;>i;;!>. ; '' Tigs panehg.alsp .demonstrated towa serKitiyity might yield additional,infonmfipn on * jpgne^ii|:i)^M.ilKiig ^^^fecfaffidel, the.panelist^first stoy^.Jb^rrlyp6,cancer latency * fiber types. ;;^Ut^udLqppeip^qgicd sfiidjes, swye considered in his analysis, the ampMbple fibers yyete .found to be ttureetiijies ^yh?ft,%?coh9t.|iphtysotile mpersand miJSerp .^Mn,C^ebecjwas omitted Jppjg this an^ysis, were foond;to Ij? neartytwo Conveiseiy^wb^i the cohort oftextile workers from South Carolina was omitted, the be more than tm times more potent than die chrysotfle fibers. Given that the conclusions drawn to r,.sensihye/to ; whetfe s^e;Sto^es,^oi^ttedjfipm|b.e anady|Sj( fins; panelist wa^tnotOiffepfif^a)i!C>l|t rwi^^fiteinoga^ fte authors, w^,gggi)j$^,tiip ;reye?!lithefeetors.or studies,dha^pppearto ^ntribjit^inps^to lung.ca^enr. *r Another panelist agreed with this feedback, and provided further comments qn;^e,roe.hi;r! analysis, noting that these analyses typically start with establishing criteria for study inclusion. hypc^cseSjand.to ,undexstaiKl/ti) c^i^r^%and(j^|prity, a^ong;the;jpdivi(hi||;stydi%. The factors ..obsesy^acipss Aestultiplestafi^apd tojjdeptify % be ijn^^^<^tiyepff3q^ure7i^tyi^^Tp;S|ari^tbe,a^pis^iapproa<^.jEhtrB9m^ijamcated oonateg^ stody,.witib, .ve e?cpc^|ire.date.hhaj: alIqwed..fopa:t^spnhb!le eS.tiimteiOf,t!re;ej(^surerreppi^jglapqDiMp; response, 3u(imuua&;jjaucsiiaia yyuu^cu-tyyiiu u& y^^4u.y|uiiMjncii^u^ai. iy^uy-raitwjrqw -p* conventionally,begin wifoetablishi^.e^licit^^y^inqtoon aiteia..31^ej^nqpsts clarified aliw09qti551!g^s0Bt)jie.jgywgeaitibjr.-ggg^^g5g^.^n.j^ws^05posed prok^l,.h^r9foerilw^.mpp;judicious.jnstelegtiitg fiieJto^eSjto eyfdyate,...=,... v r;~;;:. ^WOIU.. :> %; '.!>, fib?. IwtjiC .< v,: i/. Ifj-y' ';!' . 't 'j> ;_}>'. "!'. V.'i'b. One panelist offered additional comments on the meta-analysis. He supported,;fpr instugce, the use ofsensitivity analyses;, and encouraged the authors to conduct additional analyses to identity influential ^uc^,&^qiSJd^(c(^i|iiutq.$o risk, and the, impact of different weighting factors. .The panelist also noted that more sophisticated statisticalimethodologies (e.g., Bayesiap.. modeling, Markov Moiate Carlo) caribe used to ^aerate disMbudons ofou^iutsj rather fean ' discrete values; wMehnught offer greateruridter&ahdingrifthe inferences that can t&d&vm Scat theepideihidlOgjM'gtudiesJ ' ;" "=-.: -v/i: ' `'Bhpdratifin'dingS'ffdinthSSouth^^Card/ihaid;gM<jheCcnfi&it&'Multiple'panelists noted that the issue of the relative lung cancer potency ofchrysotile and amphibole fibers depends largely on how one interprets the disparate findings flora the cohort oftextile workers in South :Cirdliha and the cbhort'ofclujTOtUeimihers and mailers in Qtiebec; Two ofthese panelists "'''-indicatedtfiefelatiKtdpdfecy issiie likely will hot bh resolved MitU tfa^iinderiySig i&aohs for the dififerfec^lie3tweeii';fii^fe twri sthdi& are^b^tef'understood;!The other panelik vieWM the ' difftrenoe utfftfency a-rrioreiri^ortant twd'speoific dofidrisxWhda discussing these studies, two `t; athibuteSW',d%>6kire:&'siijfiibbie fibdrsfwKch.^are known to be found in trace levels&i r- -I:ibonunS!dsd,-^^o(il^(iI<r- ......ro:. y;si^ 1'*.{!. ^ :*'. ,.rr v .<1 ::*> ......./.-n sc: ' Releifdnii'i^'jfibW panelist 'nhtBd'^'dkriSh;6ffib^t durability 6ft6n enters ffi&:li^i^fOT-flS61aBvehi^'cahd6i'pdteh(gidfclEysikile and'aH^hilMefibeiScTlltiu^he !cl data--particularly thS Tactfhat lung Cancer risk does riot appfetf-ih decrease withtiroesifice last exposure, even for chrysotile--suggest that the lower durability of the chrysotile fibers might not ' be-^Ka6idC: .*&*.-. :; :h. ' V.O- ;i:'" jU'.!'u.v-v:;- an":r e-i:-: y! i j--'v v.;.: Had diffinhg opMBhii'on1 fitiwflie pfo|iosddprcitocol flteiatiure/fwa^neltltSSswd^fVe^'Iiniited'data'iffle'avallableoh qji^tativ!a^fe'0fifeift?^Morisiwith:ffib^foSxp(feuii& diffie"Sperific^^6iily:bne lung cancer ' ^ `^ten^bettveMsihokiSs ^^K^4SEn(Hotisi4)ttfi^du^d^i^t^''I%; Berman'ejqrlaih&i that tiie-$ibpoMin^racfibri^tivMismokihg'artd . the cSodd^'tt^ I>r5erffiSririotedihat'a mtiltiplicafive-'factbf in ^GSs?:S^B^BS91vc^ficick'i^gfertK^^'*6 die rBfc'inthe . ' :V;smblaji^yfa3i^83 lin^lMtlydie1 mod^ because it effect of asbestos is ^ neither the potency foctors.nor a were derived based on observations ofsmoking prevalence in ) . ,. J. s ' ,.i .v 1 . - . V.- . i.i . ... . -t-1 * .. , t ., . . ` . TSid paHeM eri^hasil&ti'thaftiie confounding effects'ofsmokiiig gready coinplicateslhe analysis of luflgxafiber potency. He htited that the relative Ring cancer risk fioiri asbestos exposure is 3-5 r* HWBUI0009882 <pom|de#AyJower a flie,ineps^ wondered JtoW the : meta-analysis can truly discern die relative potency of the asbestos fiber types from studies that pr^feiit'ind^mfofrnatibh oh cij^fe smoiotijg. ^^'paSt^f^ovi<led'afi'ataoii|>le,to^liii$6^'li^' -.,. concern:.; WP sinpfcMsJiatti tfee typi^ pQg^Safign^^, a. this increased prevalence ofsmoking alone could totally confound relative risks attributed to ' '' fasbiest&. *!& p^iist indicated that all future ah^yses ofCpMemidlo|icail; data will sufier fitorfilV ; solongjas <^^<4,p{hie^0!b^| 9no^iBig.is_qi<_a^afi^We. . .; Gek'&iii DtiK^'tiBKidfeiei*s^a!^sSd4iie'|jafi6eIlse5''offlanSaT&et^ail-fefeneiRflcbj0Ma^fe^ . jj ^,g>,it>pQ'Sedt^iiptp^pLj'Ehesejcoinjrneiits mpludbadL^nccEDS,ahojjt.i. :; . -..otoV-?'1 *: 3.1.2 mIT fr-'.'u h .. '! !* i '''-'X'fx **.v '."-.* ` *.,,'" J.vt* k-:: .l. >. '- v.ii i ! 8 Hung Cancer and Fiber Type: Inferences from Animal Toxicology and Mechanistic Studies `v tJtf/'f.y' -' . !' i'&ti 3Oa bwiOWK.v *;! nr\ j?!~ sm.- fev;=.:; ^reageyhat,<^n,.or amp&bole fibers., .... . . l.*- .'i:. 1 ':Af; .v, '>' f * '. ; -j-k ,.~.vh-; t:-........ : . :./'; *> \ U:'A:h ;-Vir>Tj .* V.- n* V- ; studi,eg.dp pot;support the 5-fo|d . fibers. m^treadlfrgm the ampialgfc^|es!; bemgs>g^^hgft:c|u^oa(^jq^y,no>Ioi?^:i^^^;y^>ifer^eig^^..cli^li^oasof;ls|^otilei?:^jS;; fibers to be an important factor. Another panelist added that exposure levels in some animal studies are not retevan^_,!^ui^sppsi^j;^. ang^rip^, h^^djat .a^recentiatj^Jatipn study (Hfph^ig et al. 1998) involved exposure levels at 11,000 fibers per cubic centimeter. Thesepftriefists indicated that the animal studies me generally more informative ofhow lung cancer potency varies with fiber v3t!;U..rtobi; " e:n u -u: rjwiiS.fl >' -i*;.. '^i<S>v ruo?"- -t- length (see Section 3.1.4), and are less informative onflow potency varies with fiber type. H--- n-'i. \ \/i . , ..; i' v4 :- ';f.rf- x; iSial1:* .'`V .' .!' 3-6 HWBUI0009883 The:j^elistsaoUH tM^ih vitro i hdirijgs, depdhdirigbn the study and X. . ' . r. -iip-ifr:- vh'ri " cr-fyiA'-a-iHlS:" endgoiatsisse^srf. J^ie panelist, for imtancg, indicated thatsomein viijrp ta^.si^gest,t|^(t;,,. chiySbii3fe'fii)feis;are actually more jjotertt than aft^phihble^fibers: Otherpanelists added ihafniany in vitro studies.show qpod,dblite being consIdmbly.more.|^Hdq gun chrysotile. These panelist.cautioned against drawing firm conclusions froniihe in vitro slMie^'hbwtever, grVefi that the study duration is far too short for any1impaQt ofdissolution to bq.pbserved. jpit^y.^qtherp^^iefened d*..fhe loteniatib^ft^ Cancer (IARO) cBJK&tefsta<OTilat:dn fiber caretooj^hesis for ' :r<(' r * v % ..... <xobc.':-.-. >.. &!b:k- o&juxiipkrf an oyeraew pfinferences that can be drawp.irom mqqjhapisfic studies: `Pypr^l, toe ayaiffli^eyjdence in mesothelioma is either animals or humans is evaluated as weak" (IARC1996). '''-V.iintT.t- 5 **`ST-jbV>r:!.;: -.vre-.i -'AX Based on the previous comments, the panelists cautioned about attempting to draw inferences from the animal to3al6^ for several rri^onsl One'-patSti^i^'id^i^ii l&rte'liMic&titifify'! bei^iu^%iuD^7<SdD^4tfTtBait&BKSldBsidl^cb^ta q|^refre,OTi3e,':afrd:`'1 because rats, when compared to humans, develop different types of tumors at different site&:Another panelist reiterated that the duration ofmost animal studies precludes one from observing dissolution effects!^'GiVeH?tf^Tmi!iafiOTS/SEw6 iJineliSis eH^pH^i2^iHM'd3n&iS&nslshburd be bai^pWth^y'oh die ^fc&>idglcai'data}- especiallycorisicfeing thevbhirffe' bf'hUmMncia^^that are available.TB&ugh " ' '" not disagreein`wii& i^'ietafflneiiiiatid^bne ' '; isr.i !f ---(V- / ;i.r y.--> - i'viv ` :)TiMg-'Cancfer:Siia^Kber 'WyflnMo1irffif#ehcSTfbinThb'Epidemibi|y'ii '' *'f! " lad'! y; r Xk}- yvu,:--.\ c -^ibufc-Kfenn V: 'efls The panelists made several observations.regarding whatcan be inferred from die epidemiology .v;d>; r# ';sy >; v-KV;: wav::;-: n; i;!u> a?- ..'. nob-*# visV.'-j.sfiof literature oil how lung cancer potency varies with fiber dimension, though they first noted that most published epidemiology studies do not include detailed data on the distribution of fiber dimensions to which, cohorts were exposed Overall, the panelists generally agreed that indirect evidence from the i-7 HWBUI0009884 qjidraMql^Gal.studies siqjpoils the proposed piptoppl's finding that longer fibers have greater for IiMg cancer, no evidence ,to support or refi ft); j/c.' -.in tencies.used ip.thp proppedprotocol longer than 10 pmheihg 300!tin between 5 and 10 ; rt.'.H-o . 1 ; * y pm). The panelists made no conmarats;abput.fiber diameter when di^cn^ing .diis.ii^der.. Specific discussion topics follow; Observationsfrom the epidemiology literature. The paneljsts> identifiedseyeral studies that provide general insights on the role offiber size in lung cancer. One panelist, for instance, noted that cohorts oftextile workers, which were believed to be exposed to relatively longer asbestos MMve&ks:than dtmJhtitfe dfthinidrs prlbementsplrottet !ityqri^,.A#dh!Jr;P3n5li0: kifeated th^stodies-oftacpnite.mineK;^^..^finngsota.(^pger et^ at 1$88) and gold miners from South Dakota (McDonald et aL 1978)'found no increase lung j, . flfanjj,|um.(scseik..ig^e's prerg^tjr^ipgjnmenits for farther infcj^tioq.on panelist added that the Minnesota Department of Health is currently updating die study on taconite miners and a publication of workers exposed to asbestos from friction brake products show no clear evidence of increased lung cancer. This panelist acknowledged that these epidemiology studies do not life asbestos fibers1 in frictit f '<> W'C/' . V,,. vit .-i-i ;f.;T L,-. i\, lUOUti V ` ' y-Reld9ahce'offib'ro'its sfiHictiifes :sHbft`er'lH'&5'p.m. .. . ; 1 - ffiari ifptEt'ifinjs M sfructutes shorter While not x"'-'-fiBe^lMve & &oad 3tSiffiu!idn:dffib I^g&Sj'viifli'felieafroaj0^tyi(75^9O%):0Mbro 5 'StniMijies being 'shdrter;tiiai 5 jit&T^s panMl^t added Ibtit indu^tmferehc^1 rah be drawn ';' fibrous stfiEfuiSsshtilter'thafi 5" pin in f1; toxpert'(Siel S^iitiy-bvaluated the isstife'ofrelative ^fen<^=dfifibera:shdrtef:thah >5 fita; however, the final repeat from that expert panel meeting was not availableontil after the peer consultation workshop. The final report has since been released, and a conclusion from that '^lef^asfiiaf^ere'i^a tit>hg Weight bf^dencetKafasbesfos>aftd-^nth^tic'vitxeouSifibers 'Vfr' ^'rt{ to fcause cancer in humans" <pR.G<20O3)i7:>`-'t'>"-'; ' v' . v isrtf> m . -,r .vv, "v;Ac . . 3-8 HWBUI0009885 Statistical analysts ffi i greater mmfflngenic potency, qne panelist fefe'gatedfeatjthe exg^qr^re^jqnse modeling by,, Drs, Berman and Cramp showed an improved fit to the observed relative risk from epicferiiiibfogys^eSwheirirising an ek^Md^'dex: that'^si^is greater'tveigffrto longer fibers'1 and np.TOk.tqJ^rs:shqrter;fhmi 5prte:An9&er-pMe%tcpnciirrad, but added feat,fee.autliors could have attempted to determine fee specific weighting (Le., between longer and shorter fibm)^fa^ffld;c^^n&:fe^fitto`tfee^i&id1%Kal'!5tHdies:ii: - : - 3.1.4 Lung Cancer and Fiber Dimension: Inferences from Animal Toxicology and MechahistlAc'iSi*atn!ed.*iidJxs- ,V. V,IVi-'' V \ f ;. _ v. -'vS'X*. "X-. H .. r aJ iCi'ti'Jih./j nTft The paraelists-genjerally agreed feat fe^animal to^cofogys&idies apdjnedsanistic sfe^fies^fepite that fiber ifrr^Sife&t rofei-liofem'feiim dfd^ta^yfeid 'xt.-nor-: t'-,, K'tp U'uv'. g ijily,; .. pattogenesiSirHowey^-pa^elis^-Jlpd differing opinions onjfee^speGjfic, cuItO^,feat.should be used for fiberdynefers arid'lengths :::''bg'?.-y:j:\ii vlir:/r/r; i:: -in-xl V: 'rr*:}&<?%; tfeatShess sbotfer than :5;pra should te ^jgne(I zerO:fK>tency), . . panelists gefienttly coneSrred >;.; i \Cibfi.j.' V/W:'t.. il- Vl :n<"5 .TiiV>o l.-'Y 5/.-S---V ; ;Jj VJV evidence featvliHig..ea^ea:;pqtency Wifejfibei: lej|g?kpother; panelist.ag^t-but had reservations about assigning no potency to fibrous structures shorter than 5 pm, based on a recent stuffy-ofrefragfery ceramic fibers (peUmqn; et|il.=2QPl);hjat fg^dtfaaifeOjincidence of .panelistifefepted feat,esg^pure;to gnafefeters,likely has spi|te;bj^iipg on fee}oxidatiYe stress .state iapdipfiamrnatipryinfee,lung, and hg sygpf^ted featfee^eaposup^TOpo^^ipiation^ip for long fijbto isightd^P^dM.corKKRpsmies .oni^ esgipsurgs,to, shorter fibgr. Based,op these -^.'pfpppscscl ris^f^@f^nitP9ian9!Ptf>9dolpgy$/Qi toxicology stofees/baMshavm feat;fibrosis; : exposures to.shf^er.fiyjiShowtng-less eyidenw:ofifibi^siis,or;4fteg;^rpage.The.paiielists mdeX/fsOe Seofio|ij4)-C :f: v , ; '>:- vwi? ..yl .VJV- .< : ....... ; hit; .!?'; sk-:,<-ir.cv i-P :..TTfier.;rffaji?^r.,Tlfeipa^^Qnjhe JJ# of fiber diameter.inihe proposed protocohNofeig feat fibg^.wife feanreter^,pp to d:.5^gifare <^p0ble of penetrating to sensitive portions of fee lung during oral inhalation, one panelist indicated feat this range of fiber diameters should not be excluded from future risk assessments. Other panelists shared the 3-9 -.S HWBUI0009886 concpna of assigning dieters, gre^tejr than 0.5 ipm, especMy^considepng that.i^irflbility ]fftfr^-m .fah^ those in hiirnans (iA^feWfg^^m^j^pdy to deposit in the humanlungjlffn-they ara'jin..the rat 'Vi' \*`: J?V; - r-.i.f' -M&hih vS^WjSfe .A.iJ:;: . ,*t i.:*.:: " :.V. SiL'-sr: V;`-Vr O-'j rj$. .*,-Tlie'panelists .also. ^isc^us^^cija'jStatonient ,in-.ti^:proposejd.pp3tppol,firaty^iew^libers^thiclcef'than 0,7 |im appear toaggchi thgdeep^PRg-'' I^t,iOj^paireli&in$fat^$it fc^projpdiad^^otpcol includes outdated information on fiber deposition patterns; he recommended that the authors pbtainimore cuTOnt-Jmights;fo%swj^9.guhUcations;,(e,g.>.Ifi|^paaja|^||^.andjfom^the latest on. , H-humans tend to,tteye|ppbrpnchpgeqic c^inpjnas, .t, . : ^carcinomas. ^o]^p>^lM%u^jned ag^insf^fen^ng ttatt;^te^,|^;.must^>osjjjon ;;-o!,j a.ccump^[^L.p|; , ,&ytungjs jfflglyrelat^fB|s^^^fon[^cm p ^inp^u^KiB,p|.;. f, miwtoM'Qj&d*.'.- .;'-m ^ra-i,,. f; si&a&k-'; 5/j;*&O^S ;?..1 *:?'frViiiX) ' '/:, '(t ' "\\ \i H s *"X<[l ?>>:?/! V'; it!** :"t - yJjj% y., .r .> y:-5ri.? ^'fiiS'- "..E1-- <- '-'J-= i. t 't:.- ! 'iv? ..'?..:! ;>;,, . '"; -";i -' >* *" ::'- 'r : "- ,.tp:.i . f. . &.;.<' .:.j\ A':! -J5.;hS-iV'V-Si;:JS; .;.. 1 = ; ;.>!. V.; j".* -,-joaq Hi tiiril'irttuivM-ui'i: -;. The panelists discussed several additional issuKfelalefi'td'the-jpSbpfisdd ^rotbct>Ts|6^iiati6h bf limg cancer|^ncy.|dpst pf|he.disci^ion/p9P^^.&e.iPtifity.pfno^T^ear;.px{^S}|jeTr^pptKpr.; modeling,butothertopics'weiealsd'aficlr^sed:" -L' V*:.* ; ' ^ -\\*.*v'- teWs';:7!'0:; 0 -f ; >. .-'IjiiiKf.iv ;[ V it: ''- .-^Ti 1; t- 'i'- l : . :.L>.:;r;. /: ^..4'.?; 0J.7; .U- ? . -v -..-:i.v-;: ntii r>.:; ^.; ' in',^M>MideraUSn :fff-Wdn^UKitirl''&^dsUre-risp&tisem03eW^^^^m^Ms'\i3&SsSQm^ . .''h.4-^;ti}Ancfrtn'fh(!pyip^hi'tb'CWifcti ;fHf:rirfirW'&d iwnthdril sh'rajlrf ftoh'sidef'ftdftiliHSi^'einlfSsurt J': lo#^^^'extiSpbWSbtt::fliis panfelst^>fcfciferVl^gMJtiiat:Sietreiriled;iffi^: ihodel i .!v'T^bp^^Sct ^pldddl'cl^i^r^ivitlefe ari improv^stadsticSl' fifto'fe&'^ffltm&ld^bal date ~'<'i^hSi COtfipaiSl tb^XV* dRff'lfeff V^`n'A^3ViiSiHAIj|Hnt'h^SM'AftafA#iijinfi Mfeiliefl'fiitrtlhratii Vi predicted for low exposures: because the slope in any* iin^ffing'cahcef'Tir^del WTlfhe-^ determined largely by highly-exposed individuals, he questioned whether the slope derived from 3-10 HWBUI0009887 ` lu^;eS^sip&:toy t1owiy^xjpasdiii^duyfe!-Tc^d^on^i^;hiscoiKiern,'tiiis rtfiVtl'iSfflHirafet-iffiaii die ^Wti'^ 'i5lta'&i<d^tfo:show that cohorts foesubset {~ gxMbll:'ii6 increased lung cancer risk (standardized >: mortality ratios not statistically different from 1.0). To account for the possibility ofa threshold or non-linearity in the exposure-response relationship, this panelist recommended that EPA :Sl: models (Lej models with aii8$ylitfe^ejqplikfi^r^^^Se'ii^kiDS'hkVing lli^aeAtSlbp&) dT'foj-lineaf models; :: Otter! ..te`rgi>^f iirai^ sdpport8^-1i&s^ d6triarSa'fi`.:iGfaB paneHstJfc'mstarice; riotSi-tfet ' - lEPAVEtiaft A^s^srteriftridicatesi'that exposure^ re^i&ielatit>n2fiipS'sfiould fiE^:bs' foeri;yimous;:a^r^K& td"^raj^3iiafo tSxj*xsiMs levels duf&de ^e4' hBlow) tiris"Km^hould rno* ri^;aiiEfong1llir^^ffirt^im#i6#4S3d^i^;slfould`Sc sioh Ofwhetefifie lung -Ja^ri8(kffi?k___ __._______ _________________ ._-________ ._, ,, *... .. hi^tforiti^THfaer panelidsmo i liMft^' bbraifee^j^Suies were riofmea&lfed for individuals; farther, a panelist clarified that appimiti^ly^^oEliS mdividuals coBsTdiCTSd in tins study were occupationally exposed. Finally, one panelist indicated that evidence from the epidemiology literature strongly suggests there are asbestos exposure levels below which lung cancer will not occur; this panelist addedjt|Mtlie;ijUna^are?of ary epidemiological stud^tfaat has found evidence of lung cancer risk at exposure levels below 25 fiber-years. He recommended that the proposed protocol at least acknowledge the lowest exposure level at UCtS^^ j- ; 1.. ,yJt.' *:< On tiie other hind, isofae p&elists were rioftforiwrioSl of ttie utility ofdoriductibg detailed ' analyses at low exposures and investigating possible.ft^holls..Qiieipanielist, for instance,, ,.. indicated that a meaningful quantitative analysis ofpotential thresholds will not be possible, so long as tire authors do not have access to raw data from additional epidemiological studies. *:.. c : ( Xj. *,y .,./ v could f-gtf^^g^.^a$gt^^^6n^^eifflJbattiily4Pt!aeafflB4=jg|pger risteamonglqwlyjgjqfpsed co$ggj$^y I jUj^y i^tyigpppgi}^ unpertajq^ jand pqt|te<?5ssan|y frgoqthe - andttmt^Jtmlysis ^.threshold ofzero (i^ftefrest fit inchatpd;fri^t-^arecwaspo. jhreshold)*. ..,, ,,.,. , .... -s 3-11 HWBUI0009888 . Consideration . -. recent rolejof,ci^re|te smoking on !ung.canper^ ajgjpng;,ehiysqtile mingis.. and millers in Quebec, Canada (Liddell and Armstrong 2002). Although the panelists generally the mo6fel,'sSftib:f' . |^to11^.(w^ not ^nvineed.Aat dip a\gijlal?ie data ^.sufficienftode^^ ... response model that accurately portrays the interactive effects of asbestos exposure and Transparency oftheproposedprotocol Several panelists indicated that the review of epidemiological data inthe proposed protocol is not presentod mh tr^paient fashion; One J ' ji:J panelist, for instance, soi^jbt more information on the uncertainty factors used in foe meta- foa|,foe|*^^.prp|^;|^^>^a-y|Jyes.j|at,were;4^imm^;%)di^i^^qlp^(^-^ ar^.hpsed orea oie^an^sig^m^fr^idgpip|pgic3lf. ..1: bn a detailed review oifjust oue or two studies. r-'.'.rx-'/-- ; Vii'.Oailii i- 1 "f.-'j-ncr-.'i'..ji>-;!. Vfl-' HtjSZrSt*!'=< * The need to obtain additional raw data sets. The panelists unanimously agreed foat.EEA.,. . should make every effort to fry to obtain additional raw data sets for the epidemiology studies, such that foe authors can further test how adequately the proposed risk assessment model . predicts mk.^^.^^i^y^iipopiap q^,t^jeport.pTOenls.foeg^e&b!,S|^ffict. ;.i > i .... ,;r; - hs-'V. . .;; i vli : -' X: -''r;.v-Wfr: kk:- . ..-r,v y."r-' >' 3.2 -v ACR'. :;,! .W?h r-i'.i'.Vi .-; ; w.ftiC'' .-MUr-'' ;.>< k1': ' :b.; ' V-'- ' i;. ''O .:= - -vH - -': " ::f!r ; ?/ ' / />!-Vs- ; fiwfcm'G. i.-v....... <*;: '. >,( b:K:`;Y .Via riVr-i -.'t/ hv.-: . . Or.jb' .t-i. v . ^.r:h Ttieffdlhvhiiig paragraphs re^Hs&fo^cha^e'ilhcshdni'^^rdm^ inferences : ;vrbbife.b.'b ;l|; . .yd' jb-'j .. :i5';>V;wK tthW5 : -b gpm foe ^idetmplogy.and toxicology. lifpratuiB,on how m^foehon^po.ten^; ^fofiber.type (Se^i5iis'3'V2>3''aiiid^i2i2)-raM3 fiferlength (3l2!3';ind3;2.4). ' ' - Utli- ;--Me&theIfo1ififiifrd^^ Iato^fure 3-12 HWBUI0009889 9 reKfrted bbth-in the reviffw3d6unifeht (Beiriiab' and Grump 2001) andri^^r&eSf'ro-aniMysis^'OFT? cohort slu^)^.(^p^so^.^dI).amton 20(30) that reportgd(atieast a panelisfe:(&mm0hteii fiirtfaBr epidemioldgy li^rature provides no scientific siij^ort fdr'dfirysotile ?:CH v.-.:!->::? ,- vte- ;.. .Th wu v>..: -f -'.a ..-ir 'situ: .-vgsi exposmes having aj^lehtcaiisation pf,roesp&eh5iparr^.ohsepfatio,n.ft^,KJg^iieiall^i.CQn^ste|it with the meta-analysis in the proposed protocol, which failed to reject the hypothesis thatchrysotile fibers havezeropotencyforipe^theiiotm. ~"*!*. ton, w+i - '`I'**'..-,- ; ./-*'.> ;*! ;/-7i . li'-f j.C *. .lx-. *... :ov X : .- r.OnUt? l;::#-...:*. :;*! anipitetiiSWBis are?dt`lea^%00'iilnfes'mSre potent tern chr^otiie fibefe,!fi^Thfes8fteli<jiiiSiW: ~ i'O.Ur' ,v:M;i v.te'? ;;* ;; -.;= A'-fr.l - .' sbl-WK: i,ffc .;l-(S' supp^i^t^!t^o,sepa^^t5]dews ,ofepidermplogicalstodij^s. fJheA|)^lis^,inade.^iditiop^pppjments on spjfficlma&eb wteiiresjridirig to this y.';j- ^io'iaiijio.f/vi\\-L>:ili'-;h.'.r:id discussion was the agreement that chrysolite is a far less important cause ofmesothelioma than are ampinfite-':'' ip-;::- - ="-w-- ,-at. --- -jth.v,.: it.;;-; ' i Eli"-- < ;< >. *0 to- >x`\ : ..-/K' VC!) j>vO-!j; i.': i'-/, '.:;)'; -;!;!' x;;;: d'.V;. Reladver&l^ofchifsotileikd'iin^hWotei'&ke pahdi& indicated fratWjtioit stafieifwith individual-level exposure-response data and the broader epidemiologyiiterSiure offi provide no evidence of increased mesothelioma risk due to chrysotile exposure. Further, this panelist noted that 33 of41 mesothelioma cases previously identified as occurring among workers primarily exposed to chrysotile fibers (Stayner et aL 1996) were later reported as , exposures to txemolite fibers found in the chrysotile mines (McDonald et al. 1997). Ibis panelist ............ noted that a recent finding ofa small mesothelioma risk from chrysotile (Hodgson andDamton entirely from chrysotile exposures. Based on these observations, this paselxk indica%i _that^the . iMt^^fresugieSs'friat 3ii$^Sle:'ai^B5ll^'lia^>lixi&t^d;>*lff%uQ^'foteliriL caiis^iifO&'iisftotha^' nonetheless supported the relative potency^attghyted^to, chrysotile in tepropG^gd proh^li^?i%) conservative measure in the overall risk assessment process. ,Spe.cifi(s c0pgptm^.pniiheC0nn%ctwutfrletiqnpro4^.c^Wr^^^^PP'9m^^:i. commented on an epidemiological study ofa cohort of workers employed at a friction products plant in Connecticut The panelist noted that the original study (McDonald et al 1984) did not identify any deaths from mesothelioma, but review of the state cancer registry (Teta et al. 1983) 3-13 HWBUI0009890 revealed..that thrre poDBo^out ^ideats who die4 omeso&elioma were.employed by the ., same friction products company. One ofthese employees had amphibole exposures during the itinie he worked for a textile1 plant was iiider the same parentcompany that`6whedaiid : operated the firictipn prpdiKts^iapL ^Ite other two cases;the p^eli^not^.were.fe^esiwhp indeed worked at the friction products plant. A pathology review found that one ofthese cases v^^'vm^i^`-id%^b%pE^i!^ntds<^^Nnra'aiKi'S years1ofexposure;the'other Case was a pesitpneal^i^theliomwhq;a!sp had asjjestosis, and worked as a clerkfor.3Q.. years. This panelist noted that it was questionable to attribute the hater two mesothelioma diaghosS to the fchfysbtfieexj epidemiological study should be revised given this new informatioa Comments on theproposed 500-fold difference in relative potency. The panelists had several comments on the finding in the proposed risk assessment methodology that amphibole fibers are SdO.tirifeS mbte pofehfiftFii^odit:fidiha!lf^h ' (Hodgson and Damton 2000). Though not disagreeing that amphibole fibers are clearly more fiieriilkaielficiabits v; ^rp^i^i^^p|gispi4ngbgpatioa.fi!r had to be made to determine critical inputs to the mesothelioma model (e.g., average exposure, !i^RdkNaofd]i|M3sin^.:'' wn ^ '"s- ' *'-= '- *tw hfe-aitt* o ocb c-.?..*:--. Other panelists commented on specific sections in the proposed protocol. One panelist, for example, recommended that the authors check the accuracy of data presented in Table 6-16 ; ... , andTaljIeJi-29 ofthe.repprt,.vriiich.iuE?.not reported: cppsisteptly. Anothergan|!is|suggest^!.,., that the authors better explain why separate risk coefficients for amphiboles and chrysotile were ' "Mctdatedfor Sdmefc6h&its (e'ig.i:Hii^&-fet,al!;;1987) butnStfof'otheis (eigi Beriy arid' ' comparable. Finally, one panelist recommended that the authors of the proposed protocol (krigeri}' aftd:Maj6r;2()02):aboht die^iialitybftfi6' expdsiiref1 v.^teprigjnally i^^|or,^e^t|enopmcojiqrt (De. -Klerk^ al;.198^).^hm,ey4^g.-5-.:i,.Trt exposure-response relationships for mesothelioma. :>':ri'^TGfedi':V%-y.:-.: ;< c-' i>y; \ v.tfiy!./. i." ;.;i i-y;: - .. . : -.in* . . Me^othejliqi^a qndyibe^.Typ^: .Ipfarienc.es Crop i^imalTpxicolpgy.and . Mechanistic Studies i: ' < regarding relative mesbthelioim potency bfdifferent asbestos fiber types. Overall' two panelists 3-14 HWBUI0009891 commehtefl feat die human epideriiibldgicai! data ''clearlyestablish tfaafexposures to ampfiibole asbestos . .?. . .X `i VI- , - .. *. I i,r . *:v s- ' fibers ppse.ajjreatermesofeeUpma risk than dp ensures ta:ehrysofile. fibers.. They added that the ariirtetitojdcolbgy data are :gafi*aaUy Wtfiisifinding,biit:ttto'inihMidata suflfer fioinsome limitations. Two panelists, for instance, npted.foat feeutifey;ofaaimaljpjtieolpgy. studies is limited by the feet that rodents are rather hKen^h^tb'ihe6fl^cfiiKL-Th^''paU^ls addetffoat&eanimal . box? fee iolsalation ekposiiKs tliat occur in'hWiiMis.The^ Ihmfetions iiotwithstanding, the panelists raised the following points when discussing fee animal toxicology and mechanistic studies: Ik. '.te. .i'Y-!r\ vi'TOi;. :1T ;it S':-VV vV-i s.A.:; btf-ic .-j: ),: K< i.-'j insights ppt.;foe dcoiniCTic6%f'itn^!hefidtm% ahiihai'^di^'.^fflhit teiie;'tiiis'p^cfelist htkddi;feg !ahHfiM!ajBa!ation studiffToimd/feweritjian lO-pa^es of rne^Jhehoi^-and fe^im^rpjr.<^^;^eace^S fp be. greatest iphibblS'fibbts: He found this consistent with fee influence of fiber type observed in fee human epid^olqgrcafdata (see Section 3.2.1). ri;T r.. 'jzi: b r- b.ir-,')*;;'' I>urihg feiSJfescu^ibn, one paneli^ tewfewfed a puBfifc4fibh'(Suaiia jmd!%eii2O0i) that'iras iftSntioned iI;; r r:- j gfe,'lh:U'.v- v?:: ASl/iK* \ ' fTidn.v- V.'.;," U '-rte.'te earlier in fee.yrarlcshqp,.Thp publication, dppurpents. the;qmounts.and .^pes of.asbestos fibg!grmeasured in samples:M:|>16uM pfe^&Wd'hamor fissbe cofetedfof-legal .'adt's a? Sr! hi/'j;: ' ": . .-fit: found-relatiyely large amounts plp^.sygg^^.fe^tfee^e .fibets ' -'mjSuv.'*r- -;oi several criticisms of fee study. First, he indicated that the samples were analyzed using a fion-standaid technique, without any controls. Second, he questioned fee major finding of fibers being detected in the pleura, b^ai& feostbfthe sariipl&mi^y^ were MctiMy'tuHhldiftisMI^,1h5^iidftlie^wroiild-iK)texpect to find fibers. The panelist suspected that fee clirysotOe fibers reportedly found in fee study likely result from specimen tntemination-ra:bias that would t^ve beenmors apparentjrad.rigQrpiisquali^pontipl procedures;been followed. Finally, fee. panelist noted .feata more rigorous, study IBoiitin et al 199b) of 3-15 HWBUI0009892 asbestos fibers, in (he parieMpleura found a mixture of %er&,4ncludwg ]cmg amphiboje fibers,, among , living patients wfifi asbestosnrelatod conditioiis.; Based on theseconcems, th$ papelist.opncinded that ... the publication of concern (Suzuki and Yuen 2001) is.^ripusly;flawed.M^ shpidd .be. : excluded from EPA's analyses. A specific issue raised;iEKfing the.analytical techmquein the,.study (Suzuki.and,Yuen 2j3Ql) was.ihg, water was used duimgjthe di^stion prog^-iNoting tiiat water may cpntain; large amounts (<:30,^0{;. . fibers/L) ofsmall asbestos fibers, pother panelist suspected frat therfibers detected in die .study migdit have leadted from con^irrunatiop introduc^th^gj.fredig^tionijprppeffl.^pe^usecpnfipl sarpplgs.. 0 ,r. were not analy2^<thejpanelBt siud the jstudy fr^y.iw*g0nsj^. flie original pleural plaques or tumor tissues. He added that studies of lung-retained asbestos fibers ioulip^.de^:prin^iK^^r thepresence ofigie shqft fibersiin;theip|ej^..r lyap yahdr^woidd nqtjjgjessarfiy. ggrpyg, thatst^:.-. fibers cause mesodreliorpa. 3.23 Mesothelioma andLFiber.Dimensipp: Inferences from.thgjEpidenUology;^;..-.. .. Literature T. MiUfjrl-:' is ' : ' ' -V' The panelists commented briefly on how the human epidemiological data characterize the role offiber size bh do not characterize fiber length distribution, one panelist indicated that these studies provide no direct evidence ofhow fiber length is .1 '.: t textile.wpttersin South C^Ur^^ep compared to.thgtfpr;^dte^^.^u^'a^'nullpts'hi, Quebec,could be.^qppprtive pf.lopger ^bers being mo^jj^teni,,smc^e^syr^in Sputh.CarpliinaihM. a largCT.percentagq.oflopgifib6^ .However, a.cohpzt qf^ementplai^workqrs-in New Orleans found to have a higher mesothelioma risk coefficient than that, pf#ie.5pptb.Qa^olina cphqd, eyen.thqq^i,.. the South Carolina workers were exposed to higher percentages of long fibers. Finally, as indirect 3-16 HWBUI0009893 ............................................... _ evkkirice thaicaro^^ fiberleogth, ttiis'pab^ist-iiol^'ttiat^iiiesc^Uom ride model tteirig Ili^l^iibsedl'eii^pSsuie iridexi wMcfris heavily weighted by Icing fibers, provided a comiddably-iinproVMfiftoth^id^o!<^cal data. ' : .-. . , The panelists briefly revisited the inferences that can be drawn from studies of lung-retained fibers. One panelist ^aih^mrtieifledfli^iSsults from a recehfStudy (Suzuki and-Yifcn`2001) shouldbe viewed with raUtioni Meadded'that general other lung flaflioIt^gy'Shidies (e.g.^McsDoii2ftd!et at* 1989, Rogers et aL 1991, Riodelsperger et at 1999) have b^"Criducted using mdre!rigoroife;ifriefrbcyj5ubh as using qpproftfBtd'Cbmibls' forage/sexi SM^hdSpitaL'TBeseisfiidieSIHshoWed that risk!ofnfesofelibtna was cauffi3id&ity$88xi a^ia^frii1ttd^fiibg5;,':'!' - Qm phielMMcflcalM ihM resets finm% study ofluag-retairied frbetsfTmbfefl et al.:'1988)Su^ejt fiber ral&iii'^a^QMiBir^Hntiii'tid^lfae^iicI^ctesiibrveijr-fiomgSothfeltbrna c&es among a population highly exposed to anthophyllite fibers, which tend to be thicker fibeirs/Gitihg'his'eariief review of mesothelioma cases (Lippmann 1988), the panelist also noted that crocidoiite fibers are both thinner thehj^ihesislhat' :v<i57--.v`!; carcinogenic potency for asbestos decreases with increasing fiber diameter. 3.2,.4.r, MfsotfeeSioBria aBd^Fiber.pimgnsion.r.lBderenc^jfrpfli ^lmial,Tr.oxleplogy and. Mechanistic. Studies ! rub on '>;/ -;,^ jre't1 t}8atbn'-iaifoftS5i :?"> n-r-' v! `''ul'-.-? : ,wnei:.v . r: The patielfils^riiade feW^ofeerv^oriB on f^di^ from liiinMl t6xfclc^sfiiidi&"rbgSt^ihg rit^otheSioma and ffi^'iti%|^'Oi)id!j^ra^^fi^dihid:fllat:fi^yn^5 ftriftftlie amoiM;tioxlB6te^"stuifie^gffi&Miy support thi owrall Bsl& arc ^eafe^^crloi^^ffimfib^Tjdwevferi'another pkhelistttoted l^fiffifesosedililifttfe f crificalfib^^fm^thefidnte'uidtKfiM:aiffiiosh vwflilefigffis between^inclTd pirn. TbJrparielist:-'-v added that fibersofthis:d^ehfif6hhrc'fribre;likely''to;tiansldc^ t8 ffih^S^h^1i&h7arc'-lo^n^fibeir^:btd 3-17 HWBUI0009894 0 he acknowlejjged that it is unclear ydiether^^fib?rs;n)ust)fiist:tianslocate to the pleura, in order to cause mesothelioma. ' .U- Some pahelisls inciicatecl that'fife durability Wcel^'plays a role in inducing mesohelidnia, based oh the feet that mesothdioma is mote easily induced in animals using administration methods (e.g^ peritoneal hfdrssblutibfi.'v'*' r' "-k.' r ' 33 Exposure Estimates in the Epidemiology fclteraturte; :i-' ' : ^ Xii.fiH-? : - . ` .-.'v?SO'i\ k::X,-A ' ,rr r (iX'i:. -h.-V -ii: :: The panelists rased fi&mCTdi&ShiieswKeh SS^Mihgfe ifie thiitSfShaige qptestioh:`Td;wdiatextent ate .asvfiy; 0? ^ :v>. ssor'i-rcsjn;- : . v-w'-. i the exposure estimates documented in the asbestos epidemiology literature reliable?" Recognizing mat tbe'expbatie ^ihitates'^sfiifc'epiddriiblbgy Studies aftb criticahihp^s to the ejqKfcureir^ponse assessment, the panelists expressed concern aboutthe .eoqtosure dat^j few sjtu^es;p^^e detailed information on fiber size distribution; many studies report exposures using outdated sampling and `.v. atarhi*;. : '"-i/-'- -o' ?=::- u?&'.Jffttfcswo^tyurV anM^c4lme.thp^lp|jes^e.g.^i^^^^^);iin&wdpl4eveJ,d^^.n^:..|iyailbJ|?^c.^^s|3pidies; and many stues;di> hot'iKj^d-deffled^dmiiten ohrpai^eterar(eig/,>ex^sure levei|i|P^suie :?m-;c' *jt.! C: r:*Srt5S<anwuxp..* Yu fid .SVfKU!:fesh'fc specific concerns on these and other matters follow: etel!:.Mv i;.'. -'./a tji-iv.; 'V >vy\- r--5s-.f\pv: : >n-. . i w Gik'iYemW^rigaiMHg-d^i^suF&esdmates. M specific stii'HiS^Spmdpanelists 'MpresfKi. . confcgfii-^ohVthe'assui^fidfis mafcfo ihtdipft!the;expS^&totirigmiUy're|iih:^[#'liie epidemiologysttidi^C'!'Que'jpairaeli^lre:%id&w6d,^p^lfi'CffeS^iib^les'ofi&^eliofroferii~ (i'Afik h;> .'nib^ripM Su9yv^do^&',li^C^dinSeSl3dltrfiiiaStii!^pn6dnbts ] ; hmts:ofnnpcflp4fe;iK> * '^fbifiiaiionfihhBw^c^ teitoste'resfiu dSti^blfNHMcalio ;. `Sgz.'&ir-'.-#, Si:.-K'i SirfO h ' -vYiHi ift sr&<\,.:' r,'r : Jii.O1.; y;.iv.: 'iftC;,:. . *" ;: 'r ,T` - ThdSnip %tu(fy'bfw6rkeigat%:NewTersey4ii^atibh fecteryfSeidmaietral':,ii986) 'JdidK0ttSpffrtM^:?pbsiiremSasti^ehis:Mrh-te&:fectbiytiidiSd;Shd'data'(Siilected : T; . \i:-- ; i-'v \ c-: f ' * ' ;>< i; ' 'f'fk,/'' ;`vf:r 3-18 HWBUI0009895 for this cohort The original study ofworkers at a Texas insulation factory (Levin et aL 1998) reported arangep|Pexjmtire.ievels(1^91JiberainL)>andtlieaudiorsofthepioppsed.protoa)l assigned an average exposure level (45 fibers/mL) to the entire cohort The original study ofU.S. insulation applicators (&tilcoff.anjd Seidmari 199,1) has..no,. . information on exposure. The proposed protocol assumes that all workers were exposed to 15 fibers/mL for25 years, based on a separate review ofexposures among insulation workers (Nicholson 1976)^ iU- The original study ofretirees from tire U.S. Asbestos Products Company (Enteriine et / aL 198),^n^rte4sig?Q??^,|?asgd.pnj^^rtsmping^^Qpling, withno,ipg?fmationi on how to convert these exposures to PCM measurements. 4. .to tfre . oftfae Wlttenoom cohort (De Klerk etal 1989) might have overestimated exposures, "j^^iyiyf^'^much^ai'afocforWlO. "* "*v =*' < "*- .. iiu;.. ?,;akjni v Jv-.;"-, :. .io.-ui.-P;. -=c -.tii : rv, . The previous comments led to a discussion on whether certain studies should be excluded from (s6e mxfbriifiytediterini). Prior'fothls disfciissidiC i -for many of the studies listed above; he en^rhasized tiiat all exposure estimates appear to be based oh'a criffiMite\ietv'of'M` litbtitiiife; and rio-estfiMates dte cofipletely Sibi&ary/iis some oflire*''1 panelists' comments implied. ' /. :! Comments on using study inclusion criteriafor the meta analysis. Given the concerns : afwpkthe (q^^ty;^f^3f|!@SMte^ta ifppjttgd in cjjidensiQlp@r.stadies, th&pgneteits debated.; expmire-iTOppn^.ai^y^is.kIh!^paaelistS;^epe.di3pdedontfcmatter,; v >:; (^ ^^^^^^ ^^(pmelisfe retfomprepdeditimt foe. author^dpvelpgjand-apply study ; inelitsipn.cptepa mfoe p^srt^fiBqjpme eyfduatiqn* as;.is commonly, dpne wtjp? conducting a i;i;mef.ranaly^i^. One,{@4elish^gMP[iagapce, recommended assessing^xppaire^response relationships for only those studies found ,fOjfniye.-gd<^irafo(,ei^ using a sensitivity analysis to examine the effect ofexcluding studies with inadequate exposure data. fo^-^sug^esti^M^^-Jiiatdie!aifliMS.|pffrip4H|oposed.protocol use. study inclusion criteria and sensitivity analyses to ensure that the conclusions are based on the best available exposure data. 3-19 HWBUI0009896 s sqRBpitpd-Jjbg current approach ofusingas many studies as ^o^^ap4agBMii^^|y.<he,qm^.offli&.exposuie measurements imtheimpert^ty.factors. Qqp.{pl|f^.|^jQ(miple> commended die autih.pr5.f0r being as inclusive as ppssible,)yhen . i.ejqppsipedata sad accountingfor. these limitations in the uqpartainty fecte fta* were uitinpately used to weight die studies in the meta-analysis. This panelist acknowledged that the exposure estimate irtsome ofthe epidemiological ^ud^mi^J^|ptg^estQatie%.i^;iw emphasized .-d^trthe estimates, pie notworthless and should npt.be discarded Other panelists concurred with diese ccMnmmts, and didnot support applying overly^restrictive study inciuston-criteria. Comments on the uncertaintyfactors assigned to.each study. The panelists made.seyeral comments on the uncertainty factors that the authors assigned to each study. Dr. Berman first e^fe|jpedfl,fpui:}inqMtakty%h}ty::^-.first%:tor jy^cteraiae^ises^diecpi^den^in, , !5fSi?Sf^^^-^spc(Mri;%^|p^|3i!e5e5jt^^i(5coijfk^ies.in theponversionto PCM analyses); dfc;dittd,faptor ^4) s^;appn^^>stne jelated fertor,to accpjJnt;fojr other^uncertainties.](f.g.3}apk of. . information on confounders* incomplete pr.inaxaitEte.mcKt^ty,^scertainn^t)r^ ftepnan described generally how the individual uncertainty factors were assigned and noted that each . f3^uld^ge&qm.l.to.5.,, ... .. r^isre-.^v *,A : . -'.' s . - *: . s'''. v_~ r ;k; '-ru. The J^uffili^^ppInmen^tprima^y fopuspd pa the .tjarKparpncy ofhow. yager^rnty-fectois were pi!fsented,aEri incpippratgd jntp the instoice,.. .... jpiptn^eEded foal future; |^dfc.a!:ta!jt?}g $j(&U$j|5kp/-j, .!,up^^rttyy^c?^)rs,assigned re.pach s<g|yj Further, Qo^^plis^su^^^d^^thie^r^OTsefi ^prptocql dcribp;th.e assjirnptions inherejnt in.the.uncgt^ty:fe^j;wei^ting aj: ,7_,.spch as ;i explajmng^hjysome factors are assigned value^-oyer a^brpader range. togm,ptheFS (e,gv, why FI values span a broader range sthaa F^ya^es).and. {fesg^ing-ityhy,,^ factors have equal weights in generating the composite uncertainty factor. Another panelist .^q^et^aa|jH4^a<|dbdL tibBrtfUi^neyised ya^to9f^^hoiB^^pc^^p^kaM^.4escribe. ' . ;fac^*g-strei^.qq||idiinjed.into the,compqsite, faGtpr,gQd.how.fiiis^gompqsite, fa^j^..afiectethe ..-we^ting^of,studips?ia-te meto^apriy5%Ejt{^d^.ptyti^|>ofinhjanpfhOT panpligt that and Km*) are actually weighted averages ofthe epidemiological studies, with the weights assigned to each study being a function ofthat study's uncertainty. This panelistalso recommended tihatfoereviseddoairnentcleariystateshowi.if.at all, foe fiactiofl ofamphibole fibere'aadfoe fraction offiberslongerfoaaTOpm are reflected ihfoe uncertainty factors. * Some ,ganefcfe^^a^&e utility ptaltematepppitapfe j^|t cqiii^ be'.usal to assign..J.7.-, uncertainty jfectois.iTwp panelist noted that the approach used,to assigning;uncertainty factors is Somewhat sfojecdve,- because different groups ofanalysts would likely assign different 3-20 HWBUI0009897 1 : uncertainly factors. To'aVotd the appearance of aAitmihes^ ffae^;panelisb''su^ested:usiing altramteineta-aiialysis1 approaches that do hdt require lisihgterartaiiity fefetoiis.j;Fheyrioted, for exaihpie, that the authors could use a ; variation is estiiriateii.' Ari&her suggestion was to cohduct serisitivity analysts examining the ; effects ofirteluding or eicfuduig stucties/dq>eridmg on the liriceKamty'factors assigned to'lhem. -' ` Anoffijer paitetist disagreed with these comments aridsupported ttfe analyses in fhd proposed protocol; this panelist'indicated that the'huthors had rio choieO hid fofmairo;judgmOTts! trased on the mfixriiiBaidnfddcomKilGe^in^lffiid'i^iiictejnnS^ UteratUtiKHe suggested tKat;EPA: consider convening a separate expert panel to assign uncertainty factors, ifpanelists do not support those : 1 selected try Drs.Berinaii arid Crump: V r- , :- 1 ! ' 'esxjrosuite estimates.bastsd^dMybh^^rt i^mgef ssumplirig^andcto'riot iiidfflfehityiiri&irEiatioii soiifh6w fe' Convert these?texposuies to levels that worddbe^t^hiM'by iriotfe'Mdifcm methorb (e.gi; PCM, panelistsnoted tKat the crinveratdri fa^or (fidra^mpcf-to fibers/niL) c^v^'ctmsid^hiyfi^to one occupational setting td thfe'ifexti -* t..-:.-:; if\ s .v.'fl : <* J/'-.r "f t;*:` Y-V . ..; =?)*,: ; i.r.;\\s ' Interpretations ofthe study ofSouth Carolina textile w&rlter'Th8jpSfifelistehSddifferent opinions on interpretations of the study of South Carolina textile workers (Dement etaL 1994). ' t3fite:|smdliSj':fof instance, ftiindtiiiS'patfcular stwi/ito'belaini'd^Sriada!^ tffe`:dther : epidemidi(%i<MSiMS;'arid he rectilfem&tled thrifthe atiflx&S exclikie'this stMy;drom'fiie ejiprbSi^re^tonse anril^sis'ttrifil the 'causes for the^iricteaSedifeMv^ riSkg dKfefvedfor this . Cdhd'rfare better tindeiMxkL Another pan^ilst suggested tiiait fflfeprbpdsCfl'proliofel should " ^l^itylfe'SouthCaroliria cohort as being'exposed to mixed!Sb^dS%ber^';tritiierthSi being .5; j'ly.yy* r: ttur.s- KV/iA;. ` >'V. ' ariSlySd ;;vV';'.`vv> lii!%riin@bffew Studies' hr which cd-idcsi^il^satiiptes'&eie collectedarid providingsife-4>fecific?dala IBSr* fflnfniigBr .'r.v ...v.iiuP. t.-;;. :. . ;r, . 4>>* . ,-.q y-i r, jrt'-i' ;; ifcrf.-j'OJ irv^ftfterreviewing a drafrSf.tbis repottj-one'p for file Soi(4!TOlinajroh9rtare:avaija^le gom,m6re than just ojne rejferencp 1S^tjp.He}sugge^ed|hat EPAuse data from studies conducted by McDonald in the 1980s ofa parallel cohort in the same plant However, he to cotisiHwShet iBfi sDiiicesfdhthiH'cbhott, given that arecerit re-aiialysis ofepidemiologicai shisttes (Hodgson and DamtohiZWftliseyerdy: criticized the data source EPA uses (Dement et aL 199% tp,the point of|hqse data being ... dropped from the recent re-analysts altogether. i-2i \ j HWBUI0009898 ) 4:' South Carolina study is an outlier; he indicted that the South Carolina study is one ofthe more rigorous epidemiology studies available for asbestos exposures, and he found no valid scientific u-..pgasons^for discarding it-JDoring.fMs^^i^gussicHi, oag^ panelistpoint qu^y^reggOTgejjftiat fte.Squth Carolina study is indeed an outlied among the textile cohorts, with a slope which is higher thah dfirer ofthe two textile iKofts;'tiits parteii^ dffddckhowle^e feat the' lim|f eanfcer riskaaiohjg;: the textile cohorts is greater than that among the mining cohorts. This panelist added that, , a ;. scientists need a better explanation for why the lung cancer risk among.the South Carolina cohort is greater than that of other cohorts before the South Carolina study can achieve credibility, especially considering that exposures in South.jGarplina ^g^sj^gpsedly. tp ``pure'V ; chrysotile. v?:'-r:. b-v ..k . ;i': : ).:f - :;o:ji&u;:o;,,u.:vL': ;S& ioaStf; .?tii >_';* ,V! V. I : **T :h'.- ? -..Fj USd* vf'ttM?-'. Sr:K*,Vj .-iT ai^v-rvi-w. S.& V `Sue; fu hrot ; ;;r--x-'yuii.'i &>.-;<; y.r ' ' -:L r rw.i '.-.a: .>?!$: .. =? r -A :*>* .;?& {tu&ti/faSrx -> V.V.. SL-'n zi'S! iZ&Z-Auih f *r!.t >. ! >r-, liv; . " -(lr." . js-i::f? ,:V rrf; ;:i i r:; .-liif.v ><.:v ..iM'Oj-,-'. ` i-f rdh;! r ;." :ijf . . i o; .py \ ;.v.: ...y .aotU. i.-rs* \ ,.L: .. W.ul 'i/si-' `O..!..?>; .vv4d-:'>'0:H : v ! . ;Kk.: * "to',-,.,. o4 ? \! 'iwrj-. ^-nths'-f- .}v..v w1 /. -:t-" ; -'.i'?1 1 1 : v. yyj-r-i 1 w-.:' : ' 'CjeRVM.'X; :.V./T a-'- i!i- -iVi'cF . *. s'lV-'4 - s:~ *& ji9o--vjav s-. .* 'u aS.i;' -jW.i a<r -,-.-.-r,r:Kdi.. = .. i;:h Mv:.' ;;i*> : - ,n;;; s>."'.s aiv ohrrt:.I-.fjn ;srs'r't iHnv-Y.nu .:!? v-ouuro.*:?- :>< A Si: ,f *)p- -i--.i.uLjft:-.; s.-ire-jrjii<?ai.'.-:7-i5 fci bii;: .') y:.;;o-'-v: ;r. _rj:. w.-i .`Iw-.ars- -iVi.-rcsO '".U'-vog.?:....fr-x .. Vi 1 .:.( Jim i ;?!= ' >'.A *';v iv'i ArivB. r'A?-..- 3f22 HWBUI0009899 (i,; ' 4; COMMENTS ON TOPIC AMEA'7:TllE PROPOSEDfEXPC)SlJRE INDEX \ 'y ;.'t - . I-;V-:; r:*.'# .'> ;'Pi / ! ' b';' _ ; Vi Hii*. ' i .:V V .v.: Hus section ^akri^mriSi^&:|melists,' responses to the charge questions jkartaffiiijng to the pitopSsed 1 !.: .-.'JO: exprearq.index. Section^l^^ andAi doeuinent tp. ctarge questions 4,5, and6reSpfectiveIyi..'.iir-.-- - -i'C *= v 4.1 :HMports'ssT-Gh1rgie::Qn'estidn'4''; r ' sxvr. ,;b-r Charge question 4 asks: `The proposed exposure index does not Include contributions fiom.fibets shorter than 5 pm. Please comment on whether the epidemiology and toxicology literature support the conclusion that asbestos fibers shorter than 5 pm present little or ho carcinogenic risk." The panelists discussed tins matter earlier in the workshop (see Sections 3.1.3 and 3.1.4 for these comments), and provided additional insights on the matter. Overall, the panelists agreed that carcinogenic potency increases with fiber length, particularly for lung cancer. Most panelists supported assigning no potency to fibrous structures smaller than 5 pm. Some panelists agreed that foe short fibrous structures are clearly less potent than long fibers, but they had reservations about assigning zero potency to the structures smaller than 5 pm; these panelists acknowledged that foe toxicity ofthe short fibrous structures might be adequately addressed by EPA's air quality standards for particulate matter. Specific comments on this charge question follow: . JP . Reference toATSDR's expertpanel workshop jon.the role offiber length. Two panelists noted that ATSDR convened an expert panel in October 2002 to discuss the role of fiber length on toxicity, and much of that discussion specifically addressed fibrous structures smaller than 5 pm. A main conclusion ofthat panel was that there is "a strong weight ofevidence that asbestos and synthetic vitreous fibers shorter than 5 pm are unlikely to cause cancer in humans" (ERG 2003). The panelists encouraged EPA to review the summary report prepared for that workshop, which was officially released on March 17,2003, and is available on-line at: www.atsdr.cdc.gov/HACyasbestospahel. Evidencefrom epidemiological studies. One panelist indicated that the epidemiological studies do not provide direct evidence of the role of fibrous structures shorter than 5 pm 4-1 HWBUI0009900 However, the panel& iadicated. that agrovring body- of evidence suggests; that the. cohorts predptonaefly closed to sh<>rterrfibgis;(e.g., .fiction-brake workers,.gold ndneis, taopnite miners) do apt five, statisticailyjagiyftcpat increased parrcer risks. Tbis panelist added.tot.the . mecbajM^c. studrK provide to stK^gt eyitoice:fpr assigning nppf^^^.j^ipp.st^tuies (see next bullied item). Another panelist agreed,with these statements, that Ms interpretation of data compiled by the National Cancer Institute provide additional indirect, evidence ofshort fibrous structures presenting little or no carcinogenic risk (see page 102 of the premeeting comments in Appendix B). The panelists briefly revisited the findings from a recent publication (Suzuki and Yuen 2001) that reported finding relatively large amounts ofshort thin chrysotile fibers in malignant mesothelioma fissile. Several jpanelMs eitdbura^dtot-tose firidiiigsMbt bb cdiiadeied in Me risk assesstont j.;,methpdology-toiB^sons.eited earligpm-to e-rfjfi . : 'different mtetpreMtfeniS^P ; :r fibers are cleared more readily than long fibers from to alveolar region ofthe lung by carcinogenic risk- This panelist acknowledged that extremely high doses ofparticular matter and other non-fibrous structures can generate biological responses (e.g., inflammation), but he doubiti&ftot sU^i "oriMbad'' conifitiidhs woMdto'relevmfto tKe'enMfiitoenM'sSiqkt^iTO that '^tHfepfipdredprotocOl'willtoiisbB tobvaluafe: "-"-s ' ` ";h '' ;v - . vk>.- ;; v ; ^Mrotor ffehMist that tong fibfeisraretelearlyrii6te potent than'tort fibrOtis stmctoes, but ' to'athblfiioh tot sfibrffibrofi rinichlfe'tovertoimpactwitoiMogemeirisk. This pahfelisfnoted ihat m&liMiMc sredife' haw'defioMtoted that toritoro^^fiicturbs and : tototojg cMriiriOTts, tot ekpomibtotorifiberstoidd cause^inflamtotionarid'gefieraton of ' d?ddMfivif&ies that increase to1 (gspbnse-td long fibers (see tiellnim' e^all! 20Ol)f- 1 (J&eritotKispanelist dcltoriiledged'tot ldng MMs'-arb mdfepertoeht-sfiMtdtoMlnThe lung and should be weighted more heavily in the r ! - ^ the short fibrous stmctures zero potency. Impiic&ite&orismtplmg antikkatytidhtmeih'd&sJ(MepaneKcommehted on'th^v' (jracfiM`iri^lKatioto!tom%'stitoi^pbMpticfiieKdf ahybhtM^to'to te'd^'JMis "`psanelistlrfidipaa&cl tofrfteaMmng all fibeiS in; envMrintorital^toxiijles wdiild riBt only Kexj^ilsiVb, butals&wdmdtotoTMTM^' ^fiifivity thaanafie'toost-preilldClVe^JcSftocer'Hrid Thistoitost' fto3to\todgbd tot human ekpcSSre is predoiTiiharitiy tefibrdus striMfres lbss'tori: 5: pin,1 but he noted totto' itobiMts'dfshbrf fibroiiS sttiictures;retiiiried'by toititng tend toto:voy:strohgly 4-2 HWBUI0009901 corrfelafed Witlffee am&iirits of long fib&refamedTiy the hirig: Due! to this correlation,-this panelik iiM^ 'te me^imji'g iorig fibdiswife sufficiMit acciiit^cy would allow one to estimate lacnoitiits of short fibfouS striiStures in a: sample. ^nu^*^eu!iefis^:radd^^tiovt^vdi^'^a-lie'Sees no ` etqposis''^fit^iMy stitictfii^ smaUCTftiak 5 (im,^ventte conclusion fiifit'such fibeis tib not teu^'fcitictir (ERG 2003)r ' ' " ; .* .O'-'. V *. -*.*;'*' 1 *-i'*: t| * 'U**.-. .> ' /- : . ' I.--.'*'.' \ :'.c:V r . . r , i r*. - - . . :V - ' ..... 4.2 Responses to Charge Question 5 ; -u.l\ Vfj/'w Cfaatgequestion.5 asks: `Theproposed ejgjqsure,^dea; .ip:v^gighed.:lr^yily by fibers longer thrnJO |ua Specifically, Equation 7.13 suggests feat tbb barafi<%emc potency of fibers longer-than lO^fiirfjiHnore V'J difference m carafiogaiSc ptitent^ witf3i,t.fVieo^leptfl j .- :!'->'=;f:n --n :*;r respoi^jtp thi question follow^.,- . = a r-.` %!? : : ` s/lv v': ei.-.V.'! - vit - sy.i'J-f = = -f: ? f'Tbepjtii'elBK' ;` >;- ,-;a -. . -. v.i .of i..- Ji! .?:!!.;q.: -.oigOtOtf: v iiGA .^ax.-'i'-:.' .IR&PgjeS8*J^.tbat fee original,, } epidemiology studies did not collect .provides direct evidence ofthe relative potency assigned to the two different fiber length categories: fibers longer than 10 pm. ttetfEp^cpiisidef-tiie results 199lVthajffifflis^ feat naesot^ellqgEC^ijb^s^s^p g|Rtoj^ipjd^di^k tyifeteuger anrounts : ,....between-5 and.,10 pm) letajp^infeeir lunj^^ofoerpanelist.^as notcqnyincedpf^fee.findings ;. from.feis sti^s ^ue;to po^ble biases,%jm^i^ti^o|cpntroJg;ncHt matched for hptj^.of ,. t^gjnj.Ibls. lung-retained fiberstudies (e.g., hdpPqpaMet; .aLbdSgp, J^^lsgpig.er et aL l^^featfeaveieund;that tficinajonty pficancer ; a* viislc.'fi)nisi^pfeeiy[op]ta'i attributed tq..e3q3q^ire^,tp.Ipnger-^ibets, even.Tdrert i;; ^ortjlbeis^;^epintoacpopont. .. \..,;,,,,.Vr.; of . -y^-i >,. 'Vi<*!*' Questions about thefiber length-dependence usedfor mesothelioma. Some panelists. literature (^gmaqndS^-l-) suggests. is most closely associated 4; -^th-e:^,.5;andlQ jimjiQng. Heindicated thayte assessment,is . consisten1;-with(pfe.eti hujjaaiijlupg eyaluatipiis.(e,g., Timbrell eta|,;i9,P)> vyhich toye.reported /.. : feat.fibers;iptaind !by^jh^g.tend,.tote4opf fe^ri fibe^,that.tr3nsiocate to fee pleura.This s panelist added-fent the epidppiiologyiliteratuie clearly suggests that lung cancer;and , 4-3 HWBUI0009902 " mesothelioma have dyiereriljjsk <aQta*,-.asti^jejftfive,^ountspfh^ an4:- . :. mesothelioma cases vary considerably from one cohort to the next Based on these concerns, this' panelist suggested that EPA; cbsteider developing sqjafaiefibfer lengfli weightMg SiMfries For . Img-canepr.and.mesoffreUoma... , . . , .otv! ; Anotfto pairielist'indicated tliaf flie!piderifroidgy provide indirect evidence that ' qaroin^enicijotengf^pears toincrease yfith Ijberlength, Specifically, he noted that. th$ studies, consistently show that mesothelioma has a very long latency period---a trend that suggests that dieWtfet d&bfe fibers (Lfei thdFongfeflbdrS) arettid mosi pdtenfcTheparieli&'aidded'that the analyses in duunposod evidence pfflQ^thelionp.ri|!s^....-;.. , increasing with fiber length: when die exposure index was used in die mesothelioma model, the proposed risk assessment methodology generated an exact '; r^jharfiSii&liy winch'mesotfiehOma is ifiduc&i' Mffieri, tme ic^KEKihec^bbut'Mitafiria^'i^fQ^nEiucli froth a-sihl^e (Timbrel!eit al;^19^); given fliat many'additidifiM^S&idieS' hirePavailable oh tom'&ifiii^dai&'Fiistj'oiae hoi^ltl&t lfie:wei^itiiig fiittors Ware dlitv&l'strifcitiy based on liing caters bbseW^'ihlalfefaiBiy aniffills,'fi{df'Be'qifeSfioned whStehofie^caii asst&ne that didiTOfi^iM ferfors can Bfe-defrasibly af^fedfe'ni^^eB6iha::Sdd6ni3, oilier piSfe^'hoted that extrapolating the weighting factors from rodents to humans also involves uncertainty, due to ! mter-sj^i^''m're^irato^^i6myi`rhacrbpKag6:si2^;`and s'itS'bfiliirig t^&rs. 'opfiiiS!liB wei^itihgScfrftS^applied doditf&eht ft><L*iw lehgfii cat^gtStiesrisingflte ailai|able `{isfiig'die'3ata 'coihpileil iri'Tabfe pfopo^protbbrit wliictfpres&i^^tinia^'of the - 'ci>fisidCrSeriWrigreparaWweighfing?4idbiB fbrlui^tlamc^aridm^3idM6ma,!Affierithari assuming the same fiber length dependence for both outcomes. -J<:; x'i . U:.' . .(::-i-;r.`V'- - iSf'.-s:si` - :- : itv-j'.-'f- ;w! ' !. !5; . ' ; ' 4.3:-;. i.-Responses.;ta-GhargeQuestion :t, K- . I 4-4 HWBUI0009903 Charge question 6 asks: Please explain whether the proposed exposure index wiU allow iheaningfiil that occurred in the work place." The panelists discussed several topics when addressing tbfe'cjuestion. because somp panelists had.different impressions ofwhat the, question was asking., Some panelists viewed the ^^ohhs askiti|'a!x>uttiie vahdity ofiow-<fose linear extrapolations (see Section 3:13 tor more infonnafion,om.this topic), and/itoers viewed the .question as asking about whefter thg proposed methodology Is ah improvement over EPA's current riskassessment modeL Asummary ofthe1-panelists' specific responses fallows: ,, riIstke. prop0sedexpqsurem4ex am improvement to asbestos rh^ tmessme0?y^n m^pi;js anipqjpaiyepientOTer EPA's 1,986 asbest^ risk modpls. These paiidisb.-a^e^diat the proposed approach is more consistent with the overall literature on hed^ jrisfeastestos, which show that cancer risks vary with fiber type and fiber dimension. Two panelists were hesitant to sail ^pg^^a^roachaiLimpro^^giitfor^Y^o^l^.'toegblheliorop risks, .....because S8camcepdp|a m,ahrojafei . ... -These.panelistsyvere paflSculariy.cpncsercjed ^at; thepn^sgd methodoloa^/mi^hjassigq lower risks %me^theliomain.<?ef^.cuqnqnrtan^.becauc^|bf.^^la^hdependmce in die. i :;. .nredKJdoIogyjis not based qn.anytoxicological,or ^ds^ippjp^cal.stodiies.ofntPfthehoma. Pqes i exposures to environmental exposures? Some panelists commented on the applicability of ..toe proposed trisk;assessment model to exposu^^3!5in the ..j-ocpupat^^sti^lip^ .Refenjngtofgbs^eritomipento^ panelists iridirat^ ^^rome ^yironmentalpcpostires in.areas;wjto^^ do not appe^;to,b!?!fi9^i!%to^y lpwei^than too^qjqwrienoed.by oc^pafional cph<}rjig..; .^otoej.pmefe agj^^toidcautiph^.'^ufdi^gi^liing OT^dptotrrent^exppstaesffi^n ,. ;occupationalJtgtosuresijhp.insira^encoikagejdiPAmd.toe,panelist^ toTocuspn.toe.^josure magnitude, re^rdl^s^ofyitoefeer it.was experienced in aniOcsopafonal or environmental,setting. One panelist recommended that EPA investigate how cancer risks for lung cancer and mesothelioma vary between EPA's 1986 model and the proposed risk assessment methodology: for different distributions of fiber types and dimensions, does the proposed methodology predict higher or lower risks than the 19^indi^-'1h^Btoitiah:mdic^d'te^t the ' proposed methodology, when compared to EPA's 1986 model, generally predicts substantially higher risks for environments with longer, thinner fibers and environments with larger amounts of 4-5 HWBUI0009904 amphiboly,fibers andspredicts sometyhat lower;risks for envitonments with shorter, thicker fibets and environments that contain only chrysotile fibets. One panelist recommended that future revisions to the proposed protocol include sample calculations, peihaps in an appendix, for the new methodology and the 1986 model. ' . i-ji. ' J'C..-: v--.t. -.V;*; >* h. . r..." . U,.'.' 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COMMENTS ON TOPICAREA 3: GENERAL QUESTIONS This section summarizes'the panelists' responses charge questkms 7-10 and' 12' Responses to charge question 11 ace included in Section 6, because this charge question sought the panelists' overall impressions ofthe proposed risk assessment methodology, rather than focusing on any one specific issue. 5.1 Responses to Charge Question 7 This charge question asks: "The proposed ride assessment approach assigns carcinogenic potency to individual fibers and to cleavage fragments (or `bundles that are components ofmore complex structures'). Please comment on whether cleavage fragments ofasbestos are as toxicoiogicaiiy significant as fibers ofthe same size range." The panelists raised die following points when responding: Terminology used in the charge question. One panelist took strong exception to the wording in this question (see pages 30-33 in Appendix B) and strongly recommended that the panelists use correct terminology during their discussions. This panelist noted, for instance, that cleavage fragments are not equivalent to bundles, nor do cleavage fragments meet the regulatory definition of asbestos, as the charge question implies. He clarified that he defines cleavage fragments as non-asbestifoim amphiboles that are derived from massive amphibole structures. Ibis panelist was concerned that none of the panelists at the workshop has the mineralogical. expertise needed to address issues pertaining to cleavage fragments. Another panelist echoed these concerns and agreed that this charge question raises complex issues. Significance ofcleavagefragments with respect to human health effects. The previous concerns notwithstanding, several panelists commented on the role ofcleavage fragments in the proposed risk assessment methodology. One panelist, for example, indicated that there is no reason to believe that cleavage fragments would behave any differently in the human lung than asbestiform fibers ofthe same dimensions and durability; he added that this conclusion was also reached by the American Thoracic Society Committee in 1990 (Weill et al 1990). This panelist acknowledged, however, that expertmineralogists have differing opinions on the role of cleavage fragments. Several other panelists agreed that it is reasonable to assume that cleavage fragments and asbestos fibers of the same dimension and durability would elicit similar toxic responses. 5-i ) HWBUI0009906 Review ofselected epidemiological and toxicologicalstudies,.^e panelists l|riefly discussed what information has been published on the toxicity ofcleavage fiagments. One ,-,^pane^ indicated tot;Apgendk.BJntte.propos^prqtpcql,(f^^ges 8^3,Jferou^.B7iO) . ^jjapipreity iiesute. &orn,ai) enimal studyjj^yis et $(,, t^l).tjfafce\^^^ !_ ;.tpnc^te,s^ples; jtoduding some that \yee primly deayage.f^^ ijgp(i$|igi$ed . .. that the studtygrovidfiS|e'wiidence that cleavage fragments <c^^^i>s^^HBSC^b^ila^.^.aiDuaii!il^.' " . ' ' '- . .-'V'. ' ...' ' '' ' ' '. ,-'a--: .\.'V-1 .'`i'iri'i *.. "/:. . . j^p^-can^^ for ..;^5^al reasons:,fhej^i^.;was not.^r reviewed; the fitejme^iH^e^lsip^jStii^rreportedly suffered tan pooc^nxiicibility; and themesothehomas observed j^th&g^^^thave reflected use p^inttffeiitt)neal injection model as.l|ie.,db5f;.,s^bc^^5|n^!rnj$ttiQ^4|^s panelist recommended that EPA conduct a more detailed review on die few studies that have examined '.n-- c, P: v.vn? >t, H^ v- ivvr ...`Vj: w* VM : .: ..-vjs.cci U* Jx V&. U ` .((McDonald .etjal; J.,78); he.ppted .that a pending.p^ticatiorrpr^n^.pp<jajqd risks among the (aconite miners. Practical implications ofmeasuring cleavagefragments in environmental samples. One panelist added, and another agreed, that measuring cleavage fragments in environmental samples presents some challenges, because microscopiste cannbicdMW^"'^^ fiagments from asbestiform. fibers, even when using TEM. 5.2 !:: Responses*! OKargtfQuestion 8: ' !' f- i r.:.JtA %ai$'($estibn''8 'asks:*Tle^ Comment bn whether the proposed^c^cef:aMSsttlmf approhcMs v ' ' relevant to all amphibolesfib^i!,df only td'^'^'Fyp^'dfari^iljti^^^ (adindlit^f aD&osife, -v: '<!??. anfhophyllite, crocidoSite, tremolite) designated in federal regulations." The panelists made the following generalcomments^response:v *" 1 ' ip-r.yti lR `Meview'dfSmdMkPfidtniojdcol&gitdi'dnd'epidemidiogicdi'studiesl^Dst'pMe^sls1 - identified,fe>y(Studies. tat.address. the .tpjtiqity ,ofmnphibole, fihqrs. pther.,tha^,actinQlite, amosite,v aidhophyllite, crocidolite, and tremolite. One panelist indicated that animal toxicology studies ' "< nis^^Hietih'vitnnhi/:fihiri with'frainir dMfktrvyU' lslndthhaavvirkipig'.s^iiriiitilaarr durability and dimensions, generally..qxhib.it similar pqtcy for fibres^, jung and . >... . mesothelioma. Another panelist added that lung cancer and mesothelioma exposure-response 5-2 HWBUI0009907 relationships for a cohort ofvermiculite miners from Libby, Montana, have been published for 'Approprwteriess &f'applying tBefitdMidio it&'k^dsbesiiJ'Sfm nmphiboles. Several panelists ag^^ti^&'^^^iis^iSsi^neiifmefliddology is teleH^nf-to-ampKibole fibers other than Tpanelists noted that/jn tffe Sbsence 6f more detailed inibmaatiofioh the imty0t1sfpmddiit'8fc&tjiiier:tfiat flxbt^dittdiniena&tini durability will exhibit similar toxic effects. Two panelists expressed some hesitation on applying the proposed model to iifepaneh^asktid hoiv C&nfidtintly one can ai^>l5? diedOTceriask &effidisits fo amlfibofo'fitesfiiat have'iid^BSeii'stikUed, and another jikiel^mdifclded'iK: was not coriitihb&'fet-ftte inddel shoold bb'a^SBed to the other" GWfefhe aitabtifit mfit,';dhe par^fe. suggested u^t{^Jflie|)ropiSs^pidSl^lSi^^'8hk%;br'n.on-asl^tifoSirii am^hibiSles beuig evaluated are asbestifoma amphiboles. V- ''/''''o.'''-- ' 53 -.mVj.v? ,.i V;'0 r:; w <.C> }fyi! .*',, .. -. \ ,V;,. Wv!'5..v. '`bljS:' S&l. Charge question 9 asks: `The review document recommends that asbestos samples be analyzed by transmission electron microscopy (TEM) and count only those fibera (qj-bmlLes)linger than 5,jmtl : Such counting practices will provide no information on the amount ofasbestos fibers shorter than 5 pm To whatextent wouh| datann s^rter.fib^sm.^i!les.be usefid offoecal^;ri^:asses^e|l;ttnd4lpdolqgy,.as^s5^t.,q|np^rcanceciHndppints)?',... jj; n!; i" . :i.V5' -yi-.O'; The panelists expressed varying opinions on this matter: some panelists .); ; ;. fibrous structures shorter than 5 pm, based on responses to earlier charge questions (see Sections 3.13,3.1.4, afld'4.1); otherprmefets;|^tyhere-is;^>me.utifitylg;TO|lec%ginfoEmafiQrt.on s shorterfifedtibsfeMjres.-partiadadyff'tfae:^inmemmlal'Malyfical^fcdsfe^ate^ipt'piShibitivelyexpehsive : ' -.Mrii? ;= !.S:V'.vV'. 17;r liKYi i?.?'-: 'T.`\ t-il' ' QfdotoOM'bi.S vJRilrthTV\>`.'. and ifcounting short f(hers,dogs.not CTjn^tqmissaspttate CTJtrotepflpng;fibers.;.ThepanelistSjiaised theiblfowitiigspecificissiies*inte$fitf&v; ; ' ; " 5-3 HWBUI0009908 recommendation in the proposed protocol ofusing TEM, rather than PCM or some other method,'to cMract^^ future emphasized that future measurement methodologies must focus on generating accurate counts oftire most biologically active fibers, or fibers longer than 5 pm. analyzing samples for fibrous structures shorter than 5 pm would compromise analysts' ability to accteafeiycoiirtt^^the:rtmc^t^bfldi^dr'ffl>ets'thMaie'6fgiea^biolo|icM:cdh6enL Sbme * r: associated wfocqimtmg fflbereinimil^le, length categories, including shorterthan 5 pm. The panelists did not cite firm cost figures for ifiyasahalyses^Howevei, notiiig that'Oaitifoiniitentel sai%lesTypicaIlycoiaaln''mbfe thari<90% stunt fibrous Structures, one papelil* trakbuiwuu^uiE.apyiici wuuiu .. .. considerably increase the time a microscopist needs to analyze samples, and therefore also '! fire analysts! XpaiiblMindicafedl'tfaat the b^ts and'^^M . i benefits qfbowtipg.fibqSr^rte^tim 5 p^m^t bejapp^^p^priatelyjttebatodbetwgetijj.;;.,;;.; microscopists and risk assessors, with inputs from industrial hygienists and mineralogists. exposures to fibrous structures shorter than 5 pm can contribute to asbestosis in occupatioiral|y exposed individuals (Lippmann 1988), but he doubted associated with asbestosis would be experienced in non-occupational settings. Another panelist any, on these other non-cancer endpoints. Dining this discussion, one panelist indicated that the tojficityoffibrousstructuresshorter than S'pta mi^frt be adequately adtiresse&by EPA's" . p?uticula^.nratterstodar^;|w.{.: .... ...... . ... 5.4 Responses to Charge Question 10 Charge question 10 asks: "The proposed risk assessment methodology suggests that exposure estimates should be based only on fibers longer than 5 pm and thinner than 0.5 pm. Is this cut-off for fiber diameter appropriate?" Before the panelists responded to the question. Dr. Berman first clarified that the exposure index optimized from the animal studies (see Equation 7.12 in the proposed protocol) 5-4 HWBUI0009909 assigns a fargreater carcinogenic potency to fibers longer than 40 pm; with diaineters'less than 0.4 png he noted that the proposed diameter cut-off(0'5 pm) vras based on an ad hoc ac^ustment. . The panelists agreed that the proposed cut-offfor fiber diameter (0.5 pm) would likely include most fibrahfolikKd&'ooliicam^*li^i9i^v<^im^^teo*'u^Ai&ck%i^y agieed^t die exposure indek sfeuld not exclude thicker fibers that ate knwn.to be.r^>irable in faunpns. The main .argun^.da.( given for inereaSh^tfie cut-offis that fibks withdiameters as large as l.5 pm (or wiforaeatodyfiami& diaihetersas large as ,4-5 pm) caapepetrate fo, smashing airways in humans. Other panelists proyjSed.pddftipnal specific comments, gehierally'su|^ortfiig Lrtchrsiori ofthifckeir fibers in theproposedexposutehidex- One panelist, :forexample, adyfced.jagaii^t|>asfog the,fiber diameter cut^ofTstrictly, on obperyatioiB fipm rat inhalatiAft Stridies,' due tri iritef^q^ies' differriric^ in respirabifiiy; Further, riotfi^lMat die proposed cutofffor fiber diameter would likely exclude some amosite fibers and a considerable portion oftremolite fibmrthdi'kriown (SrrimogMb^ten^, another pahelMericbiifag^tlmt the pibpted;expbsrire index .rw v. : ..r;';.,noi.; Y:`i 'V.'-'-.-.i.-r-': .-oil: r->- ;.:oi - The panelists, noted that coasid^ratiort t$$cec than 0.5, ptp vyas sriewed a^ beipg.most important for te iuii^ i^&'ns^&steOTentttSdeh- ais risksfor mesottielionia S^teaftdl^ more "V -i ; ;V- ' veto \ . closely linked to exposures to long, fop fibers,(s^,Section.3.2.3). Further,, some panehsts^uspected that increasing the fiber diameter cut-offin the exposure index should be accohnpiffiied by fcMihges to foe exposure-response coefficients in the risk assessment models, but the panelists did not unanimously - .agree on this issue. ; .Sr'r:-j ' ;s,:i .- ` v -ah >..: v yj/,-: ' ./ .i - a- - . v ... 5-5 ` '. HWBUI0009910 Vt '--? . / .;<.- 's'dS'fifr/l (ghaige questioail2,as!s55 "Section8,2 .ofthe review document presents ,three options for assessing : cancer risks from asbesjos exposure. Pie^fiomrnent.qnthetechnical merit offee proposed risk, assessment cations'liThe panelists.brieftgjreviewed die.stiengtlis.and syealanesses of the three options, presented in the proposed protocol for assessing asbestos-related cancer risks. The panelists agreed that the first option--direct use of EPA's lung cancer and mesqtfaefipmirisk.assessmmtf :. , . u , a models--allows for die greatest flexibility in evaluating site-specific exposure scenarios, particularly this .option teing c^ext-into. The one issue discussed in greater detail was how sensitive predictions using the first option are to the HWBUI0009911 6. COMMENTS ON TOPIC AREA 4: CONCLUSIONS AND RECOMMENDATIONS This s&fion reviews the pariehsts' individijai conclusions and recommeftdations residing the propose*! pmtocdl (Section 6; l^dswdl^ how die panelists developed &eir overall corfelusidns" and ! >''be'. iectihunenditi(^istfiat aippeMifrthdOxeeiitive suiramaty of 6.1 Responses to Gbafjgti Question 11 :.-V! s. OSB^psKn ILSsfe: -Diksilss-Wheffier the iftoposed cancer askssntenfctippriJiich,'as a wfiole,' is5a reasonable evaluation'ofdi&avMlable health effects-data. WfratlispScfc ofthe propds^cahcef 1 ! asse^raS^s^ix^chi ifahy, are incdmMeht with'flie epidetfiiology oftoxicology literature for,J:; 1 asbestos?' The paiifelists Offered individual sumim^;statem^ hot*distossedorddbated; i among the panel. Following is a summary of the panelists' individual summary statements in the urddil'; they were given: onjcieyj|lppiiig thepppo^d risk asspssnjtent prohx:pl,and,puKtQ5^1;u^e ofgpaod^l that. , accounts for die fectors (e.g., fiber type and dimension) that are most predictive ofcancer risk. ^JM^LjppmaM^ppoSfed^e aiffidis' atteriipt to' make iM\i^'hPtfie:e?^tiiigdaftifa&fl to ' '*r: fipj^^e|pijfcmiolpgical(studies. He stipp^3yecwgirn^|cle^make every effort to obtain imhvidual-level data from additional epidemiological studies. Dr. Lippmann : v. - eyaligte:&euncp|ain!jes in exproure^rasurementsfrpml^ori^pceppat|(>nal datasets..Pr..^-,.. V <>aw*Mn mMMna^iL4 am ntt'namrAW^n i<*/fl/'tAW t-A AnnAatot am nntnlAl (nKAIrtflAn (dlinirlimnfr Overall, he encouraged that future work on the proposed protocol ^tinu^;thjjugh use of;>; additional expert panels, to make more informed usage of the human exposure data. Dr. Teta*s summary statement Dr. Teta indicated that the proposed protocol is an impressive integration ofdie animal toxicology data and the human epidemiology data. She commended die authors for developing a scientific methodology that successfully reduces the variability in results across the epidemiological studies, suggesting that the studies might be more consistent than, were previously thought Dr. Teta recommended improvements to the meta-analysis of 6-1 HWBUI0009912 epidemiologicaf,studies, such.as establishing and applying criteria for.uge, ofbuman.data in chruaderizihgexpasurerrespoiise relationships. Overall,-Or.. Teta fpjinrhno. inconsistencies between foe-proposed protocol and.the larger, body, ofepidemiology literals!, including.studies ofcohorts (e.g., gas mask woricers,,iailroad workers, friction brake, workers) that dopotfanve well-defined exposure information. Though not disagreeing with the utility ofother, panelists' ".convening additional expert panel%Dr. Tela encouragedEPA to move forward expeditiously w^eon^tetmgifbe|eposed protorol anddiscoHragedimplementing.addifipn4:sjeps that mlg ..delay, the overall.piojfect -.iv ...... . r v; ... "i' . >". " .' .. . *?'. .`l.-i.0. Sr. Jfoei%summaty,statement. Ehi.Hoelendouraged.the use.ofntorejSpp3ti#cated;modeliBg ( exposure, cessation ofposurft.amd imcertakty!mexposnre->P^Hod,aloisttpngSy;... ,:; ,; more ofuwiertpiq^-rTo ensure Ihatfe lung cancer; model is, not roidounded by-oig^^ ^oking^Dr. Hoel recommendedthat I^Bamaa and Oumpmopajelr^ly evduate;.#.ayailable;d3^yah the interactions between asbestos exposure and cigarette smoking. i'frv :L:A.i- ;V:. .?.s.v.r'.vi'V,v.v. nr':;.".::*Ve...V0 Sm Steenland.'s -summa^r, statgme?ii, 'Tk-. Steenlaird indicated. that-the proposedis a ..... ,f ^..forward, in asbestos risk ^essmenhh.owever^heted^yeral rfoornmendatior^ for,. imt^ying:greian^ysis;Of:epidentioSogicd,stotfies;JiorinistandeiPr..;S.tO!S,n^d;u^^ted-,j|iatthe ;..authOrs'rtot^u^jtoS^n^ressfon analyses using;tte prig^vexp9S^r?^gB?!^ ?gpfkrifei in y#Qhrpredictpriyai^te.mdudeffl^sire,.^^;type,',foeestima^:|^enfage.>i[>faSJK|!fbtoies> - ,.pe.r^ntegetoffibengi^teEtiianJp!iin^and:Sategorical groupingpfstadi^;accgpiing to.quality. . ..itasis. cnjho^|h^)!!^lig^4n.t ^^iUyS!H?mg;r>)ayra>iciu.icisuiJJ4ucS;0E`t.. ^i?sr;lXlttciesassig)^.to,dyifiFOTntfiirer;lOTgfecat!egopes;Optimi|se thempdel's,fitito;the q>ideiniok>gicaldata. ^-o.- v&'h; ;-..-v?w-v;'.->ri.; A: J- / rco'- . ., u ,.; ,j(,l?octising;!m.speeific!topics,,Ik. Steeplandmdicated that-he disagrees witfcthe.'apptStachQf Js^tg)Da^fl^an^jhB0b(^B&J^^sjj^5ng.jtip^:gisa*egn||sg-aipe-f|S^fi^r than cb0so,fflefi^eis, . :;; :.ei^WyiPsi^pg:tiiat foe:statistica!,^salysis,jn ;hypdtij^%.foatitpffiWfxjfofiber? and .chrygotile: fibers-ara dually.potent Fuifoer,d|e,adyopated .. ^^",;a^tion.pipxpioHng;foe,ade^cy pfofcer^^^xposurp,response modelsXegj.non-hnear hi suspected th# cigarette sinpkinglikely,w^;P.<Ahe?a;cdnf0pndjing :,_j factor: inoxppgire-resppijse amalyses JFor two reasofis.rFirs.4ihe noted tbatdrffereriGes in smoking [^qtices;!b^e^.dtotkhae- populations and general populations typically do,not cause 6r2\ HWBUI0009913 substantial differences in standardized mortalsfyiatias.' Second be indicated that it is highly unlikely thatprevalettCe Ofsmokinpvaries with' workers' exposure levels. Dr. Steenland. - encouraged that EPA referto a recent publicatipn<(Liddell and Armstrong 2002) for similar "insights on uiteractiom between astetos: exposureand cigarette smoking. . i-'.. ' -or.: ori-.i: .. `Piv-.v -\i Dr.'Crape's summitry statementlk: Gra^'Cdmplitoe^ed Dra.i Berman and Crump on : preparing ttee t^cerrisfcassessment methodology, andihe suppbjl&l-the^general approach of ex^i^ing;'caiic0rtislc!as a function ofasbesfos'fibertypeafid Itb^'dimbosion I>r.'eiapo indicated that the proposed protocol reaches several defensible conclusions; such- as assigning greater mesothelioma potency to amphibole fibers and to longer fibers while assigning no risk to 'fibers less than#gm in length.However,1 he was concerned about some specific issues that are " not yet adetjuat^yresolved. FOr instancd,'Dr. Grapo feltadditional-date are needed to rigorously definehowmesofoelioma (Le.* fibers longepfiian 10 pm;beiog'3dO"tirii^ 5 ihd 10patf).rBE'Crapo iecoifintertdedltijat EPAj v^n-fcvismglhO plropo^ pibttidol^exploie more sophistiWited . threshold' effefetsV.He'i s'-- "elqa&aiie adtdv - - ; ` kr- -b-i:.; *.v A'i- Dr. Sherman *s summary statement Dr. Sherman first indicated that she concurred with stetements bn the proposed exposing index^ recorfimeriding that DS. Berman and Crump use theqpiddouold^data'to finthCT investigate ofiibr forinuMoMefianrexposure Index; E)r. exposure aMBSs shatter- 4jMf40pfti)V'Furthef,3she recortimended-thafthe ahth&re' a'tterrtpf tcMCjptlb^b-ttt6^bl^^!W^ili^^3cto(b.in-fhei exposure index to thfe epidenuologieal data.' Finally- given;that j^eliste'eXpr^Ssieoricfeniregarding how ' and CrumpctohsKMpde^e{6pl%:t#odiffefeiit:ej4^s^!^~^^dptiifiiaedfor'liingGai2ebr, and :dte ofoe^fof>m^dfefi0ii& Df.-Shrartriaii added that^&'geaaeraaiygi^jported the Ihhg cancer and.mesbtheUttnrta%xpo'sufe;ipbiise-mbdels,'a^.'<pfesfibh^:jdieiheiiusifigmorecompficated models would necessarily lead to a better understanding of the data. - - . . . . "Df. Castmnova*s summary staterHentDiFC^Srmovk concludedffiattbe proposed protocol is a sipfifficaht adyanfce in asWtos risk a^essmefttmefo6dolc^fftfe stroiigly supported the :: lecoiri&eniidtibtftfiaiFfuture mgaMremeofs- be perforktiy3ruslhg t^M;'lfathef;diari'PCM.:Dr. : Castrariova'&iso supported tteiappSjach 'df^Mgrii^' ecpalrraraii6geific potency to cleavage fiagrihents ahd'asbesfos fib^r^te^^niiiailF-ISifn^Sf^sftxn--corildbe tested in " 'an ammaluihalatibfi^stu%.Further, Dfi'Gastfiriova agrefcd iJratifeM-i^bestifdrm'ampluboles and 'asbKto^'iari^Mto^olfdlb' same dimensibifshould be as!gpied^iat:eaimogehic potency. Dr. C^tranova indicated that foe epidenuology 'aj&i toidcblbgyliterature'clearly indicate that 6-3 HWBUI0009914 ' mesofcelipina-ppfeacy varies with^fiber type, but he was ppt convinced that fhis Etgjature. . . . supports a dffi^cemlung.cancw poteiKjy between ffltnphibole and chiysoffl.Q.`fibers.:.. . *r -J}r.fPrice.^mmma/ysta(e/ffeni.;Br. Pdce, fqmd. fbsproppsed protocol|q,bo.an impressive ; compilation oftheepidei^olo^ i^d to^coipgyiMteratiiio into a canc^risk as^sfaent model thafraddrpsses iBQSt^but notiaii, risk factors debated since EPA-'s l^p^deL Dr. Price urged ;.EPA to explore^^siueriiespotise models otherjthantoe models that inyoLve ^npar, |ow=dose extrapolations, which he vieyyed.as.bemg incofisistent wito.toe epidemiology Uterabire.:Dr. Price . indicated tiyrt.fiitiire reyistons to.the protocol shopld defimtely:comidOTmn-lmsar models and threshold effects.. :. bu.i- . s;~- lyy*.: < ' . -f.Y.t.v rYY. r v 4 . . , : As*.art\adkiiiion3l>.coiirin!ient^Eh^^tice.^ginpfinsi2jed-thrt Ae two iBam.elemgnjS ofitije, ,q -,i jiprotocpl^-thfr-grppre^ e^pqgpre index and tog pigsty ioter- .; relatedandsubsequent change tt}:-iAg,pSPP0Sg4if5P9sm idlest: pould affeef,toefobustgess of ,, .>.thepveraU:modelinaelfort;Asanejrampieofbisajjpegnii Dr. Pjjc^motadjtijatriiic^ishtSrft*6 fiber diameter cut-offInJbe. esspcspre index; fipm 0,5; pm.to 0 observer comment) lead to dramatic differences in toe number ofcleavage fragments counted in mvkonmjmtisatopNs hpweyeryhfindicated flat toe animd^todips .use4,|o (lejvYfcthe original - .... . a9qpflpit^Aj^tea^^iM^incjdg<4eavs^P..;anejpisiTC,;iijd^.drayi^:tipmfye^rSpecifieo>??<^nre<^5^tlom.iitapimd;^h^^;te;Ovgluate hum^n-healtli4sks.asspolatediwito,exgosiirra Qf^^triimj^.jC&GfeRat encouraged further study ofcleavage fragments, toe role ofcleavage fragments. nM& Case congratulated Ejrs. Bennan.and;Cnimf>.;for., compiling what he viewed asa,r^omble evaluation, oftoe available.tojacologyvand i ..;^idgtmslr.lite!3ti^ andjielslmp^y.siiPpQrt^ toe gen^;apprpach.o.fA#pripg;fitetype Dr. Case indicated.%ath?.iS5^4'W%itoe - :;i i toafjmpliilmle fibers ljay&$glitly: greater lung cancgr {Kjtencyftoantio ol^^^fibers, %$fiber dose,:^fij^rjfespgfe.ande^ecially^smoking^Jtistpty,an|.t^.pf . vjew%fhe ....-itifistissue, and;ho.encourag^EB^..toolassify.tog;j^hort;ofSoitfhCam!inatex.tde^p^ke^ as being ejfposedltoipiked;asbestos,fibere, ratoer fhan being exposed to onlyiphrysotj|sifii.bers.2 . /r. .. l ;s. .: -r. - j ... xvt ... .. ft- -vi; .=. ':. v =(,. y>.' ' ' :. ^When presentingiihesurtimary;statc!naiits,'0`ne panelist (ES) indifcated thatNfQSH isre-analyziftgiilterari. :> thatiwere oollectf'd inthe.l,?<*0s fiom ths-S^uth Carolina textile p!ant,;and these re^auialyses shcjuld.indicate. the distribution of fiber tjpes in this cohort's exposures.rAnother panelist 0C) noted.that these re-analyses^wijl not , characterize earlier exposures to amosite fibets, which are believed to have occurred primarily before .1950 (based'on findings'frSm stiiSies o^ltmg-cetamed fibbrs).' ' ' ' ' ' : '' 6-4 HWBUI0009915 Dd Case:made several recbnuhendatioris for further evaluating the existing epidemiological data and fortolleiaing additional date. First; Df. Case Indicated that it is critically importantfor any lung cancer risk model to consider confounding effects ofcigarette smoking, and he encouraged EPAtomcorporate interactions with cigarette smoking into the lung can^ model fo tire greatest extent possible;-Second, Dr. Case supported Div Lippmann's recommendation ofconvening an additional expart?pdi^:wtdkshop te critically review inferences that should be drawn from the 'exposure measifreriiktls nrtade in the epideiinioiogical studies; such a paheh Dr, Case noted, would'jetjuiie ihpiits fromtexperts in mineralogy, industrial hygiene; and measurement . mefrodoldgies; T&nd} he support^ toftimehts recbmnie&fing that EPA examinetetFllpear and threshold exposure-response models. Finally, Dr. Case agreed that conducting an diurnal inhalation study is probably the best way to examine whether tremolite cleavage fragments produce lung cahcerrbiitcfid not advocateiisirig ratiinhalatidn studies to exanuhe whaher these fragments mducemesotMeHoma, becauseresidts fibrin1 iat inhalation studies have been'Sftbtyn to -te,a'pbbfiiiibd&ifi&^ addeC however, that it woulffquife ptobabfy only to "cleavag^fi^sienls" 61-`%drt&hestifckrri'iiWis"'with?riO:ashestifofmfibfepfosentat'a!L . : :' : ; :';;i . -a ' Dr. Stqytier's sutHmaif staiement Dr.-Sfayner teipported the ^neral concepfof ^ - ihcorpbratiiSg1 fibeffype add fibfer dfinertsioremto carreer risk assesstoen^^iie isfeorittriended ; that additibdal whirkljei coridifcted before EPA'aeceptsfoe proposed protbieol'aS!;|iSwysk asseSsrnetit paradipa.:'Dr.' Steyter indicated that-his cohfidehee ih tfe propoSSd protocol varies betwete thS^^^ aifo `S ;1 '` For lung cancer. Dr. Stayner indicated that the available epidemiological date should be able to suppOffa hew-risk'asseSrinent'rhodeii'but'&'recomfomded that EPA consideffoe' pkiel&ts' !? many rerommendatiaiis for how tiie nihta^ahalysis can he1 improved (eg, using differentstatistical models," developiiig arid aqp^yli^mulihntaL^tl&l^:id(^uskMntcriteria,- conducting additional sPsitivity"ahalyses)i Concurring with Dh Steenktoffssumrnafy statement,IM Stejte&added that' dgare&fOTioldtig is vi^ tmlikeiy to bea coDfotindhig factor iri the'lurgt^pS,:BiiEi4ie?.aijd he 1 quesHteMwhetiieftte'avatebletey Would si^poffg^qurattifativeaksessiifeat ofthbfiitfetaction Effects; WhMe'&;Ste}mefsupported tlierecoriimendation for evaluating noa-lmear'expduirSprire mddel^ire'noted that the mdiyiduai-lhvel'Mta'rieeded to cofistraet:these mbShls .are iteravailable fof'rhtKt epiddmidlbgjcrilstudieS. Di? Stayner addedfhat obtaining raw datifteoim additioSal occupational cohorts wbrfld prowde tfebest bppbrhihity for mdre detailed: ! ;Kexploration of non-linear exposure-response relationships. Dr. Stayner expressed greater concern about the foundation ofthe mesothelioma risk modelrHe mdieated;>forimtenee,; that;the relative potencies included in the proposed exposure index are basedentireiy on'foxicblogy studies for'lung cancer, and riot on any epidemiology or toxicology": studies. specific to mesottieiiprna. Despite thdse cpnoems atreut the biological testsTor1 thb : . proposed mesothelioma model, Dr. Stayner noted that the proposed model.'does provide an . . 6-5 HWBUI0009916 improved fitto the findings from the epidemiological studies..He iecominended;ifaat,EPA consider optimizing the relative potencies in file exposure index to the human data, especially if EPA can access raw data from additional occupational cohorts to evaluate how exposureresponse varies with fiber size and fiber type. Dr. McClellan *s summary statement Dr. McClellan congratulated Drs. Berman and Cramp for integrating the toxicological and epidemiological data into a reasonable evaluation ofasbestos cancer risks. Overall, Dr. McClellan found the proposed protocol to be a substantial improvement over EPA's 1986 models and urged EPA to continue to move forward with completing the protocol based on the panelists' feedback. Though he found the presentation of information in the draft document to lack transparency on many important matte, Tk. McClellan indicated that the authors' presentations at the workshop addressed many ofhis concerns regarding the transparency ofhow the proposed model was developed. One suggested improvement to fee protocol's transparency was to clearly describe what literature were reviewed and to specify what studies actually factored into fee quantitative analyses. Addressing specific topics. Dr. McClellan indicated that the analyses in fee proposed protocol adequately characterize the general roles that fiber type and fiber dimension play in cancer risk. He supported suggestions for involving additional experts, perhaps in another expert panel review, to further review interpretations of the epidemiological studies. Further, Dr. McClellan agreed wife other panelists' recommendation that EPA explore fee utility ofnon-linear ) exposure-response models, consistent with fee agency's proposed revised Cancer Risk Assessment Guidelines. If linear, low-dose extrapolation models are ultimately used, he suggested that EPA explicitly acknowledge the uncertainties associated with such an approach. Dr. McClellan indicated that obtaining raw data from additional epidemiological studies might be particularly helpful in fee exposure-response modeling. Finally, Dr. McClellan emphasized that fee exposure characterization in the proposed protocol is closely linked to fee exposureresponse assessment; thus, fee authors must carefully consider how revisions to fee exposure characterization affect fee assumptions in fee exposure-response assessment, and vice versa. 6.2 Development of Final Conclusions and Recommendations After presenting their individual conclusions and recommendations, fee panelists worked together to draft summary statements for the peer consultation workshop. Every panelist was asked to write a brief synopsis of a particular topic debated during fee workshop. These draft statements were then displayed to the entire panel and observers, edited by the panelists, and then compiled into this document's 6-6 HWBUI0009917 executive suirinikty, wMch should'fie Hnewed as the expert {janel'S final conclusions arid ceocnxiiiiQnd^pmihe . 'i- t . " '' ' V -i ... " ' > . . ' :ii . ''v ' V xi: J?i -iaC- :' ' !~ xii ii; 'v?.?v.- .-> ./ 'it .-v . . ... . . : i. :/:! .. :-f ' V .' V >'. . 'nil-. riviltv. . ** /V: *i* * ,; . . :. ? ' ii = : . '<=5 V-!-' ' '' .i ftlii-.f -..-fif ' ';>rr- . * : 'Gm' ' V/"/' JGlii '= :ir.v ' ' Vi;:-: j!. /..IV :>r .ov/ " - -i ' ' i b'. . - , .>! '-'ji'ZUiXrtK -V- JVS'm : ' Wi" '.1^'.'. v.-i;: ;= r'f /V-J ` v ';t V;-iOs3'r:?' ! ' . .,, .. 3,'? . .i'r-X. t.-'-J-K'. IfC'.'b ` -Y .:>;:! .T J v"'.:.1 >; ' 6-7 HWBUI0009918 . -Hi.-REFEBECfC^S \\ A,.- -t ifjA -Vi.-. B Bellmann, H Muhle, O Creutzenberg, ct al 2001. Effects ofnonfibrous particles on ceramic fiber (RCpl)toxjrity, ia.fgtsi.fchaHatjpftTjaq9kjgy.jL309)|^r^l4. ;-r. . DW Berman, KS Crump, EJ Chatfield, JMG Davis, AD Jones. 1995. The Sizes, Shapes, and Mineralogy, of *#SQ%liaixia m AF/HAN Bats ; >5 Following Inhalation; B&kp&nalyrisdS^ ; .i./.j ' -.d \ .r .v C' .*' ` . ^ l : v'-=!-`'v DW Berman and KS Crump 1999. Methodology for Conducting Risk Assessments at Asbestos Superftm|iSites; Bait 1:Protocol. Final Draft. Prepared.%f UJ|. EnvironmenMprotection Agepcy; <-. Febniaiy.l?* 1999..*. / - . ;,,;r ; v> rie. .U'.v/. ^ DW Berman and KS Cramp 2001. Technical Support Document for a Protocol to Assess Asbestos- R'riate^.gjdr,.^pfil EnvhrohmegtaI;l^teptiop;Agcy: ,aodU:S. Depai^ppt^C TransportationSeptember 4,;2001. = r > . . -yvrVfrSrr? G: Berry;and: ML Neysthouse.; 1983^A^srjtaUtyof^orten5,Mfeiyfectorpig-FrictionMaterials Using j. Asbestos. British Journal offadustpal^MedicinedO.Tp?.', - . .>S;;. : K..- CBoutin, PJhmprtipi:,)RR,ey, ft al. 1996.: B,lack sppl^pppcaiteate pnt^genicasbe^tos fibprs infte parietal pleura. American Journal ofRespirato^.Cri^c^;.ti^iand,M^.pt9S^rl^3:4^b449.., . M Camus, J Sie^tycId,rB,M^k 1998,:Npnoccupaticinaltgdsrjip tp'ohrysotiie asbestos arndtherisk. oflung:cOTcer.^wBpgl3pd.|pi^,pf',Medicine3.38jl56%-l|7;l. , ...... > WC Cooper,,:0 Wong^antf R, Ciraebnpr.; 18?8:Mprtaljity ofs^orkfis in byo Minnesota taconite^rmning; and rii31^.^pa^(pos!!<JiQunihIr JMG Davis, J Addison, C McIntosh, BG Miller, and K Niven. 1991. Variations in the Carcinogenicity ofTrempliteiDust SarppleofDiffering.Mprpholog5fi.Am^dJ;tiie`Ne^r Yo|k Academy of^egges,;^ 473-490. : . ?i; -n; PE Enterline, J Harley, and V,Henderson.; 1986- Asbestots,andijCaneer-^V Gphort,Followed toEte?itk. Gjggyg^SchOpl-v s .; ; ; I ' N De Klerk, B Armstrong, A Musk, M Hobbs. 1989. Cancer mortality in relation to measures of ! exposup&lD .0n^dq^.^.pittgppjgn Gpige in Western Agstalia4 ;Bri^sh Journal ofIndustrial Medieinp:j; 46:529-536. :L.-... . 7-1 HWBUI0009919 JM Dement, DP Brown, A Okun. 1994. FoiloW-up Study of Chrysotile Asbestos Textile Workers: Cohort Mortality and Case-Control Analysis. American Journal ofIndustrial Medicine 26:431-447. -.r,-.. i-.rr-:" EPA1986. Airborne Asbestos Health Assfefemerit Hpdate. US. Environmental Protection Agency. EPA 600/8-84-003F. 1986. ERG. 2003. Report bn the Expert Pdtiel bnffealtfa Effects ofAsbestos ahd-Sjtoffietic VitrebuS'Fibers: The Influence of Fiber Length. Prepared by Eastern Research Gtoupj4nfc.ffor'tire' Agency for TtSxic! Substances and Disease Registry. March 17,2003. .-.KW-i- ` I- -T-. *y'- .*;?j TW Hesferberg, GA Har^JCberaileriefal; dose in determining the chronic inhalation effects ofX607, RCF1, and chrysotile asbestos in rats: Toxicology and Applied Pharmacology 153:68-82. . |Sj- .. *< s:' employees in relation to taconite dust exposure. American Journal ofEpidemiology 118(5)?710-;719^ J Hod^riarid ATrarirfcii^OOO.^e (JiMifitative RhskbfMesotoeliorik aridLdrig'GaifeMfiRelatioh to Asbestos Exposure. Annals ofOccupational HygtChfe'dd^^SdS^ijOL''' '<'>* <' 4! i- Plants. Brifish%Wiid:6t&dusti^y[etUbme:44?I6i-i74. ' IARCfl996: ABKahd, PB6ffett^R`Sira'eci-aSrf3D WMboteri Mech^iiimSs bfFibkb - r, ; ; Carcinogenesis. Mermtional Agency fdrResfearc'fi on Cancer: Oxford University Prtiss 140:1-9:. JE'Levini'JW McLarty, GA Hurst, AN'SMth, and All Frank.'. 19981 -Tyler'Asbestos Workers: Mortality Experience in a Cohort: ExpoSed fe'Amosite: Occupational arid Environment^ Medidrife: 55:155-160. Viviu^Ohi :V:1 ;J : '-.I , i. /!/:! arid exposure in Quebec chrysotile miners and millets. Annals of Occupational Hygiene 46(1):$^13. -1 FDCiddeU,;AD'MbDonkld, 4id JOMetoaIcUl997. The 1891-1920Birth'^GohorttofQuebbcT Chrysotile Miners and Millers: Development fibmi904 and Mortality !&}:1'992. ArSdls bfQ&mpatibnSl Hygiene 41:13-361 ;;: * : < i." v .y .-'IS'1 ` "X* J ...w <- l'. '\. * -`1^: [ ;.-' :i , .-s7:. 'M-* 'i FDTiiddell;- AD MtiDbaald^-tind-JG^dDbriScf 1998:T5iist exposure arid lung: fcaiifcef-irr Qiiebec:: ' chrysotile miners and millers. Annals of Occupational Hygiene 42(l):7-20. :! ' M Lippmann. 1988. Review: Asbestos exposure indices. Environmental Res 46:86-106. 7-2 HWBUI0009920 M Lippmann. l994..Deposition and retention offibets:;Effects oa incidence of lungcapper and mesothelioma. Occupatiemai and Environmental MedicineI.:793a798. JC McDonald; GW, Gibbs,'FD Liddell, and AQ Mpljonald. 197S..:Morality after, long exposure tQ ciimmlngtomtei^mnerite: American Review ofRe^jiratory Disease ill8(2):271-277. / r . AD McDonald, JS Fiy^AJ Woolley, and JC McDonald. 1984. Dust Exposure and Mortality in an JC McDonald, B Armstrong, B Case, et al. 1989. Mesothelioma and asbestos fiber type. Evidence fromlwng;fissue.analysjs.Canoes:63:1544^1547,. .1: AD McDonald, BW Case, A Chutg, A Duftesne, GW Gibbs, P Sebastien, and JC McDonald 1997. MesoftidipjrtainQirebecsdhiys^e.naiinei^attdtnillers: epidonrtioiogy.andttetiolpgy. Annals of..; i;.;/; Ckcupati.onalHyffene4.1(<^:707^719. .* <. ,k,= n.j::r ^ors-dHsqjretS'-- JC McDonald,^Harrisi.-atid B Ajnnstrong,v20ft2i Cohort ifiqrt^ty.study ofyenm^tendftere,exposed to fibrous tremohte: an v-nsD -scaoid. i WJ Nicholson, d976; Part EJr.Recent.ApRroacbes to the..Coalrt>l.ofC^rc!hogerdc ExpospresilG^Sie,';' Study.. 1: Asbestos-r-The .TLY-Approach. Annals.pfNew.YptfcAcademyof Science. 273 i152^369: C-G Ohlson, T Rydman, L Sundell, et al. 1984. Decreased lung function in long-term asbestos cement workers: A ao^section^stody. America Journal pft!pdl|stria|Medieinf;:5:3597-366.;.;: ; ,vy K Rodelsperger, H-J Woitowitz, B Briickel, et al. 1999. Dose-response relationship between amphibole fiber lung burden and mesothelioma. Cancer Detection and Prevention 23(3):183-193. AJ Rogers, J Leigh, G Berry, et aL 1991. Relationship between lung asbestos fiber type and concentration and relative risk ofmesothelioma Cancer 67:1912-1920. A Rogers and G Major. 2002. Letter to the Editor. The Quantitative Risks of Mesothelioma and Lung Cancer in Relation to Asbestos Exposure: Hie Wittenoom Data. Annals of Occupational Hygiene 46(1): 127-129. H Seidman, U Selikofif and SK. Gelb. 1986. Mortality Experience ofAmosite Asbestos Factory Workers: Dose-Response Relationships 5 to 40 Years after onset of Short-Term Work Exposure. American Journal of Industrial Medicine 10:479-514. 7-3 HWBUI0009921 U SeUkofFand H Seidmdn. 1991. Asbestos-Associated Deaths amohg Insuiation Workers in the; ; United States and Canada, 1967-4987;;Annals ofthe New YotieAcademy of Sciences 643:1-14; LT Stayner, DA DankbviCj RA: Lehiehi 1996'. Occupatibtial Exposures to Chrysolite Asbestos and Cam^ Risk: A Review offe 'Ariiphibote Hypothesis. America Journal of Pubfic Health 86(2): 176-186. V Timbrel!, T Ashdtofl, B <3loldstein,'et aL 1988. Relationsh'ps&tweentetained amphibole fibers and fibrosis in human lung tissue specimens. In Inhaled Particles VL Annals ofOccupational Hygiene : 32(Sl):323-340. Y Suzuki and S Yuen. 2001. Asbestos Tissue Burden Study on'Hinnan Malignant Mesothelioma.' Industrial Health 39:150-160. ' -:v . ' . - - . -.. * \ ; ; . : . / , : O / /. -v ,, . Mf Teta, HG JW^Mfei^ietali ;1983. Me^othelibma in Confledticut: 1955-1977 =;. Occupational and geographic associations. Journal ofOccupational Medicirie;25(10):749-t756. -7 A'To^vaihen; M KbtiWttei^^Takafehl, G and E Vatdialai^OOl^AttipMbOte FiBras in Qunese Onysotile Asbeste;Attilals6f*Odeilpatiofiai HygidSn.^-4S(2>: M5i152: : H Weill, JI^Abraham, JR Balfftes, B Case,1 AM Qnirg;>J Hiighes.M'Scherik^and RSebastien. 1990rHealtfa: Effects ofTrt^oUte;-'OMci^fStaterneht ofthe American'Thotacic Society;American . Review of Respiratory Disease 142(6): 1453-1458. '!=;':r :..}. n; '-Ju ui .' : .77" .h r- vT: . //.;, j . E Yano, ZM Wang^XR Wang, MZ^Warig, ahd'YJ Lan::2001. Cancfer Modality among WoikersExposed to Amphibole-free ChrysotUe Asbestos. American Journal ofEpidemiology 154(^:538--543. J 7-4 HWBUI0009922 '*1 'tYO:?.Wf HWBUI0009923 Appendix A List of Expert Panelists HWBUI0009924 App'endli B : `'1 `" Pre^eefeSg'^osiiril^n^AiphkfceiSzei'ly AnthOr' '*' '''"' (includes bios of panelists and the charge to the panelists) ) Note; This appendix is a copy of the booklet of the premeeting comments that ERG distributed at the peer consultation workshop. One panelist (Dr. Bruce Case) submitted an edited form ofMs premeeting comments to ERG at the workshop. That edited version appears in this appendix. HWBUI0009925 HWBUI0009926 Appendix D Agenda for the Peer Consultation Workshop 9 vi> Jt*. ) HWBUI0009927 b Appendix E Observer Comments Provided at the Peer Consultation Workshop Note: The peer consultation workshop included three observer comment periods, one on She first day ofdie workshop and two on the second day ofthe workshop. This appendix includes verbatim transcripts (to Are extent that specific remarks were audible from recordings) of the observer comments, in the order the comments were given. ) HWBUI0009928 Appendix F Observer Post-Meeting Comments HWBUI0009929 m Appendix A List of Expert Panelists v*. r. ) HWBUI0009930 o 4%, |rlll'l"l%Jl, United States attui-Ugi Environmental Protection Agency --BOffice f Solid Waste and Emergency Response Workshop to Discuss a Proposed Protocol to Assess Asbestos-Related Risk Westin St. Francis San Francisco, CA February 25-27,2003 List of Experts Bruce Case Associate Professor McGill University 462 Argyie Avenue Westmount, Quebec H3Y 3B4 CANADA 514-398-7192 #00521 Fax; 514-398-7446 Email; bruce.case@mcgill.ca Vincent Castranova Chief. Pathology & Physiology Research Branch National Institute for Occupational Safety & Health 1095 Willowdale Road (L 2015) Morgantown, WV 26505 304-285-6056 Fax: 304-285-5938 Email: vid@cdc.gov James Crapo Chairman, Department of Medicine National Jewish Medical Research Center 1400 Jackson Street Denver, CO 80206 303-398-1436 Fax: 303-270-2243 Email: crapoj@njc.org David Hoel Professor Medical University of South Carolina 36 South Battery Charleston, SC 29401 843-723-1155 Fax: 843-723-7405 Email: whitepoint@aol.com Morton Lippmann Professor New York University School of Medicine 57 Old Forge Road Tuxedo. NY 10987 845-731-3558 Fax: 845-351-5472 Email: fippmann@env.med.nyu.edu Roger McClellan Advisor, Toxicology & Human Health Risk Analysis 13701 Quaking Aspen Place, NE Albuquerque, NM 87111 505-296-7083 Fax: 505-296-9573 Email: roger.o.mcclellan@aU.net Bertram Price Price Associates, Inc. 1 North Broadway - #406 White Plains, NY 10601 914-686-7975 Fax: 914-686-7977 Email: bprice@priceassociatesinc.com Claire Sherman Biostatistician A-l \ HWBUI0009931 California Environmental Protection Agency 1515 Clay Street. 16th Floor Oakland. CA 94612 510-622-3214 Fax; 510-622-3211 Email: csherman@oehha.ca.gov Leslie Thomas Stayner Chief, Risk Evaluation Branch National Institute for Occupational Safety & Health Robert Taft Laboratories. C15 4676 Columbia Partway Cincinnati, OH 45226 513-533-8365 Fax:513-533-8224 Email: Its2@cdc.gov Kyle Steenland Professor Rollins School of Public Health Emory University 1518 Clifton Road Atlanta. GA 30322 404-712-8277 Email: nsteenl@sph.emory.edu Mary Jane Tela Principal Epidemiologist Exponent, Inc. 234 Old Woodbury Road Southbury. CT 06488 203-262-6441 Fax: 203-262-6443 Email: jteta@exponent.com A-2 HWBUI0009932 Workshop to Discuss a Proposed Protocol to Assess Asbestos-Related Risk #)' Consultants' Premeeting Comments February 2003 HWBUI0009933 Notice Premeeting comments were prepared by each consultant individually prior to the meeting. They are preliminary comments only, and are used to help consultants become familiar with the document and charge questions, develop the agenda, and identify key issues for discussion. During the meeting, consultants may expand on or change opinions expressed in their premeeting remarks and may introduce additional issues. For these reasons, premeeting comments should be regarded as preliminaryand do not reflect the final conclusions and recommendations of iMdividiiai.corisuitairits. ...These premeeting comments will.^included as an appendix in the meeting summary report, along with other background materials. ^ ) B-i HWBUI0009934 Table rof 'Ooritehts Charge to Consultants .........- B-1 Pre-Meetincj ^ftiimienfer'',. Bruce Csise 1 Y:".. Vincent CastranoVa..A -..-.i . . .. JamesiC.OrZa. p6:AT,,l!~.c'Ti-vv;V-. .V.: David feel: A-";\ * . V-:-: - ; :. i'i- i ... Morton Lippmann Roger McClellan...................... , -V--r-:vA , Bertram Price .VVAv-. I nttV -J\ 1 . . It?:, Claire"Sherman- :';!rr-;';'.r.r:Vv . Leslie Tfjomas'StaJrier .. . v.1:';. Kyle Steenland A";V;-... . '.I.. ; \`v; i,' "=:.r Mary'JanbTeta;.. . A .. / , v.'V!5'. .V "*> vi- *. *:- :.S . , . -7':%. : -,\S; - - H*?'. ;'{} / r.-y . , 1 ,, /; ; ; .'1 J _ . .V; ^. : C-i i : . , * /> *; ry . ^ v : V' ': f; J-J}}. ' .J-ri-. - vi'U^V''- - i,- 1 -s>=V v- ,:B-7 ............. B-43 . - :lWQY: ... B-71 .......................... i->. -v .. i \- C` * : f B-83 : %i&7 ^:r - i: ` < ' ` v, ..;-.e-.v ` m-. J;:-: -,o. ; ;^B-145i' v- ;.-3: ...:J'S tiC<f ' ' -:Tf ..t'v; i: .-:.C .'f-'-.-f.;.-' .U-=;' .1?.? f:-.a > :: W. / ..u |i:-.v ..-.t:' v- . ; ;u '' 'i;v. > r. ..-..t; ! ."'.V;'i'r ;< vr;;-.:- ...j-;<. . ; .. > ::.s -i'--: :.-n .' - j.; "... .- ' ;i ; -.p;;: i r<: s:' -s. !'m'. y -I- . .. : fl'K-.:-.. i: S;; \-.:S .-..'.`i. . ?' ;. ' :>' - .v;;'.J.;:' ! :.-r; >::. ' ..-V /iv'-..- . : . i^!': ;;; ' ; , .. .. . ..H: : - ' i-. :: A' , \l\ ?Tii HWBUI0009935 Workshop to Discuss A Proposed Protocol to Assess Asbestos^Related Risk Charge to the Peer Consultants The U.S. Environmental Protection Agency. (EPA). is conducting a peer cohspltapgn vyprkshop .. to solicit feedback from a panel of experts on issues related to the draft document. "Proposed Methodology for Conducting Cancer Risk Assessments for Asbestos' (Berman and Crump 2001). Eastern Research Group. Inc. (ERG), a contractor to EPA, is organizing the workshop. Discussions at the workshop wiil focus primarily on issues raised in this charge, yvhich lists questions that EPA would like the peer consultants to discuss and answer. The charge questions are not intended to limit the peer consultants' discussions; they merely address issues that are important to EPA. Peer consultants are invited to raise and discuss additional relevant topics, as noted below. This charge provides background information, instructions to , the peer consultants, and the charge questions. Background EPA's current assessment of asbestos toxicity is based primarily on an asbestos assessment completed in 1986 (EPA 1986), and EPA's assessment has not changed substantially since that time. The 1986 assessment considers all mineral forms of asbestos and all asbestos fiber sizes (i.e., all fibers longer than 5 micrometers) to be of equal carcinogenic potency.,Howver. since 1986, there have been substantial improvements in asbestos measurement techniques and in cur understanding of how asbestos exposure contributes to disease. To incorporate the ^ knowledge gained over the last 17 years into the agency's toxicity assessment for asbestos, EPA has contracted with Aeolus, Inc. to develop a methodology for conducting risk assessments of asbestos. The proposed risk assessment methodology distinguishes between fiber sizes and fiber types in estimating potential health risks related to asbestos exposure. The . . proposed methodology and the charge issues (Berman and Crump 2001) are the subject of the peer consultation workshop. A key step in the determination of whether the proposed risk assessment methodology can be used to support decisions at asbestos-contaminated sites is gaining feedback during this peer consultation workshop. During the two and one-half day workshop, EPA will seek feedback from the peer consultants on the technical issues outlined later in this charge. Time will be set aside each day to hear from observers. The Agency will consider feedback received at the workshop in making decisions as to the applicability of the updated risk assessment methodology. Instructions to the Peer Consultants ERG selected eleven scientists to serve as peer consultants for the workshop. The peer consultants have extensive expertise in related fields, such as inhalation toxicology, pulmonology, cancer risk assessment, and biostatistics. Before the workshop, each peer consultant will be asked to read the proposed methodology and technical support document for a protocol to assess asbestos-related risk (Berman and Crump 2001) and to prepare and submit pre-meeting comments, which are to be written responses to the charge questions listed in the next section. ERG will distribute a compilation of the pre-meeting comments to all peer consultants and will make copies of this compilation available at the peer consultation B-I HWBUI0009936 workshop. At the workshop, the peer consultants will actively participate in discussions that will. focus largely around the charge questions and they will help draft summary statements of their conclusions and recommendations. Following the workshop, a technical writer from.ERG.will' prepare a draft summary report that documents thpieehnical discussions at.the workshop, ,? including the obseryencprnm^nts./ After the peer consultants review and comment on thedraft summary report ERG will submit a final summary report to EPA. i , When preparing written comments, please write each question, .followed by your comments (or,:: state why you are riot responding). Please include your name at the top of each page, but do not paginates; Please refer to the enclosed "FormakGuidelines for, Preparing Written Comments!" Younwritten comments are due to ERGino,later than February 14,2003. ' . . - *- = : ' ^CHARGE QUESTIONS'.. - ... - ... . Topic Area 1 -Iriterpretationsofthe epidemiology and-fo'xiPotogy literature/ : P 1) For lung cancer. A] trifluehce of the ekterit to w|tidi'the: epidemiology . literatureand medhariiWc %tdfe suggest that terctridgehfcipdte:hcy:yaries front one fitter . type to the next (e.g., chryslffle^ersus^mphiboiefibeis). RdWadequate is the '; * information in the epidemiology literature for supporting dose-response analyses for S^ek^i^l|y7to,vMieft^eritxld'ybQ-tifihlifttiie(|Nrdpt^5ed risk coefficients in Table 6-29 are supported by the epidemiology literature? - ; B] Influence of fiber length: Please comment on the extent to which the epidemiology literature and mechanistic studies suggest that careiriogeriid'potency vdries with-fiber ; length. How adequate is information in the epidemiology literature for supporting doseresporiS^ariafysiesfordiffetgnt'fiber lengths? In general, is it.appropriate to assessfcancer ; risks using art exposure iridex'(see Equation 7:13) thahis weighed heavily by fiberslonger' than40.micrometers: ( pm)? (Ndtef>Topic area:2 includes more detailed questions on Hie. .;: proposed exposure index.) CJTo what fejderit doianirrial studies (e.g:; studies by DaVis andothef researchers) sug'gest that cardridgeriie potehey YarieS with Wb'er fyp'e and' fiber length? . N :/ D] Please comment on the extent to which carcinogenic potency is a function of fiber properties (e.gir diameter/aspecfcratio, surface'properties).otherthamfiber typeandfiberlength/Rowiadequate^is .information in thb epidemiology^orloxicoiogyliteratureTbr -.;-i < supporting these other properties into dose-response analyses? : -o :r ... ... .0 B-2 HWBUI0009937 2) For'mesothelioma:. . . AJ Influeriderof fiber type: Please comment on the extent to which the epidemiology > literature and mechanisfic studies suggest .that carcinogenic potency varies from one fiber ' fype tothenext(e.g:;chrysolite versusamphibote fibers);Howadequatelsihe: -v' information in the epidemiology literature for supporting dose^response analyses for different fiber types? Specifically, to what extent do you think the proposed risk coefficients in Tabte 6-29 are Supported by'the epidemiology literature?- v . . - ' *- ; ' V.:--- ' V'"V= i:"'. B] Influence of fiber length* Please comment on the extent to which theepidemiology ;;; literature and rnecfianis&cstudies suggesi-'ibat' carcinogenic potency varies with fiber ; length. How adequate is information in the epidemiology literature for supporting dose- response analyses for different fiber lengths? In general, is it appropriate to assess cancer risks using an exposure index (see Equation 7.13) that is weighed heavily by fibers longer than 10 micrometers ( pm)? (Note: TopiC-'afea 2-iriclodes more detailed questions on the proposed exposure index.) | To what extent do anfmatetudies (e4j.,;studiqsby Davis and oihppresearchers),.; v suggest that carcinogenic potency varies with fiber type and fiber length? D] Please comment on the extent to which carcinogenic potency is a function of fiber propertips-(ei.g,., diameteri-aspectJtatio, surfac.prQperties)!qfi[ierifriaq.flber type.apd fiber pie,.length., Hqvy, adequate is information in epid(etmp(pgy,pr jtgxipglqgyilfteratureTor. ; supporthgftesepttierprppertiesintodqse-fesfpc^isjaf.nalypes? - ; . ..- ' ' ,'*. :V.- \ ' ' ' '{V i.?l ;V "l*'. v'lV.1.- ' ' * ' v\ ' ` ! V f- X : ; `V i\ 3) To what extent are the exposure estimates dqcun^eqted.in, the asbestos epidemiology. literature reliable? > .. ; topic Area -2: ' . . The proposed exposure;,index.;, . . .. . ... 4) The proposed exposure index does, not indude-contributions from fibers -shorter than 5 pm. Please.:Comnrtent on whether the epidemiology and itoxiccrfogy. literature support the . ; . condusionthat asbestos,fibers.shortep.than'5 pm. present lrttle. or no carcinogenic rtsk, - v 5) The proposed exposure index is weighed heavily by fibers longer than 10 pm. Specifically, Equatiori}fj.13 suggests: that the carcinogenic .potency of fibers longer.tham.10:|Jmi*s rrsore than 300 times greater than thatof; fibers .with.lpngths; between 5 aqd ;1;0:pmicHgyy; consistent is this difference in carcinogenic potency with the epidemiology and toxicology literature? 6) Pleae':e)q>lain whether the proposed exposyreiiridex will allow, meaningfut'Oornparisgrisyr; : . between current environmental exposures to asbestos andfristorical expcures;toasbestps ` that occurred in the work placea^ i -rv-.-f-'.V - . oe- B-3 i HWBUI0009938 Topic Area 3: General questions. 7) The proposed risk assessment approach assigns carcinogenfcipotency toindiyidHalifibefpvn, and to'deavage fragments (dr^bundles that are components of more'complex structures?)..; . . Please comment on whether deavage fragments' of asbestos are as toxiGotogicatlyr significant as fibers of the same size range. 8) Please comment on whether the proposed cancer assessment apprpaqh is relevant to all ... a. amphibole fibers or only to the five types of amphibote fibers (actinolite. amosite, anthophylliie; croddolte;dremotite) designated in federal;regutafipns..;v .,i v^. ^ {Sf'. `"V.. 9) The review document recommends that asbestos samples be analyzed by transmission electron microscopy (TEM) and count only those fibers (or bundles) longer than 5 pm. Such counting practices will provide no information on the amount of asbestos fibers shorter than 5 pm. To what extent would data on shorter fibers in samples be useful for future evaluations (e.g,, validation of the cancer risk assessment methodology, assessment of non-cancer endpoints)? 10) The proposed risk assessment methodology suggests that exposure estimates should be based only on fibers longer than 5 pm and thinner than 0.5 pm. Is this cut-off for fiber diameter appropriate? 11) Discuss whether the proposed cancer assessment approach, as a whole, is a reasonable evaluation of the available health effects data. What aspects of the proposed cancer assessment approach, if any, are inconsistent with the epidemiology or toxicology literature for asbestos? 12) Section 8.2 of the review document presents three options for assessing cancer risks from asbestos exposure. Please comment on the technical merit of the proposed risk assessment options. Topic Area 4: Development of Conclusions and Recommendations At the end of the workshop, the peer consultants will be asked to draft conclusion statements identifying their most notable findings on the proposed methodology. As a prelude to developing these statements, the peer consultants are invited to provide any additional comments or concerns, both strengths and weaknesses^ on topics not specifically addressed in the previous charge questions. After completing the discussions the peer consultants will prepare their conclusions, and they will also be asked to develop recommendations for how EPA can improve the methodology. Please note that although recommendations for future research projects are welcomed, the focus of this workshop is on the proposed risk assessment methodology and related charge questions and issues. . .l :B-4 HWBUI0009939 References Berman DW&hd C^mpTC12001'Technical Support Document for a Protocol toAssess Asbestos-Related Risk:ipifiafDraft Breparedfor U:S. Department'of Transportation and U.S: : Environmental Protection Agertey; September 4,2001: ;> -j,-, ?.' . Berman DW and Crump K. 1999. Methodology for Conducting Risk Assessments at Asbestos Superfund Sitesl''PaVi-ft'<Pr6td^li4lhfefim;Vefsion: February 15:1999.: ' -f s .O?,:u3:-..>=. - V-.'-'. Vfv . ; v: : EPA1986. Airborne Asbestos MealthAsSessment Update. U.S. EnvironmentalProtection. . i . Agency. EPA 600/8-84-003F. 1986. : - '. ' ' V ' ' '(Tis-: ' " ; - : s. s:;. ' .. ' 'r 1?-'- 'fn>; Hi-. .v, v ..MU' ; , '-J ' ' ,'U :i; ' 'jli'SV l. . 'l; - ';-*--***' < ` ' >. 'i" * OUl.-i ; V': - ';v" -i, . , . - '-s. j'.-.-: " .... ;. W:;f r ' . ...foVV: 6 Cfc ft-' . > '. Sf . 'O-:.- \ .: >!.. = W-5-- ''i- vi: !'.:?/ ! -fir;, i : .V '-v- v;- or.1- \ ; ' L, ,=f- V v '/ * . 2/1/.*:*', -hy. WV- " . ` _ ' *,i; \ *y,.' t,` '.'.'/c- .V rL - ;V rtv **;:* -.O'?'' r Vi::- ; ol I;-:?;v:- 'v.'r'ypA f;-r: -rv- '. A;,-. ^ f-A :p -.-; ' D -I..; - -a / -y. '0 "" .-.I =< ; . Vtv-.y .fn -s '.v;VC'-.' rCSiMfe- V; jVlSb-ib* V . ' . T:':-.- . - -.i'fiN-';r :!> ' i-y r-- ' j. . . .'/-lAa'i IcS'r:' '>?' -4x'- if- .... i ; : vi'c . V; ) f.. - j.' . ' '.! -f V r':'. n B-5 j HWBUI0009940 B-6 HWBUI0009941 Bruce Case B-7 HWBUI0009942 Bruce Case Associate Professor ... . McGilliJJniyersity 462 Argyte Avenue Westmfaunt; Quebec H3Y 3B4 CANADA ' ' 514-398^7192t#6o!K1 Fax; 514-398-7446 Email: bmce.case@mcgill.ca Dr. Case is a pathologist and epidemiologist at McGill University In Montreal, Canada. Following his residency in pathology at McGill University he obtained the Diploma In Occupational Hygiene at McGill. and worked as a post-doctoral fellow and instructor at the Mount Sinai School of Medicine, New York,/1 from 1980-1983. While there, he performed some of the first studies on asbestos-mediated free radical release, with the help of the Young. Investigator's Award of.the.American Lung Association. On his:netum to McGill he joined the. Dust Disease Research Unit The focus of this group was the epidemiological study of diseases1reiated tdmineral fiber exposure ufeihg ltmgifetaHied fiber in exposure assessment. In 4986, he received. th .^atisnal peatth. J^ofarsb.ip of. NHRDP. (Canada) for his work in the field. In 1988, he moved to thW university bf'Piffeiiurgbriwbere' he surxt&cfecf Dr. Philip fenteriiri'e as" Director of the t3:S. EPA Canter for Envfconmpntal Epidemiology, through ttjete cooperative agreement with ttie University, of * Pittsburgh School of Public Health, where he was also associate professor of epidemiology. He returned to McGHHn-i992-and continues research; teaching,>anid clinical work there ir* pathology, epidemiology, occupational health and in the McGill School of Environment Dr. Case has participated in workshops, given lectures, and provided peer reviews and advice for many national and international agencies and professional sodefepn tfie subject of the. exposure assessment.and health affe^ pf.rpineral fibe/s, including: EPA, CDC (through ATiSOk arid filOSH), theO'.S'. Consumer Product Safety'Commission (CPSC), the. hj^ptgfonal[Aoeney.forResearch ;qn Cancei;.(l^lC),.:ttie.jnjemafional..1Commission on. Occupational Health (fCOH), the British Occupational Hygiene Society (BOHS), the American Thoracic Society (ATS), the. Geological Society of America (GSA), and;the Pollegiurn^RapnajzinUjlis research on asbestos and other mineral liber and particle exposures and related diseases has been fancied'by American and Canadian public dgencies4niduding.EPA;vyRC'(Canada) and NHRDP/(Canada). Dr. Case has published over 100 papers on these subjects. --s-. B-8 HWBUI0009943 Brace W. Case WORKSHOP TO DISCUSS A PROPOSED PROTOCOL TO ASSESS ASBESTOS-RELATED RISK*; .'SAN FRANCISCO; FEBRUARY 25-27,2003. COSftffiPfTS ARRANGED BY CHARGE QUESTIONS Topic Area 1: Interpretations of the epidemiology and toxicology literature ...... I) For Lung Cancen-. -x, ' Note l: Lung cancer risk-conveyed by asbestos-exposure is principally related to degree of ' y asbestos:exppsure and subsequent retained asbestos.dose; tpsmokinghatbit; to,.%>e otindus^y-j . ,,(!ii occiipatiqigi'atposwe' situations), aiid;to #pppwtotely thaj o^f^of priority. *^ Hence ffie following'"section ls best addressed Bepriiiing`witK iteiti (D); with sdrife" >" ' ` - - ; -supplementation, father than items (A) through (Q, although roanyof these, factors are'inter- ' ' .rbistcdi - r;.- ,'u . ' ,i V- !.>>." ` . . \:if - - .fit'":".- -*. . ' V. \VU.! ' . ifote2:'Wliileirfrnot n&ciedeafwfa&Ts questioii^ltelow ifisawtuitei! that wfcialis meant isail animal and toxicibJdglcSti: : including both celhfiee arid in-vitro:systems. hi fefctjih vitro and ceU-ftee'^siems hve t not as yetproved successful'in usein risk:assessment;miid should no.tbe considered . (these are given too much attention in the documentation ofthe proposed model). This has been established by a fairly recent consensus statement by [ARC in Scientific Publication 140; the Consensus Statement has been circulated to the panelists (IARC 1996). Briefly, although a total offive possible mechanisms for asbestos carcinogenesis were considered in some detail, "The exact mechanisms leading to the development of cancer after exposure to asbestos fibers are poorly understood.. .Overall, the available evidence in favour ofor against any ofthese mechanisms leading to the development of lung cancer and mesothelioma in either animals or humans is evaluated as weak". However, with respect to the two parameters principally considered in the risk assessment model under consideration by the panel, the IARC panel accepted as fact feat "Fiber dose, dimensions and durability are currently accepted as important parameters" (Emphasis in the original). B-9 J HWBUI0009944 Brace W. Case In the following sections therefore "mechanistic studies" which do not rely on a;.- whole animal exposures Will hot be commented upon and (in this observer's view) should not'have any input into cunfeiit risk assessment In addition, for whole anitnal'stadfes, bhiy those bused on inhalafioii (which is tHfeihbdel most useful fofffiman risk ; !i described by the proposal as "(human) pathology studies" but is actually a subset biTsuch studies which includes (but is not limited to) lung-retold internal dose studies (sometimes called `lung burden studies") will be commented uponhere where relevspf, as spch stqdjjes are most directly relevant to human exposure assessment and have been (in this panelist's .view)|d%dedtpp.litt|e emphasis by,the authors, be^u^ ofa assqggri&nrihg ti^. sptpplingfor pitch studies,is virtually always "qppo^^ : authors also appear to ignore the possibility of human exposure indices such as broncho- 'alveolar lavage (BAL) and sputum asbestos body analysis irilirdng subjecfsj befor f!V relatively simple tedhhiqu6s withBAL being quite reprorfocible^spuliM prddhetiori-M the other hand is hig)dy affected by snioHeg status unless an "indtittibh" techiutjiieis iiseri; it has neverihdl&s proved us8M in some situations and in at least one sittiatidh is a better predictor of asbestos-related raSologjcai abnormalities than is estimated exposure (Sebastien P, Armstrong, B., Case, B.W. 1988 .). A] Influence of Fiber Type: Please comment on the extent to which the epidemiology literature and mechanistic studies suggest that carcinogenic potency varies from one fiber type to the next (e.g. chrysotiie versus amphibole fibers). How adequate is the information in the epidemiology literature for supporting dose-response relationships for differentfiber types'? Specifically, to what extent do you think the proposed risk coefficients in Table 6-29 are supported by the epidemiology, literature? ..\ai-= . - i; .. >. . - - . This is a much more difficult question for lung cancer than it is for mesothelioma, where there is a clear preponderance of the evidence for a very large effect of fiber type. This panelist B-10 HWBUI0009945 Brace W. Case agrees with the authors of the proposal-and with the:recent analysis of.Hodgson':and Damton (Hodgson JT and EJarnton A 2000) of seventeen cohorts for which exposure data are available that (even haying accounted for smoking, dose, and industry tyge) there is at least a tenfold increase in lung canceriagbejtosrrelated risk for^np.hihole asbestos exposures over chrysofije asbestos-exppsures; it is difficult to differentiatehowever between amphibole fiber types, and also difficult to differentiate between "asbestiform" and "nonasbestiform" or "cleavage fragments of massive amphiboles" and "asbestiform" exposures ifthe latter exposures are to structures having similar dimensions, regardless oftheir crystal structure. An effective test of this is provided in the data oh chrysofiie miners, millers and factory workers of Liddell et al. (Liddell FD, McDonald AD and BdcDdiiaid JCI99S), iit 'wbich^"if is how clear tliat for all practical purposes (Mrig chncer risfe) was corifenedto (One tinningatea), ''prdbabiy"clue largely to fibrotih kemolite arid in dust conditions '(averagjri|;)':'. .7 mpcfor Vfty roughly;24 fibers/tril". The proposed*risk; coefficients-in .Tables-6t29 and.6-30.appear to. be highly conservativewith respect to what is knowfnyabout,the differential, effects, of liber. type: for.lung, cancer risk, with only a.fiverfold differeag^ .Since others have suggested that there fi? m fact a difference that is somewhere between ten and fifty-fold, this sennas reasonable. jGiyea ^xfe-eme importance of the other factors noted aboye and.described in more detail in section D] below (dose, smoking habit, and type of industrial setting (the latter perhaps being related to fiber length); a coefficient which is conservative for lung cancer risk and fiber type seems reasonable, as long as the other factors are taken into sufficient account by the risk model. B] Influence of Fiber Length: Please comment on the extent to which the epidemiology literature and mechanistic studies suggest that carcinogenic potency varies withfiber length. How adequate is information in the epidemiology literature for supporting dose-response relationships for differentfiber lengths1 In general, is it appropriate to assess cancer risks using . ' .. vtw.'- ' an exposure index (see equation 7.13) that is weighted heavily by fibers longer than 10 micrometers (pm)? This question was recently explored in part by an expert panel for ATSDR, the report of which is pending. Specifically, the latter panel .yvas asked to assess charge questions which addressed any proven or putative risk for "short fibers", which were defined operationally as B-ll Brace W. Case those havinglength less, than S y.sn (AIDR 2002), for both cancer and non-cancer endpoints. The aim was not a consensus statement but,to .use. the; information presented during the expert panel meeting to aid in developing scientifically sound public health evaluations for exposures to "short.fibers" definedasabove. Because,the.final draft of.this document has not been released it cannot be cited or, quoted, but hopefully it willjre made available to the current expejrt panel for EPA as: it is. directly relevant to issues of fiberJength. and' risk: There is no,Reason to "reinvent the wheel" for, the part.of the cunreqtdisctission which overlaps the previous panel's . deliberations, although,.additional input .from panel members,not involved ;in. the ATSDR- . convened panel<will he,a valuable.addition.tp this.discussion. .White the ATSPR-conyened panel was not charged with looking at the converse proposition that longerfibers convey greater risk of the endpoints in; question; (including lung cancer)*.this is the other side of the. same,coin and was . certainly discussed. ,.. : torr. As actoowlpdged.byvlhe,authors of the current proposal.to EPA,- there is little epidemiological dataavailabte.w.hich specifically assesses, the ,role of fiber, length.pn lung.cancer risk. Most of the..available epidemfological dataron lung,cancer risk.for,which atiy exposure, assessment is available comes, from occupational cohorts in-.-which that exposure,was, assessed ,either,fryjmidget. .impinger ,coun.ts-(which historically counted 3II.particles as rqillion .particles-.per ...cubic foot>(MPG^iv.isometr?P;paittei^ as well, as fiber?)-. Dfhis,method dealt -with, oil particles visible.by.light.microscopy;andihad a low resolution of approximately..I pm.diameter^withpp information on particle length. . Some epidemiological studies have as indices of exposure to asbestos data derived from the ,ipem.brane. filterjmc^od though..co,undng via. ph^e. contrast optical nii.crosc<opy,:(PCOM). Results are expressedas.fihers.per cubic centimeter or,,miHiIiter,(fibers/:ml,),..tof:arealways. UmUedjofibers longer than/Sipm. ..As-notedby.the, authors-of the current Brop,osJ.JP. E?A^ a. priocipal weakness of the membrane filter method and of. RCQM,counts is that they-arenot. >,capabte,pf,deteimWng whether,the ^j^hi^.b^g.<^Mted^ui|chially"a^^tos't. .^although the authors .do not appear,,to address the use of dispersion,gtainiiag. techni.ques.in. this- regardL- It is. important thqfEPA: receive competent mineralpgiQal.gr industrial hygiene advice as to-the suitability ofdispersion staining techniques in association with POM/ membrqng,filter counts to improve\Upon the identification of "asbestos ", and individual types ofasbestosfiber B-12 HWBUI0009947 > Bruce W. Case 'isinglightmicroscopy alone, especially giverhthe'increased costs (and perhaps decreased sensitivily) oftransmission electron microseopic techniques. *. 'Some-epidemiologicalstudies corhbiaeboth types of exposure index (MPCF arid'fibers/ "thI), using' data-tferived coriversioti-lactois 'fro'ih MPCF which vary from an approximate threefold tti an approximate eightfold multiplication of the MPCF value in question-to derive an analogous'value lii'fibers/'mi.1 .The conversion factors1 appear to be to some'degree study and wodcplace^specific; are by definition' approximations,': and -should -be used with': caution; the-most "'commonly used-conversion factor is-ah-ap{iroximate:Chheefbld mUltiplicatioii of MPGF.- -- Since all situations in'whfch theiis is^expdsiire to asbestos fibers comprise a site distribution with respect to fiber length rather than a specific fiber length compartment,'it is-not surprising-firat epidemiological studies Have hot addressed thisissue toicgffeat'exterit: It should Be'Ien^Tirbzed!hdwe'Vef that all existing:risk- assessmentmbilels, ihcluding*the'198fr-EPA risk assessment,'are fargeiyderived OsVthe exposure'- -assessment side from measurernerits'df, or 'approxitnatiotis''of:Rieasiirements,of or converSitfnS of othermeasurements to, exposures to 'fibefs'loRger!'ih'an 5 piri." Hi'addition it is Well knowhbotir fr&m-Studies of-sfee;disfiributions of asbestos iexpijstires'aad ofasbestds retainSi-dose that there' is-good correspondence''of asbestos c6ricehtrafibttS"(eveh.when'broken doWn into'indiVidtial fiber'types) across fiberile'hgth:' categories. '.-aV:-' o'j:v' ..if:- '" ' :1 ..;.v? 'J':So,nib''data; does fcjdst'fioihepidenudfogi'cal'slftidiesiW'hich' may inforinas tO'efFefcts'-df fiberiCngth on lung cancerincidence orinorfalify^TTiere are two extremes'for'-'fiberTerigtM -in 'epidemibldgicalStudies which AaveheSii'ekarain&Tmth respeCftothe'sha'pe-ofdistributions:-' Studies-of-tofotcers iri asbestos textile -industries, in whiCh'-therCis-some evidence that there is more!s'k;ew ofexposure fiBer-Ieii^h-distributidnsto-foriger-fibers; have generally shdwfra' higher difee^tosp&nse gradieht-for lung fcaiicer risk (Kndx:iF;'Hblmes"S, Boll RCt'al; 1968;-'Newhoiise - ;ME;%eniy^ Howard s^ ef al. 1977; Peto J 1980;V McDdhald-AD, Fry JS; Woolley AJ fet- al. 1983; McDonald AD, Fry JS.-Wdplley AJet all 1983; `Pact E Biiiatti E and Geddes M 1987; Sebastien P; McDonald JG; McDonald AD et al. 1989; Dement JM and Brown DP 1994; Dement JM, Brown DP and Okun A 1994; McDonald JC 1998; &-!3 HWBUI0009948 Brace W. Case - Case BW, DufreSfte A,-McDonald AD et af.< 2000;''Hodgson JT and Damton A 2000) . Conversely, studies of studies of gold mine workers in South Dakota and taconite miners in Minnesota suggested no lung cancer risk for a largely short (< 5 pm) fiber distribution. The South Dakota workers were exposed to cummingtonite-gnmerite material wkh'94% of airborne fibers being less than 5 microns in length. Gilliam-et aL(GilSam JDj Demeaf JM, Lemen RA et at. 1976) found increased mortality from malignant respiratory disease among workers with at - least 5 years 'ofexpdsbre: However, a follow-up study of-this cohort which considered longer Tatency-and thd^ittOSf hrgMy exposed workers fSiiad no such increase at es&naled'average?" ' eXposufd cohedtiftSfidas fiberspeaf'hiitbte een.timetef^MfcDonald JC,; Gibhs"GW, Liddell FD et al. 1978). ?A'later study of-3,444: then employed for-atleast 3 months in Minnesota - taconite mining operations (also believed to be exposed to a short-fiber distribution) during the. , .* (years 1947 to 4958-(86,307personryear!of observation) found 41 deaths from respiratorycancer --an :SMR-'of onIy;6l to- 85 (for.USotrhfte.'inale rates or Minnesota- rates.respectively)-.(Cooper WC,:Wong.Qand:Graebaer-Rii988).:-i- -. i.- i It seems reasonable to weight the exposure indices in question to assign greater risk for greater fiber, length.. It.alsO seems-nnreasonable based on current knowiedgesto assigmany .weight at all to fibers of less.than.Sjpm m length. Finally, while ft seernsxlear.from what we kriowof.. .mechanistic studies* that himorrhazard is related to increasing length; a coefficient thht-assigns incrementally increasing weight,to. fibers -in; a continuous length distribution would .be preferable to-one thatsimplycategorizes lengthSi'iThisibowever..ifiay. be;quite-iiripractical.fortrealrworld assessments-of hazard; iHavingisaid'all;this,.the paucity ofrdirectdata-on fiberleagth in the .`.epidemiological studies makes itimperativ'eto answer the-question.as pdstid4-r-ff-scis-i-it.'> != i>t.iappropriate.to assesscancer risks-iising ah exposure Ladex (per equationi?:!!?) that is? weighted heavily by fibers longer than 10 micronieters;(piti)?"^ its the negative;>if^neis referring toAhe supporting evidencefrom epidemiological studies alone. Nevertheless, the very heavy weight put'on the-longesbifibers fOr.Ttaiig .6ancer risk-in? this equarion .does seerit--reasonable taking all of -the availableidata into-account-:<Strict!y speaking, an equation which putgreater weight-on t increasing-length-intervals,would be better-and ittnust-be remembered'that thevanishingly Small B-14 HWBUI0009949 Bruce W. Case coefficient for fibers^between 5and 10 pm in length will belmodified by the:fect that.those fibers are far more numerous (and more likely to be disproportionately counted by any available technology, .including transmission electron microscopy). .- Cf To.wKat^extent do animal studies (e.g. studies by Davis and other researchers) suggest that -carcinogenicpobemtymne&.mdkfibertype.Biidfiber lengfk? .. .. .. These studies, are, clearly outlined in the protocol provided by the authors of this proposal, Ingeneral, inhalation Studies support the role of fiber tepgfh (especiallyifiber length . greater than;1.pm,, or in Hne;^i^.giealKM$'|Mn) inlung cancer risk and also.-suppost ttie;assertidh;that-theifts no. excesslung cancer risk in these models tinder.5 phi'.1: "" DJ: Pleasexomnieation the extent to:.which carcinogenic potency. is&- function of fiber properties (e.g.-, diameter,-aspect iiatiOj-surfece properties) fiber type.and fiber length: How adequate is information in the epidemiology and toxicology'literature-for supporting these other properties into dose-response analyses? -* v ...r .. ' Aspect ratio is;sinipIy.'the.ratio oflength.to widthand-therefore should have no role in risk assessment independent from :length and width. Surface properties, especially surface iron, may well- be related-to lung:^ancen.risk through the-mechanisms .oflung cancer production (such as, for example, free radical 'generation and cell signaling mechanisms), but in my.view are insufficiently;developed oruadeistood-at this time,tobe useful for-risk-assessment/and ;are certainly not ready tobe iricorporatedinto dose-respoifse analyses.! Thiswas also in essence the conclusionof the lARfJ panel,' which wassconvehed1in~.order to determine whether mechanistic 'Studies could contributed risk assessment-protocols and in-the consensus statement concluded in effect that current evidence-is "weak"(IARG. 1996)..>:.:-?! s ,-q .!* . ; u-f i .:=M:rto.t;ed abpve the,pricipql.factctrS. driving risk-for lungioncer: relatedto asbestos: exposuffiln approximate order ofpriority, are not /fiber factors perse butasbestos dosty.degree i' ofsm&kmg'co-rexpoiiure,ttype'Of.industry, (in an industrial setting},andfibertype,: With the exception of the latter, which was dealt with above, these are not necessarily directly related to fiber factors, and are more important thanfiber, factors (particularly fiber type and length) and B-15 i-PSSIES-IS HWBUI0009950 > Bruce W. Case should to the degree possible be accounted for m anyridbassessmentmodel. They are.in fact accounted for in-one way or another in the-proposed model. . Fibir-'dose (derived fromfiber exposure) is so obviously related! risk that.Little further need'beVsaid herein facbthecharge questions assume the importance of;this factor, while i; "jumping the gun" to assess the effect of other factors.-on "dose-response-analysis". One.cannot begin without a discussion of the influence of (externally measured) exposure, and subsequently of retained dose, persk; The authors oftheproposahin fact do so in a number of Ways, although their model itself is highly- depCndenton; fiber fasAotsiin addition to dose.-. The.question:.of.linear extrapolation,; thegeneral.use of the linear;.model (as oppbsed toother models), and .thequestion .. of threshold also arisesitn relation to the issue of total exposure and resultant total dqse, . ;= ..vi,, . Indmdual.smoMug history, is. the second mpst.iin|tbrtapt;fgctoir.in.risk after.ajbsolute exposure and absolute dose. The previous (1986) EPA model and the current model appear to assumeithioughitheiderivatiotoof.the-.temis that riskfor.smokirig and,asbestos.are multiplicative, with both 'assessmentsibeing heavilyreliant*on an early andilawed analysis of this relationship by SelikofF ;and Hamm6nd((SelikoffiIJ,Hanunond ECandSeidman H- L9.79) This. is.;assumed : through.the;use ofa model '^yhich uses relative risk (to the underlying, population) ,in which most of the absolute riskds -dueitbismoking*;This maytoverestimate.lungcanceerisk as the actual synergism between'smoking and asbestos exposure is. now,-generally thought to be less than multiplicative, although still more than additive (Liddell FD and Armstrong BG 2002) . Type ofindustry remains a powerful influence in risk. It is often-assumed that fiber] - v. factors (perhaps especially fiber length) may be important in this regard, but this remains unproven and ba^ed largely.on some assumptions abot^t the large differences in the doseresponse analyses between asbestos textile cohorts and asbestos mining cohorts, particularly those commonly associated with chrysotile. In fact, while there is no doubt that large differences in the slope of lung cancer risk e|qst between these industnes,.it remains;runproven that these can be accounted for entirely by differences in fiber length, and recent thinking on this subject suggests a more complex explanation (McDonald JQ 1998; Case BW et at. 2000; Hodgson JT and Damton A 2000) in which other factors (including but not limited to fiber type, and including other processing steps in industrial settings) play a role. For example, it is clear that B-16 HWBUI0009951 Brace W. Case while exposure (externally measured) may show a greater proportion of longer fibers in, the. textile ton in the mining setting, forany given fiber length interval the lung-retained .. concentration of fibers is greater in the mining situation -- and it is the mining situation which shows lesser.'lung caiicerrisLv It dotes appear from close examination.of the data'however that the ratio ofretained'dose to exposure is higher in the textile situation for.the longestfibers , (unpublished analysis ofdata- from (Case BW et a!. 2000)): ' It is hard to-say .how, if at all; this element which-is a powerful-oim in industrial settings r '-eaa'be'bhnslated' into:risk-assesSments forenvironmental settings unless it is,possible, to -.. sdetertnnte'for a given enviroiiiaentalfsetting (or site) .which Iniustiiahcohoitjis,niost.>Sinailar^. For most stiperfiind sites dealing with former mine sites; for example, mining .cohorts (tKdsehvith a lower slope of lung, cancer risk) should clearly be those applied and the textile data Is of little relevance. :The'iiiodel offere<l'dd&vnot account for this possible 'discrepancybefwteen sites. >1 ' '"Finally, as noted abdvtei fitter type, dock play an- apparenbroleih risf6forilitag:ahcteri.with a Sen to fifty-fold excess risktoviifgtoen-saggested byittie best available-analysis (Hodgsctn'JT -artdDarntonA 2CK)0)-for commercial amphibole exposure as opposed to chrysotile,-arid for 'virtually alhof-toexcesslurig 'cancer risk in the chrysotile. miningsituation being explained by co^exposures to tre'molite.'.aHeast.imthose with exceptionally.heavy.,ekpostire (specifically greater tots 300-riiiUion particle per-cubic foot - years (MPCE-Y). -,. (Liddell FD et al. .199.8). 2) ^oi'mesdihdionfa:- ' `W. ::! tu:- tr..\r oqiV !-,<: . -slkT/S --xfv; ;'ftgtvXp:'v A] Influence ofFiber Type: Please comment on the extent to which the epidemiology literature and Oi'- rr -U sil} . f\ : .:*!' h\ \ 1 :f; mechanistic studies suggest that carcinogenic potency varies from onefiber type to the next (e.g. , \ v .... . . ^ :\j-:-r- chrysotile'versus amphibole fibers). How adequate is the information in the epidemiology literature for ; v;p':: viti'Ai vta!.::> -.Ikiv: ..'Wvr?-. ! ;- supporting dose-response relationships for differentfiber types7 Specifically, to what extent do you think the proposed risk coefficients in Table 6-29 are supported by the epidemiology literature? V/i; The epidemiology literature provides definitive evidence that carcinogenic potency varies from onefiber type to the next. Indeed, tore is currently no real scientific support for the proposition that B47 HWBUI0009952 Brace W. Case chrysotile'is a cause of malignant mesotfaelioma from available epidemiologicaliStudies. This^is. true , , across a wide range pf industries and studies, including cohort.studies of workers in a variety of asbestos. industries^ case-control studies ofmesothelioma and occupation, and.a variety of studies,of non- . occupational'exposure. to asbestiform amphibples, including but not limited to, tremolite asbestos and.to "cleavage fragments". of massive tremolite amphibolchaving dimensions"similar;to; those, of asbestiform : ~ = 'w tremolite fibers.. Even efforts to gather together all reported "cases" ofmesotbeliorna.related '"rnainly" to . chiysotile exposure inevitably-come;up with small numbers of such cases limited.mainly to chiyostite,,,,;.-.; ;; miners and millers also exposed to. tremolite.(e.g. (Stayner LT/Dankovic DA* and Leraen RA 1996). , Mesothelioma is related to amphibole asbestos exposure in approximately 80% of cases in epidemiolo&cal'and pathological studies (the attributable.-risk varies from, abput;6P% (McDonald.AD. and McDonald 1C I980;1 Yeung P and Rogers A 2001).to about 88%-(Spurtas R,;Heineman EF^ Bernstein <>-v L et apilW);depending on:the population;and time period, covered. This issuppoitedi.bYStndies whiph assess exposure t6'humansdirectly;throughTung-Tetaincdfiber content (syhat the;authorsrqf>die,.prpposal.)v:.; ;.. call "pathology studies"; for exampIe.(McDoha!dJC, Armstrong B, .Case.fi et at 1989; Rogers; AJ Leigh. . J, Betty Get ah l^li Rodelsperger.lQ.Woitqwitz.HI, finickel.B et al,:l999).c>r by occupational inquiry.- : (McDonald AD and McDonald.1G :1980; ;Tfita Ml, Lewirtsohn HC, Meigs. JW. et al^1983 :Spirtas R. et.al.. ...... 1994;Witowitz HJand-Rodelsperger:0994;TeschkeK,;Morgan.MSiCheekowayH;etaL l<t?,7) (d-. properlyeonductedin a tme analytical epidemiological study, as opposed to.a surv.ey, "registry", >or i.-. collection of "cases")..-. -. : ..- ,, k .... v- ; > .; - .. ... >' ;. . I ..I,!.:, The percentage is higher in occupations: with, heavy amphibole jsbestos.exposure, arid in .. relatives of those in some such occupations, or occasionally in areas of endemic exposure such as the neighborhood of some shipyards, factories* and mines. It is important tp note in this regard that. . ; exposures thpjighMo be.-.TrqnQCCupalj&nal" may fitsfof all simply-have inadequate '.occupational history/ .. and secondly-may be-tiuly ^rionoc.cupational'^but nonetheJess.be associated witir,ex,cepti,ona!ly .high dose... .A;i An example.ofboth-of.fte.latterisj.offered.bya receqt.case contol.study qf pleural rnesotheHoma ampng . . women-,living in. the neighhorbeod ofchrysotile.minesr .of ten cases-dfecovetgdj at! had worked outside , the home;;ftve;..wereknpwnto:haye worked in.the indusfry, nine had at--lived withat jcastone and more. .... frequently, more, than one asbestos worker, find all lived in the- highesttremolite,area (Case BWi CM, , .-. RichardsontL, Parent M-E, Desy.M; and Siemiatycki.J 2002) . Jn addition exposures were very, high,.. estimated among cases on average at over 200 fiber/ml -- years and never under 100 fiber-m! years. A . , . B-18 HWBUI0009953 Brace W. Case similar situation for-environmental exposure to crocidolite'has recently'becmreported from China {Luo S, Liu X, Mu S it al.'2003); where-'crocidolite was found.in the surface soil in a rural county.where 'the .. average number of mesothelioma cases was'6.6 per year in the'1984^95 period and 22 per year in'the : 1996-99 period, in a population'of 68 000. The anhuahtnOrtality rate for. mesothelioma was reported:as . . 85 per million,:'I78 peomillion, and 36S per million forthree separate cohort stadiesj.and therehere were: no cases df mesothelioma iir comparison groups where norcrocidoiite was known=to:exist-in the. ' v environment This provides att'object tesson'for parts ofCalifornia in which asbestiform tremolite has- been identified in the surface soil arul therehas been a large degree of recent and planned housing- ; ; development. '.S'-:-.:. ji-.-V''---- .! . Most exposed mesothelioma Cases mothef'stadies cithfer Worked-with,6r more.iarelylhad -.;i <.r .. relatives'who' forked withicbriuheicial amphiboles /whether crocidolite (AnnstrongBKj'de Klerk-NH, Musk AW et ah T988; de Kletk'NHl Armstrong BK, Musk'AW et ah: 1989; de-Klerk NH/Armstrong BK; r Musk AW et al. T989rde Klerk NU Mtisk AW; Cookson'WO et aL= 1993j<Hansen J,: de Klerk NH. -j :-: . - r<- Eccles'JL ef al. 1993; Hansen J/de KletkNH, MuSk-AW ef al>!1998) and/orramoslte(Sluis`CremerGR 199V, Shiis^Cremfer-GK 1991; 'Slnis-Cremer GK, Liddell FD, Logan WP-et al.sl992);although large > quantities of noncommercial aitaphibole fiber (tternolite 'Or btHet niiflerals ih lhe tremolite-acdnolite series) associated with chrysotile iii'mining occupations/rriined a&4frdusfirial "tklc^'(Ab'raham JL, Hull,' M., Case, B:W. 2002) or vermiculite (McDonald JG;McDonald AD; Armstrong B et al. 1986; Amandus t HE and Wheeler R 1987; Wright RS, Abraham JL, Harber P et al. 2002) may also be causative. Relatives of such workers who are subject to domestic (household) exposure to mining or milling fibers brought home'ori clothes or'Shoes-arfe'also subject to'fnesO'thelioma-risk.'- ' ' Mesothelioma wais -first '<to'nc!usive?yTtriked to <1fel^<^^-XG.;-|Wagiiw;jif'Sputh'A|nCa^nk'vU'!j!;.v I960 (Wagner JC; Sieggs CA'aiid'Marchanii P T96()jin a'largostodj' of'Cases-taken from tbe Cape crocidolite mihes. Sohie.pathologists'iaeluding the late Dr.`Wagner Still'believe that crocidolite is the- most iidportahf:or'even''the'oniy'c'aiisatii'e fiber; but-most-how ;aCCept'amosite'as:feS|j6nsibleri'oraS`'.many or morercaSijS'(af letist ih-the';Uhited;States),'''and limg-rettoffed'-fibef Su'rveys'Of'cas'es by Chtirg. and by. ' Roggli et al: (Chiirg A and Green F:1990; Roggli VL, Pratt PC and Brody ART993; Ghurg A and Vedal S 1994) have established that the less potent amosite fiber is responsible for the largest percentage of cases in the United States, at least1 among plaintiffs in lawsuits from which their cases were mainly drawn. "' " ' ' ; "' ' B-19 HWBUI0009954 Broce W. Case A recent meta-analysis of 17 cohorts with established exposure histories has reconfirmed the over-arching importance of ampbibole exposure, in. mesothelioma:,causation, including in cases of -exposure to mixed fiber types, including situations where chrysotile. is.byJar the most prevalent exposure (Hodgson JT-and Damtbn A 2000) These authors estimate the. relative,risks of.`fiber types for >,... . mesothelioma as crocidolite: amosite: chrysotile 500:100:1, even making, the conservative assumption that the chrysotile-related fraction includes the mining cases. Crocidolite, the .form first shown to cause mesothelioma,, remains the.most potent cause,- although, use has been-essentially banned in North America and Europe and the .number, of. future cases, has been.... overestimated according to die most recently available.data. More North American workers (at least insulation workers.andthose in-allied trades) have now heeh.-.mfposed to amosite, and, therefore .more. . . - cases are produced by it, even though; ;giv.en equal exposures,:the.propoition;of workers deyeloping . mesothelioma is higher among,those exposed to crocidolite. - - .. . . ,(! - : ; -v.-U.'V - Studies of chrysotile miners arid millers in Quebec (well-described by the proposal's authors, in , : general) show a mesothelioma death rate of approximately 0.4% (3378009 or I in 240 deaths in recent years (CaseBW, Churg, A. Pufresne,-A. Sehastien,P; McDonald, A:D.;.and'McD.onald;-JiC. vi997;.,. McDonald AD,: Case; B%- Chutg-A et aL< 1997).' Jamg^sap analytic Study of mmere from'different, . : - ' locations show unequivocally that what was thought to be "chrysotile-rtelated" 'mesothelioma occurs oply , in tnining-and milling situations .where-tremolite-is prespilt in sufficient;,quantity;tq,pjroduc^.high,levels.qf . .. long, thin,-high-aspectrratio tremolite or tremoiite-actinolite fiber in the lungs of workers.-. .. . .. In these studies.the area, in .which mesothelioma risk.was in greatest excess, was that where the. ampbibole tremolite was (a) geologically likely to be present in highest concentration and (b) present in excess (compared, to Other chrysotile mines) in. the jungs^pf.miners and millers, . . , ... : Commercial amphiboles, on the other hand, have long.been.knowntocause.mesothelioma, and at . ; far-lower dose/ .-Wagner established the.causal relationship between "asibtos" and mesothelioma in a . .. crocidolite mining region,- as noted.alm.ye. AVork:by. Hansen and colleagues bave.shqwn,at the -Witenoom. 1 1 Thisiapplies to the 33 of38 cases in this study,who were miners and millers of.chrysotile.: Another 5 cases worked in a factory producing asbestos products and used crocidolite asbestos. The total number ofdeaths giVen however also includes deaths among the srnailuumbC'r of factory workers) B-20 HWBUI0009955 Brace W. Case mine in Australia the- causation of mesothelioma by crocidolite exposures as brief as one week and as small as 0.4 fiber-years'(Hariseir-J et al: 1998). Similar work in South Africa has produced comparable results, both for crocidolite and for amdsite,-although the'quantification of exposure is not as good as'that observed in the Australian studies (Hodgsonand Damton 2000).' Recent work-from China suggests that in one rural province there the situation'may be similar (Luo S et al. 2003).- : , Surveys of individual asbestos industries have confirmed that within, those industries fiber type remains the key factor in mesothelioma production: ' effectively, wherever crocidolite;or. amosite have been used commercially'some mesothelioma risk has:been introduced. Acheson and others (Acheson: ED, Gardner MJ, Pippin! EG et al; 1982)'looked at female respirator manufacturers^- groups followed for 40 or more years. One'grtmp -made "civilian* respirators containing chiysotile - and shbwed.no mesothelioma excess (arid: bnlyonecase; who had worked in the otheriplapt as'well). The othermade "military" respirators (containing crocidolite) and bad increased'inesothelioma mortality.- 'Similar results were observed for Canadian workers making military gas masks using crocidolite (McDonald AD and McDonald JC1978). .U; i '!'< : : :! . -.ili; A similar.pattern waif demonstrated-for two asbestos cement plantsinL&'uisianaby Hughes -and Weill (Hughes IM, Weill H and Hamroad YY1987): Mesothelioifta risk occurred in the plant in which - . crocidolite was used in one manufacturing'process. Similarly, Gardner'observed One case of mesothelioma in a cement plant'using-mainly chrysotile- but noted that the case was- believed 'to be due to exposure elsewhere (Gardner MJ, Winter-'PD, Pannett B et al. 1986). A'very recent study from Norway has again demonstrated the importance of a proportion of crocidolite in the cement manufacturing process in inducing mesothelioma risk (Ulvestad B, Kjaerhetm fC, Martinsen JT et al. 2002). _ The manufacture of ftictioh'prddtictsisa'particularly usefhl area iii which to'look at thedistinctive differences in epidemiologic risk by fiber type. This is because for the most part these products were made With ahrysotile asbtestbs; >with only occasional "special conhacts".in some plants having used' crocidolite;" MrabtfieKdma;risfc;has''been limited to those situations.' ' This is true whether the studies have been of the plants'in-whtehfnfction materials were manufactured (for example (McDonald AD and Fry JS 1982; Newhouse ML, Berry G and Skidmore JW 1982; Berry G and Newhouse ML 1983; McDonald AD, Fry 7S, Woolley AJ ei al. 1984; Newhouse ML and Sullivan KR 1989; Berry G 1994)), or whether the studies were case-control studies of mesothelioma in which end-product users (including B-21 x ' -J HWBUI0009956 mx> Bruce W. Case identified groups ofworkers who worked with brake linings in garage settings) were included (McDonaldAD arid McDonald JO 1980;:Teta MI et al. T983; Spirtas R etaLI994; Woitowitz HI and Rodelsperger K 1994; Testhke K et al. 1997). A recent- meta-analysis has added statistical power to the latter analyses by combining them and again-finding no mesothelioma-risk for end-users of automotive friction products (Wong O 2001). - . "Mechanistic" studiesof mesothelioma,add little of value to the question fdtber type.-This-is because-of the large degree of interspeciesdifferenceas -well as the technicaldifficulty ofperforming - inhalation experimentswitif raesothetionia-a`s:an endpoint One intriguing, mechanisfic pointthat has . - - come to the foie with recent in-vitro and cell-free work has been, the-'questiontofthe presence of iron and- its effection fide, radical generation and'related effects. ^While'this'appeSrs afcfitst blush to be'relevant . : 1 / - due to the "structural" ironcontent of the commercial asbestifonTv.amphiboleS'(crocidoIite'arid:amosLte) > (as well ah the-femiginous`'asbestos.bodies"!), it does;is6t explain the .effects'of some of:the other amphiboles. Furthermore^ cKrysotiie is not always "iron-free", as.'iron may-be substituted in its structure or absorbed onto its surface: ' = - . - ........: - The. proposed risk co-efficients in-Table 6-29 are quite consistent-with tfre.enhanced effectof amphibole fibertypes-on mesotheiidma-risk observed in epiderniological-studiesi '-The coefficients < ,, ' appear to be conservative in that they assign any mesothelioma risk at all to chrysotile asbestos for mesothelioma. It is interesting that although a different method was used than that of Hodgson and Damton (2000),-the "bottom line" in this model appears to bedhe sarae.or even-greater: - an approximate five-hundred fold increase in risk for the amphiboles ona fiber-for-fiber basis:':' . . Bj Influence ofFiber Length: Please comment 6n>the extent to which the epidemiology, literature and : mechanistic studies suggest that carcinogenicpotency varies withfiber-length. How adequate is : information-in. the epidemiology literature.for supporting dose-response relationships for. differentfiber lengths? In general,-.is;it appropriate to-assess cancer risks using an exposure-index,(see equation 7.13) . that is weighted heavily-by fibbrsTonger than 10 micrometers (pm)?-j' r - For the most part,. epidemiology studies do not inform with respect to-carcinogenic potency for. mesothelioma for fiber length. This -is because, as pointed out by the authors,.the existing epidemiology B-22 HWBUI0009957 Brace W. Case studies have not used methods for exposure assessment which are capable of assessing fiber length, other, : than (if PCOM.is used with the1membrane filter' method or an approximation of or, conversion to .PCOM. values used from MPCF) limiting exposuresito those longer than 5 pm. Of "mechanistic" studies which inform as to fiber length, the. classic studies remains those of Stanton (Stanton MF,- apd Wrench C .1972; : Stanton MF 1974; Stanton MF, Laynard M, Tegeris A et al. 1977; Stanton MF, Layard M, Tegeris.A et........ al. 1981), although the method of "exposure" in those experiments was neither physiologic nor in any way related;to actual, human exposure^ ^Nevertheless, no discussion of mesothelioma and,fiber length can ignoretheStantonjmodel,-for which, there has been additional support in many.animal studies since. It--. - must be realized however that.the classic.Stanton "Carcinogenic" fiber dimension (fibers having length. . greater than 8 pm and diameter ies$,than 0.25 pm) were not met by all-, carcinogenic,fibers, and .with . specific respect.to tremolite -- a,>fiber-foj;iwhlch two-preparations produced a i00>% tumor response in the model - Stantontspecifically reported thiat his<model did not fit the response, and that "...relatively high correlations (with tumor response) were aISo-noted.with.fibers mother size categories haying-diameters-, v up to' lv5 micrometer and ledgths!greaterthan-4.micrometef>'(Stanton MF et al. 19.81). On.the. other. . hand, there is no evidence that structures having the same chemistry and crystalline.structure-as "asbestos" but length less than 5 pm behave as fibers rather than in the same way as isometric particles, nor is thereievidence that such particles.convey any .risk for malignant mesothelioma. There is also a great deal of-animal data which suggests. the!converse, much of which is- listed by-the.authors of the. -. ' proposal. - - !.......- . ' i ii. - -. - : .. Cj To what extent do animal studies;(e.g.istudies by Davis and other researchers) suggest that" carcinogenic potency varies with/Ifeer type and fiber length?.. Animal studies are of little value in assessing the carcinogenic potency of fiber type. Animal studies?which assess' mesothelioma risk using -the exceptionally, sensitive peritoneal injection model in rats are in my view of little valuer and intratracheal instillation models are similarly flawed, in the latter , case in part-because of the difficulty of assessing either, the size or the nature',of the administered ,dose in terms of fiber number or morphoIogyyVEven animal inhalation models-have> proved disappointed in : '.assessing the risk posed by different fiber types,- principally because rats, are rather insensitive in this , model. A recent review (Muhle H and Pott F 2000) summarizes this well: "Inhalation experiments with rats need fiber exposure-concentrations...about 4,000 times higher (than those of asbestos workers) to reach the same mesothelioma risk; Also, the.spiking difference between the low lung burden of B-23 ) J HWBUI0009958 Brace W- Case amphibole fibers of asbestos workers with mesothelioma and the more than 1,000 times higher lung burden of rats:.with\a.low mesothelioma ;riskdemonstrates the low sensitivity of the inhalation test model for the carcinogenic potency evenof.crocidolite fibers."- Fortunately.-the effectof fiber type for mesothelioma is established beyond question by the epidemiology studies, at least for the relative effects s :: ofchiysotile as compared to commercial amphiboles and tremolite asbestos. Todhe degree that fiber.length.categories can bp.separated for the purposes of exposures in .is animals (there is''nosuch.thingasa(^rfectpreparationiriwhichthere.are`TioIong:fibers"or-"nb>short fibers") the animal studies do indicateincreasing mesothelioma risk with mcreasuig fiber length, > -sfc. although the'fiberlengtfr .varies somewhat from study'to. study. The fibeEdength most often mentioned ..l above which a mesotheiiontaresponse-was.6bserved''is^0.|!.m'.ia.more.recent:studies;; These.-ard well-;.::.' : described in the proposal and will not be repeated here: key references include those with sized fiber preparations, with-characterizedlength distributions,'and with theoretical calculations (Davis 1 Addison J, Bdfrbn RE fetal. 1986;.Davis JM and Jones AD4988;T;ippniann M 1990;:McConriell Axten C, Hesterberg TWet al; 1999; Miller. BG, Sear! Ay:Datvis JM et al.-1999). -.While the-same;. problems.exist for-sfedies using the intraperitoneal iiijectiori modelin the rat with length as the . . .. .... .. . independent variable as those for fiber type, one: studyithat was not peer-reviewed prior to publication of . six naturalty. decumng.-fremolite preparations-does suggest some effect (Davis JM.i Addison J;McIntosh :! C et al. 1991)'. .However the:main purpose of this-stady.was-to .test the-relative effects of "asbestiform" versus "nonasbestiform" tremolite prepafations,(sefr'below)^... - . .. D] Please-.cbmmenfion>the-extent tp:;which-.carcinogenic,potency'.is-a.fiinctioirof fiber .properties diameter, aspect ratio, surface properties)-other than fi.ber.type and-fiberdength;: How.adequate: is . informationindhe; epidemiology and.-tdxicology literature for 'supp6rting-these.other..properties into dose-.. response analyses? U ..:; s It iscfrpportant here: to distinguish between respirabUity>and carcinogenicity, with respect to fiber diameteri>;Asrjrioted.aboye,:thejqHginal Stanton studies actually-showed effects at diameters ofjess.-thfui.-i,:: 1.5 pm, not Sipm..A cutoff.of 0;5. pm is. probably inappropriate, although it is quite true that almost all chiysotile and.crocidoEte.fibers will-be included. This,is somewhat less true for amositeacidis.not;: acceptable at ati for.tremolite,which in many situations Will almost reach an arithmetic average of.Q.5> . . pm diameter. In general, as-demonstrated by Berry:(unpublished-data on Witenoom and (Betty G 1999). B-24 HWBUI0009959 Bruce W. Case ), who has shown that "the incidence .of mesothelioma after exposure to asbestos is propoftionafto the intensity of exposure'(libers pet milliliter, of air) and the duration of exposure, and ,to the timedhat has' . elapsed since the exposure. The incidence increases with time since exposure to a power of between 3 and4". V . : - The latter variable -- time since first exposure -- is a very powerful component of mesothelioma risk in epidemiological studies across the board; if they are large enough and have long enough follow up. No' model which ignores this-timing factorcan'be considered.adequate.for predicting risk.- In addition Berry has recently demonstrated a large-effect of elimination time on mesothelioma risk-by < applying this-modelfo Witenooip mesothelibriia moitality.data (Berry G;nmpublished.data presented at : . Internatidhal Mesothelioma- Interest-Group-meeting,-:Peithi -Australia,. December-2002). -`r.r < 1 willtake the opporturiity'hete.to'separateiy-'ahd.briefly discuss.Iung-retaihed:libersttidies-in.:i-. human subjefcts'iform'es'othdlioma';:--.''a` separate category ofistudy which is halIed"pathol6'gy studies" by - the authors which-is capableofisOlhting effectsrof fiber type.and length with;the understanding.that- -~ ;/ . analyses are performed at an endpoint;(either lung biopsy; pneumonectomy, or autopsy) which integrates .. lifetinie dose^and clearance at a'single point in time.'It is.iionetheless-useful; althougftto some degree' dismissedbythe'.authdirs of the model for 4 number oftheoretical reasons, chiefamong them what'thei.i. y authors ca!l "opportunistic" sample site selection and-whaf the authors believe is poor repeatability of' .h. results. In fact, if such studies are well-controlled,- sample/selection is not opportunistic; in ithafsamples-:-' from cases and controls, taken at the same time and in the same way by the same pathologists in the same hospitals; are very likely to -be comparable.- Similarly, there is little evidence other than a few studies' based on very smalt numbers of samples'thht thereis in fact significantly poorreliability.tosuch . measuremdnts'so lohg as foey-are comparedyrtthin father than acrdss labotatories^-.Reli&bilitydsfatdeast:: as good as that for TEM fiber measurements in air. In fact, in Quebec, this is the method used foutinety to characterize exposure for workman's compensation purposes (when lung tissue sections are available). We have had the experience of{nindreds ofsuch-analyses and our results do well in cross-disciplinary validation?studies-incomparison'wiih'semiquantitative job-based indices ofasbestos exposure;-We'have not enfeoiintefed difficulties-'with'reliability; our published studies in fact- are capable of distinguishing. trends of fiber- retention with age, with nudlHirban -gradient, and with distance' lived froth and time lived ! ; in mining areas for environmentally-exposed individuals (Case BW and Sebastien P' 1987;Case BW;' - Sebastien'P and McDonald JC 1987; Case BW-and Sebastien P 1989; Case BW 1991; CasedBW 1994; B-25 o \ ) ) HWBUI0009960 Brace W. Case Takahashi Case BW, Duftesne A et ai. 1994). Here for example ate results from our most recently analyzed mesothelioma case; note the consistency, across samples. . , : : Sample site . ' - r Asbestos body concentration- .< Grocidolite i (AB/ gram dry lung, PCOM fiber at 320X!, detection lunii'40 concentration* ' ABAgram' dry lung) .qi -(and number) Right lower lobe #1. 31,520 AB/ gram dry lung . 722 fibers/ mg dry lungiri4=22) Other asbestos fibers . detected; detection limit 35 fiber^/ mg dry lung! . -ii.- None detected; Rigit'ifiHWe lobe}' Right lower lobe #2 26,880-AB/ grarri dry liihg 28,320 AB/ gram diy lung 620'fibers/mg dry lung (hf=18). 790 fibers/ mg diyJlung:(N^2'3)^ None detected: ' None detected A ..-.' ..i -its;-,. Right upper.lobe. , -26^20AB/grarn dry lung t . , 55,0, fibers/, mg. None detected . .-..v dry lung (N=16) * Fibers (longer than 5 pm, aspect ratio greater than 3:1) identified and counted by transmission electron'hucrdscopy'at'13,500 X inaghificatioh^id by'energy dispetsivfe'X-raysiiecjrtim^tty'fEDS).'' ' ' ' ' ' -I . V >> r..- Vi' i- Jisjbi.jc With specific,,reference to mesothelioma causation, several case-control studies using this type of exposure index have produced interpretable results which lend strong support to both the role of (ampbibole) fiber type and of increasing fiber length. In one such example, McDonald et al. studied 78 .'l'Vs'UM1 ... yl.riii . : .<;it?. ,d rA.--'i case-control pairs of lung, samples from mesothelioma victims and.controls matched for age, sex, st?" '-..isifv'.c- -ilani.-j-'ii |- .,, i..!- . nis; ' >!>; .-ivs-iit! hospital, and time of acquisition ofsample. (McDonald JC et ai. 1989). There were "substantial differences...between cases and referents for amosite, crocidolite, and tremolite. Much less difference was noted for anthophyllite, talc, and chrysotile... Statistical analysis indicated that short fibers were not v -r->i i. ."u,:- - .. a.-. . .>:/.:= ; . - : associated with iacreased.risk for mesothelioma." It should be noted that no special care was taken to match sample sites for cases and controls or across cases or controls; this is in fact not necessary if cases- .>* v"`. x A * * ' ; . j' . . j yv*.*. .-,.1 and controls are matched by hospital and era as it is the routine practice ofpathologists which, determines sample site selection; in other words, while the authors of the proposal were justified to in their belief that-such studies might use "opportunistic" samples which are not from simitar sites within the lung, the actualpractice ofpathologists taking lung samplesfrom autopsy orfrom resected lung tissue is quite consistent in this regard, with most taking centralparenchymal samplesfrom fixed sites in a manner learned during any pathology residency. 3)' To what extettt'afe the exposure estimates documented in the asbestos epidemiology literature reliable?' ' ' y/' B-26 HWBUI0009961 Bruce W. Case This, question is unclear, and may-not be the most relevant to ask. More importantthan the.. reliability ofexposure estimates is their validity, which: in general is excellent within the latest . and best studies that have been generally used for risk assessment (combining them in meta- anatyses.has proved more difficult.and eohtiovereiad). Siuulariy, reliability is good across the largest individual studies but much poorer between studies, due to. the differences in r- methodology employed.: This'is well discussed by the authors .of die proposal and they suggest . some additional work whictfmight help to ameliorate thk difficulty.' However, the authors tio i appear to be unaware ofsome ofthe controversies, extantaboutthe^eestirnafes2.* Fotexample,-' . . ` * they make use the Wrtehctom dafa wthdut referring to the controversy and debate between; . . v Australian researchers aboutthese (Because oftheir exceptional importance.these comments ' are attachedWtft'ese'cbmmenis as appendix A). The'aiiithbrs doriidtS'ihe exclusioii &f thfei': :- "Charleston (textile) dalaby Hodgson and DarntOh but choose to include it; ih iriyvtew this is hot critical to their conclusions a|ftougt> the Charleston data is .clearly an anomaly even within. studies of textile workers and should be viewed with extreme caution! It should only be used if balanced with use ofthe Quebec data on exposures in the mining and milling of chrysotile. Finally, the set of Quebec data, as well, has attracted both positive and negative comment, the latter usually based on its exclusive use of midget irfipinger (MPCF) data. The iatter.are ; 8 ; unavoidable (that was the data available); the data are extensive and internally consistent, and the authors of the current proposal do a good job of discussing this type of data. . : ... - - t I 4 t For purposes of risk assessment my own opinion is that the operative question is "Can ; exposure be measured in such a way in sites which require evaluation that the exposure ..... . . . ... . ' ... ...... i'... 'X y;<;y y!>.{'. assessment is both valid and repeatable". Again, this is somewhat controversial. Rogers, for example is on record as feeling that "A `clear dose-response relationship* does not validate the actual exposure values used, but the decision about exposure values of course determines the V -VO. : .. . Vii:. ' :; ' - '-.V " ijh: -V' 'V";' slope, which influences the apparent potencies of different fiber types". My own view is that a ,, , / ` .*,* *\ V"' ' : *,VV:V,r V '*? '4 clear dose-response relationship does validate the use of the exposure values; if the data are good enough to establish a dose-response relationship then they have internal validity. However, 2 See the letter, reply,.and editorial comment recently, published.as regards the Witenoom exposure data attached to these comments as Appendix A: (1) Rogers A and Major G.` Letter to the Editor. Ann Occup Hyg (2002)46:127-128; (2) A.W. MUSK and N.H. DE KLERK. Reply. Ann Occup Hyg (2602)46: 128-129; The Editors, Ann Occup Hyg: (3) Editorial Response. Ann Occup Hyg (2002) 46: 129. B-27 HWBUI0009962 ). Brace W. Case . .it iis quite-true that iaabsolute:teims;one,qf the studies camgive absolute confidence as to, \yhat the actual exposure:levels were-inthese historical cohorts.; . . Analytical,sensitivity, however. is,also especially important,. Use of transmission,electron microscopy, coupled with energy, dispersive spectrometry-ofx-tays and in some instances. selected-area electron diffraction should allow* at a;minimum, the .detection,of fiber.types and lengthsin any'such,situation at a-specified detection limit At the Oakland conference of May . ZOGl.iDr.. Patrick Sefiastien suggested that-for enyirornneutaliexposqres.fbe; best,use of TEM/ EDS is the qualitativeddentificafion ofthe presence of individual:fiber types ratherthan their fall -chaiacterizatioadn quantitative .tgcjns. .The guthora-of thf^proposal appear to believe that , ^environmental" sites may Ite less, homogeneous in thefcasbpstos. jcpiJtenfeand perhajp^ more* v dilute in their asbestos.content, tl$p exposures,in tott . true in cites where little is known, about-past use or exposures, itjis,certainly;ppf necessarily true in superfand sites such as old mine sites. The method of sampling is the key factor.for evafuatiog<pnvironinental e,xps^ue^ryf example, Superfand) sites: for example, simple measurement of air samples in an undisturbed ajea^hich co^taLgs. lpw.concentrations ; i.. ' '^-siter- ne' csxample'is-ofered-by''a study.ofivbhtiieulite insulation its the1 ceilings ofra Ganadiad army Base wfecffunfortunately has Ifaen'pubilsHefi dhl^a!s tKe'folldwihg abstiact (and'wKicfris directly,rgleyant to the exposure situations, in Lijbby stpcl tqJthe question of.exposurei tp amphibole from attic, insulation) note the ejttrepe effect.of congucting.the air samgyng.during the demolition<wo}rirk>: c, o>ncentrations of "asbestos" whic!h)w etgre-^gUeinVerally less, t,hJa;7n 0,1% by weight became tremolite levels by TEM of up to 172 fibers/ ml Cowan BW[1997J. Elevated Asbestos Exposures from a Building Demolition Which ...v .. / vr::,,<j. i k.i J ; dy -J. ?h::; : Contained Vermiculite Insulation. Proceedings of the American Industrial Hygiene Conference and Exposition (AIHCE 1997). Paper 65. ':B;Wt''C?ewan,iBdverhmeat'OfManitofeajBfhridonV^BfCanaiia^'' Venpiculite is :a, silicate mineral, which has been,installed in many attics; as a .bjiilding insulation. An asbestos consultant collected bulk insulation samples from several locdtibhs.schediiledfor demolition on a Canadian Forces base. Asbestos concentrations ranging from less then 0.1% to B-28 HWBUI0009963 ) Bruce W. Case "5-10% Actinolite and/or Treraoiite-weredetected In this proactive survey; The majority;of test results were quite low; generally iessthaa Ori-% asb'estosjto&wever, the potential existed lor asbestos libers to become airbbtnte during a routine demolition project. Alrmoiutoriiig. was conducted during the demolition work; which utilizedmo'dusPsuppresstoit/ to determine: representative worker exposuresto Sitborrie asbestbs;duSt Ten>samples were'&nalyzed by transmission electron microscopy (TEM) inaccordanbe with' NIOSH Method 7402'and:;' Concentrations ranged fionilB'tb 172 libers' per mt.' The results of-this study indicatcd-eleVated levels ofhirboriie asbestos^fibers wete generated during 'the ceiiiag demofrtsoa and appropriate asbestbs abatement prbcedutes-'had to be Initiated* T6eserifieliided the installatioh'ah'dtbjjerafion of a negative 'pressuie Ventilatloh system and a 'deContaitsiiiation-facility, the wearing ofadequate personal prOteCtive'eqiiipmeiit/the lirewetting of the asbeStBs1 contaminatedtnateHalvthe prttper ' baggingof all'bSbestos wasteland'regular bn-site'air;riKriitoring'tb record the levels-ofaiibome fiber concentrations. wirt; i *vr. " *?- TOPIC AREA 2:' The prepdexpbsure index ; " * ti. ?!** - *!> .t.rv.r*- n ,< 'O'-' :I. 4) The pifopds&d expdsiireiiidex'dofes ribiWcliide' cfihtnBittipnsfroBfi^bere'skbrter than S ju& Please, comment ornwhether-theleppeiniology,hnd itoxlcotogyrliteraitare s^upporf the cqpclusion.that asbestos ;p)tprs,shorter than 5 pm pr^ent little or np carcinogenic risk Such strictures (they aremot fibeis kid ffisteiMBg5a point to'chH theiri-`rasbe&ds?^`! ! presdattittle oir iio cafcihbgeait risk This was dealt mill fully in the refcehf AiPSBR' '' r " woritshop^TSiSRlOoilahdwiUhoitereprat^'fierejkthbu^fljepahelists'&idulcilf' possible be provided with the current report 4om the ATSDR meeting in lower- hlamhatjan in i--;;*!/; ->i lj:-r'rrr %*? w;' ?' itifcWb';} the fall of2002, even though it has not yet been published. 1 sincerely hope we do riot waste much time on this. i i '' >; .?= - . r.i, : 5) The proposed index is.^^hj^i^||ef|iyi|y',!b]t f^sri |f^e)r;|^|t.l0;)||ni.. iSpfpi^cally, equation 7.13 suggests that the carcinogenic potency of fibers longer than 10 pin is more than 300 times greater than that of fibers between 5 and 10 pm. How consistent is this difference in carcinogenic pofency with the epidemiology and ' tpsicoJogy literature? ., .. . . . . ........ ,v, B-29 HWBUI0009964 Bruce W. Case It cannot be said to.be "consistent since as fljeraythprs:: themselves point out that the epidemiology literature lacks such date ?mtk the.exegptipn.of lung-retained fiber studies or what are described by the authors as "pathology studies"). On the other hand ibis quite consistent with die.toxicology literature;and indeed anargument < could be made that the Critical length shoiilrife^Ojirri rather'than 10. / The use ofthe more - conservative 10 jam; althbughlt will make"mariy rrimaalogiists unhappy (sindethey would not1 even regard siicK structures as "fibere"), is actually' !qjiMte conservative mfluihiegaircL r ulU-'.i . j--.-.iJui. the authors do provide convincing evidence ofthis. tV. v -f vt;i- . is in its predictive ability; r :.,r .'tV !< W- . 6) Please explain whether the proposed'exposure index will allow meaningful'comparisohs "f betWeea'curreht environmental exposures*.asbestos,aHd;historical exposures'.:to:aSbestbs . that occurred in. the workplace. . ., ... ... .... `.This will- be 'exceptionaHydifficultsince,-asthe;authors;note;virtualIy,.aIi ofthe:published?- v literature on.'workplace exposures (at least in thefcontexbofitheiepideibiOlogical studiffs>referredto)'5i j' do not use similar methodology. In a broad qualitative sense'the'proposed exposure ttfdeafcwilb'ofFers better estimation of exposure than do the exposure measures offered in the historical workplace exposure measurements, since Aeyincludethebiologicallyiniportaot.descriptionsof fiber types and--' iv'i " length (with fiber type, in particular being, of proven importance in the,epidemiology,studies,-.althbugh.:/<.-ji5;i B>t:.fromithe'hist6rical.measures of exposure! but morejftomithe .qualitative descriptio.nS:fiexposuE&;:Lvw offered in`those studies; for .example comparisons across imilalr; industries havingrdifferenfefei in- .'1. -'' it:;- fiber type which are not necessarily quantified.- ? a..i: >r TopicAiea3:yGeBeraVQuestiOBS*- : : .>. . '. . - 4.'. ' . .. r1 .M.'.Cjurh . `*v-* . ! * 7) Tfae:pro>posed 'risk Assessment approach .assigns carcinogenic potency to individual fibers'": t \ and fo cleavage fragments (r "bundles that are components of more compleXjStructures"). Please comment on whether cleavage fragments of asbestos are as toxicologicaliy significant as fibers of the same-size range.' rt.:-- Br30, HWBUI0009965 Bruce W. Case This questiontfhust' be withdrawn and reworded, it is badly misstated and contains errors of fact:Wifii1'n: its'structure. ,v ' ' ` l* ; ; " ' First; it is-not clear whether the'person or. pereons writing this question do not understandIhe distinction.between "cletryage-ftagments". and ."fiber.bundles" (which are. completely different .... ammafs),;w.hether,they ape asking only about "cleavage fragments", or whether they axe. tusking, about both cleavage firagpients and fiber.bundles. Second, "cleavage, fragments" are, by defi^itiop:. is clearly pointed out in the proposal), not "asbestos", although this does NOT mean they are without effect. Third, the limitation of the question to toxicological significance ignores the published data on human exposure to, "cleavage fragments" which is of greater importance: than toxicological data (for example it has recently been estimated in a very detailed mineraiogical study at the mine site that the nonasbestiform portion of the Quebec tremolite associated with one mine (the Jeffrey mine at Asbestos, Quebec) is 99% "nonasbestiform"). Fourth, the expert panel as.constituted has no , ,, mineralogists origeologiSL^makmg any disciissioniofitheserpoiatssomewhatperilous: -ThwlVf question, which is an exceptionally important one that has freeri a&'dresse'd By tiie^authars of the proposal sho.uldtbe rewortled.'i:TAe question .commented-upon-by.this.observer is reworded hs the following;. T weommendllhatMteJot.a-.consemm rewording, preferably,With.expert mmerahgwal.) input, besubstitutedBEFORE the. meeting; 7 REVISED) - The propoSe.drisk assessment approach assigns.carcinogenic potency to Individual fibers'and to cleavage'fragments derived.from massrve ampb.ibole'structare (that is,'-' ;hi". nonasbestiforra amphiboles): Please.cotnment on whether cleavage fragments of this riature are as significant with respec$ito, buman health effects, as fibers o(:the same size, range, including.;.:. reference to the toxicological and epidemiological literature;,..... * r Again, cleavage fragments are NOT "bundles that are components of more etaipplex.-s.tniStuie&" ^-The.* question of cleavage fragments of massive amphiboie is a very important one, and the question of the assessment bf complex bundles (which may rir may.not be 'composed of;aggregatesibf.:asbestifonrif '. structures, hdaasbestifohn structures^ or ili)'ss an important b'uf entirely separate Issue 'The'phrase (or "bundles that are components of more complex structures") must.be reitioved-frorarthis charge question before the meeting. If it is not the discussion of the exceptionally important issues surround B-31 Brace W. Case exposure assessment to cleavage fragments of massive amphibole, "nonasbestiform" amphibole, and socalled "transitional fibers" will be confused by this error. The following discussion responds to the '"' restated charge question above (7 ftEVISED): it makes no mention of and does not apply to "bundles that are components of more complex structures". This (inclusion of cleavage fragments of massive amphibole on the strict basis of structure" . dimension) is one of the greatest strengths of the proposed risk assessment approacK' rad'iiiay make; up for the catastrophically inadequate approach taken by OSHA in their removal of such fibersyfodm the'.'j ' asbestos standard in 1992. It may be recalled that the latter action was taked'a^ifist the adyiceof . NIOSH, of the scientific branch ofOSHA itself (OSHA scientific staff, personal cdtnjmiifu^'fidn)^ij the ATS Committee on the Health Effects ofTremolite (Weill HW AJ, BalriSigJ;'Case BW, Hughes I, Schenker M and Sebastien P. 1990; Case BW 1991a; Case BW with excluding "cleavage fragments" and/or "nonasbestiform" amphiboles (pfbize^d shapeigmii^r,t< analogous asbestiforra amphiboles) from risk assessment were .V '. . . Kt:it- :i&i'/r:n; , I' (a) That as a practical matter there was a debate as to whether there was a "bright.line'Vseparation between them; (b) That they often occur together, sometimes with only a small propdrfida of "as^egiforpt" structures; , *- > (c) That they are difficult to separate analytically (in fact they cannot be separated by fta ' microscopist with certainty, not even with high-magnification \ on this point for example Patrick Sebastien has stated "To be able So-tell whetherfibers qrek - asbestiform or not under the microscope is quite impossible. To'hi^thdcbnCepfbf-y-\' "asbesdform " is not a microscopic one. Geologists may tell us wh'd'her'M fiber | asbestiform, but certainly the microscopist cannot". toac* r- .. .i (Sebastien P, Discussion Part 14, Ann NY Acad Sci'643: page;505)l ; : ' (d) That most important, there is no convincing evidence that given similar dMensions arid similar'' ' durability in the lung there is any reason to believe that "cleavage fragments" might be less toxic. Reproducing the ATS Committee document from page 1 on "Mineralogic Issues" and from the Conclusion; 'O:* ... r; B-32 HWBUI0009967 Braes W. Case Htnirdoptc flfumOT As noted show, the foots oo tnanofe has rated theissur.of theimportance of.dcav? sgeftagmettBjK oppose#"to asbestilbm f^^T^fuB^mmssaiBrns si vnimWm> fibrous pMttcics of Idoitieai.siw.aad shape wffi have different Mahi04!propertiei if the BVtktte are pfejes of.m&efal.i&M. Irtw.ttokea off 8 iii^ ka^'gtafMki io.' .cfjfstal. faw detosge ftwgtneats) m opposed'to pwtkbs tlijt:tereo||lflsiMjp.giOwala:a: fi brous hate jfit, whmifimn' iffieisj; It became apparent, bothfrpjn otoreview. . of tin literaturerad framsufeMoM tirade to this comuiuee.ligr experienced, Eunsstogists, that the dbtbicticMi.btfweeiiifcarage fragments md jtshtgiIfonit {%ta aStfeoush tJwwetkailrel^ iMirft)iSohwsaiiMd(^tti,b&yethtt,ihNc. two tntfipfpjE^ Sredfwhjsi dlaiixst; Htermotbenfadb8eijMt.tbe}ritMdej)iff<nip. tan the Q^Trt8<^ii8i|attifly',feBn8' (hgSsefHe).oteJPiiraeraf^Mmsetteis^ ajy&tgft!&BbirsitBpteused to vmsm eat- pettatai as lkstifoa fiber* or.cteavage fragment lb.canipficatcjnituen,)c w bo suggested totte'iiiSPtJt^ tkra b not that between ctecrtoge fragment? wjdwbsalfotm fito.fettt.tefeemrtenss- bestifbtm rad asbefctfonfrfftKb............ Became oftht leek of consensus among miseTaloffet$,aswMat.OelMitesllBfjHm3- .=. '' iiil&sd 1 thepaniclesUsedwnbsirwdraiByhrt Itbeti <wcleavage fraenem^.wehawso^greai^-. tent ignored the dhtmmttfand eniled op trsaiir^n^bfthciiiiia & K&& oil ^fihns^ or variww ilzes. The oownaiitee recognises that i&Ssto ntot aaideal sbitttiop, md.vAan. stronger evUma of tho cleavage ftagmeot. orasbmlfhratMartofa particular fifeex ists, we.have.notcd It: However, until'there breasonshfeMncraioticuna^uiiiitj'hoshoft . .. -i: ' jt ' ' >`b >; ^ v t-:- ' ' ' ' : - : ; ' : n*:;Wr: {::\v . ' ''- :': . : - -lU .-At . ..... (continues as "general definition and the classification of specific samples, and then animal experimentation with such classified materials, it appears to us impossible to draw general conclusions about biologic effects based on the distinction between cleavage fragments and asbestiform fibers" and from the conclusion: B! 33 i HWBUI0009968 Bmce W. Case " 3. The evidence forbiologic effect distinctions based on mineralogic parameters, other than . fiber dimension and fiber number, is currently inadequate;. .. . 4. At present, the prudent public health policy course is to regard appropriately sized tremdlite "fibers," in sufficient exposure dose (concentration and duration), as capable of produ'ciiig the recognized asbestos-related diseases, aiid they should be regulated accordingly" ' " : ' :- (Note: It is strongly recommended that panelists read the full statement in the American ; ; -:V ..r. ' .r.i. . ' .; Review of Respiratory Medicine as referenced. Panelists should also be aware that the Environmental and Occupational Health Assembly of the American Thoracic Society has recently obtained funding to reconvene a new panel to update this statement, which is currently working on revisions and will meet in Seattle iii May, 2003). 8) Please comment on whether the proposed cancer assessment approach is relevant to all Mbers'oi only to the' fftfe types ofampHibble fibeits!tactih6litei ani6Sife,'anthophyilite crocidoIite,.htm>lite)-des!gnated in.federal reguladons- . . . .. The proposed cancer assessment approach is certainly relevant to all amphibole fibers which have been identified as capable of producing the recognized asbestos-related disease. In addition to the five designated types these include richterite, winchite, and possibly edenite in one location tangly. Given the.yety.large.iitinibe;ofair[phibtoles|oYer 50) it seenis.U^ely .th^.others may be found tofiavfe forms Which rnayact'insimilar ways,' but- PariPhofhware'dfahy at present. It should alsobe noted, that "amphiboles" comprise a huge pprtipn of the.earth's crust, and it would be totally impractical .to try.to regulate ajj..fonns.ofall arnphiboies.; In this regard the ..authors' proposal is .very useful in that itiimifs, the ^non^l^tifonn amphiboles assessed to those which.have Sh^sa^ ^memipnalchamcteqstics_ffsihe amlogom asb.es.tiform varieties.. 9) The review document recommends that asbestos sample^, be, analyzed .^ahsfnissibn.electron microscopy (TEM) and count only those fibers (or bundles) longer than 5 pm. Such counting practices will p'rwide ho information on the amount of asbestos fibers shorter than 5 phi. To what extent would :data,on<shorter fibers in samples; be useful fo>r. future.evaluatioas (e,g., validation of the cancer risk assessment methodology, assessment of non-cancer endpoints)? / .f-`i >," . r'" ;. i> This was answered above, with the exception of the point on "assessment of non-cancer endpoints" Again the panelists should he referred to the as yet.unpublished rVTDR 2002. document which deals specifically with this issue; there is a general'consensus that such'short structures are not important in JB-34 HWBUI0009969 Bruce W. Case non-canber endpoints -- specifically lung fibrosis - but there: are (unlike the ease- fbr tancec endpoints) at least a few studies which contradict this. 10) The. proposed risk assessment methodology^suggests that exposure estimates should he based only on fibers longer than 5 (tm and thinner than 0.5 |im. Is this cut-off for fiber diameter appropriate? .t a\ While the use of this cutoff would include most chiysotile and crocidolite fibers of concern, it would not count some amosite fibers and would not count a substantial portion of tremolite fibers ofproven toxicity. Hence this cutoff is not appropriate;, perhaps a weighted index could be applied similar to that for fiber length for thicker fibers, but ultimately it must be realized that no . `ii'K :**'. ,`v V r ,4 . i ; * s` - i* dv.-' r: single technique for assessing exposure by electron microscopy in this regard will be equally applicable to all waste sites, and the hazard may be severely underestimated in some locations shoujcf'such. a.liberal definifion.ofdiameter be adopted. In particular, it is not appropriate to exclude tremolite fibers under 1.5 pm in-dianietef from concern hodfifth inclusionan assessments of sites where tremolite is the major mineral of concern. 11) Discuss whether the proposed cancer assessment approach, as a whole, is a reasonable evaluation eRfects'tfafir. What aspdcis of tbe proposed cmicer assessment approach, if . any,iaredncqnsistentf.witj!;lhe..epidemiology.or tpxicology literature, for asbestps? . "' &s`a Whole the proposed cancbir assessment approach does appeikto be a reasonable evalUhtio'nrof the available health datd, aitticiu^t'it is mistaken in 'satire details. Thfese were" described in previous sections.! The emph'asis'iin fiber type in riric assessment is long overdue; evidence1 for fiber length' criteria'iff the approach' is' perhaps less solid, although certainly it is true that structures having length less than 5 pm need not be assessed, and indeed (through the feet of `skewed'length-distributions) mclusibff-'bfftltis Sire category actually would-jprovide'tisk : assessment.^hicb may either pyerslate.or understate health .effects. Use .of the greater-than-10 pm criterion as: the-most heavily weighted'fraction; and foe exactweigKtto?attach'to it'(or io some other fraction), requires discussion'by the panel. V-h *.::*! . : *'>*"'. "'-'i- ' . .-:rfrn . <> ? 12)'SefctkWV 8.2 of the review docuroeht'preserits three'options for assessing'cancer risks from .: , asbestos exposure. Please .comment on. the technical merit of the proposed risk assessment options. yr* B-35 HWBUI0009970 I will leave this to.the actual paneL'discussion. , .. ' Bruce W. Case A- ; Topic Area 4:-- ....the peer review .consultants are invited- to-provide, any.-additiooal ,, comments or concern|, both strengths and weaknesses, on topics not specifically addressed in the previoas;charge;qBestio'ns,. ....the focus of this workshopvis.on the.proposed risk oas at asbestos-contaminated sites. r ' -WC-Y (signed) Brace W. Casej'M.D^MiSc* Monday,February, 17?;2M3 ,, ... . . . f'.C tC- lit i,-,. u.j;.. .. v f uvv "jy.T ; -. t * - O).. / . {] ' *1. . -^7 I'A XliiS' V.: . ' J -IV. Iti WH r , :J - .* * !> : -I i , - ; , .-i> ;:';vC) 'i : ' i v V i ' Vi - ,;*; ' *.sl r't.., tv' -':-t J . ``j b- . : /i .J :T< .1 - i&Ki r.h h. -:r<rt. l.i : . *-.*. V-.diT M ' .UUkuAXlv'Y-'' I- .. : T" cl ' Y- '-v - ;.s :i-* .1' J ' M6 HWBUI0009971 Bruce W. Case Abraham JL, Hull, M. Case, B.W. (2002). "Mesothelioma Among Workers and in the Vicinity of Asbestiform Fiber-Bearing Talc Mines in New York State." Ann Occup Hvg 46(S1): 132-135. Acheson ED, Gardner MJ, Pippard EC and Grime LP (1982). "Mortality of two groups of women who manufactured'gas masks from chiysotile and crocidolite-asbestos: a 40-year follow.-up." Brd Ind Med 39(41:344^8. . Vvw''' 'i'-tl '*'*.' ! ` :: . '?** . .v I - . .. ,,.**; - Amandus HE and Wheeler R (1987). "The morbidity and mortality of venruciiute miners ana millers expbsed totremolite-actinolite: Part II. Mortality." Am 1 ImfrMed 1J(1):v15-26.' ; Armstrong BK, de Klerk NH, Musk AW and Hobbs MS (1988). "Mortality in miaers and millers of crocidolite in Western Australia." Br J Ind Wed 4Sd): 5-13. ATSDR (2002). "Report on the Expert Panel on Health Effects of Asbestos and Synthetic Vitreous Fibers: The Influence of Fiber Length (DRAFT)." IN PREPARATION. Berry G (1994). "Mortality and cancer incidence of workers exposed to chiysotile asbestos in the friction-products industry." Ann Occup Hvg 38141: 539-46, 413. (i>,.;rr 'v Berry G (1999). "Models for Mesothelioma Incidence Following Exposure to Fibers in Terms of Timing and Duration of Exposure and the Biopersistence of the Fibers." Inhal Toxicol 11(2): 111-130. Berry G and Newhouse ML (1983)V "Mortality ofworkers manufSctoring ^friction materials using . r asbestos." Br J Ind Med 40111: 1-7. ; Case BW (1991). "Health Effects of Tremolite. Now and in the Future." Annals of the New York ' Academy ofSciences 643: 491-504. Case BW (1991). "On talc, tremolite, and tergiversation. Ter-gi-ver-sate: 2: to use subterfuges." Br I Ind Mfid 48(5): 357-9. Case BW (1994). "Biological Indicators of Chrysolite Exposure." Annals of Occupational Hygiene 38(4): 503-518. Case BW, Churg, A., Dufrcsne, A Sebastien.P. McDonald, A.D. and McDonald, I.C. (1997). " Lung Fiber Content for Mesothelioma in the 1891-1920 Birth Cohort of Quebec Chiysotile Workers: A Descriptive Study." Ann Occup Hvg 41(S1I: 231-236. Case BW CM, Richardson L, Parent M-6, Desy M, and Siemiatycki I (2002). "Preliminary findings for pleural mesothelioma among women in the Quebec chrysolite mining regions." Ann. Occup,. Hye_ 46(S1): 128-131. Case BW, Duftesne A, McDonald AD, McDonald JC and Sebastien P (2000). "Asbestos fiber type and length in lungs of chiysotile textile and production workers: Fibers longer than 18 mu m." Inhalation Toxicology 12:411-418. Case BW and Sebastien P (1987). "Environmental and Occupational Exposures to Chiysotile Asbestos a Comparative Microanatytic Study." Arch Environ Health 42(4): 185-191. Case BW and Sebastien P (1989). "Fiber Levels in Lung and Correlation with Air Samples." Non occupational Exposure to Mineral Fibers. J. Bienon. J. Peto and R. Saracci. Editors 90: 207-218. Case BW, Sebastien P and McDonald JC (1987). "Lung Fiber Analysis in Accident Victims a Biological Assessment of General Environment Exposures." Meeting On Epidemiology In Environmental Health Held At The First International Symposium On Environmental Epidemiology. Pittsburgh. Pennsylvania, lisa. June 43(2): 178-179. Churg A and Green F (1990). "Re: Mesothelioma in railroad machinists [letter; comment]." Am I Ind Med 17(4): 523-30. Churg A and Veda! S (1994). "Fiber burden and patterns of asbestos-related disease in workers with heavy mixed amosite and chiysotile exposure." Am J Respir Crit Care Med 150(3): 663-9. Cooper WC, Wong O and Graebner R (1988). "Mortality of workers in two Minnesota taconite mining and nulling operations." J Occup Med 30(6): 506-11. B-37 I ) HWBUI0009972 Brace W. Case Davis JM, AddisonJ. Bolton RE, Donaldsoa Jones,'AD arid Smith T | 1986). "The pathogenicity of. . . .long versus short fiber samples of amosite asbestos administered to rats By inhalation :and - irifaperitoneal injection." BrJExp Pathol 6701:415-30. : :: . Davis JM, Addison J, McIntosh C, Miller BG and Niven K, (1991). "Variations in .the carcinogenicitypf tremftfite dust samples ofdiffering atOrpholopyJ?; Ann N Y Acad Sci 643: 473r90. Davis JM and;Jones.ADc(1988). "Gomparisc>ns;of the.pathogenicity .of long and;short fibers-ofchiysotile asbestos in rats." Br I Exp Pathol 69(5): 717-37. : de KJetk NH, Annstrong BK,MuskAWrand Hobbs MS (1989).'JlCancer.mortality in reiation. to .. .. measures ofoccupational exposuretocrocidplite gt. Wittenoom Gorgejn Western Australia." JBt UffiLM^L .46(8):. 529r36.. . . -V-.?'- - ... ../ -V:-v. de Klerk NH, Armstrong BK, Musk AW and Hobbs :M (1989). "Predictions of fututocases, ofasbestosrelated disease; among?former miners andmitlers of.crocidolits'in; Western.Australia-[see. . . comments]^,MedJrAust 151(11-12): 616-20.:.. ........ . . , . de Klerk NH, Musk AW, Cookson WO, Glancy JJ and Hobbs MS (1993). "Radiographic:abnormalities and mortalityanisubjects-.with.expQsure to crocidOlite.?,Br MndMed 50n0):~9Q2T<i::. ;' -- ..K- Dement JM and Browa;DP.(t994);;flftingBancer.fnotteJity.among .asbestps.texti!e. workers- .a wktR^nd update." AnnQecup-Hvg38141:-525-32. .412. .,> -w'); ."? r M Dement JM, Brown DP and Okun A (1994). "Follow-up study ofclsrysotile asbestos textile workers;cohort mortality and case-control.analySbSi" Am J ind-Med 26(4): 431r47. ,0 ' . v. Gardner MJ, Winter PD, Panned B and Powell CA (1986). "Follow up study of workers manufacturing chrysqtileasbgstos cement products." BrJ IndMed43f 1 Vs: ?26-32v .. : ` ii-.-l'fi , itonpGsM Gillam JD, Dement JM, Lemen RA, Wagoner JK, Archer VE and Blejer HP (1976). "Mortality patterns among htoLroCkgoldsniaCrs exposed.to an ashestifonn mineral.">Ann N Y Acad.Sei271.~'336r- '. .. v. . ' . . "j. - nns : .'j >i Hansen J, de Klerk NH, Eccles JL, Musk AW and Hobbs MS (1993). "Malignant mesothelioma after-; enyironmcntalexposuretoblueasbestos.*'ilnt J'-Gancer i54(4);;57fe81-..- . ; ,7/v ' .rn I.. .i'V; Hansen J, de Klerk NH, Musk AW and Hbbbs,MSY,1998-)i!:r^vitaiMnea>al exMBim-to crocidplite-and mesothdioma: exposure- response relationships^?.-Am!j-.Respir..drit^Care =Med,157fl): 69.-75: ... 'V. Hodgson JT and Damton A (2000). "The.quantitative^lsipf'mesothelioma and.lung cancepin.relation to asbestos exposure.?; Ann Occup Hve 44ff:-S6S-601. .H r. .V; .> ..< ,f. : wit ; Hughes JM^.'W^ill H.aijd;Hammad YY (1987).; "Mortality.of,workers. employed in-two asbestos cement manufacturingplants." Br J Ind Med44Q): I6N74. .y k .?><-. " .. .icr;-.,r ,ir IARCngg6),jGonsejisus Statement.Mechanisms of.FibenCarcinogenesis;iKane AB. Boffetta.-P.:,.;. ri iu.- - Saxacci, R., Wilboum, J.D. Lyon (and Oxford), International .Agency for Research,on Cancer; .,.-.I!MHQ/ OxfonIvlJn.iversily Press.--(4:-.lj9. Knox JF, Holmes S, Doll R and Hill ID /. / causes among t . workers in an.asbestos textile factoty." Br J lmdMed 25(4):'293.-303i:. . .: , . .. . < ' Liddell FD and Annstrong BG (2002). "The combination of effects; on lupg.cancer of cigarette smojring .. ande^posjir^iiii guebec chtysotile miners and milters.". Annals of Occupational Hygiene 46fl): ; 5-13. - '' " Liddell FD,;^|cI)pnald!.AD..and McDonald JC. (l9g8). "p.ust.exposure apd luiig}cancer in Quebec . . . chrvsotile miners and millers." Ann Occup Hvg 42(lV:;7-20/ . /. ... : . .. LippmanpM (1990). "Effects.of.fiber characteristics op lung- deposition, retention, and disease." Environ Health Perspect 88:311-7. j... . . Luo SjiLiu X,;Mu S, Tsai SR and.Wen CP (2003). "Asbestos .related .diseases^ from enyiro.tunental , exposure to crocidolite in Da-yao, China. L Review of exposure and epidemiological data." Occup Environ Med 60111: 35-42. B-38: HWBUI0009973 Bruce W. Case McConnell EE; Axteri G, Hesterfoer^TW,`Chevalier J,.MiSHer WC, Everilt>J, OberdorsterO,.'Chase GR Thevenaz P and Kotin P (1999). "Studies on the'inhalation toxicology of-two fiberglasses and amosite asbestos in the Syrian golden hamster; PartlL 'Results ofchronic exposure^'1- Inhal Toxicol 11(91: 78S-83S.: /< * V : ;:r v: ,, ; , McDonald AD, Case BW, Churg A,.Duftesne .A, GibbsiQWv'Sebastien-P and McDonald JC (1997). "Mesothelioma in Quebec chrysotile miners and millets: 'epidemiology and aetiology." Aha Oceup Hyg 41(6): 707-19. ' y- v > McDonald AD and Fry JS (1982). "Mesothelioma arid the fiber type in ttoeeiAmerican asbestos factories preliminary reportScand J WotfcEriviron Health 8 SuppU: 53^.:s-- " ;0 McDonald AD, Fry JS, Woolley AJ and McDonald J (1983). "Dust exposure ahd'inortality in an'> . - American chrysotile textile plant" Br f ind Med 4d(41: 361-7. >:' . McDonald AD, Fry JS, Woolley AJ and'McDonald JC (1983)f "DUst exposure and mortality in Sri American factory using chrysotile, amosite, and crocidolite in mainly te3ctilet.mahiifacture.";Bci IbdlMed40r4h--368.74.v .. ;C to**.- * \-! < - McDonald AD, Fry'-JS) Woblley AJ,and McDonald JG <1984). 7Bust'exp6sUr*`and mortality in an" American Chrysotile asbestos friction productsplant" Br-TIndMedtflCZ):' 1S1-7."; " ' McDonald AD and McDonald JC (1978). "Mesothelioma after crocidoliteMexposiire during gas mask:' manufacture." EnvironResT7f3):'340-6.::' -ff-'' -K McDonald AD and McDonald Jff(1980). "Malignant mekotheliotna'in'North America."Cancer 46(7): : 1650^6:- ' : . v- ' ' ^'--V , v g r, .iJH *;it| .. McDonald JC (1998). "1 Infinisheri -business:' the, aifoastokitextifes mystery [e~ditdrial)-.^iAnn Oc'cup' HVg 42(l):'3-5. * ' -`iV \ ; `-'/V ,Ai; > >; /-'i 3 ..' McDonald JC, ArmstrongB,.Case B,'Doell D, McGauglieyWTE,'McDonald`AD ahdSebastien'P (1989). "Mesothelioma and Asbestos Fiber Type. Evidence from Lung Tissue Analyses." Cancer 63(8):; 1544^1547:* ' ` ,>vU< T - : >.-=! McDonald JC, Gibbs GW, LiddellTD and Mc;Doriald1Al):(l978')."Moitality;after.ioing exposure to" cummihgtonite-gtuneiite:'* Atii~Rey-,RCSpirPis'lT8(ffi%7-l7.' '' * ' ' ' . ' McDonald JC,'McDonald:AD,'ArmStrortg:Bvand:Sebastien-d* (l'986):' ?-Ooht>rt study of mortalitymf- venniculite'minersexposedtotremolite."iEclJitiMsii'43(7'):-'436-44,.` ''- Miller BG, Searl A, Davis JM, Donaldson K, Cullen RT.'BSltbrkBiE^Buclianari-.D and Soutar CA (1999). "Influence offiber length, dissolution and biopersistenceroh'the production ofmesothelioma in the rat peritoneal cavity." Ann Occup Hvg 4313):' 1554>6J.o:O.U-.i V:. Muhle H and Pott F:(200i).'"Asbestos^ asTeferehce mateMal fot fibef4nduded:cancel" Int Arch Ocfcup ' Environ Health 73 SuppltS53>9. : ' :........ " ' 'i Newhouse ML, Berry G and Skidmore JW (1982). "A mortality ^tiy'Ofwofkers'mariufacturin1frictkm materials with chirVSotile`-aSbgstos."`-Ann Occap1'Hv|';26M/^4)V`899-9Q91 ' ' '' Newhouse ML, Berry G, Wagner-JG add Turok ME ((9.72). A' study df tKe'ntortality of female asbestos workers." Br J fed Med 2912J: 134-41.: >. ='' :i- ' Newhouse ML and. Sullivan KRf(1989). I'Amortality study of Woifeis manUfacfUHiig friction materials: 1941-86." BrJ Ind Med 46131: 176-9. Paci E, Buiatti B and GeddeS-:M'(l987). "A case-referent study bf lung'tu'ifrore in nori-asbestos textile : workers." Am-J Fnd Med 11(3): 26i-7X ; rr. ; c . Peto J (!980j. "Lungcancer mortality in rtlatiori to measured dust levels ih an asbestos textile factory." ` IARC Sci PubK30): 829-36. ;: Peto J, Doll R; Howard SV, Kinlen LJ and LeiVinsohn HC (1977). "A mortality study among workers in an English asbestos factory." Br find Med 34(3): 169-73. B-39 HWBUI0009974 Bruce W. Case Rodelsperger K, WoitowitzHJ, Bruckel B,ArhelgeriR,'Pohlabeln H and Jockel KH::(1999)-vDose-,:-.; .. '' ffilalihnship between amphihoie. fiber lung burden.and:mesbthelioma:"-Cancer Detect , Prev23f3T>: 188-93*- t.,- 3- 'V--' .?.> ... H Lj-:.v . Rogers AJ, Leigh J, Berry-.G,-Ferguson:DA, Mulder HBand. AckadM (1991). "ReJationslup.ibetween." luog asbestos fiber type and concentration and relative risk of;raesothelionia. A:case-control . study;" Cancer 67(7.1; 1912420. .. vtj ..V:-7) s i,-- d...- 5>ar. -Av Roggli VL, Pratt PC and Brody AR (1993). "As&esGg&fit^dyi&j!) malignant mesothelioma: an....; analytical Scanning electindn.microscopic study f94;c.dses [see:fcomments).r Am JJnd Med: ;- fy-- 23(4):.605-14;- ; :> .,ia* c.mi'do . i" :. Sebastiea P, Armstrong, B.;.ease; B.W.S(1988;i),amphibole.exposute ifipin. asbestos body and macrophagereouhts in sputum: survey in veimiculite miners:" Ann QcCup Hvg 32: 195- ' :- 201. . Sebastiea P, McDonald ie,-.;McDonald AD,, Case,JBi and Harley R:(J 989).' "Respiratory^caflcer in, . ;.,yp>y./ chtysotile textile and mining fadurajeSdexpostaw, inferenges^fiom lun^nalysis!" Br JInd Med '*.460):,180%fS .yiv;va'v-' l".?.'-"''. -. tSHd..*-i .Viticv-'.-r. ' V;j'.v'.' SeIikoff;D;|laa^dnd^G,dntliMdtaan'H.(;l979).x.'Mdrtalityi.expe4cticeoCi.nsiilajion.w.Oikers.intthe:;. United States and Canada, 1943--1976." Ann N Y Acad Set330: 91-116. js SIuis-CremerGK (IWlX.^jAsbestosdiseasfcatdow.exppsuidjaftetlongiresidenceit.iiiiemainphibiple.::,, * .r....., j miners." Toxicol Ind Health 7( I-2>:-89-951 < * ..ip.,.;-. yv :y 7: Sluis-Cremer GK (1991). "Asbestos disease at low exposures after long residence times." Ann N Y Acad Sfii 643:182-93. Sluis-Cremer GK, Liddell FD, Logan WP and Bezuidenhout BN (1992). ""the mortality of amphibole miners in South Africa, 1946-80." Br J Ind Med 49(8): 566-75. Spirtas R, Heineman EF, Bernstein L, Beebe GW, Keehn RJ, Stark A, Harlow BL and Benichou J (1994). "Malignant mesothelioma: attributable risk of asbestos exposure." Occup Environ Med . 51(12): 804-11. Stanton MF (1974). "Editorial: Fiber carcinogenesis: is asbestos the only hazard?" J Natl Cancer Inst 52(3): 633-4. Stanton MF, Layard M, Tegeris A, Miller E, May M, Morgan E and Smith A (1981). "Relation of particle dimension to carcinogenicity in amphibole asbestoses and other fibrous minerals." J.ifall Cancer Inst 67(51: 965-75. Stanton MF, Laynard M, Tegeris A, Miller E, May M and Kent E (1977). "Carcinogenicity of fibrous glass: pleural response in the rat in relation to fiber dimension." J Natl Cancer Inst 58(3): 587- 603. Stanton MF and Wrench C (1972). "Mechanisms of mesothelioma induction with asbestos and fibrous glass." J Natl Cancer Inst 48(3): 797-821. Stayner LT, Dankovic DA and Lemen RA (1996). "Occupational exposure to chiysotile asbestos and cancer risk: a review of the amphibole hypothesis [see comments)." Am J Public Health 86(2): 179-86. Takahashi K, Case BW, Duffesne A, Fraser R, Higashi T and Siemiatycki J (1994). "Relation between Lung Asbestos Fiber Burden and Exposure Indices Based on Job History." Occupational and Environmental Medicine 51171: 461-469. Teschke K, Morgan MS, Checkoway H, Franklin G, Spinelli JJ, van Belle G and Weiss NS (1997). "Mesothelioma surveillance to locate sources of exposure to asbestos." Can J Public Health 88(3): 163-8. B^40 HWBUI0009975 m Bruce W. Case Teta MJ, Lewinsofin JHC; Meigs JW, Vidonb RA,:MowaditiZ and Flannery.IT (1983). "Mesothelioma m Gohhecticuhl 955-1977.' Occupational aridtgedgraphic associations." J OccupMed 25f10): 749-56. Ulvested B, Kjaerheim K, Maitinsen JI, Dainbeig .G, Wannag A, Mowe G and AndfciseirA (2002):-./- "Caiifeeflncsflfendirairi'ong workeiS Snthe. asbestos-raeint producing industeyrin Norway." Ssaasi. JWoricEnvironHealtii28(6);411-7:: : i r- u-' ..o-/-.: Wagner JC, Sleggs CA and Marchand P (I960). "Diffuse pleural mesothelioma and;asbestos exposure in the North Wfestetw>Gape Provinfcei* BritJ TndifctpMed 17:260-71.1. i.,.. -i:'s / Weill HW.AJ, BalmeS:J,:<GaseW; Gbnrg AMj-Hughes.J^SchenkerM and.Sebastien P (1990)..rHealth effects of treinolite. This official statement of the American Thoracic Society was adoptedby the ' "ATS Board of-Piroctors; June* d990.**-Am :Rev .Respir-'Dis 142(6 Pt 1): 1453r8. . vi... *. Woitowiiz HJ and Rodelsperger K (1994). "Mesothelioma among car mechanics?": Ann Occup Hvg 38(4): 635-8. Wong O (2001)/ "Mnlignant'tnesodielibnta'aiid.asbestos exposiure Eurio'ng auto'.mechanics:;appraisal of .sfcmhtific evidence:* Repd Toxicol Pharmacol34(2): 17(K7.k;: . .. . .. : . , v:i Wright RS, Abraham JL Harber P, Burnett BR, Morris P and West P (2002). "Fatal'asbestosis SO years aftef brief high intengltyexposurein/a?veriiunilife-lEitj^adiioii;plant.":AmjJ RespifrCrit Care Med . , 165(8): 1145-9. rfK'u.r YeungPandRogeis''A(2001'):'?Aiioccupatiottiindustiy matrix^ analysis ofmesothelioma cases in ... < Australia 1980-1985." Appl Occiip Environ Hvg 16(1): -404. i - -`S -: -. - *ii . n:.-\ .* :7 ' <i if.* .......................... . ........ V'T.U- HWBUI0009976 Br42 HWBUI0009977 Vincent Castranova B-43 A HWBUI0009978 Vincent Castranova Chief, Pathology & Physiology Research Branch National Institute for Qr^cugafional Safety & Health 1095 Willowdale Road (L 2015) Morgantown, WV 26505 . . ; ; ,, 304-285^6056 Fax: 304-285-5938 ______________________ Email: vic1@cdo.gov Dr, Castranova received his B.S. in biology from Mount Saint Mary's College (magna cum laude) and his Ph.D. in physiology and biophysics from West Virginia University School of Medicine; >He served as a NIH fellow,and research fai^Jty.p^J^Jn the .Depa^entof;J?hy^qIpgy at .yle>!Jr4y!sity before he took a research ^psitidn.at.^libi^H.^.iie is a CDCi^stinguished Fellow apd IMsfingyistied.tJonsultanL He is a'pfbfessor'in the Department.of-feystojogy arid Phanhacolqgy atjhe West Virginia Oiwersity's Robert C. Byrd Hehlth Science Center aroJ also vras a professor of qm||yeonal;anid environmental medidne at-University of Pittsbtfrgh's School of'Pubiie Health in 2002L ;Hfe resdarcfrlntefests indude the isolation and chahacterizatioijpf fheflhysfofogica.f properties of fung-ge|ls, in particular,. alveolar macrophages, polymorphonuclear leukocytes and alveolar type II epithelial cells; and determining mechanisms.inyoSyedin disease initiation and progression after exposure to silica, cpaj mine .dust, diesel exhaust particulate; libera, cofehSlsfe^orgartic1 cfusts, anffbfiKifdbrdl: products such Ss^e'n96fbxin. His research has;rtetittedin:the publicafiori bf two books as co^editdrartdl over 280maritiscfiptsiih!peer- reviewed joiroatyisn#chapters.in,bdpks.;,vHqis:qltrtf.rnbjer.qfthe:/?aneHcaRPhysio.togica|^edety and the Sodety^fjlQXicolpgy,. He.is, op .the^^na? boppl of ,0re.Annuls of Agricuttufal agd, Epwrpgrpeptal 9Medidne'apT" xii^i^'y and.^plt^ Phanoacology. ' ' .. l`> :Ai i *1 , - .... *\/ . .-I. ,V:! .;;; .; =\ 1 1-.. : ' fli- . i . - .'-v y-.r :;-!i - = .\.-v >; . r;_- . , ` --i -= ' `V ;`3-'-i. Br44 HWBUI0009979 OWJRGE: QUESTIONS ' Vincent Castranova Topic Area 1: Interpretations of the epidemiology and toxicology literature. 1)'ctmcer: ................ . aJ. Influence.offibertyper.- Pleasecammeafon the exterd to,whh the epidemiology. ...is.I analyscsj^feer /j^pes?,-Specifically, to what estmt'do you.think the proposed risk; Coefficients in Table <*-29 are supported bythe epidemiology literature? - >&: Response;. A large /bKo>.i3y o^data ekisf coiiipai^ rate^pste^. fei in of fibers ofcfififeCTt dtonricai catsnpoations.; A good copeladon e?ds^:! betwfehttese in vitro dissolution data and bjodurability data collected teanimafr.:. - .x . :tWS8SB.* 'Firifitemwfe.Wcoirelati&n ekistslfetw^en durability vaiues offibers to cause fibrosis, lung cancer amimesothefiorm in animal models; M Vitro dissolution data indicate that chrysotjJe is less durable than amphibole fibers. However, in vitro toxicology data and animal studies do not consistently fine chrysolite to be less bioactive (in vitro) or less fibrogenic or carcinogenic (in animal models) than amphibole fibers. The report proposes that the time frame of in vitro studies (hours-days) and animal studies (2 years) is too short for the dissolution of chrysotile to become a significant factor. In contrast, the 30 year time frame for asbestos-induced lung cancer is sufficiently long for chrysotile dissolution to influence the results. This is a reasonable argument, and ifis supported by the modeling ofthe epidemiology data The risk coefficients for lung cancer given in Table 6-29 and 6-30 suggest a 5 fold greater risk from amphibole exposure than from exposure to chrysotile. My view is that the epidemiological data support a greater risk coefficient for hing cancer with amphiboles than chrysotile. However, a 5 fold difference in risk is debatable considering the uncertainties inherent in the data used in this model. B. Influence offiber length: Please comment on the extent to which the epidemiology literature and mechanistic studies suggest feat carcinogenic potency varies withfiber length. How adequate is information in the epidemiology literature for supporting dose-response analyses for differentfiber lengths'! In general, is it appropriate to assess cancer risks using an exposure index (see Equation 7.13) that is weighed heavily by fibers longer than 10 micrometers (pm)? (Note: Topic area 2 includes more detailed questions on the proposed exposure index.) B-45 ) J HWBUI0009980 Vincent Castranova Response: In vitro mechanistic data generally support the hypothesis that long fiber are mote bioactive than short fibers. Animal data for fibrousdnd lung cancer support this conclusion. Modeling ofepidemiology also supports the hypothesis that long fibera aie'niore potent in inducing lung cancer than shortfibetsi!; Equation 7:13 IfevUywei^K tiie-contribution offibers > 10 pm vsthosfe between 5-10: pin in lra|th:by'a faitor ofgfeter than 300:1. The equtifitindismisses. particles<;5^^inldfj^ as Mving rid MuerM dfpulmoiKiiy response: Mechanistic mtint daUHton CeU ptoliferatioh; generation ofreactivdspecies, and cytokine and growth fe^or prodtictioa mdirate feat short ptirticles are dot without an effect Indeed, although long fibers have been shown to activate transcription than shok fibers, a reMonsblpto surface area was ridfed (Ye etal^Amrir Physiol 276: L42-L43'4* 199^/-JBiorChem276;-536ft-5367i AtitarfUnd ^idemibli^icat studfelrifddjtestosfoxicity iridkaiefhat short fibeiSiatfe RiMvely less5 pbtehtthan lodg fibers.- However* these were relativelypure expostiteS.- In a non-fibrouS particlfcsis high. ip-The tito lo prri seetiis high. forfibersldiiger O. To Vifhat extent do animal stufees(e.g;; studies by Davis and other researchers) stiggesi feat carcinogenic potency varieS-wito:jfifer-type andjib&'lehgfff!'`! Z '1 .' :w>i< Response: Animal studies do not support the 5:1 difference in lung cancer potency ofamphiboles to chrysotile.: The report's suggestiorofeata 2year animal ' ;study is.too short for dissolutionofchrysotile to be an inqrtmtfectorhas merit : AnimM;Studi support fee hypothesis that Itmg fibers are more potent . , carcinogenesis .than short fibers:: HaweveF, animal studies,do notsuppqrt the hypothesis that short, fibers ort&pherical particles are essentially inert; D. Please comment on,the extant-to .which caminpgenic.pptency.isa.fimctiqn offiber properties (e.g., diameter, aspect ratio, surface properties) other than fiber type : arid fiber length.. How adequate is information in. fee epidemiology;or=toxicology literature fen supporting these other properties mto dose-response ahalyses?- Response:The major influence of'fiber chemistry ^ expressed as differences in fiber durability. Surface properties, such as the ability ofchrysotile vs amphiboles to generatereactive oxygen species, havenotproven to greatly influence fiber carcinogenicity in animal models. Diameter and aspect ratio affect fiber deposition in fee iungi However, fee influencebn carcinogenicity in animal models as independent of deposition has not been adequately evaluated^ 8-46, HWBUI0009981 Vincent Castranova 2) For mesothelioma: A. Influencefiber:, type'. Please comment pa the extent tp,-which the epidemiology literature and mechanistic-studies suggest that carcinogenic,potency varies from one fiber.type tp-foe ne3$^&, jdbn^^e-^gecsiis^axnptBbole^fi^f^l. Homj adequate is the information in Are ^ideiniology Kteratoe ^rsupporting rlp^teqiionse^analyses for differentfiber-, types! Specifically,!to tfie..proposed risk .coeffidentsmTable&-29aresr^pportedby^^tfa^epidgmirfogylitodpre? ... Response: fotraperitoneal instillation daia do not support a great difejmee between . \Ab potency <^dteyspt^.tind.aDipP)Ql^ to( induce mesotheiioina. -^yitop.; mechauaistic data.# not support a great rfifference in potency byffoertype.: However, .- .sa#addata.#p!glj#^atefotf chrysptite.is..]^.pql#|;%m.aE^lifopIes.in. . producing mesothelioma.- Ibis is supportedby epidamiol^<^4fe%.>fTh;ielative ; risk coefficients ofampbibples ys cbrysotile for mesotfaeiioma:in. ,Tabte^729 and Table6-^0.are50&600:1. Datasupport a large.dlfference.mml%,, , 6 . i. .* * \ * ; .j;.` * * ` * j r., -I'/liO W B. .Influence offiber length: Ple^e ccffiriment.pn thq.e$tent Jo. w#di:.thq.^|^niology length. How adequate is information in the epidemiology literature for supporting dose-response analyses for differs!fiber lengths!. In general is itapprqpjrrate to assess cancer risks psing an expqguuohidex Equatioji 7.13) that is weighed heavily by fibers longer than 10 micrometers (pm)? (Note: Topic area 2 includes more detailed questions on the proposed exposure index.) '.Response: tatraperitoneal instillation data support a strong dependenceion fiber length. In vitro mechanistic data support a relationship between potent and fiber length, although the rel#on^ifo:is not all or nope. Modeling epidemiologicdata strongly:support that long fibers are more.potentthan short fibers.in inducing mesothelioma. Equation:7il3 indieafesrthaffibers >10 pm should.beftreig'hfed 300:1 over fibers 5-10 pm in length for mesothelioma. The weighing for length arid 1 .V''' -Vr:vi-"q G. To whatextent do animalstudies (e:g.; stadies by Davis and other r^fexeters) riiggest that carcinogenic potm^mxies.wibifiber.type-.mdfiber length?:: Response: The difference in potency ofcbrysotile vs amphfooles and long vs short ; fibers to cause-ntesotbelionia is supportedbylanima! inhalation studies.;-/.>. -?> D. Please comment on the extent to which carcinogenic potency is a fimctiori;qffiber properties (e.g., diameter, aspect ratio, surface properties) other than .fiber: type and ; 'fiber length. . How adequate is infonnation in the epidemiology; or toxicology . ; literature for supporting these other properties into dose-response- analyses?- B-47 . \ HWBUI0009982 Vincent Castranova Response;.CJhe major influence of fibesxheppstiyjs ejtpressed as differenceyn fiber. : durability.;. Surface properties, such as.the ability,ofdny^ptile ygamphiboles to generate reactive oxygen spgpiesj havenot proyep to giratly influence fiber carcinogenicity in animal models. Diameter and aspect ratio affect fiber deposition in .the lung. ..However, theiaflifence on c^q^m^s^^|i#^a)o4^..s^^peEKie^ ofdqposition has not been adequately.eydvated. , ..... _v h, -v;tV ^ . 3) .o Aat ettent gsg the exposure ^tionatps'.documehted! hi the asbestos epidemiology ., Uterkure reliabie?;; ........... - ... ,v. . y..-. ....:. Response: The problem with these data have been adequately/discussed in the report. Fiber characterization is not complete. Exposure levels for pastexposures are often estimates. These uncertainties don't affect the conclusion that long fibers are more potent than short fibers or that amphiboles are more pot^tit^xhrysQtiJe. ^However,; they do make absolute quantitation ofthe potency differences duncuit Topic Area.^i;yhe.prpppsed exposure inc|.ex. -r.u i?c h". ' * * 4) The proposed exposure index does not include contributions from fibers shorter than ."SjmL 'support'^the.cbnclusroh'thatasbestos fibera:Wiorfer tfikn'5 uifri presentlittfe oifho carctnogentc risk. Response: Cohorts fpr epidemiologic studies were chosen for the absence ofmajor mixed dust expjpsrae. Ai^i^.9bD^^wae''c^M^Ued^jfof fibCT expo^^(aiPnp. Therefore, the buwteh jumtnk^i j^jaslan^^dli experimental desijAk AtSo# biMiens, burden would elects Ati oHdki|hiflaikrat^iy set pointand Inidrefee the reprise to iongfibeik thkpointwas.'dfcoSsedin IB. . ' '' 5) :'-TKfe proposed exposure hKlesx is vfeighedlifeftrlily by''flben:l(Mew-ttaii -10 fiftt ' Specifically, Equation 7.131 than 10 pm is more than 300 times greater than that offibers with lengths between 5 " ''''rAii'Tdp^'T^^'a^lii^'&ftuit'mAreDHd'^tiluchioli^bj^teQ^'wiA'Ae'^ e^K&oiibldgy ami^xBbi^rliteiaitoh? ~'' ' ' - ~ '* tV' 'Response: See reSpbriSe IB'and'4. : ' .-;- B-48 HWBUI0009983 Vincent Castranova 6) comparisons bdweericurratif environmental exposures to asbestos and historical exposure td?asbestos/tMtdoiWM in thewdrfc place. " ^ Response:' -It g6et?is^jifeible'tl^PajMeftt and futu&eiiqrosures of environmental concern would be to mixed dustsh&ther than pine fibers: The proposed'exposure index would dismiss what might be a high exposure to spherical particle or short fifes. ftei^iidTrafe'Cm^fsite is ^'eXStapIe offech a fiuxfed'tiust exposure. There are in vitro mechanistic data which would suggest that the 'respohstiierreSs to long fibers might be enhanced ifthe system was under particle-induced oxidative . ste ami infliMmiteih. ` ' 4 ' "' 1' -.Vi . ' Topic yyfda'3:-General qd^ifitfhs; x' -r- --ii) " jVjJj- Ik - ;rtriv>. 7) The proposed risk assessment approach assigns carcinogenic potency to individual fibers and to cleavage fragments (or "bundles that are components ofmore complex structures"). Please comment on whether cleavage fiagrirenfi 6faSbiStds &e ai; toxicologically significant as fibers of the same size range. Response:.Assigiurjg ej^valeht potracy to individual fibers and cleavage fragments ofequmdimens^pn is a|^^ia|>|g^^ip^:h. Data ]from u^vito meOTams^d'shidies do riot indicate fliat cells ran discern a difference between a single fife or a'bundle of equivalent dimensions. 8) Piea^ comment o. n w'.;3h, ethfetoptofesed cancer assi^meot approach js:relevant to `It* - (. . T '*o' - *; ; v',>--v 'f-1 "y^. *;*.* . < J^e'spppsg:Remise to, pp^ii.gpveriieaJby dqse, jdurapi|^,.'fttid dMe^tons. No biological response in the lung. Therefore^ long durable fibers not currently labeled as astetos.ifinhaled at a ,similarjdqse,would he expet^.to/tespU^a.afliUw;<lfe,. -p" if'pghql-ogy.. . ' ;* * ' ' ** * ` \ " % .'-VV" 9) The, reyie^v dpeurpentre^nap,eni.JEhaLa^festos saiprles be ap-jlyped By. transmission electron nntiroscojiy (TEM) and count only thosefibers.(or; bunc|e) longer ton 5 pm. Such counting practices will provide no information on the amount ofasbestos fibers shorter than 5 pm. To what extent would data on shorter fibers: in samples be useful for future evaluations (e.g., validation ofthe cancer risk assessment methodology, assessment of non-cancer endpoints)? B-# HWBUI0009984 Vincent Castranova Response: Use ofTEM rather-tfaan PGM allows thin fibers to..be counted .This, is appropriate, skce long dun fibers-would be expected to be highly potent: hr: evaluating risk offiber-inhalation aspart ofa mixed dust exposure, it is possible-teat particles less than 5 pm in length could enhance fteresponseto long fibers. -The : proposed assessment approach would ignore fills possibility. 10) Use proposeirisk assessmentmetfaodology suggests.that exposure estimates should be basedpaly oii fibeis longer ifaan`5 pmapdtfainneron 0.5 pm.ris 'thls cut-olT for.,-, fiber d/mwererapprepriate? !." >; ,!-vcr- : : --:.1 Response: Since fibers up to. COpm cdn-betdeposUed. fine- respiratory zone oftee :luhg, itseemsmoreapprcpriatetbraiseAecuttoff to;this valued-: .. . .. 11) Discuss whether the proposedcancer assessment approach, as a whole, is a reasonable evaluation of the available health effects data. What aspects ofthe proposed cancer assessment approach, ifany, are inconsistent with tee epidemiology or toxicology literature for asbestos? Response: The concepts that amphiboles are more potent team chrysotile and long fibers are more potent than short are reasonable. The debate is the weighing ofthese potencies. The approach used to mode! existing epidemiologic and animal data is reasonable. However, uncertainty oftee weighing factors exists due to tee uncertainty ofexposure and size characterization in tee individual studies used in tee model. 12) Section 8.2 of the review document presents three options for assessing cancer risks from asbestos exposure. Please comment on the technical merit of the proposed risk assessment options. Response: All three options assume that tee weighing factors for fiber dimension and fiber type are adopted Given that assumptionoption 2 appears to be simple to apply to environmental conditions. Each option suffers from the uncertainty oftee weighing factors and each option ignores tee situation ofa significant mixed particle exposure. Topic Area 4: Development of Conclusions and Recommendations At tee end ofthe workshop, tee peer consultants will be asked to draft conclusion statements identifying their most notable findings on tee proposed methodology. As a prelude to developing these statements, the peer consultants are invited to provide any additional comments or concerns, bote strengths and weaknesses, on topics not specifically addressed in tee previous charge questions. After completing the discussions tee peer consultants will prepare their conclusions, and they will also be asked to develop B.-50 HWBUI0009985 Vincent Castranova reccmimendafi&as for how- EPA can improve the nrethbdology. Please note that, although recommendations for future research projects are welcomed; the .focus ofthis workshop is oiiifae proposedriskassessment methodology and how it mayHe used to.support decisions atashestos-eontaminated sites. ' . / ; ; Response: The proposed methodology is founded strongly on the premise that lung cancer risk due to asbestos-is independent of other exposures. :This isinot the case with smoking andasbestos exposure; ' Mechanisms for asbestos-induced caficer include oxidant damage, deregulation ofgrowth control, production of'inflammatoty cytokines and proliferation factors, down regulation ofapoptosis, etc. Considering the current mechanistic unddstandingo&fiberrituiuced^caiK^.mductiomit^is nmxrnieasonable'to B-51 HWBUI0009986 HWBUI0009987 James Crapo (s* B-53 \ HWBUI0009988 ' James Crapo Chairman, Department of Medicine National Jewish Medical Research Center . . -'.i.. x .1400 Jaeksqrj,Street. ' .. T '' "/\jDenyer,'.'C>'8S2ie 'aagmlfM' Fax; 303-270-2243 . ?? - yp- Email: crapoi@hjc:(>rgi Dr, Crapo is a professor of medicine at the University of Colorado Health Sciences Center, Director Of the - Ph.D. Program for Graduate Health Care Professionals, and Associate Dean of the School of Medicine, as ttoaffe1 serving as thb;Gh'aInft'art bf the Department df Mekiiane of tffe National Jewish Center. < >w:; Pre\Hous; fo his appoinlments Inf Colorado, he was a professor of medicine and profeSsorofpathology; and dirtecfbr of extrapolation rhddelfng at DuKe'UniVetSftyoWe'is a member Of the American Thoracjb^Spfety, Arhertcafi'Fede'raKon of GimitiSl Research; Society OfToieicbtogy^and'ihe ifeneffraii Physiological-Society, as Well as a fellow of the Amencan Coltege oFPHysidaWsJJ He rdfsivedihis B.srTOagna aotimdaude.fi'brTi"' Brigham Young University and his M.D. from the University of Rochester. His certified medical specialty is inteiaarfHedldrtis,,With'assubspieaal^in'pulnit)rtary'disease,.;::He b memberfefcfee^editorial bdardstfoH < ifthaiatibn ToWSDlo^|rnt4rPi^ntafHeattt?.PefepSetives; and-the.Apierican Journal of-Physi6togy:sLMng>: , GelltoSrtandiMoledulafPhyd'oiogy--;He:haSi'pdblishedise'vbFal1texff>eiSks incfudtrig TdwcS3.!5^ybfthe:tirnSi;' > TExt^jMiafibrtohDosiiWdttfbRStetionships-for Ifihaled^articlesartd Gases,', and TextboolcpfRulmonaiyiM. :; lsea'es.'vHe'ha^'fiubltehed1hynierou's reviews^editorialsr and'booH.chaptere incfeding "Aspeelsiot.ri:: ?. lespir^l^ tiadsffd^erarid fenciidh important for dosirhetry modeling: inteispecies!je0mp.afison;--Fafe; aSM :trahslOralibnrdf^ere^MOdels for Studying airWdys Response to Environmental Injury,*cTApplieati&n.; : of Morphometric Methods.to:Study Di"fWSeahd Fd^l Injury in the thhg GaUse`d by^6>icAgehts,^ana> i- ' j. v. ` Morphologic, Morphometric, and X-ray Microanatytical Studies on Lung Tissue of Rats Exposed to hrysbtile!Asbe'sto^iri'lrihalaticih Chawiber^."`,'>He;has'piib;tished!many papers relatedJo asbestos - v;;' *3 irt'diit!ing"PUlmbnary'maar6phage acctimij)atiiCMi and asbestosrtnduced lesions at- silesof.fiber - . . .; rte'p&SW0;'''efih'ractefi^b6on of fhree%pes of ehrysotile'asbestdS'aftep aerolization,' Airway Branching . Rafffrf-lnfltiertGi0:;Asbestds FiBirtLbca!idn ahd The'Extenf'ofTlssu'e' Injury in tfteffelrctonbry>' Piferichyroa'.5;:j>.'.i!"j^j sit.'-:- .v?- -of ..-: r m ., -T? y.J *n' " '. .- .. : .. . :: - . ... . ;i '. . : ' . X'jj' * .. .-- : -i-.jr, .... . . i;)).-:.i.,v . ' - ::'i: - ,.i.- -'.v,'-= v ; V : yjfJ S-.' ;-;w >*'!'. v -iii- n-v., .- . -! . iv-'.*: 0:: v ; "r- A ' i-:; :s.' ' oc. ;V ' . v:> . ' ..-.i'fef-.o ' ;!,v ::: ;;o: .. . .> .. -:i . n- : rx.- m;:1/..a ; :; : rt}i- iii: ir;;\ y::^ . t' .* ! . . . - ..>K = j:_ /.. vir,. .................. :..., . .: . . ..i. p. . .I?:..-..,.; C-.'j- . f-v . v. .. . :.-i- ... , u:.' . B-5.4 HWBUI0009989 James D. Crapo, M.D. Workshop to discuss a Proposed Protocol to Assess Asbestos-Refated Risk Response to Charge Questions Topic:Area 1: Interpretations of the epidemiology and toxicology literature. 1) 'for lung cancer. . >r A] Influenceqffiljerfype: please,comment on the extent to whichlhe epidem^ogy literature and (riechanistic sttidies;suggesf that cardnogenit potency varies from.pnefibertypgtp. the next (e.g.v ohrysptile;versus amptiibole. fibers}, How,adequate issthe. information in Jie epidemiology. literature,:fpr suppprting-doser - response .analyses /or ftifferent.-fihersjyp.es?,: Specifically; to wtiat extentd;you thin.k.fb&propqsed risk coefficients' ln;TableL.6-29 are supported by^ theepidemiology literature? . (.* u-....,-.... s .*. I concur?thafefiie epidemiology literature and mecbanistic.studiesnow^trpnfll^.s.uggest thatthftoardripgenic fibetlypes.; :With resp.eAtQ.iCQmmerdally.used.'asbe.s.tos prewjuctsiittie-repbarcb sup{^>its.!the,cansfijogbnie poteneyas being:.. -Jd!eld.c^e>famosjte..^ neceiibreyfew, dcmeiby. Hodgson anduDdrton and fthe, analysis, prepared by rs.-JiBennan. and iGnuppi proyidejMQiapproaclies do assessingjlharejatiye.potency ofifiber types!with similar;outcomes. The epfderniofogi<S{|at|iiSingw.suIificierit. to suppoit'devetoping differenfirisk coefficfents fprdifferenfcfibet,types, fThe-cbefiMentsishowri^on fabl.eJ&yH) are.stipportqd.byjhe fiterature.but,are.conservative.. lithesmafysfedonfe byJrlodgsjort.atid-sDartpnjW^iUsed, it would rpsult ip latger diferences.in the. risk coefficients ftian.shpwij-ioiirahte^BiSB. }><*. k j.';. : r:-.... .Y 'flu.- >;>!; 'ir.fiO.'.i'i.V; -.0-..-l'.",'-*.-'. BJ Influence sof. fibec.flength;; Please .comment on -the:,extent to which ;thei;epidpmlplpgy;.:iiterature_ an<f mschanisticstudies suggestthatcarcinogenic potency,varieswith fiberlengtti. Howadequate is infprmaBon: iriithe.epidemiology literature forsupportingvdqse-responseanalyses fopfflferentiSjer lengths? Incgengrat Is it appropriatetpassesscancerrisksusingan exposure index/see.Eqqfttpn 74#) that ?S:Mighed.heavily by fibers longer than 10 micrometers (pm)? (Note: Topic area 2 includes more detailed questions qn the proposed exposure index.) The epidemiology and mechanistic literature shows that the carcinogenic potential of asbestos is strongly correlated with fiber length. There is sufficient literature to support the development of dose-response relationships for different fiber lengths. The mechanistic literature shows that fibers less than 10-15 microns in length are cleared by macrophage action. The epidemiology literature supports the conclusion that the longer the fiber, the greater the carcinogenic potential, with fibers longer than 20 microns in length carrying most of the associated risk for carcinogenicity. Based on the additional studies generated over the past 15 years, it would now be appropriate to develop cancer risk estimates that are heavily weighted toward fibers longer than 10 or 20 microns. C] To what extent do animal studies (e.g,, studies by Davis and other researchers) suggest that carcinogenic potency varies with fiber type and fiber length? Animal studies also suggest that carcinogenic potency varies with fiber type and fiber length, although the differences are often less than that suggested by human epidemiologic studies. This difference is likely due to the fact that animal studies are commonly done using extremely high doses (often given by injection or instillation) and shorter periods of observation (limited by the animal's fife span). These differences have the effect of removing fiber durability and clearance as substantial factors in determining carcinogenic risk. Thus, differences in carcinogenic potency between fibers based on fiber durability are not adequately evaluated in animal studies. In spite of this, animal work in general supports the concept that carcinogenic potency varies with both fiber type and fiber length. DJ Please comment on the extent to which carcinogenic potency is a function of fiber properties (e.g., diameter, aspect ratio, surface properties) other than fiber type and fiber length. How B-55 ) HWBUI0009990 James D. Crapo, M,D. adequate is information in the epidemiology: or toxicology literature for supporting these otfier properties into dose-response analyses? Fiber diameter is an important tement tn oardnogenic potency probably by influencing the ability of the fiber ;.jobe.inhaled intothe.depp lung:. ;,jj).e recommendation by.Berman and Crump.that.risk assessments should be focused on fibers with diameters, of 9,5 microns, or Jess, is reasonable, Aspect-ratiQ.does not appegrtb-. be a factor in determining carcinogenic risk. Aspect ratio is a valuable function in characterizing fibers from other inhaled.materials, but there is no evidence that aspect tatio is an important: factor in-predicting fiber toxicity. There.ISjSome evidepce that other fiber charaderfetlcs,;W!b.ich include sjjrfaceprpp.erties qridiemical compqsifipn^ niay lnfluerice cardnogeniGpptentia.j. althQughjhis has not yet:bden;sufl^enfly.deifihed to be .. used in developing specific risk estimates. The current epiderrflptogy ppd toxicology literature would support . using fiber diameter as an important factor in determining carcinogenic potency, but would not support using aspect; ratio as a factor,and-is insufficient to develop-specific risk estimates for.other fiber.propertiqs.;;,:.;?.- ... .i-.'V '.li? . : .vrii to -ife'ift'lAjr';'.. *i@ne-factomotadequatety considered in tha current document is the-interrelationship hejwgen smQkipg':`afld. asbestos exposure Jn. causation ofJung cancan Many, historical studiesiwere-not appropriately.controlled for cs.moWng.vSmokiog/l^; a higher, risk factor fot causaflon; of canoe?:,than, is asbe.stos exposure-andiiisvcan easily confound risk estimates that.focus only?pn asb8tqs?e.xpos.une, The epfcfenriioIPfl'd liter^rfeasses.sing 4 theabpy.ofiasbestasiexposure tQ.contributetQqancer causation Jn the.absence cf smsktrigjs weato.^riomer important Issue in devetoping correct estimates for asbestos exposure contribution to !ung;cari<r:ifi;5k;i.s whether or not asbestosis is required before cancer risk is elevated. There is a substantia! body of literature . ojragasfing.tbalformation ofiasbestosis.is.required toefona asbestos exposures.wgfi fnereasejunp cancer rfsk. 2) For mesothelioma: jlnfiqenoa of5fiber:type: Please .comment;.on;;the;.extent to which ihe^idejntology|tgrature and -mechanisticLstudies suggest that carcinogenic potency. - .varies -from, ope fiber type ti^beipgxtiCe.g,, , < chrysolite .versus amphibde1 fibers). How. adequate is ifie InformationJr? fije epide^IggyTiteraUipe fcr;iS.upj^ifirig. do5e^spQose. analyses (gr'dijjierghtft . tbink.ibe;proposed risk coefficients in Table 6^29%e.s.uppqrte.d,.byiihe epidernioipgy literature? My.commeptsiprinesothelioma are similar to those f^rJung cancer. .Tbe.caranpgerac.potenc^ yaries,,. between fiber types. The epidemiologic literature shows a much larger difference in carelpogenic.potential . (based on fiber type) for mesothelioma than for lung cancer. The risk coefficients shown in Table 6-29 are conservative estimates based on current literature. A,cridcal.questiOT nqtfijBy.resolved by current,,. - : literature is whether common human occupational exposures to chrysotile result in a low risk of . *chry's6ti|e|jfily cohorts.^fvJcist mesbmielio^as,fp.urid iri;,d>'rysQ{ile exppse^cohqrts are' associated with the mining environment MacDoriaid and colleagues have suggested that the' mesothelioma risk irfchrysbtile those B] Influence of fiber length: Please comment on the extent to which the epidemiology literature and , . ,, ^,rn;gchani(sfiqjstudtes suggest ttjat carcinogen^ potency vajies..with fi^^r^t|),Ho)rif'^c(pc^ate. is .tjL '! n^gerieral, is: ifappropriate to i^^.cariber j^^^i^f^`e)q^>su'rejindex fseot" ... .. 'Equation 7.13) (Note; topic area 2 includes more detailed qiiSs'tioris on the proposed exposure index.) '' 1 cdtibur with the assessment by Berman arid Crump that longer fibers cany the'primary risk for development of mesothelioma. It is appropriate to use exposure indices heavily weighted for fibers longer than 10 microns (or 20 microns). Fibers less than 5 microns in length have not been shown to carry significant potency. B-56 HWBUI0009991 James D. Crapo, M.D. C] To what extent do animal studies (e.g., studies by Davis and other researchers) suggest that carcinogenic potency varies with fiber type and fiber length? Animal studies, in general, support that there are differences in carcinogenic potency with fiber type and fiber length. Depending on study design, those differences may be under-estimated or not present due to the dose and/or route of administration of the asbestos and due to the shorter duration of animal studies. The effects of fiber durability in determining carcinogenic potency are not adequately assessed in animal studies. D] Please comment on the extent to which carcinogenic potency is a function of fiber properties (e.g., diameter, aspect ratio, surface properties) other than fiber type and fiber length. How adequate is information in the epidemiology or toxicology fiterature for supporting these other properties into dose-response analyses? Carcinogenic potency has clearly been shown to be a function of fiber diameter which influences the respirability of the fibers. There is no data associating aspect ratio with carcinogenic potency other than its ability to identify a fiber as opposed to a particle. Other factors such as surface property and. chemical composition likely play an effect, but this is not adequately defined by current literature. For example. Faux et at. `(2001) showed using rat pleural mesothelial cells that croeidolyte had ah impact on-growth factor expression not seen with chrysotile and which was removed by milling the croeidolyte. ('would-expect mechanistic studies to eventually define chemical or surface characteristics of fibers which could be included in risk estimates. 3) To what extent are the exposure-* estimates documented in the asbestos epidemiology literature reliable? Most of the asbestos epidemiology literature contains relatively crude estimates of exposure. Most estimates are qualitative and, at best, contain only intermittent assessments ofexposure levelsunder specific work conditions. Even in those cases, exposure conditions are not generally well characterized as to fiber type, fiber length, or fiber diameter. The exposure 'estimates in the epidemiology literature are adequate for general conclusions but do not commonly allow rigorous comparison between-studies. It would be advisable to recommend new criteria for assessing exposures which would include time-weighted exposure conditions and greater, characterization of the' fibers, including a more complete assessment of fiber length and fiber diameter distributions; Topic Area 2: The proposed exposure index. 4) The proposed exposure Index does not Include contributions from fibers shorter than 5 pm. Please comment on whether the epidemiology and toxicology literature support the conclusion that asbestos fibers shorter than 5pm present little or no carcinogenic risit The epidemiology and toxicology literature support the conclusion that fibers1 shorter than 5`rnicrons in length do not significantly contribute to carcinogenic risk. There are sufficient epidemiologic studies at the present time to exclude fibers shorter than 5 microns in length from carcinogenic risk estimates for asbestos exposures. . 5) The proposed exposure index is weighed heavily by fibers longer than 10 pm. Specifically, Equation 7.13 suggests that the carciriogemcpoteiicy of fibers longer than 10 pm is more than 300 times greater than that of fibers withiengihs between 5 and 10 pm. How consistent is this difference in carcinogenic potency with the epidemiology and toxicology literature? The fiber length coefficients used in Equation 6.7 and Equation 7.13 are consistent with the epidemiology and toxicology literature. B-57 \ HWBUI0009992 James D. Crapo, M.D. 6) Please explain whether the proposed exposure index will allow meaningful comparisons between current environmental exposures to asbestos and historical exposures to asbestos that occurred in the work place. The proposed exposure index will be somewhat difficult to apply to historical exposures in the . : workplace because dataregardingfiber length and width characteristics are not consistently available in that literature. However, many reasonable assumptions can be made based on known fiber characteristics from different products. Use of the proposed exposure index should enable a reevaluation of historical workplace exposures and may help reconcile some of the unexplained risk differences between various workplace environments. Changing to a new exposure index will lead to problems in comparing to historical data, but this should not inhibit moving to .a more correct exposure index. One problem not adequately considered in the current document Is the relationship . of smoking and asbestos exposure in lung cancer causation. When considering- comparisons of current environment conditions to historic conditions, one must also recognize that there are major changes in the smoking characteristics of.today's workers. This will confound interpretation of risk estimates related to asbestos exposures when comparisons are done to historical studies. . Topic Area 3; General questions. 7) The proposed risk assessment approach assigns carcinogenic potency to individual fibers and to cleavage fragments (or Abundles that are components of more complex structures). Please comment on whether cleavage fragments of asbestos are as toxicologicatly significant . as fibers of tire same size range. >. My interpretation of the existing literature is that cleavage fragments of asbestos are tojcipologically significant only if the fragments remain of sufficient length (10-20 microns or longer). I am aware of . no data showing that short cleavage fragments of asbestos show carcinogenic potential: 8) -.Please comment on whether the proposed cancer assessment approach, is relevant to all -amphlbole fibers or only to the - five types of; amphlbole. fibers. (actlnolite,- amoslte, anthophyUite, crocldollte, tremolite) designated in federal regulations. It is my general assumption that the proposed cancer assessment approach would be relevant to all amphibole fibers, however, there is rigorous data only on a limited number of amphlbole types -- most of the data is focused on crocidolyte, amosite and tremolite. 9) The review document recommends that asbestos samples be analyzed by transmission electron microscopy (TEM) and count only those fibers (or bundles) longer than 5 pm. Such counting practices will provide no information on the amount of asbestos fibers shorter than 5 pm. To what extent would data on shorter fibers in samples be useful for future evaluations (e.g., validation of the cancer risk assessment methodology, assessment of non-cancer endpoints)? Based on current literature, 1 would not expect counting asbestos fibers shorter than 5 microns in length to significantly enhance one's ability to validate cancer risk assessment methodology or known cancer endpoints. It is, however, difficult to make firm statements about data one does not have. The critical question is the cost of including short fiber counts vs. the potential future value of the data. If costs were low, I would include such counts. The current data do not support including counts of short asbestos fibers at a high economic cost. 10) The proposed risk assessment methodology suggests that exposure estimates should be based only on fibers longer than 5pm and thinner than 0.5 pm. Is this cut-off for fiber diameter appropriate? B-58 HWBUI0009993 James D. Crapo, M.D. The use of counting methodology identifying only fibers longer than 5 microns in length and thinner than 0.5 microns in width Is appropriate. This proposed change in methodology would be a substantial advance over the current use of a 3:1 aspect ratio. 11) Discuss whether the proposed cancer assessment approach, as a whole, is a reasonable evaluation of the available health effects data. What aspects of the proposed cancer assessment approach, If any, are Inconsistent with the epidemiology or toxicology literature for asbestos? The proposed cancer assessment approach is consistent with the epidemiology and toxicology literature for asbestos. My primary concerns relate to the absence of an adequate assessment of the confounding impact of smoking on lung cancer risk assessments and the absence of evaluating the rote of asbestosis as a factor in determining lung cancer risk. The epidemiology literature shows that both of the above factors are major components in determining lung cancer risk in asbestos exposed cohorts. Neither of these factors have been dearly shown to have a linear correlation with asbestos exposure atone. Table 8-xxx on page 8-10 makes an attempt to assess smoking impact on both chrysolite and ampbibole exposures. This assessment: should be expanded and internal inconsistencies in the table resolved. Duration and intensity of smoking need to be more fully characterized: Looking at Table 8-xxx, why would a male nonsmoker who is not exposed to an amphibote have a 4 times higher lung cancer risk than a male nonsmoker not exposed to chrysofite? 12) Section 8.2 of the review document presents three options for assessing cancer risks from asbestos exposure. Please comment on the technical merit of the proposed risk assessment options. All three proposed options have significant limitations. The use of a risk table is simpler for general use but is limited by factors such as the assumption of a constant exposure in both intensity and fiber characteristics, ft is also limited by crude grouping with other characteristics such as smoking. Intensity and duration of smoking are also huge factors that modify the risk;assessment. I would, in general, favor estimating risk using a unit risk factor if this approach were adequately developed and expanded, particularly if this unit factor could be accurately integrated with other major factors in cancer causation such as smoking, other exposures, and the formation of asbestosis. Topic Area 4: Development of Conclusions and Recommendations My initial recommendations are included in the previous comments. B-59 HWBUI0009994 B-60 HWBUI0009995 ) David Hoel B-61 HWBUI0009996 David Hoel Professor Medical University of South Carolina 36 South Battery Charleston, SC 29401 843-723-1155 Fax: 843-723-7405 ' __________ ;;'' ________________Email: whttepoint@adl.cbm Dr. Hoel received his A.B. (Mathematics and Statistics) with highest honors from the University of California at Berkeley, and his Ph D. in Statistics from the University of North Carolina at Chapel Hill. He is Distinguished University Professor at the Medical ' University of South Carolina, Clinical Professor, Department of Radiology at the University of South Carolina School of Medicine, where he also served as Professor and Chairman, Department of Biometry and Epidemiology and Associate Director for Epidemiology at the Hollings Cancer Center. For twelve years he served as the u .-. Director of the Division of Biometry and Risk Assessment, National Institute of Environmental Health Sciences in Research Triangle Park; North Carolina. He is a . member of international Statistical Institute and a Fellow of the American Statistical Association. He served as the co-editor of Biostatistics in;Cancer Risk Assessment. Scientist, Inc-Tokyo. 1991 and Multimedia Modeling and Risk Assessment (co-editor; with J Regens and C Travis), The Medical University of South Carolina Press, 1999. He is the Section Editor, Journal of Environmental Pathology, Toxicology and Oncology,; Contributing Editor, American Journal of Industrial Medicine; Member, International Agency for Research oh Cancer Working Group on the Use of Mechanistic Data to Evaluate the Carcinogenicity of Chemfcals to Humans, 1991;' Member, U.S. Consumer Product Safety Commission's Chronic Hazard Advisory Panel (CHAP), 1999. He is a member of the American Statistical Association, the Royal Statistical Society,' the Biometric Society, the International Statistical Institute, and the Society for Risk Analysis, among others. He is a member of EPA's Science Advisory Board's Environmental Health Committee (1997 ) and a member of the U.S.. Consumer Product Safety Commission's Chronic Hazard Advisory Panel (CHAP),(1999-). He has published over 150 papers, including "Perspective and Overview of the Concepts and Value of Hazard Identification as the Initial Phase of Risk Assessment for Cancer and Human Health." Scandinavian Journal of Work Environmental Health 18(1 ):83-89, 1992, Huff J and Hoel DG; "Concordance of Carcinogenic Response between Rodent Species: Potency Dependence and Potential Underestimation." Risk Analysis 12:115121,1992, Piegorsch WW, Carr GJ, Portier CJ and Hoel DG:; and" Multistage Models of Carcinogenesis arid Their Implications for Dose-Response Models and Risk ' Projections." Cbhfefence Proceedings: International Conference oh Radiation: Effect and Protection. Mito, Japan, March 18-20, jpp 123-126, 1992, Hoel DG. ' B-62 HWBUI0009997 Response to the Charge Questions David Hoel This is a very,JnteresOng and a very complex risk assessment I am in support of what the authors and the agency are attempting to due. The question is whether relevant analysis and review can be accomplished in the short time period we have. I have restricted mysetfto the area of epidemiological data and the quantitative models being used with this data. t . - The general comments I have so far are as follows. Models: .- For both lung cancer and mesothelioma, two specific risk models are used. These models are applied to the fitting of grouped epidemiological data using Poisson regression.- The models appear to describe the epidemiological data in a reasonable manner. I have several questions concerning the adequacy of these models and the impactthey make on toe final risk estimates; ; For lung cancer.-a simple relative risk model using cumulative exposure is used. For this type of data. one,often sees the estimation, of internal rates without the need of incorporating . external lung cancer mortality.rates. The authors are not clear, as to why they prefer the. use of external rates followed by an estimation of the alpha.parameter, which allows an adjustment for the difference between the backgroundJung cancer rates of the cohort and those of the general population. ,.. . Another issue is the choice of a linear relationship of cumulative exposure to' risk as opposed to the separation into exposure rates and duration of exposure. For example, the lung caricer and cigarette smoking modeling of Peto and Doll find a linear quadratic effect of smoking rate with a 4*1 to 5" power of duration of smoking, For mesothelioma, the model assumes that risk-is proportional to cumulative exposure. . Further, the effect is proportional to the 3,d power of time since first exposed, with a ten-year latency.. Again, the question is whether this model is the appropriate one for dealing with the various cohorts that report mesothelioma. .. it may be that the quantitative results of the overall analysis of the epidemiological data are fairly robust with respect to these two cancer risk.models. If this is.not the case, then it is important to understand the.impact of'the quantitative risk results on the bhdlce bftHese two very specific cancer models. Risk Estimates: The optimized risk coefficients for pure fiber types are given in Tables 6-29. Table 6-30 gives conservative values. It would be more informative if simulations incorporating the estimated model uncertainties could be carried out and used in place of table 6-30. B-63 i HWBUI0009998 0).) Topic. Area .1. David Hoe! 1) Lung Cancer: At this point in my review I believe that the epidemiological data is supporting the questions raised in A) & B). I have not reviewed the animal data so I have no answer for C). Based on the human data I do not believe we know beyond fiber type and length as|in D). But I arn still.looking at this question. ' 2) Mesothelioma: Same answers as with Lung cancer; .' 3) hiot my area of expertise. . ...... . . . Topic Area 2-4. I hope to have answers for a number of these questions as we get closer to the meeting Bine. . ' M.generalJ to appropriately answer many ofjhe specific charge questions will necessarily require reviewing a Iqrge^puntppmary research papers. ... , . , \ ...... CHARGE QUESTIONS ,, Topic Area 1: ' v '> . Interrelations of trie epidemiology arid toxicology literature. = ! Fot lung cancer. . .. .. , . A] Influence of fiber type: Please comment on the extent to which the epidemiology literature and mechanistic studies, suggest thatcardnogenic pptpncy vanes from one fiber.type to.the next (e.g.. chrysotiie versus amphiboie fibers)- How adequate is the information in. the epidemiology literature for supporting dose-response analyses for different fiber types? Specifically, to what extent do you think the proposed risk coefficients in Table 6-29 arei supported by the -epidemiology literature? Answer: A irteta type analysts was used to group studies of similar fiber type . from theepidemiological literature. These^ studies,appeared tobefattly . ; Heterogeneous and the weighting factors were modified t?y: lticprporaOhg,ad hoc measures of study quality which resulted in increased confidence intervals. The ' resulting weighted potency estimates with confidence intervals by fiber type were not specifically given. However there did appear to be a difference in potency by fiber type (pure chrysotiie v. amphiboles) although they may not necessarily be statistically different. They linear, RR model fits the South Carolina (Chyrsotile) example very well . while it was necessary to include an additional parameter (alpha) in order to fit the Wittenoom miner data (crocidolite) which continued to appear to be nonlinear: The reason for assuming that the spontaneous rate for lung cancer in this cohort being twice that expected is nbt clear othef than the data is poorly fit HWBUI0009999 : X David Hoel without the additional parameter. How well the linear model describes the data for other cohorts is not described with respect to residual patterns. The risk estimates in Table 6-29 depend upon the concept that potency for a given asbestos type depends primarily length and diameter of the fibers. This is the resuit of animal inhalation studies (Davis'et al.) which are assumed tp directly apply to man. If this is correct the one can say that thp Table 6-29 results,are not inconsistent with the epidemiological data. The estimates can not apparently be derived solely from epidemiological findings. Q] Influence of fiber length. Please comment on the extent to which the epidemiology literature and mechanistic studies suggest that carcinogenic potency varies with fiber length. How adequate is information irt tfie epidemiology literature,for supporting dose-response analyses for different fiber lengths'!1 Ili general, is it appropriate to kssess cancer risks-rising an exposure index (see Equation 7.13) that is weighed heavily by fibers longer than-IO rriidromSters (j^m)?'(N6te::Topic area 2 includes more detailed questions on the proposed exposure index.) Answer As stated above the epidemiology literature does not provide adequate information on fiber length and potency. Using the animal data to develop the exposure index 7.13 and applying it to the epidemiology data does not change greatly the forest plots given in Figures 6r3 and 6-4 with regard to heterogeneity. C] To what extent do animal studies (e.g., studies by Davis and other researchers) suggest that carcinogenic potency varies with fiber type and fiber length! Answer. It would be useful to have Appendix C available to answer this question. Based on the information .from the animal studies it is clear that potency varies with fiber type and length.. D] Please comment on the extent to which carcinogenic potency is a function of fiber properties (e.g., diameter, aspect ratio, surface properties) other than fiber type arid fiber length; How adequate is information in the epidemiology of toxicology literature for supporting these other properties into dose^response analyses? :-r . Answer. The epidemiology data does not provide adequate information on these measures with regard to cancer risk. . . 2) :: . .X For mesothelioma: A] Influence of fiber type: Please comment on the extent ta which the epidemiology literature and mechanistic studies suggest that carcinogenic potency varies from one fiber type to the next (e.g., chrysotile versus amphibole fibers). How adequate is the infoimation.iathe epidemiology literature for supporting dose-response analyses for different fiber types'! Specifically, to what extent do you think the proposed risk coefficients in Table 6-29 are supported by the epidemiology literature? HWBUI0010000 David Hoe! Answer The epidemiological data is somewhat limited for mesothelioma, however the available data shows a strong difference in potency by fiber type. Because of the limited data, potency is necessarily assumed to be linear in concentration. The model which assumes a third power of lagged duration since exposure is not specifically used. The exact method employed by the authors is as | understand anonparametric description of time since exposure component This is a reasonable approach which should be better than theparametric approach. The data is too limited to determine whether the parametric model is realistic. The coefficients in Table 6-29 are reasonable but because of limited data I have less confidence than for the lung cancer values. B] Influence of fiber length: Please comment on the extent to which the epidemiology literature and mechanistic studies suggest that carcinogenic potency varies with fiber length. How adequate is information iq the epidemiology-literature for supporting dpse-response analyses for different - fiber.lengths! In general, is it appropriate to assess cancer ris^s using, an exposure index (see Equation 7.13) (hat is weighed heavily by fibers.longer: than 10 micrometers (pm)? (Note: Topic area 2 indudes more detailed questions on the proposed exposure index.) Answer As with lung cancer the epidemiological data areinsuffipientto estimate potency basedi on fiber length. .- , ;... C] To what extent do animal studies (e.g., studies by Davis and other researchers) Suggestlhat carcinogenic potency varies with fiber type and fiber length? Answer The Davis data does show length arid type differences but only, a total .of .13 tumors are available from the 18 experimenigl groups for tfie. estimatiori of the differences. There are therefore large, uncertainties which are notestimated and incorporated into the model. There seems to be the assumption that the fiber length and width effects for lung cancer are similar for mesothelioma. D] Please corriment on (he extent to which carcinogenic pofency.is a function of fiber, properties (e.g,, diameter, aspect ratio, surface properties) other than fiber, type and fiber length. How adequate is information in the epidemiology or toxicology literature for supporting these other properties into dose-response analyses? Answer. The epidemiology data does not provide adequate information on these measures with regard to mesothelioma risk. B-66 HWBUI0010001 David Hoe! 3) To what extent are the exposure estimates documented in the asbestos epidemiology literature reliable? Answfer. I am not qualified to comment on the industrial hygiene aspect of the epidemiological studies. However, it seems that the comparisons between lung burden and air concentrations are reasonable given assumptions concerning retention of the fibers. ; Topic Area 2: The proposed exposure index. 4) The proposed exposure index does hot include contributions from fibers shorter than 5 .pm. 'Please comment on whether'the'epidemiology and toxicology literature support the conclusion that asbestos fiberS shorter than 5 pm present tittle or no carcinogenic risk. Answer: The animal data is clear that there is no cancer risk for exposures to fibers less than 5um: The epidemiological data provides Wo information'dift this issue due to the mixed fiber sizes in the occupational exposures. The ' ' epidemtplogical dta is not inconsistent with this animal finding. The proposed exposure index is weighed heavily by fibers longer .than 10 pm. Specifically, Equation 7.13 suggests that the carcinogenic potency of fibers longer than 10 pm is more than 300 limes greater than that of fibers with lengths'between 5 and 10 pm. How consistent is this difference in carcinogenic potency with the epidemiology and toxicology literature? Answer The analysis ofthe animal inhalation data produces this finding. ;What is not given is the statistical uncertainty of this result Also there may be physiological differences between rat and man that suggests that the species extrapolation may not be valid. This I simply do not know would like to see a discussion of the-issue. ' " 6) . . . ... , . .. ...... ,, Please explain whether the proposed exposure index will altovii meaningful comparisons between current environmental exposures to asbestos and historical 'exposure's-to 'asbestos that occurred in the work place. Answer Since the historical exposures are the basis for the risk models it should be reasonable to estimate risk from current environmental exposures. One issue I have is whether or not the simple linear assumptions are appropriate for relatively low current exposures. If not the environmental risks may be over estimated. There is simply no way of knowing this unless mechanistic data can provide an answer. Topic Area 3: General questions. B-67 HWBUI0010002 David Hoel 7) The proposed, risk assessment approach assigns carcinogenic potency to individual fibers and to cleavage fragments (or`bundles that are components of more complex structures "). Please comment on whether cleavage fragments of asbestos are as toxicologically significant as fibers of the same size range. : ; ..... Answer. At this point I have no opinion on the concept of cleavage fragments. 8) Please comment on whether the proposed cancer assessment approach is relevant to all amphibofe fibers or only to the five types.of amphibole fibers (actinolite, amosite, anthophyllite, crocidolite, tremolite) designated In federal regulations. Answer I simply do not know enough about asbestos libers to say whether an extrapolation beyond the five types isreasonable. I feel that the risk estimates . -, using the types reported in the animal and epidemiology data are reasonable. - - The review document recommends that asbestos samples be analyzed by transmission electron microscopy (TEM) and count only those fibers (or bundles) longer than 5 pm. Such counting, practices will provide no information on the amount of asbestos fibers shorter than 5 pm: T6 what extent would data on shorter fibers in samples be useful for future evaluations (e.g., validation of , the cancer risk assessment methodology, assessment of non-cancer.endpoints)? -. ' Answer Obviously data on shorter fibers would be useful in future studies in order to confirm the currently proposed dsk analysis. to) ' .... The proposed risk assessment methodology suggests that exposure estimates should be based only on fibers longer than 5 pm and thinner than 0.5 pm. Is this cut-off for fiber diameter appropriate? , ,. . Answer: Based, upon the limited animal and .epidemiological data this seerrts reasonable to me.. If this is corre.p| the txjrttrtbutjpn to risk for fibers outside this, range.would be very small at,best.; . 11) l-: "` ; "' Discuss whether the proposed cancer assessment approach, as a whole, is a reasonable evaluation of the available health effects data. What aspects of the proposed cancer assessment approach, if any, are inconsistent with the epidemiology or toxicology literature for asbestos? Answer. The only issue I have.ls; ^ethdr:effecfe are proportional to exfbsiire. The alternative approach has be^n to consider the specific 2-stage model of. Moolgavkar. I would also be interested in Seeing an application of the more traditional Armitage -Ooll multistage model as has been used recently with diesel exhaust and lung cancer. .. . 12) ' Section 8.2 of the review document presents three options for assessing cancer risks from asbestos exposure. Please comment ori the technical merit of the proposed risk assessment ) B-68 HWBUI0010003 9 options. David Hoel Answer. I prefer the second method since it is an estimate of the actual risk fora individual classified by gender and;smoking status. It should be extend to cover scenarios of varying or terminated exposures and smoking status. The other approaches are crude general estimates of increased risk. Topic Area Development of Conclusions and Recommendations . At the end of the workshop, the peer consultants will be asked to draft conclusion statements identifying their most notable findings on the proposed methodology. As a prelude tb developing these statements, the peer consultants are invited to provide any additional comments or concerns, both strengths and weaknesses on.topics .pot specifically addressed in the previous charge questions. After completing the discussions the peer consultants will prepare their conclusions, and they will also be asked to develop recommendations for how EPA can improve the methodology. Please note that, although recommendations for.future research projects are welcomed, the focus of this workshop is.on,the proposed risk.assessrpenf methodology and how it may be used to support decisions at asbestos- contaminated $Kes. ,, . . .. ... . . Answer. For both lung cancer and mesothelioma; two specific risk models are used. These models are applied to the fitting of grouped epidemiological data in a Poisson regression manner. The models appear to describe the epidemiological data in a reasonable manner I have several questions concerning the adequacy of these models and the impact they make on the final risk estimates. For lung cancer, a simple relative risk model using cumulative exposure is used. For this type of data, one often sees the estimation of internal rates without the need of incorporating external lung cancer`mortality fates. The authors are not clear as to why'they prefer the use of external rates followed by an estimation of the alpha parameter, which allows an adjustment fof the difference between the background lung cancer rates of the cohort and those of the general population. Another issue in the model is the choice of cumulative exposure as opposed to the separation into exposure rates and duration of exposure. For example, the lung cancer arid cigarette smoking modelirig of Peto and Doll find a relationship of a linear quadratic effect of smoking rate arid a 4,K to 5,h power of duration of smoking. v; . For mesothelioma, the model assumes that risk is proportional to cumulative exposure. Further, the effect is proportional to the 3rd power of time since first exposed, with a ten-year latency. Again, the question is whether this model is the. appropriate one for dealing with the various cohorts that report B-69 HWBUI0010004 mesothelioma. David Hoel It may be that the quantitative results of the overall analysis of the epidemiological data are fairly robust with respect to these two cancer risk models. If this is not the case, then it is important to understand the impact of the quantitative results on the choice of these two specific cancer models. Finally, as I mentioned in response to question 11.1 would be interested in the use of the multistage model as it describes degrees of initiation and promotion. Also the meta-analyses used appear to'coirefctiy use random effects model due to the heterogeneity of the studies. Publication bias was not considered i.e. funnel plots etc. References Berman DW and Crump K. 2001. Technical Support Document for a Protocol to Assess Asbestos-Related Risk. Final Draft Prepared for U.S. Department of Transportation and U.S. Environmental Protection Agency. September 4,2001. EPA 1986. Airborne Asbestos Health Assessment Update. U.S. Environmental Protection Agency. EPA 6G0/8-84-003F. 1986. B-70 HWBUI0010005 Morton Lippmarin B-71 HWBUI0010006 _________ Email: lippmann@env.med.nvu.edu Morton Lippmann Professor New York University School of Medicine 57 Old Forge Road Tuxedo, NY 10987 845-731-3558 Fax: 845-351-5472 Dr. Lippmann is a professor of environmental medicine at the New York University (NYU) School of Medicine. He holds a Ph.D. (NYU, 1967) in environmental health science, an S.M. (Harvard University, 1955) in industrial hygiene, and a B.Ch.E. (The Cooper Union, 1954) in chemical engineering. At NYU, he directs a research program on human exposure and health effects and the EPA-supported Particulate Matter Health Effects Research Center. He has been the recipient of numerous awards for his research and contributions in aerosol science and pulmonary physiology, human exposure assessment and dosimetry, chemical transformations in the atmosphere, population studies of exposure-response............... relationships in occupational and community cohorts, and factors affecting1 the toxicity of airborne fibers. Much of this research has been focused, on specific chemical agents,, notably, ozone, sulfuric acid, and asbestos. Dr. Lippmann is a past president of the international Society of Exposure Analysis (1994-1995), past chairman of the ACGIH (1982-1983), ofthe EPA Science Advisory Board's Executive Committee (2000-2001), EPA's Advisory Committee on Indoor Air Quality and Total Human Exposure (1987-1993). and.EPA's Clean Air Scientific Advisory Committee (1983-1987). He.has .also chaired and been.a member of numerous National Research Council committees, including committees on synthetic vitreous fibers, measurement and control of respirable dust in mines, indoor pollutants, toxicity data elements, arid in-vivo toxicity testing of complex mixtures. His publications include 260 research and review papers in the scientific literature arid reference texts on environmental health science. B-72 HWBUI0010007 Responses to Charge Questions Morton Lippmann Topic Area 1: Interpretations of the epidemiology and toxicology literature. 1) For lung cancer. A] Influence of fiber-type:- Please comment on the extent to which the epidemiology literature 'and mechanistic studies suggest that carcinogenic potency varies from one fiber type to the next (e.g.,.chrysotile versus amphibole fibers). How adequate is the information in the epidemiology literature 'for supporting dose-response analyses for differentfiber types'} Specifically, to what extent' do you think the' proposed risk coefficients in Table 6-29 are supported by the epidemiology literature? Response: The epidemiology- literature, controlled animal inhalation exposure studies, and mechanistic studies cited by Berman and Crump are among the most appropriate for representing -the differential, potency of clirysotile''and amphibole fibers for causing increased rates of lung cancer. The K, '.coefficients listed in Table 6-29 represent the best estimates currently available and are based on a reasonable interpretation of the available literature. B] Influence of fiber length: Please comment on the extent to which the epidemiology literature and mechanistic studies suggest that carcinogenic potency varies withfiber length. How adequate is information in the epidemiology literature for supporting dose-response analyses for different fiber lengths? In general, is it appropriate to assess cancer risks using an exposure index (see Equation 7.13) that is weighed heavily by fibers longer than 10 micrometers (pm)? (Note: Topic area 2 includes more detailed questions on the proposed exposure index.) Response: The epidemiology literature and controlled animal exposure studies that have provided adequate data on fiber length and diameter distributions in the exposure atmospheres and/or delivered tissue dose clearly demonstrate that fiber length is a critical determinant of carcinogenic potency. The conclusion was firmly supported by the recent ATSDR Workshop Report: "Report on the Expert Panel on Health Effects of Asbestos and Synthetic Vitreous Fibers: The Influence of Fiber Length" (Draft Final of 12/23/02). The epidemiology literature supporting exposure-response analyses for different ranges of fiber lengths is still quite sparse, but a formulation that is weighted heavily for fibers longer than 10 pm is certainly justified. It may need further refinement in the future (e.g., giving greater weight to fibers longer than 20 pm) but the B-73 J HWBUI0010008 Morton Lippmann proposed formulation is clearly superior to the pre-existing formulation, that makes us distinction beyond length > 5 pm. C] To what extent do animal studies (e.g., studies by Davis and other researchers) suggest that carcinogenic potency varies withfiber type and fiber length! Response: The controlled exposure studies in animals (rats) by the John Davis group in Edinburgh and the Chris Wagner group m Penarthare among the most informative concerning the influence of fiber type (e.g., amosite, other. amphiboles, qhrysotile, and erionite) and fiber size (length and width), as summarized;by Lippmann (1988,1994), and the discussion Berman and Crumps document would have been strengthened : . by a more complete reference to the analyses cited in those papers. D] Please comment oh the'extent to which carcinogenic potency is a function of fiber properties (e.g:, diameter, aspect ratio, surface properties) other than fiber' type and fiber length: How adequate is information in the epidemiology or toxicology literature for supporting these other properties into doseresponse analyses?' Response: Carcinogenic potency can be influenced by fiber diameter and surface properties, but aspect ratio, per se, has no biological significance. Fiber diameter can be influential in two different ways. One is that fiber diameter is closely related to aerodynamic diameter, which in-turn largely determines deposition probabilities in the conductive airways and lung, parenchyma. The mucociliary and macrophage.rnediated clearance pathways and residence times at deposition sites are determinants of toxic potential. The.other way that fiber diameter affects carcinogenic potency is that very thin fibers appear to be able to penetrate through pores in.the respiratory epithelium and thereby gain more ready access to interstitial lung cells, and lymphatic drainage pathways. Surface properties can affect dissolution rates and. thereby, biopersistence, the generation of reactive oxygen species, and the. release of mediators from lung cells, and all of these factors may be important to carcinogenic potency for. lung cancer. Aspect ratio, i.e.,'the ratio of fiber length to fiber width, has no known biological significance in and of itself. Fiber lengths and widths themselves are the critical determinants of toxicity, as discussed above and in the Berman and Crump document. The information in the epidemiology and toxicology literature B-74 HWBUI0010009 Morton Lippmann provides quite adequate support for these conclusions in regard to exposure-response relationships for lung cancer. 2) 1 For mesothelioma' ' A] Influence of fiber type-. Please comment on the extent to which the epidemiology literature and mechanistic studies suggest that carcinogenic potency varies from onefiber type to the next (e.g. chrysotile versus amphibole fibers). How adequate is the information in the epidemiology literature for supporting dose-response analyses for differentfiber types'.? - Specifically, to what extent do you think the proposed risk coefficients'in Table'6-29 are supported by the epidemiology literature? - Response: The epidemiology literature, controlled animal inhalation exposure studies, and mechanistic studies cited by Berman and Crump are among the most appropriate for representing the differential potency of various fiber types for causing mesothelioma. It js .clear that, in terms of potency, erionite fibers > amphibole asbestos fibers > chrysotile fibers for given ranges of fiber diameter, and fiber length. Table 6-29 provides,coefficient estimates for mesothelioma (K,,) associated with amphiboles and chrysotile fibers that are based on an incomplete evaluation of the relevant literature, and need to be adjusted to reflect the influence of fiber length, as discussed below. B]' Influence of fiber length: Please comment on the extent to" which the epidemiology literature and mechanistic studies suggest that carcinogenic potency varies with fiber length. How adequate is information in the epidemiology literature for supporting 'dose-response analyses for different fiber lengths'} In general, is it appropriate to assess cancer risks using "an exposure index (see Equation 7.13) that is weighed heavily by fibers longer than 10 micrometers (pm)? (Note: Topic area-2-' includes mdre detailed questions on the proposed exposure index.) Response: The epidemiology literature arid coritolled animal inhalation exposure studies clearly- indicate that fiber length is a critical determinant of potential to cause mesothelioma. As discussed by Lippmann (1988), short amphibole fibers (< 5 pm long) are essentially innocuous, in both studies in human lungs (Timbrel!, 1983) and rats (Davis, 1986), and. the critical fibers for. mesothelioma induction are those between 5 and 10 pm in length. Fibers longer than 10 pm are not effectively translocated to the mesothelioma. Thus, for B-75 HWBUI0010010 Morton Lippmann mesothelioma, it is not appropriate for the exposure index to be. heavily weighted for fibers longer than 10 pm. . ........ C] To what extent do animal studies (e.g., studies by Davis and other researchers) suggest that carcinogenic potency varies v/ithfiber.type and fiber length? Response: Potency for mesothelioma induction clearly varies with both fiber length and fiber type. As noted above (in 2B), the critical fiber lengths are those between 5 and 10 pm, and, as rioted (in 2A), fiber type is also a critical determinant, with erionite > amphibole > chrysotile.. In. fact, as. noted by Lippmann (1994), the mesothelioma associated with exposure to commercial chrysotile arp most likely due ..to the tremolite component of the commercial chrysotile. :D] Please comment on. the-extent to which carcinogenic potency is- a function of.fiber properties (e.g., diameter, aspect ratio, surface properties) other than, fiber type mid..fiber .length. How. adequate, is information in the epidemiology or toxicology literature for ^supporting these other properties into dose- response analyses? . .... Response: As noted in ID-above, surface properties can affect dissolution rates and thereby biopersigtence, the generation of reactive; oxygen species, and the release of mediators from, lung cells, and ail of these factors may be important for carcinogenic potency. . Accessible internal surfaces within fibers, such as that characteristic . for,.erionite fibers, may .account for the . exceptional potency of erionite for producing mesothelioma in rats (Wagner et al., 1985) and humans (Baris et al., 1987). As noted in ID above, aspect ratio, per se, has no influence on carcinogenic potency. 3) To what extent are the exposure estimates documented in the asbestos epidemiology literature reliable? Response: The exposure'estimates documented in the asbestos epidemiology literature dearly have weaknesses associated with:- a) the different exposure indices measured (total dust count, PCM counts of fibers > 5 pm- in length that.could not detect very thin fibers and could not discriminate among fiber types, SEM, and TEM); b) the lack of information on fiber length and fiber diameter distributions in the PCM, SEM and TEM measurements; c) the relatively few long fibers seen in SEM and TEM measurements; resulting B-76 HWBUI0010011 Morton Lippmann in limited statistical validity for long-fiber counts. A significant contribution made in the Berman and Crump document was its ability to locate, access, analyze, and document better fiber distribution data from archived sampling filters collected during past epidemiology and controlled animal inhalation studies. 4) The proposed exposure index does not include contributions from fibers shorter-than 5 pm. Please comment on whether the epidemiology and toxicology literature support the conclusion that asbestos fibers shorter than 5 pm present little or no carcinogenic risk. Response: The recent ATSDR Workshop Report: "Report on the Expert Panel- on Health Effects of Asbestos and Synthetic Vitreous Fibers:' The Influence of Fiber Length" (Draft Final of 12/23/02) clearly indicates that fibers shorter than 5 pm present little or no carcinogenic risk. 5) The proposed exposure index is weighed heavily by fibers longer than -10 pm. Specifically, Equation 7.13 suggests that the carcinogenic potency of fibers longer than 10 pm is more than 300 times greater than that of fibers with lengths between 5 and 10 pm. How consistent is this difference in carcinogenic potency with the epidemiology and toxicology literature? Response: The heaVy weighting of fibers > 10 pm in length is qtiite appropriate for risk assessments for lung cancer,' as documented in the literature review provided by Berman and Crump. On the other hand, as- noted in my response to' charge ' question 2B), such weighting is not appropriate for risk assessments for mesothelioma, where the risk is most closely associated with Ftbeis between 5 and 10 pm ini length 6) Please explain whether the proposed exposure index will allow meaningful comparisons between current environmental exposures to asbestos and historical exposures to asbestos that occurred in the work place. , Response: The proposed.; exposure index is based largely on analyses of the past relationships between cancer incidence in asbestos exposed populations- in the mines and- mills-, in Quebec, a textile plant in South Carolina and crocidolite exposed workers at Wittenoom in Australia, and historic and retrospective analyses of the airborne fiber concentrations in those work environments. The extrapolation of that experience to the carcinogenic hazards associated with contemporary environmental exposures to people exposed to tremolite ') HWBUI0010012 Morton Lippmann fibers in. Libby, Montana, various California communities around surface deposits of serpentine,- people exposed to dust from the World Trade Center collapse in New York and New Jersey, and other places is reasonable and prudent insofar as the exposure concentrations in these communities are within about two orders of magnitude of those in the historic occupational cohorts. 7) The proposed risk assessment approach assigns carcinogenic' potency to individual fibe'rs arid to cleavage fragments (or bundles that are components of more complex structures). Please comment on whether cleavage fragments of asbestos are as toxicologically significant as fibers of the same size range. Response: The toxiopotential ofinhaled mineral and vitreous fibers, has been shown to depend most strongly on fiber length,- fiber diameter, and biopersistence. There is very: little, evidence that amphibole asbestos cleavage fragments in the fiber diameter and fiber length range ofconcern are less hazardous than comparably sized asbestiform fibers. In fact, the only directly relevant comparison, i.e., the Davis et al. (1991) comparative study of six tremolite asbestos samples (three asbestiform fibers, and three cleavage fragment dusts), which was discussed in some detail in the Berman and Crump document (pp. B-3 through B-10), showed that the risks from the tremolite cleavage fragments, when appropriately adjusted according to their protocol structure formulation, had quite comparable potency to the asbestiform tremolite. 8) Please comment on whether the proposed cancer assessment approach is relevant to all amphibole fibers or only to the five types of amphibole fibers (actinolite, amosite, anthophyllite, crocidolite, tremolite) designated infederal regulations. Response: Since all amphibole asbestos fibers can be expected to be biopersistent and be found in diameters and lengths that are associated with cancer causation, there is no good reason, based on biology, to limit regulations to the five specific types now regulated. 9) The review document recommends that asbestos samples be analyzed by transmission electron microscopy (TEM) arid count only those fibers (or bundles) longer thari 5 pm. Such counting practices will provide no information on the amount of asbestos fibers shorter than 5 pm. To what extent would data oh B-78 HWBUI0010013 Morton Lippmann shorter fibers in samples be useful for future evaluations (e.g., validation of the cancer risk assessment methodology, assessment of non-cancer endpoints)? Response: Fibers shorter than 5 pm can contribute to asbestosis in occupationally exposed individuals (Lippmann, 1988). However, the asbestosis risk is not closely related to fiber number, but rather to fiber surface area. The counting of fibers < 5 pm in length would serve no purpose in cancer risk assessment, and asbestosis requites exposures to asbestos at concentrations far higher than any likely to be encountered in nonoccupational environments. 10) The proposed risk assessment methodology suggests that exposure estimates should be based only on fibers longer than 5 pm and thinner than 0.5 pm. Is this cut-off for fiber diameter appropriate? Response: There is no good reason to exclude fibers between 0.5 pm and 1.5 pm in diameter (~ 5 pm in aerodynamic diameter) in a risk analysis for lung cancer. Such fibers can penetrate to small lung airways, and same asbestos minerals produce many fibers in this range of diameter (especially anthophyllite). On the other hand, there is little risk for mesothelioma for fibers thicker than 0.15 pm (Lippmann, 1988). 11) Discuss whether the proposed cancer assessment approach, as a whole, is a reasonable evaluation of the available health effects data. What aspects of the proposed cancer assessment approach, if any, are inconsistent with the epidemiology or toxicology literature for asbestos? Response: The Berman and Crump cancer assessment approach is quite reasonable for lung cancer risk assessment. However, as discussed in my responses to charge questions 2B and 5, it is not optimized for mesothelioma risk assessment. 12) Section 8.2 of the review document presents three options for assessing cancer risks from asbestos exposure. Please comment on the technical merit of the proposed risk assessment options. Response: The three different risk assessment options proposed by Berman and Crump are all usable, albeit with some variation in the convenience with which they can be applied. The easiest to use would be Option 2 (Risk Table), but as acknowledged by Berman and Crump, this could lead to errors for short-duration exposures. B-79 HWBUI0010014 Morton Lippmann For application of any of these options, reliance on Equation 7-13 may be appropriate for- lung cancer risk estimation. However, it is almost certainly misleading for mesothelioma risk assessment, where its emphasis on fibers longer than 10 pm is not warranted. References Baris YI, Simohato L; Artvinli M, Pooley F, Saracci R, Skidmore J, and Wagner JC. 1987. Epidemiological and environmental evidence of the health effects Of exposure1 to erionite fibres': A four-year study in the Cappadocian region of Turkey. lot, I. Cancer 39:10-17. . ... Davis JMG, Addison J, Bolton R, Donaldson K, Jones AD, and Smith T. 1986. The pathogenicity'-of long versus short fibre samples of amosite asbestos administered to rats by inhalation and intraperitoneal injection. Brit. J. Exper. Pathol. 67:415-430. Davis JMG, Addison J, McIntosh C, Miller. BG, and Niven K. 1991. Variations in the carcinogenicity of tremolite dust samples of differing morphology. Ann. NY Acad. Sci. 643:473-490. Lippmann M. 1988. Asbestos exposure indices. Environ. Res. 46:86-106. * Lippmann M. 1994. Deposition and retention of fibres: Effects on incidence of lung cancer and mesothelioma. Occup. Environ. Med. 51:793-798. Timbrell V. 1983. Fibres and carcinogenesis. J. Occup. Health Sci. 3:3-12. Wagner JC, Skidmore JW, Jill RJ, and Griffiths DM. 1985. Erionite exposure and mesothelioma in rats. Br.J. Cancer 51:727-730. Some General Comments on the Berman and Crump Technical Support Document This document needs a lot of editing for both technical content and organization. For example, there are numerous places where a statement in an earlier chapter relies on text in a later chapter. The text is overly encyclopedic and cites many papers whose relevance to the issues of concern in relation to the development of a better model for asbestos fiber risk assessment is not apparent. Also, there are indications of references to be supplied (see pp. 5.7. 5.8, and 5.10) as well as incomplete references in the reference list. Who is to do the needed work to make this document a better support for the recommendations offered? How much help for B-80 HWBUI0010015 Morton Lippmann this needed work is the responsibility of the Workshop's Peer Consultants?. The merits of the basic formulations and recommendations of the Berman .& Crump document should not be discarded because of the quite sloppy presentation in their document. Some Specific Technical Comments on the Berman and Crump Document 1) Replace, "dose-response" with "exposure-response" in all of the numerous places where the epidemiology and controlled animal inhalation exposure results are discussed. 2) Replace "asbestos-related risks" with "asbestos fiber-related risks". Nonfibrous asbestos dust exposures are a differentIssue. 3) - The discussion of dust counts based on midget i'mpinger samples on p. 4.6 needs to be clarified for most potential readers of this document. : 4) Their reliance on Raabe (1984) for a discussion on the quantitative aspects of particle deposition, and of Figure 7-1 from that paper to illustrate it. is inappropriate as an up-to-date and authoritative reference. A more appropriate reference is ICRP Publication 66: Human Respiratory Tract Model for Radiological Protection. Ann. ICRP.Vol. 24. Nos. 1-3. 1994. 5) The 4th, 5th, and 6th bullets in Section 7.1.4 are wholly or partially incorrect statements. 6) The first paragraph on p. 7.16 misspells "mucus" live times. 7) The last bullet on p. 7.18 indicates, incorrectly, that diffusional transport influences asbestos retention in the lung and other tissues. 8) There are various places where the authors have notes to themselves to reconsider or complete the text (see pp. 7.48,7.65, and 7.103). B-81 HWBUI0010016 ; B-82 HWBUI0010017 Roger McClellan B-83 HWBUI0010018 %j Roger McClellan Advisor, Toxicology & Human Health Risk Analysis 13701 Quaking Aspen Place, NE Albuquerque. NM 87111 505-296-7083 Fax:505-296-9573 Email: rdger.o:mccieilan@att.net Roger O. McClellan is currently an advisor to public and private organizations on issues concerned with human health risk analysis, inhalation toxicology, and strategic business analysis for science-based organizations. He is President Emeritus of the Chemical Industry Institute of Toxicology, having served as Chief Executive Officer and President of the Institute from September 1988 through July 1999. During his tenure, the organization.achieved international recognition for the development of science undergirdtog important environmental and occupational health regulations. Prior to his appointment as President of CUT, Dr. McClellan was'Directorofthe Inhalation Toxicology Research.Institute, and President and Chief Executive Officer of the Lovelace Biomedical and Environmental Research Institute, Albuquerque, New Mexico. He began his career with Lovelace in 1966. During his -22 years with the Lovelace organization, he provided leadership for development of one of the world's leading research programs concerned with the toxic effects of airborne materials. Prior to joining the Lovelace organization, he was a scientist with the Division of Biology and Medicine, U.S. Atomic Energy Commission, Washington;'DC (1985-1966), and Hanford Laboratories; General Electric Company,. Richland, WA (1$59;1964). He received his. Doctor of Veterinary Medicine degree from Washington State Univefeity'ifi '1960'arid a Master of Managenierit Science degree from the University of New Mexico in 1980,- Dr. McClellan has served in an advisory role to numerous public and. private organizations. He is past Chairman of the Clean Air Scientific Advisory Committee, Environmental Health Committee, and'Memberof the Executive Committee, Science Advisory Board, U; S. Environmental Protection Agency; Member, Advisory Council for Center for Risk Management, Resources for the Future; a former MernOer, Health Research Committee, HealttvEffeicts Institute; and service on National Acaderny of Sciences/National Research Council Committees on Toxicology (Past Chairman), Risk Assessment for Hazardous Air Pollutants, and Research Priorities for Airborne Particulate Matter. Dr. McClellan serves or has served as Adjunct Professor at Duke University, University of North Carolina at Chapel Hill, North Carolina State University, University of New Mexico, University of CairfomiaT-os Angeles, and Washington State University. He is active in the affairs of a number of professional organizations, indudirig past service as President of the Society of ToxidoliSgy arid the American Association for Aerosol Research. He currently serves as Chair of the B.oard of Trustees, Toxicotogy Excellence in Risk Assessment. He serves in an editorial role for a number of journals, including service as Editor of CRC Critical Reviews in Toxicology. He is a diplomate of the American Board of Toxicology and the American Board of Veterinary Toxicology. B-84 HWBUI0010019 Roger 0. McClellan Preliminary Comments for Workshop on "Proposed Protocol to Assess Asbestos-Related Risk" In addition to responding to the 12 specific charge questions formulated by the U.S. Environmental Protection Agency I believe it is appropriate to respond to a more general over-arching question. Specifically, "Has the Agency, and its Contractor, reviewed all of the relevant infonnation on the carcinogenic risks of asbestos arid interpreted, synthesized and integrated trite information in a scientifically adequate manner for regulatory decision making"?' In the followingcomments I will ' address the pver-atching question I have posed. .. . .. . I. The material provided by the Agency as background material for the Workshop does not reflect a comprehensive and thorough review, of the literature. Neither does- the material, provide a high v degree of confidence 'that all the relevant literature, has teen reviewed,, interpreted, synthesized and integrated in a scientifically sound mariner that'lends confidence to the finished-product meeting the high standards required for use in regulatory decision making. Three primary documents were provided to the Panel in sequential fashion; (a) a document labeled, "Final Draft - Technical Support Document for a Protocol to Assess Asbestos-Related Risk" prepared by D.W. Berman and K-' Crump dated. September 4, 2001, (b) a document labeled "Final - Methodology for Conducting Risk Assessments at Asbestos Superfiind Sites, Part 1: Protocol, Interim Version" prepared by D. W. Berman and K_ Crump dated February 15, 1999,'and (c) a document, EPA/60Q/8r84/003F, June 1986, Airborne Asbestos. Health Assessment Update prepared under the auspices of the Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency. Taken in aggregate these documents do not represent an up-to-date summary of the voluminous literature available on the health effects of asbestos and, specifically, the lung cancer and mesothelioma risks of exposure to asbestos. The base document, "Airborne Asbestos Health Assessment Update" was prepared by an EPA contractor. Dr. William I. Nicholson, nearly two decades ago and reviewed at that time by the Environmental Health Committee of EPA's Science Advisory Board. In the intervening years, numerous additional papers on the health effects of asbestos, including new epidemiological analyses and mechanistic studies on the carcinogenicity of asbestos, have been published. New and improved analytical methods for characterizing exposure to asbestos have also been . B-85 HWBUI0010020 Roger O. McClellan developed and adopted. The two other documents noted above, are also dated. Despite .the intervals from September 4, 2001 (the Support Document) and February .15, 1999 (the Methodology) to present, the ^documents remain "works in progress" with incomplete references- and omissions, ft is a challenge to the reader to follow the logic being used to synthesize very complex data sets into relative simple algorithms to. describe exposure-response relationships for lung cancer and mesothelioma induction by exposure to. different types of asbestos fibers with varying dimensions. The apparent haphazard and protracted approach to developing a scientifically sound approach to characterizing the risks of asbestos exposure is clearly not related to this, being a "back burner" issue. During the last two decades; the issue of asbestos-related-.health effects has received substantial attention in the courts and resulted in the bankruptcy of some 6Q companies. To get-the "asbestos-rrisk characterization" train on the track, so to speak, the Agency . might consider using.an approach that has served the Agency well in dealing with the criteria air. pollutants. That approach is multi-phased. In the .first phase, a criteria document is prepared periodically for each criteria pollutant by the Agency's National Center for Environmental Assessment, Office of Research and Development, with input from knowledgeable scientists both from within and outside the Agency. These encyclopedic documents describing all that is currently known about the pollutant are reviewed by. the Clean Air Scientific Advisory Committee (CASAC), a part of the. Agency's Science Advisory Board. CASAC notifies the Administrator by a "closure letter" when ithas reached a consensus that the criteria document provides a scientifically adequate review of all the available information in the pollutant In a second phase, the Agency's Office of Air Quality Planning, and Standards, Office of Air and Radiation Programs, prepares a Staff Position. Paper; that draws exclusively on. information in the .. -..criteria document, to critically assess the information specifically germane, to assessing the risks of exposure to the pollutant in question. The Staff Position Paper is also reviewed by CASAC and when a consensus is reached by the Committee that the document provides a-scientifically adequate basis for .regulatory decision making, a "closure letter" is issued to the Administrator. -The agency then proceeds to use the resulting information.to set National Ambient Air Quality Standards and take other regulatory actions. The process described above is transparent, open, and engages the scientific community, interested parties and the public. The process is not without controversy. However, the open and B-86 HWBUI0010021 Roger O. McClellan participatory nature of the process results in controversy focusing on scientific issues. Legislative mandates for review ofcriteria pollutants every five years have rarely been met. Nonetheless, steady progress has been made in reviewing new information on a regular schedule. Without question, the Agency-would benefit from having an up-to-date comprehensive review of the current state of knowledge on the health effects of asbestos. The credibility and scientific and public acceptance of the- review would be enhanced by obtaining input from a -number of knowledgeable scientists in addition to Drs. Berman and Crump and having rigorous peer review by. the Agency's Science Advisory Board. " A subsequent risk assessment prepared using information included within the health assessment dociiment would have enhanced-credibility if it were based on the input of a number of knowledgeable scientists. This statement is not intended to question the credibility and scientific credentials of Drs;. Berman and Crump who are clearly two of the world's experts on the'subject at hand. Despite their credentials, I submit that involvement-of other-scientists in a participatory and transparent manner would enhance the scientific Credibility and acceptance of the final product. As a third step, it would be appropriate for the Agency to-provide a brief document detailing how the asbestos risk assessment will be used by the Agency in fulfilling its regulatory and enforcement agenda. The present documents leave these important -matters open to speculation/ This includes the scientific reviewers who do not know how the science, the associated uncertainties and the various assumptions will be used. For some applications a' high degree of uncertainty and the Ose of ' many assumptions may be scientifically defensible: For other applications, this may not-be the case. 2. Using Only the three documents provided; it is difficult to assess if all the relevant information on asbestos-related health risks has been considered. Without question, the 1984/1-986 Assessment is out of date. Thus, attention focuses on the two other documents. The manner of presentation in these documents is such that I am uncertain if other knowledgeable scientists could reproduce the calculations and quantitative results. The basic assumptions used in the various calculations are not always clearly spelled out. This leads to uncertainties as to the linkages between the various tables and related text as the document builds to summary conclusions (Tables 6-29 and 6-30). 3. The documents in numerous places acknowledge the substantial uncertainty in developing quantitative estimates of exposure-response coefficients for various types of asbestos (with B-87 HWBUI0010022 Roger 0. McClellan varied size characteristics) producing lung cancer and mesothelioma. Nonetheless, these uncertainties are rarely quantified and are absent from the summary conclusions. (Tables 6-29 and 6-30). 4. Two key inter-related uncertainties that are not adequately addressed in the documents . relate to (a) the shape of the exposure-response relationship over the range, of observations from epidemiological studies of occupationally exposed populations, and (b) the basis of extrapolation from observations at high levels of generally prolonged occupational exposure to much-lower levels of environmental exposure. These issues have been a focus of attention in EPA's revised cancer risk assessment guidelines, It is of interest that the Agency's proposed revised cancer risk assessment guidelines are not even referenced in either document. . .. The proposed revised cancer risk assessment guidelines emphasize the importance of using a two-step pro'cess. First, characterize exposure-response relationships over the range where observations, can be made. Then,in a second step, extrapolate to lower .exposure levels. Neither step is adequately documentfeti iti the material at hand. Intuitively; one'would anticipate'Considerable variation in extrapolated risk at environmental levels of exposure. To the extent it is possible the uncertainty should be quantified. 5. During the last two decades substantial progress has been madeiri understanding the mechanisms by which fibers may induce cancer. The present documents' focus orl advances in understanding the role of fiber dimensions as determinants of carcinogenic potency. However, thft,documents do not adequately address a related issue, biopersistence, and especially the role of fiber solubility, in biopersistence. Advances'in'this area'hive been extraordinary with regard to man-made fibers and have led industry to make revolutionary changes in commercial man made fibers, i.e., increasmgsolubilityand, thus, reducing their potential f6'r causing human cancer. This body of science should be reviewed'in the document because it may Have applicability to some situations involving asbestos fibers. Specifically, provision should be riiade for changes iii-risk coefficients for asbestos fibers if it can be shown that the solubility of the fibers differs from the solubility of the asbestos fibers purported to induce cancer in the epidemiological studies used as the basis for the exposure-response models'that have been advanced. 6. I am uncertain at this juncture if the proposed risk assessment approach is sufficiently B-88 Roger O. McClellan well developedand' validated and the associated assumptions and uncertainties identified to warrant its use in the field for regulatory decision making. However, I do see substantial merit to the approach and urge the Agency to continue with development and validation of the approach on an accelerated basis. This accelerated process should include provision for broader scientific community participation in the development process and more peer-review than has occurred in the past B. Specific Comments Topic Area 1: Interpretations of the epidemiology and toxicology literature. * , *; : . . . I) For lung cancer. a] Influence of fiber type: Please comment on the extent to which the epidemiology literature and mechanistic studies suggest that carcinogenic potency varies from one fiber type.to the next (e.g., chrykotile versus amphibole fibers). How adequate is the information in the epidemiology literature for supporting dose-response analyses for different fiber types? Specifically, to what extent do you think the proposed risk, coefficients in Table 6-29 are supported by the epidemiology literature? ft is my professional opinion that the epidemiological literature and mechanistic studies provide strong evidence for the hypothesis that carcinogenic potency varies from one fiber type to another; crocidolite >.amosite > chrysolite. There is also evidence that within a fiber type, differences in carcinogenic potency may also exist. The proposed "optimized risk coefficients" in Table 6-29 may well be appropriate. However, the document in its present form does not clearly relate, foe origins of the "representative values" in Table 6- 15 and their linkage to the "optimized risk,coefficients" in Table 6-29 and foe "recommended risk coefficients" in Table 2-1 of the protocol document. The Hodgson and Damton (20Q0) analysis, cited in the document, provides different coefficients. The basis, .for the difference is not clear.. . In .future reports on this topic, it is important that additional attention.be given to clarify of presentation including the origin of any values and associated assumptions.and uncertainties. Whenever . possible uncertainties should be quantified. . . b] Influence of fiber length. Please comment on the extent to which the epidemiology literature and mechanistic studies suggest that carcinogenic potency varies with fiber length. How adequate is information in the epidemiology literature for supporting dose-response analyses for different fiber lengths? In general, is it appropriate to assess cancer risks using an exposure B-89 J HWBUI0010024 Roger O. McClellan index (see Equation 7.13) that is weighed heavily hy fibers longer than 10 micrometers (|im)? (Note: Topic area 2 includes more detailed questions on the proposed exposure index.) It is my. professional opinion that the epidemiological literature and mechanistic studies clearly :: show a strong correlation between fiber length and carcinogenic potency for asbestos. If an integrated., exposure index is developed and used,.it is appropriate to give substantially greater weight to fibers greater than 10 pm. in length as Berman and Crump have done. c] To what.extent do animal studies.(e.g., studies by Davis and other researchers) suggest that carcinogenic potency varies with fiber type and fiber length? Theanimal studies.am clearly informative on the topics of fiber type and fiber length. This includes the early work of the Wagner group and the more recent work of the Davis group. .This section of the report would be strengthened by more careful consideration of previous analyses including those of Lippmann.(1988 and .1994).' ... d] Please comment on the extent to which carcinogenic potency is a function of fiber properties (e.g., diameter, aspect ratio, surface properties) other than fiber type and fiber length. How . adequate is information in the epidemiology of toxicology literature for supporting these other properties into dose-response'analyses? Fiber diameter is an important determinant of the carcinogenic potency of fibers. Fiber diameter is a major determinant of the aerodynamic diameter of fibers which strongly affects the deposition probability of fibers. In contrast, fiber length has only a small influence on aerodynamic diameter. The diameter of fibers influences the surface area of fibers which, along with surface chemistry, influences the dissolution rate of fibers and the interaction of fiber constituents with biological systems. The aspect ratio is of importance in defining what is or is not characterized as a fiber. The definition of a fiber as an elongated particle with an aspect ratio of greater than 3 to 1 as typically used seems reasonable. 2) For mesothelioma: a] Influence of fiber type: Please comment on the extent to which the epidemiology literature and mechanistic studies suggest that carcinogenic potency varies from one fiber type to the next (e.g., chrysotile versus amphibole fibers). How adequate is the information in the epidemiology literature for supporting dose-response analyses for different fiber types? Specifically, to what B-90 HWBUI0010025 Roger O. McClellan extent do you think the proposed risk coefficients in Table 6-29 are supported by the epidemiology literature? The results of epidemiological investigations supported by mechanistic studies provide substantial support for a variation in mesothelioma induction potency associated with fiber type: erionite > tremolite/crocidolite > chrysotile. Because of difficulties in interpreting the various, studies, it is not possible to rule out the hypothesis that pure chrysotile exposures are not associated with mesothelioma induction. The proposed "optimized risk coefficients" for mesothelioma in Table 6-29 may be appropriate. However, the linkage to the individual studies from which they are derived is not always clear nOr is the linkage to the "representative values" in Table 6^15 or the "recommended risk coefficients" in Table 2-1 of the protocol document. In future reports, it is important that additional attention be given to clarity, of presentation' including the origin of all values, explicit statements as to assumptions used and statements ijf theunderlying uncertainties. Whenever possible uncertainties should be quantified. b]. Influence of fiber length. Please comment on the extent to which the epidemiology literature and mechanistic studies suggest that carcinogenic potency varies with fiber length, How adequate is information in the epidemiology literature for supporting dose-response analyses for different fiber lengths? In general, is it appropriate to assess cancer risks using an exposure index (see Equation 7.13) that is weighed heavily by fibers longer than 10 micrometers (pm)? (Note: Topic area 2 includes more detailed questions on the proposed exposure index.) The epidemiological literature, supported by the results of controlled animal exposure studies, clearly indicate that fiber length is a major determinant of the potential for fibers to cause mesothelioma. In ray professional opinion, fibers less than 5 pm in length are unlikely to induce mesotheliomas. The role of fibers 5 to 10 pm in length is less clear. Fibers 10 pm to 20 pm in length are most likely to induce mesothelioma. However, my statement as to the role of fiber lengths must be coupled with knowledge of the fiber type. c] To what extent do animal studies (e.g., studies by Davis and other researchers) suggest that carcinogenic potency varies with fiber type and fiber length? It is apparent that erionite and the amphobiles have the potential to induce mesothelioma. The available literature is not persuasive that pure chrysotile induces mesothelima. B-9I ) HWBUI0010026 Roger 0. McClellan d] Please comment on the extent to which carcinogenic potency is a function of fiber properties (e.g., diameter, aspect.ratio, surface properties) other than fiber type and.fiber length. How adequate is information in the epidemiology or toxicology literature for supporting these other properties into dose-response analyses? As the diameter of fibers decreases the relative surface area for a given mass of fibrous material increases. Thus, there is a greater opportunity for the surface of fibers to interact with the biological systems. Surface area will also influence the rate ofdissolution of fibers. And, clearly, surface characteristics will influence the interactions between fibers and the biological system. Unfortunately, ... t the specific surface properties ofconcern are not yet well understood. As noted earlier, knowledge ofexposure-response relationships extending from the high occupational exposure levels studied epidemiotogically to environmental levels of exposure is lacking. The linear extrapolations from epidemiological studies ofoccupationally exposed populations to environmental levels of exposure have major uncertainties that have nof been adequately stated in the Berman and Crump documents. - 3) To what extent are the exposure estimates documented in the asbestos epidemiology literature reliable? The exposure estimates for asbestos reported in the occupational exposure asbestos epidemiology literature, are highly uncertain. In some cases, there is considerable uncertainty as to the fiber types to which the individuals were exposed. In other cases, major uncertainty exists as to the physical dimensions of the fibers because of the variety of evolving techniques used to characterize asbestos fibers. The extent to which other particulate matter or other toxicants were present is not always known. And for most studies there are only a relatively few exposure concentration measurements available for populations, exposed for many years making estimates of cumulative exposure highly uncertain. To the extent occupational exposures are under-estimated, the estimated risk coefficients will be too high, i.e., over-estimate the true potency. Conversely, if the occupational exposures have been over estimated, the estimated risk coefficients will be under-estimates of true potency. For each study used to develop risk coefficients, the authors should provide a clear statement of their confidence in the exposure estimates and, if possible, provide a quantitative estimate of the uncertainty associated with the exposure estimates. These estimates of uncertainty for exposure should be carried over into estimates of uncertainty for the potency values. B-92 HWBUI0010027 Roger O. McClellan 4) The proposed exposure index does not include contributions from fibers shorter than 5 pm. Please comment on whether the epidemiology and toxicology literature support the conclusion that asbestos fibers shorter than 5 pm present little or no carcinogenic risk. In my professional opinion, the asbestos fibers less than 5 pm in length do not pose a carcinogenic risk. Thus, it is appropriate to exclude them from the exposure-response index for asbestosinduced cancer. 5) The proposed exposure index is weighed heavily by fibers longer than 10 pm.. Specifically, Equation 7.13 suggests that the carcinogenic potency of fibers longer than 10 pm is more than 300 times greater than that offibers with lengths between 5 and 10 pm. How consistent is this difference in carcinogenic potency with the epidemiology and toxicology literature? In my professional opinion, it is appropriate for the exposure-response index for lung, cancer to be weighted toward the long fibers. The human literature is less certain with regard to mesothelioma induction. 6) Please explain whether the proposed exposure index will allow meaningful comparisons between current environmental exposures to asbesto's and historical exposures to asbestos that occurred in the work place. Embedded in this question are several issues. Historical exposure assessments are what have been reported. Whatever the technique and the reporting criteria used is what we have to work with, if it was phase contrast that is what we must work with! The second issue is the extent to which these .t measurements are truly reflective ofthe historical exposures of the population. The third issue following from the above is the degree ofuncertainty In the derived'estimates of exposure-response relationships. A fourth issue is whether these exposure-response relationships are valid for contemporary environmental exposures. A key consideration in this matter is the substantial extrapolation involved in going from historical occupational exposure levels to contemporary environmental levels including levels established for clean-up. Topic Area 3: General questions. B 93 HWBUI0010028 Roger O. McClellan 7) Theproposed risk assessment approach assigns carcinogenic potency to. individual fibers and.to.. cleavage fragments (or "bundles that are components of more complex structures"). Please comment on whether cleavage fragments of asbestos are as toxicologically significant as'fibers of the same size range. In my professional opinion, the cleavage fragments have toxicological significance to the same extent as intact fibers of the same dimensions. 8) Please comment on whether the proposed cancer assessment approach is relevant to all amphiboie fibers or only to the five types ofamphibole fibers (actinolite, amosite, anthophyllite, crocidolite, tremofite) designated in federal regulations.............. v The proposed exposure-response index, if appropriately validated; would be appropriate for use in assessing the risks of asbestos fibers equivalent in type and size to those on which the index' was based Use of the index with other asbestos fiber types woukfinvolve ah extrapolation of unknown uncertainty.' It should also be emphasized that use of the index with asbestos or other fibers that have biopersistence characteristics different from those of the fibers used to develop the index would be inappropriate. 9) The review document recommends that asbestos samples be analyzed by transmission electron microscopy (TEM) and count only those fibers (of bundles) longer than 5 pm. Such counting practices will provide ho information on the amount of asbestos fibers shorter than 5 pm. To what extent would data on shorter fibers in samples be useful for future evaluations (e.g., validation of the cancer risk assessment methodology, assessment of non-cancer endpoint)? The document makes the point at several places that the output of the assessment of exposure must be matched to-the exposure-response model being used. I strongly agree with this statement Thus, if the Berman-Crurap exposure-response indices are to be used, then it is appropriate to analyze samples .'by transmission electron microscopy and count only those fibers.(particles with an aspect ratio n/greater than 3 to 1) or bundles-longer than 5 pm. This approach is justified if the only use of the exposure data is. to match it to the Berman-Ciump exposure-response, indices. However, it must be recognized that, for many situations, exposures may be evaluated for multiple purposes. For example, the exposure estimates may be used as input to an epidemiological investigation ofa specific population. In such a situation, it may be very useful to have a more comprehensive assessment of exposure. This might include enumeration of fibers by different increments of length, i.e., less than 5 pm, 5-10 pm, 10-20 pm, etc. Indeed, in some cases it may be B-94 HWBUI0010029 m Roger O. McClellan advantageous to have information collected in a manner that allows characterization of the variability of both fiber diameter and fiber length analyzed independently or in a linked manner along with electron diffraction analysis to provide information on chemical composition. The specific information must be matched to its intended use and also the cost ofcollecting the additional increments of information. 10) The proposed risk assessment methodology suggests that exposure estimates should be based only on fibers longer than 5 pm and thinner than 0.5 pm. Is this cut-off for fiber diameter appropriate? This question addresses the inter-play between the definition of a fiber (an elongated particle with an aspect ratio [length to diameter] of 3 to I), fiber length and diameter, and fiber aerodynamic diameter. Fibers, with a length of5.0 pm or longer and diameters up to about 1.5 pm could still meet the traditional definition of a fiber and have an aerodynamic diameter of about 5.0 pm. Such objects would still have a low probability of being inhaled and deposited in the pulmonary region. On this ground, there is no basis for excluding them from consideration. On the other hand, the proposed exposureresponse index appears to have merit when only fibers under 0.5 pm in diameter are included. 11) Discuss whether the proposed cancer assessment approach, as a whole, is a reasonable evaluation of the available health effects data. What aspects of the proposed cancer assessment approach, if any, are inconsistent with the epidemiology or toxicology literature for asbestos? This issue is addressed in my general comments. 12) Section 8.2 of the review document presents three options for assessing cancer risks from asbestos exposure. Please comment on the technical merit of the proposed risk assessment qptipns. It is appropriate for the document, and any subsequent versions, to provide multiple options for assessing cancer risks for different situations dependent on the information available. However, it would be appropriate for the document to more clearly define thecircumstances under which it is appropriate to use each of the options. The "decision rules" for selection of options should be crafted to avoid providing the opportunity for a regulator to attempt to select an option to gain a particular pre-selected outcome. B-95 HWBUI0010030 Roger O. McClellan I strongly favor retaining an approach that matches exposure-response risk coefficients to the particular type of asbestos fiber under consideration and calculation of risks separately for smokers and non-smokers. B-96 HWBUI0010031 Bertram Price B-97 HWBUI0010032 % .. Bertram Price Price Associates, Inc. 1 North Broadway - #40$ White Plains, NY 10601 914-686-7975 Fax: 914-686r7977 Email: bprice@priceassociatesinc.com Dr. Price is the president and founder of Price Associates Inc., where he designs and conducts statistical studies and regulatory reviews, as well as conducting studies concerning risk and risk management including environmental and occupational health regulatory issues. He develops and evaluates study desighs/rneasurement methods, and data quality criteria. Previous to founding Price Associates, Dr. Price was a Vice President, Risk.Assessment Consulting Group, at Marsh & McLennan Companies, and was the manager of the Program Office for Statistical Studies at Battelle Memorial Institute where he managed and directed studies conducted for EPA related to TSCA. He received his B.A. in Mathematics from Wittenberg University, his M.S. and Ph.D. in Mathematical Statistics form Ohio State University. He is a Member of the ASTM committee D22 on SaVnpling and analysis of Atmospheres, and the ASTM subcommittee D22.07 on Asbestos Measurement He served as a peer review panel member for the report by the World Trade Center'Indoor Air Task force Working Group on selecting chemicals of potential concern and setting health-based benchmarks, he is a member of the American Statistical Association, the American Association for the Advancement of Science, and the Society of Risk Analysis. He has authored numerous technical reports,.articles, and presentations including "Standard Practice for Determining a Detection limit for Asbestos Measurements Based on Counts," Trends in Incidence of Mesothelioma and Evaluationof Exposure to Asbestos," "Risk Assessment for Asbestos and management of Low Levels; of Exposure to Chrysotile Asbestos* 'Cumulative Asbestos Exposure in Epidemiologic Studies of Lung Cancer and Mesothelioma,' and * Transmission Electron Microscopy and Its Application to EPA's Proposed Asbestos Worker- Protection Rule." He has served as an expert witness in several court cases related to asbestos on the behalf of W. R. Grace. Armstrong World Industries, and Flintkote Company. Dr.-Price has prepared several technical reports for the U.S. EPA on Airborne Asbestos Level in Schools, Analysis of Variability Associated with the Measurement of Fiber concentration by Phase Microscopy and Transmission Electron MicrbScOpy for the Office of Toxic Substances. B-98 HWBUI0010033 CHARGE QUESTIONS Bertram Price Topic Area I: Interpretations of the epidemiology and toxicology literature. I. For lung cancer. A] Influence of fiber to which the epidemiology literature and mechanistic studies suggest that carcinogenic potency varies from one fiber type to the next (e.g,,' chiysotile versus arriphibole fibers). " How' adequate is the information in the epidemiology literature for supporting dose-response analyses for - different fiber types ? Specifically, to what extent, do you think the- proposed risk . coefficients in Table 6-29 are supported by the epidemiology literature? Answer: The epidemiology literature suggests that carcinogenic potency for lung cancer varies across fiber types, but the.evidence is scattered throughout the literature and is not overwhelming. A unified analysis that incorporates ail' the lung cancer epidemiology data and that is focused specifically oh the hypothesis - "potency for lung cancer varies with mineral type" is needed to answer, this question. The'Berman & Crump report (B&C) provides such an analysis. I am not aware of any other unified analysis of the lung cancer epidemiology'data. The B&C analysis is innovative and, by necessity, employs various assumptions and interpretations of incomplete data. Before accepting the B&C conclusion, we need a better understanding of the B&C assumptions and data interpretations. A more detailed evaluation is needed of the B&C assumptions and applications ofincomplete data than was possible at this time. (Note: Access to raw data used in B&C would be required for a detailed evaluation.) Since there is no competing unified analysis of the lung cancer epidemiology data that concludes otherwise, the "potency for lung cancer varies with mineral type" hypothesis should be accepted. Concerning the risk coefficients for lung cancer in Table 6-29, the only way to determine if they are supported by the epidemiology literature is to conduct the type of unified analysis I mentioned above. Note that these risk coefficients are determined not only by the epidemiology data, but they depend also on the new proposed exposure index, the fiber size distribution adjustments to and the assumptions and data that were used to determine those entities. The B&C unified analysis, if B-99 HWBUI0010034 Bertram Price ft survives more detailed peer review than was possible at this time, is itself a; statement that the epidemiology literature supports the risk coefficients in Table 6-29. However, the recorded values of the lung cancer risk coefficients in Table 6-29 are very likely incorrect because the B&C analysis relies on linear extrapolation of risk to low-exposure levels. An alternative unified analysis needs to=be conducted that incorporates "threshold" models.-for lung cancer risk. Some researchers claim that, epidemiology and clinical data suggest an - exposure -threshold for lung cancer of 25 f-yr/cc.- Although there, may be no asbestos exposure level where the -risk of lung cancer is an absolute zero, the size of the potency coefficient for exposures below 25 fyr/cc, or an-appropriately determined alternative "threshold", exposure, is likely to be substantially less than the size of the potency coefficient for exposures greater than the "threshold." The epidemiology literature supports the existence of this type of. "threshold." Most, if not all the epidemiology data from studies used in B&C. indicate "no statistically .significant elevation of lung cancer cases" for exposure categories with exposures less than 15 to 20 f-y/cc. (As an example, my calculations applied to the Dement data analyzed in B&C (Table 6-2) indicate no..statistically ) significant elevation of lung cancer risk below the exposure interval, (28-60) f-yr/cc. A simple linear-linear.fit to these data picks a "threshold" exposure at 21.3 f-yr/cc.) The "threshold" approach needs to be explored. However, simply fitting a standard exposure-risk equation to the full set of data from an epidemiology study will not necessarily solve the lowexposure' problem adequately. Standard exposure-risk equations lack flexibility. The risk values at high exposures .tend to puli the curve upward even at low exposure levels and it is likely that a statistical test will not be able to differentiate an s-shaped curve from a linear model due to the limited number of data points. Therefore, other approaches may be required, similar to the general approach in B&C that combines judgment based on information from animal studies, lung burden studies, and cellular studies with epidemiobgy data and statistical, analysis. The "threshold' - low exposure linear extrapolation issue must be resolved before adopting new values for lung cancer potency. BJ Influence offiber length: Pleaseicomment on the extent to which the epidemiology literature and mechanistic studies suggest that carcinogenic potency varies with fiber length. How adequate is B-100 HWBUI0010035 Bertram Price information in the epidemiology literature for supporting dose-response analyses for different fiber lengths? In general, is it appropriate to assess cancer risks using an exposure index (see Equation 7.13) that is weighed heavily by fibers longer than 10 micrometers (pm)? (Note: Topic area 2 includes more detailed questions on the proposed exposure index.) Answer: Fiber length and' fiber dimensions in general are extremely important factors in asbestos risk assessment The epidemiology literature alone does not contain adequate data to determine the effects of different fiber lengths: Information concerning the lung cancer potencies of different fiber dimensions can be determined from animal studies:and lung burden studies. An exposure index that weights long-fibers more heavily than short- fibers is- justified for assessing lung cancer risk associated with asbestos exposure. C] To what extent do animal studies (e.g., studies by Davis and other researchers) suggest that carcinogenic potency varies -withfiber type and 'fiber length? Answer: These studies indicate that carcinogenic potency varies withfiber length. D) Please comment'bn the extent to which carcinogenic potency is a function of fiber properties (e.g., diameter, aspect ratio, surface properties) other than fiber type and fiber length. How adequate is information in the epidemiology or toxicology literature for supporting these other properties into dose-response analyses? Answer: The epidemiology literature does not contain adequate data to determine the risk effects of fiber properties such as diameter,' aspect ratio, and surface dimensions. For mesothelioma: A} Influence offiber type: Please comment on the extent to: which the epidemiology literature and mechanistic studies suggest that "carcinogenic potency varies from one fiber type to the next (e.g., chrysotile versus amphibote fibers). How adequate is the information in the epidemiology literature for supporting dose-response analyses for different fiber types? Specifically, to what extent do you think the proposed risk coefficients in Table 6-29 are supported by the epidemiology literature? B-101 ;\ HWBUI0010036 i Bertram Price Answer: The epidemiology literature clearly establishes the significance of fiber type for mesothelioma potency and supports different exposure-risk analyses for differentfiber types. Concerning the risk coefficients for mesothelioma in Table 6-29, the only way to determine if they are supported by the epidemiology literature is to conduct a unified analysis such as the B&C unified analysis. (For a more complete explanation, refer to my discussion above of a unified analysis for lung cancer). To answer this question, a more detailed peer review than was possible at this time would be required to test B&C-assumptions and to dissect how supporting data were used (e.g., the calculation of fiber size adjustment factors for iy. In addition, the "threshold" concept that 1 described above for lung cancer risk assessment also needs to be considered for mesothelioma risk assessment to avoid problems associated with low-exposure linear extrapolation. B] Influence offiber lengthi Please comment on the ektent. to which the epidemiology literature and . mechanisticstudies suggest , that carcinogenic potency varies with fiber length. How adequate is information in the epidemiology literature for supporting dose-response analyses, for. different fiber lengths'! In general, is it appropriate to assess cancer. risks using an exposure index (see Equation 7.13) that, is weighed heavily by Fibers longer than. 10 micrometers (pm)? (Note: Topic area 2 includes more detailed questions on the proposed, exposure index^) Answer: Fiber length and fiber dimensions in general are extremely important factors in asbestos risk assessment The epidemiology literature alone does not contain adequate data to determine the effects of different fiber lengths. Information concerning mesothelioma potencies .of different fiber i dimensions can be determined from animal studies and lung burden studies. An exposure , index that weights long, fibers more heavily than short fibers is justified for assessing mesothelioma risk . associated with asbestos exposure. ; C] To what extent do animal studies (e.g., studies by Davis and other researchers) suggest that carcinogenic potency varies withfiber type and fiber length"! Answer:. These studies indicate that carcinogenic potency .varies withfiber length D] Please comment on the extent to which carcinogenic potency is a function of fiber properties B-102 HWBUI0010037 Bertram Price (e.g., diameter, aspect ratio, surface properties) other than fiber type and fiber length. How adequate is information in the epidemiology or toxicology literature for supporting these other properties into dose-response analyses? Answer: The epidemiology literature does not contain adequate data to determine the risk effects of fiber properties such as diameter, aspect ratio, and surface dimensions. To what extent are the exposure estimates documented in the asbestos epidemiology literature reliable? Answer: "Reliable" is a relative term. . To answer this question, the word "reliable" has to be interpreted in a context. The context is ``decision-making based on risk estimates derived, in part, from exposure estimates documented in the asbestos epidemiology literature." I am referring to decisiotfmaking applied to selecting exposure-limits, managing or removing asbestos-containing materials in buildings, cleaning asbestos waste sites,' or implementing product bans. The decision making process must account for uncertainty in risk estimates, which is due, in part, to the uncertainty (i.e., the reliability or lack thereof) in the underlying exposure data used to develop the risk estimation method. B&C describe most and possibly all the well-known problems wilh exposure estimates in the epidemiology literature. We cannot claim to know the exact airborne fiber concentration or makeup of fiber types and sizes for any particular worker who is a subject in an epidemiology study. However, the collection of exposure estimates associated with the epidemiology studies, which have been developed from various and often disparate sources of information, appear to provide a relatively consistent characterization of exposure that is sufficient for developing a risk assessment method. Provided the'uncertainty in risk estimates is treated with an appropriate degree of respect in decision-making, the exposure estimates documented in the asbestos epidemiology literature may be characterized as "reliable." Topic Area 2: The proposed exposure index. The proposed exposure index does not include contributions from fibers Shorter than 5 pm. Please comment on whether the epidemiology and toxicology literature support the conclusion that asbestos fibers shorter than 5 pm present little or no carcinogenic risk. HWBUI0010038 ) Bertram Price Answer: The epidemiology literature, alone does not contain adequate data to determine the effects of different fiber lengths. The toxicology literature supports the conclusion that long asbestos fibers are associated with greater carcinogenic, risk than' short asbestos. fibers. The assertion that the 5 pm limit is a "bright line" separating carcinogenic fibers from non-carcinogenic fibers is doubtful, but it is clear that fibers shorter than 5 pm have diminishing potency. An evaluation of the carcinogenic potential of short fibers also can be addressed from a completely different perspective, using a different set of epidemiology data - cancer incidence data collected by the National Cancer Institute in its Surveillance, Epidemiology, and End Results (SEER) program. Briefly, the trend over time of mesothelioma incidence for PS women does not reflect the pattern that would be expected if exposure to .short fibers posed a significant carcinogenic risk. These data indicate that although exposures to .short fibers, may.have increased over-time, they have not resulted in an epidemic of asbestos-related cancer. 5) The proposed exposure index is weighed heavily by fibers longer than 10 pm. Specifically, Equation 7.13 suggests that the carcinogenic..potency of fibers longer than 10 pm is more than 300 times greater than that of fibers with lengths between 5 and 10 pm. How consistent is this difference in carcinogenic potency with the epidemiology and toxicology literature? Answer: The epidemiology literature alone does not contain adequate data to determine the effects of different fiber lengths.. The. toxicology.literature generally supports the conclusion that long asbestos fibers are associated with greater carcinogenic risk than short asbestos fibers. The proposed exposure index is consistent with the toxicology literature. There exist no data at this time other than those used in B&C to further confirm the use of the proposed classification of lengths and numerical weights. 6) Please explain whether the proposed exposure index will allow- meaningful comparisons between current environmental exposures. to asbestos and historical, exposures to asbestos that occurred in the work place. ) B-104 HWBUI0010039 Bertram Price Answer: I believe the question should be - Can the proposed exposure index be used to evaluate cancer risk associated with current environmental exposures, given that the index was derived from animat data and the risk models were derived from data collected in occupational studies? The answer is "yes" with qualifications. "Yes" because the potency factors in the proposed risk models ' were adjusted to be applied with the proposed index. The qualifications are the uncertainties concerning the methodology and use'of data to derive the adjustments as discussed in answers to earlier questions. Topic Area 3: General-questions. 7) The proposed risk assessment approach assigns carcinogenic potency to individual 'fibers and to cleavage fragments' (or bundles, that are components of more complex structures). Please comment on whether cleavage fragments of asbestos are as toxicologically significant as fibers of the same size range. Answer: Froin toy reading of the scientific literature, it appears that cleavage fragments may be less potent'for asbestos-related cancer than asbestos fibers. As a practical matter, it would be very difficult to evaluate the proportion of structures that were cleavage fragments in -historical' exposure measurements. Therefore it would be difficult to use a current exposure measurement' that was adjusted for cleavage fragments in a risk assessment model. 8) Please comment on whether the proposed cancer assessment approach is relevant to all amphibole fibers or only to the five types of amphibole fibers (actinolite, amosite, anthophyllite, crocidolite, ' tremolite) 'designated in federal regulations. ' Answer: The proposed cancer assessment approach is applicable only to the mixture of fibers that constituted exposure in the epidemiology studies. If it were subsequently confirmed that other mineral-types were, in fact, included in the exposures (e.g., winchite and richterite' at the Libby mine), the proposed cancer assessment approach, subject to adjustment of potency factors, could accommodate other amphiboles. 9) The review document recommends that asbestos samples be analyzed by transmission electron B-105 \ HWBUI0010040 Bertram Price microscopy (TEM) and count only those fibers (or bundles) longer than 5 pm. Such counting practices will provide no information on the amount of asbestos fibers shorter than 5 pm. To what extent would data on shorter fibers in samples be useful for future evaluations (e.g., validation of the cancer risk assessment methodology, assessment of non-cancer endpoints)? Answer: The evidence is reasonably strong that asbestos fibers with lengths less than 5 pm have minimal potency for asbestos-related cancers. Also, there is no history of an association between low level environmental exposures, which probably included a high percentage of short fibers, and asbestosis. There is no reliable evidence at this time that other non-cancer endpoints are associated with low level asbestos exposure or short fibers. Counting fibers shorter than 5 pm would increase the cost of measuring airborne asbestos. The cost would not be justified if the only use of the data were to validate the fiber length component of the cancer risk assessment We need more information through a debate that has not yet been conducted to determine if the risk of specific non cancer endpoints potentially associated with .exposures to. short fibers is sufficiently established to justify the extra cost of including short fibers in asbestos measurements. The proposed risk assessment methodology suggests that exposure estimates should be based only . on fibers longer than 5 pm and thinner than.0.5 pm. Is this cut-off for fiber diameter appropriate? Answer: Determining the correct weights for fiber lengths is more important than fixing a specific diameter limit The cut-off for fiber diameter should account for fiber, respirability. and clearance mechanisms. I.do not have a recommendation at this time.: Discuss whether the proposed cancer assessment approach, as a whole, is a reasonable evaluation of the available health effects data. What aspects of the proposed cancer assessment approach, if any, are inconsistent with, the epidemiology or toxicology literature for asbestos? Answer: As a whole the proposed cancer assessment approach, is an impressive.analysis of a wideranging collection of data to produce an .asbestos cancer risk model that addresses almost all the significant risk issues that have been debated over the past 20 years. It is a reasonable evaluation of the available health effects data with one extremely important exception., ft does not address the B-106 HWBUI0010041 Bertram Price "threshold" - '"low exposure linear extrapolation" issue. The analysts, by virtue of this exception, is inconsistent with the epidemiology literature for asbestos. 12) Section 8.2 of the review document presents three options for assessing cancer risks from asbestos exposure. Please comment on the technical merit of the proposed risk assessment options. Answer: Each of the three proposed options is an approach with a counterpart that is currently available and has been available since 1988 when EPA last updated its Asbestos IRIS file. The simple equation reported in IRIS (counterpart of B&C Option 3) that determines asbestos cancer risk to be 0.23 risk'units for each PCM fiber/cc measured in units of lifetime average daily exposure (LADE) is usually identified as "the EPA asbestos risk assessment". However, if is not the only option available to a risk assessor today. One may- choose to utilize Tables 6-1 through 6-3 in the EPA Asbestos Health Assessment Update (1986) for separate risk estimates of lung cancer and ' mesothelioma by sex and smoking status (counterpart of B&C Option 2), or may use the underlying equations for lung cancer and mesothelioma with life-table - data to estimate risks (counterpart of B&C Option 1). The changes in the currently available approaches that define the three proposed options are: (i) use of a new exposure index that explicitly accounts for fiber dimensions; and (ii) differential potencies' based on mineral type that also are different for lung cancer and mesothelioma. These B&C innovations are significant, but more is needed. Option.3 does not distinguish lung cancer from mesothelioma, and requires averaging over smoking status and sex. Option 3 may have some merit for "quick" asbestos risk comparisons, but is inflexible and subject to error. B&C does not explain how to implement Option 3. EPA should not rely On Option 3 for'estimating risk. Option I and Option '2 need to address "the low-exposure linear extrapolation"' issue. EPA's risk assessment is intended to evaluate risk at low exposures. The currently available risk assessment methods lead- to questionable risk estimates at low exposures. For example, using the current EPA unit risk equation published in IRIS, the incremental risk of asbestos-related cancer corresponding to a cumulative lifetime exposure of 0.30 f-y/cc is approximately 1 in 1000 (1x10 _J). However, epidemiology data suggest an exposure threshold that' may be as large as 25 f-y/cc for lung cancer. Although there may be no exposure level where the risk of cancer is an absolute zero, it is highly B-107 HWBUI0010042 Bertram Price unlikely that 0.30 f-y/cc. lifetime exposure would lead to a lxlO'3 risk of cancer. Option . 1 and Option 2 are likely to overstate risks at low exposures because they incorporate low exposure linear extrapolation risk assumptions. Finally, Option 1 and Option- 2 require estimates of. mortality due to all other causes in order to produce risk estimates-for lung cancer and mesothelioma. ff&C provides mortality data that they use to.create risk tables for Option 2. Since mortality patterns have been shifting (i.e., survival to older ages) and mesothelioma has a long latency period, the mortality data used in the. model, may .be:an-important-factor, especially for Option 2.. (For example, using. 1970.mortality data;-may. lead to different risk estimates than mortality data from 2000.) -The effect may be.smalh. but. it needs to be assessed before a particular set ofdata are locked-in to Option2. B-108 HWBUI0010043 Topic Area 4: Development of Conclusions and Recommendations Bertram Price At the end of the workshop, the peer consultants will be asked to draft conclusion statements identifying their most notable findings on the proposed methodology. As a prelude to developing these statements, the peer consultants are invited to provide any additional comments or concerns, both strengths-and weaknesses, on topics' not specifically addressed in the previous charge questions. After completing-the discussions the peer consultants will prepare their conclusions, and they will -also be asked to develop- recommendations' for how EPA can improve the methodology. Please note that, although recommendations for future research projects are welcomed, the focus of this workshop is on the proposed risk assessment methodology and how it may be used to support decisions at asbestos-contaminated sites. B-109 HWBUI0010044 Et-110 HWBUI0010045 Claire Sherman Bin HWBUI0010046 Claire Sherman Biostatistician California Environmental Protection Agency ' . 1515 Clay Street, 16th Floor , . Oakland, CA 94612 510-622-3214 : ... Fax: 510-622-3211 ___________ ________________________________________ _______________ Email: cshermant5toehha.ca.Qov Dr. Sherman received her B.S. in. mathematics from Pennsylvania State University, tier M.A. in Biostati.stics ffbrti the University of CalifomtaBerkeley, arid her PfiD. in statistics from the University of Waterloo. She is a Biostatistipian with.Catifomia Environmental Protection Agency; where she specializes in quantitative cancer risk assessment She has served in various positions at NIEHS as a Biostatistician and has co-authored a numberof papers with Dr. Christopher Portier including `Multistage stochastic models of the cancer process: a general theory for calculating tumor incidence," "The two-stage model of Carcinogenesis: overcoming the nonideniifiability dilemma." The utility of the Kolmogorov backward equations in stochastic Carcinogenesis modeling," and." Numerically calculating, the cumulative distribution furjctipn.fqr the time to an Qbseryable tumor in multistage models of Carcinogenesis." She is the author of a book chapter entitled "the potential effects of chemical mixtures on the carcinogenic process with in the context of the mathematical multistage model." in Risk Assessment of Chemical Mixtures: Biological and Toxicological Issues. R. Yang {1994). She serves as a reviewer for several professional journals, including Biometrics, Environmental Health Perspectives, Journal of the American Statistical Association, and The Journal of Toxicology and Applied Pharmacology. She has presented numerous papers for government agencies and universities including . "Assessing ...Cancer. :Risk.. from Targe Epjdemiplogic Cqho.ijs: TunprIncidence, Hazard Functions, and Identifiability," Improving the mathematical modeling of Carcinogenesis via intermediate events and biomarker data." She is a member oftheAmerican Statistical Association,,the Intemational.Biometrics Society, and the New York Academy of Sciences. .. B-112 HWBUI0010047 Claire D. Sherman, Ph.D. Prior to submitting these written comments, I would like to acknowledge the invaluable assistance arid guidance of my colleagues at California EPA/OEHHA. Drs. John Budroe, Stan Dawson, and Melanie Marty have (probably) collectively spent more years working on the subject of asbestos than the number of years that i have been on this earth; Without their support, many of the questions that have been 'addressed would have been without comment My only regret is that we did not have ample time to more thoroughly answer all of the questions within the charge. Topic Area 1: Interpretations of the epidemiology and toxicology literature. 1) For lung cancer: A] influence of fiber type: Please comment on the extent to which the epidemiology literature and mechanistic studiessuggestthat carcinogenic potency vari.es from one fiber type to the next (e.g., chrysotile versus amphiboie fibers). How adequate is the information in the epidemiology literature for supporting dose-response analyses for different fiber types? Specifically, to what extent do you think the proposed risk coefficients in Table 6-29 are supported by the epidemiology literature? As has been documented throughout the asbestos literature and conditional on the relative risk model that has been used to describe asbestos induced lung cancer, carcinogenic potency varies for chrysotile and amphiboie fiber types. What has not been reconciled are the results of Hodgson and Darnton (2000) with this report's conclusions regarding fiber type. Hodgson and Darnton (2000) determined differences in carcinogenic potencies for crocidolite, amosite and chrysotile. In this report, carcinogenic potency differences between the amphiboies are not reported nor is there a discussion to settle this disparity. The overall valuesofKL of Table 6-29 appear to be in an appropriate relation to the adjusted individual values in Fig. 6-4 for pure chrysotile and pure amphiboie and even for mixed fibers, suggesting agreement with the central tendencies in the epidemiological literature. This approach, however, does not give sufficient recognition to the high chrysotile B-113 s HWBUI0010048 Claire D. Sherman, Ph.D. coefficients obtained in the South Carolina studies, a recognition that is needed for adequate health protection. B] Influence of fiber length: Please comment on the extent to which the epidemiology literature and mechanistic studies suggest that carcinogenic potency varies with fiber length. How adequate is information in the epidemiology literature for supporting doseresponse analyses for different fiberlengths? In general, is It appropriate to assess cancer risks using an exposure index(see Equation 7.13) that is weighed heavily by fibers longer than 10 micrometer^ (mm)'? (Note: Topic area 2 includes more detailed questions on the proposed exposure index.) The adjustment of the risk coefficients for fiber length seems to be an appropriate concept applied to the animal studies. However, extrapolation to humans' who have different airway geometry than rodents and may well respond differently to'thb sanie~ : ` fiber dimension' requires justification. The report needs some substantial basis Tor an extrapolation that will ultimately require a complex model to fit the human data. C] To what extent do animal studies (e.g., studies by Davis and other researchers) suggest that carcinogenic potency varies with fiber type and fiber length? Hesterberg et al. (1998) exposed Fischer rats to chrysotile asbestos and several man-made fibers by nose-only inhalation for 6 h/day, 5 days/week for'2 ' i. : years. The chrysotile asbestos inhalation concentration was 10,600 WHO . . . fibers/ml (WHO fibers defined as being 5 pm in length and > 3 pm in diameter and having a length/diameter ratio > 3). The geometric mean, length and width of the dispersed .fibers was 1.2 and 0.08 pm, respectively, suggesting that the : non-WHO fiber concentration was higher than the WHO concentration. . Additionally, no fibers were > 20 pm in length, and very few were > 10 pm in . lengffi. The geometric mean length and width of the fung burden of deposited chrysptile fibers after 104 weeks of exposure and 23 weeks of recovery were 1.6 pm and 0.07 pm, respectively. B-114 HWBUI0010049 Claire D. Sherman, Ph.D. Chrysolite asbestos caused significantly increased incidences of both lung cancer (12/69,17.4%, adenomas and carcinomas combined), and pleural mesothelioma (1/69, 1.4%) compared to controls (lung cancer incidence 2/130,1.5%; mesothelioma incidence 0/130). These results suggest that relatively short chrysolite asbestos fibers are capable of inducing both lung cancer and mesothelioma in rats. The authors stated . that "fiber-induced.lung toxicity, is not always strictly dependent upon the numbers of long fibers retained, in the lung", and "these data demonstrate that the toxic potential of . chemically different fiber, types cannot be predicted solely by the dimensions of the fibers retained in the lung. In the induction of fiber-induced pathogenesis, sheer numbers of fibers.may thus be able to compensate for a lack of iorsgf fibers". O] Please comment on the extent to which carcinogenic potency is a function of fiber properties (e.g., diameter, aspect ratio, surface properties) other than fiber type and fiber length. How adequate is info^ination in the epidemiology, or. toxicology literature for supporting these other properties into dose-response analyses? No comment. 2) For mesothelioma: , . . . A] Influence of fiber type: Please comment on the extent to vyhich the epidemiology literature and mechanistic studies suggest that carcinogenic potency varies from one fiber type to the next (e.g., chrysotile versus amphibole fibers). How adequate is the information in the epidemiology literature for supporting dose-response analyses for different fiber types? Specifically, to what extent do you think the proposed risk coefficients in Table 6-29 are supported by the epidemiology literature? As stated in Section 8.1.2, Hodgson and Damton (2000) find substantially different cardncKjenic potencies for ampiboles and chrysotile. Even though the report agrees with the conclusions of Hodgson and Darnton (2000) on this point, there have been references B-115 HWBUI0010050 Claire D. Sherman, Ph.D. in the literature over the years to differences in potency between crocidolite and all other asbestos minerals. The overall values of KM appear to be substantially less than the individual values in Fig. 6-6 not only for pure chrysotile and pure amphiboles, but also for the mixtures. This appears to represent an irreconcilable difference between the optimal Values given in Table 6-29 and the individual values for the epidemiology studies. B] Influence offiberlehgth: Please comment on the extent to which the epidemiology literature and mechanistic studies suggest that carcinogenic potency varies with fiber length. How adequate is information in the epidemiology literature for supporting dose-response analyses for different fiber lengths? in general, is it appropriate to assess cancer risks using an exposure indexfsee Equation 7.13) that is weighed heavily by fibers longer than 10 micrometers (mm)? (Note: Topic area 2 includes more detailed questions on the proposed exposure index.) Nolan et al. (1994) examined the lung contents of six workers who had been occupationally exposed to chrysotile asbestos. Five were lung cancer cases from Quebec, Canada. The sixth case was an American worker who had developed pleura! mesothelioma. An analysis of two parenchymal lung tissue specimens from the pleural mesothelioma of the American worker demonstrated that the predominant, fiber type was chrysotile. Chrysotile fiber length percentages in those parenchymal lung tissue specimens are described in Table 1. Fibers < 0.5 pm in length were not counted. , B-116 HWBUI0010051 Claire D. Sherman, PJlD. Table 1: Length distribution of chrysotile fibers from two parenchymal lung tissue specimens from an American pleural mesothelioma case (from Nolan et at., 1994) I Specimen f Percentage of fiber length I =4.99um 5 -- 7.99 lim >=8 urn A 96.7 2.5 0.8 B 98.8 1.2 0 The authors stated that "the fiber length distribution of the chrysotile recovered from the U.S. mesothelioma case was indistinguishable from that of chrysotile specimens known to produce mesotheliomas in rats". These data suggest that short fiber chrysotile may be capable of inducing mesothelioma in humans. A study by Suzuki and Yuen (2001) characterized asbestos fibers in the lung and mesothelial tissues (niesotfi'etiomatous tissue and hyaline plaque) taken from 151 human malignant mesothelioma cases. The most common asbestos types seen in the lung were a mixture of chrysotile with amphiboles followed by amphiboles atone and chrysotile alone. The majority of asbestos types seen in the mesothelial tissues were chrysotile alone, followed by chrysotile plus amphibole and amphibole alone. The majority of asbestos fibers detected in the lung and mesothelial tissues were shorter than 5 pm in lencjth. Only 4% of the fibers found were 8 pm in length or greater! The authors stated that chrysotile asbestos can induce humari malignant mesothelioma, since,'in some of the mesothelioma cases, asbestos fibers dete'eted in both the lung and mesothelial tissues, or lung tissue alone or mesothelial tissues alone were exclusively chrysotile fibers. Additionally, the authors concluded that "such short, thin asbestos fibers should not be excluded from those contributing to the induction of human malignant mesothelioma". These studies suggest that short fiber chrysotile asbestos is capable of inducing both lung cancer and mesothelioma in rats, and may be capable of inducing mesothelioma in humans. } B-117 HWBUI0010052 Claire D. Sherman. Ph.D. Simitar to the case of lung cancer, the adjustment of the risk coefficients for fiber length suffers from inadequate data applied to the animat studies. Use of the same fiber-length adjustment obtained for lung cancer to mesothelioma, though not contraindicated, is not supported in the asbestos literature. Extrapolation to humans who have different airway geometry than rodents and may Well respdhd differently to the1 same fiber dimension requires justification as well. CJ To what extent do animal studies (e.g., studies by Davis and other researchers) suggest that carcinogenic potency varies with fiber type and fiber length? See lung cancer section, part c. D] Please comment on the extent to which carcinogenic potency is a fuhctioh of fiber properties (e.g., diameter, aspect ratio, surface properties) other than fiber type and fiber length. How adequate is information in the epidemiology or toxicology literature for supporting'these other properties into dose-response analyses? No comment. III. To what extent are the exposure estimates documented in the asbestos epidemiology literature reliable? .. The exposure estimates documented in the asbestos epidemiology literature suffer from many of the exposure uncertainties inherent in occupational epidemiological studies. Exposure uncertainties related to non-representative sampling, poor evaluation .of job exposures, retrospective estimation of exposure levels, and the conversion of samples from counted particles (particle concentrations in million particles per cubic foot) to fiber concentrations (fibers per milliliter). Topic Area 2: The proposed exposure index. IV. The proposed exposure index does not include contributions from fibers shorter than 5 mm. Please comment on whether the epidemiology and toxicology literature B-118 HWBUI0010053 Ciairc D. Sherman, Ph.D. support the conclusion that asbestos fibers shorter than 5 mm present little or no carcinogenic risk. The authors assume asbestos fibers shorter than 5 mm present little or no carcinogenic risk when insufficient information exists to validate, this assumption. Potential counter-examples to this assumption would include Nolan et al. (1994) and . Suzuki and Yuen (2001). Their conclusions were that short fiber chrysolite (< 5mm) may be capable of inducing mesothelioma in humans. ... 5) The proposed exposure index is weighed heavily by fibers longer than 10 mm. Specifically, Equation 7.13 suggests that the carcinogenic potency of fibers longer than 10 mm is more than 300 times greater than that of fibers with lengths between 5 and 10 mm. How consistent is this difference in carcinogenic potency with the epidemiology and toxicology literature? . Equation 7-12 adequately fit tumor incjctence data across 13 separate animal studies, but there is no justification for using the proposed exposure index to evaluate asbestos-related , cancer risks for humans. Furthermore, as has been cited in earlier questions relating to fiber length, the induction of fiber-induced pathogenesis can be the result of the sheer numbers of fibers when there is a lack of long fibers. VI. Please explain whether the proposed exposure index will allow meaningful comparisons between current environmental exposures to asbestos and historical exposures to asbestos that occurred in the work place. Given the lack of justification for the proposed exposure index in human studies, it is difficult to answer this question. : Topic Area 3: General questions. VII. The proposed risk assessment approach assigns carcinogenic potency to individual fibers and to cleavage fragments (or bundles that are components of more complex B-119 HWBUI0010054 Claire D. Sherman, Ph.D. structures). Please comment on whether cleavage fragments of asbestos are as toxicologically significant as fibers of the same size range. Cannot comment . VliL Please comment on whether the proposed cancer assessment approach is relevant to all amphlbole fibers or only to the five types of amphibole fibers (actinolite, amosrfe; anthophyilife, crociddlife, tremolite) designated in federal regulations. In the absence of better information, it seems prudent to use the existing amphibole numbers, obtained from crocidolite or arriosite studies or both, for other fibrous amphiboles. Based upon the study data of Amandas et ak(1987), tremolite has a potency between crocidolite and chrysotile for mesothelioma. For lung cancer, the potency .of tremolite is more similar to chrysotile. IX. The review, document recommends that.asbestos samples be:analyzed by transmission electron microscopy (TEM) and count only those fibers (or bundles) longer than 5 mm. Such counting practices will provide no information on the amount of asbestos fibers shorter than 5 mm. To what extent would data.on-shorter fibers in samples be useful for future evaluations (e.g., validation of the cancer risk assessment methodology, assessment of (ion-cancer endpoints)? Data on shorter fibers would certainly be useful to validate any cancer risk assessment methodology that is in current practice or development. Suzuki and Yuen (2001) characterized asbestos fibers in the lung and mesotheiial tissues and noted that a majority of the asbestos fibers detected were shorter than 5mm in length. They concluded that short, thin asbestos fibers should not be excluded from those contributing to the induction of human mesothelioma. e proposed risk assessment methodology suggests that exposure estimates should be based oriity on fibers longer than 5 mm and thinner than 0.5 mm.is this cut-off for fiber diameter appropriate? ' Cannot comment. ' XI Discuss whether the proposed cancer assessment approach, as a whole, is a reasonable evaluation of the available health effects data. What aspects of the proposed cancer assessment approach, if any, are inconsistent with the epidemiology or toxicology literature for asbestos? The proposed assessment is predicated on the adjustment for fiber length, i.e. interim exposure index given by Equation 7.13, to be reasonable for humans. Without adequate justification, one cannot determine whether the approach outlined within the report is a HWBUI0010055 Claire D. Sherman, Ph-D. reasonable evaluation of the available health effects data. In addition, the proposed approach for developing coefficients has two serious problems: (i) For lung cancer, the potencies of the South Carolina textile studies for workers exposed to chrysotfle are not adequately recognized. These should be included to afford greater health protection, (ii) For mesothelioma, the overall optimized coefficients are substantially below the trends of the coefficients for the individual studies. X. Section 8.2 of the review document presents three options for assessing cancer risks from asbestos exposure.:P!ea$e comment on the technical merit of the proposed risk assessment options. AB three optioi&'coUld be used, dependingon the application. Option 3, Estimating Risk from a Unit Risk Factor, has the advantage of being the most simple to apply and has been traditionally implemented. Option 3 would be particularly useful for inexpensive screening calculations. ' :. . .. . Technical Comments: . Comment Table 6-12 and Figure 6.3 display the likely ranges for the KL estimates. However, the uncertainty factors used to derive these "likely ranges' are not defined in a manner that allows one to replicate these analyses. A protocol that provides decision rules for assigning such factors is. needed as well as.the range for each factor. Thus, the text that describes the variation, in the KL estimates could be misleading since the confidence intervals are effectively expanded. Rg. 6:35:Among "pure" amphiboie studies, the lowest and highest of the best-estimate KL values vary by a factor of approximately 20.... However, these two estimates are not statistically difference (based on comparison of their confidence intervals). Comment: The inference suggested above can be statistically, tested via likelihood-ratio tests. By confining the slopes of the "pure" amphiboie. studies to be. equal and then comparing the likelihood, from this model to a model where the slopes may vary, one can objectively assert whether there is a statistically significant difference in the KL estimates. B-121 HWBUI0010056 B-122 j HWBUI0010057 Leslie Thomas Stayner \ B-123 HWBUI0010058 ' ..... -" ' Leslie Thomas Stayner Chief, Risk Evaluation Branch National Institute for Occupational Safety & Health Robert Taft Laboratories, Cl5 ' . 4676 Columbia Parkway Cincinnati, OH 45226 513-533-8365 -. = Fax:513-533-8224 '- Dr. Stayner has been selected to co-chair the workshop. He recently served as a visiting scientist for the International Agency for Research on Cancer, where he worked with Dr. Jeny Rice on . monographs: for. man-made, mineral fibers and numerous other epidemiologic projects. He is the Chief of the Risk Evaluation Branch, which includes working on research on characterization of - occupational health'and safety risks and the development of better methods to .Characterize theses ris^s. He wgs. the, ?000 recipient of the NIOSH Special Act Award for. orgajiizing a workshop 9oa "Future Research for Improving risk Assessment Methods." He has lectured and served as an instructor'oii risk assessment arid risk management for academia and 'professioriarsbcieties,'and . international.orgamzations. He has published numerous.papers including "Exposure Response ...... Analysis of Respiratory Disease Risk Associated with Occupation Exposure to Chrysotiie Asbestos," "Silica; Astiestds, Man-Made 'Fibers, and' Cancer," "Occupational Exposure' toChiysotile Asbestos and. Cancer. Risk: A review of. the `Amphtbole Hypothesis," "Cqncordance.pf Rat and Human-based Risk Estimates for Particle Related Lung Cancer," Exposure to Crystaiine Silica, Silicosis and Lung Disease other than ;cancer m Diatomaceous Earth Industry workers: A' Quantitative Risk Assessment"- He has made numerous presentations at symposia, seminars,.and workshops including "Using Epidemiologic Data for a Risk Assessment of Silica Exposure, 2001," "The Molecular Epidemiology of Asbestos and b&fer Fibers, Harvard SPH, 1996; arid "Ah'Exposure-Response Analysis ...of - Respiratory. Disease .. risk.Associated with.Occupational Exposure to Chrysotiie Asbestos." ' Eniail: B-I24 HWBUI0010059 1) For lung cancer. Leslie Stayner A] Influence of fiber type: Please comment on the extent to which the epidemiology literature and mechanisticstudiessuggest that carcinogenic potency varies from one fiber type to the next (e.g., chrysotite versus amphibole fibers). How adequate is the information in the epidemiology literature for supporting dose-response analyses for different fiber typesft Specifically, to what extent do you think the proposed risk coefficients in Table 6-29 are supported by the epidemiology literature? The epidemiologic literature does hot provide compelling evidence that the carcinogenic potency differs by fiber type for lung cancer. This was the conclusion of a review that I authored about 5 years ago [Stayner et al. 1997$ and I have not seen anything in this document or elsewhere that has changed my position. In fact, the epidemiologic literature provides in many cases evidence that dhrysotile is just as potent as amphibole for inducing lung cancer The studies of textile workers provide very similar estimates of potency (1^), despite the fact, that some of these studies involved pure chrysotile exposures [Dertient et al. 1994], and others had mixed exposures [Peto .1985, and McDonald et al. 1983b). In a study of cement workers, Hughes et al. [1987] observed an exposure-response for lung cancer that was nearly identical for workers exposed to chrysolite or to mixed fibers [In fact. 1^ .= 0,4. in both ..plants, see Table .6-16 of this, report].. The "meta analysis of Kts presented in this report does not provide support for the hypothesis that chrysotile has lower potency for lung cancer than the amphiboles. In Table 6-21 the test for the hypothesis that the ratio of potencies (RPC) differs by fiber type was rejected (p=0.42 or p=0.14 depending on whether K was adjusted or not). Although this analysis resulted in a potency estimate for chrysotile that was either approximately 2 times (unadjusted K J, or 5 times (adjusted KJ lower than amphiboles these difference were not statistically significant, and therefore could be explained by chance. In the end, 1 strongly suspect that decision of whether or not chrysotile is as potent as amphiboles for lung cancer is highly influenced by the disagreement between the Quebec miners and millers study, and the South Carolina textile study. It would be highly informative if a sensitivity analysis could be performed in which each of these studies as well as other studies were dropped from the analysis, i also suspect that differences in slopes may be more a function of industry type than fiber type, and it would interesting to see the analysis attempt to adjust for this factor. B-125 > HWBUI0010060 Leslie Stayner While there are some mechanistic arguments that have been advanced.to suggest that chrysotile may be less potent.for lung canqer than, amphiboles [e.g., Mossman et al. 1993], it is difficult to accept these arguments given that we do not presently know the mechanism and that; these . arguments appear to conflict with the empirical evidence from the . epidemiologic literature discussed above (and toxicologic literature discussed below). In summary, I do not believe that the choice of using separate lung cancer risk coefficients for . chrysotile and.amphiboles. is well justified. B]Influence of fiber lengths Please comment on the extent to which the epidemiology literature and mec.hanistic.studi.es suggest that carcinogenic potency varies with fiber length. How adequate'is information in the epidemiology literature for supporting doseresponse analyses for different fiber lengths? In general, is it appropriate to assess cancer risks using an exposure index (see Equation 7.13) that is weighed heavily by fibers longer than 10 micrometers (pm)? (Note: Topic area 2 includes more detailed questions on the proposed exposure index.) There is substantial evidence that fiber length is a critical factorIn the carcinogenic potency.fpr lung cancer. Unfortunately, )his evidence, is from toxicologic studies, and there is little available information from epidemiologic studies. This is because the- epidemiologic studies have not generally included characterizations of the fiber size distributions, There is some indirect evidence from epidemiologic studies. For example. Dement and Wallingford [1990] reported that the percentage of fibers greater than 10 pm was higher in the South Carolina textile facility than what had previously been reported in the Quebec mines and mills, or in asbestos cement manufacturing facilities. Thus differences in the fiber size distributions is a possible explanation for why a higher carcinogenic potency for lung cancer was observed in the South Carolina textile facility than in the Quebec mines and mills, and the cement manufacturing facilities. Although there is limited epidemiologic evidence to support the need for an exposure index that gives greater weight to fibers longer than 10 pm, there is inadequate epidemiologic evidence to support the choice of the specific cutoff and exposure index that is proposed in this report [Equation 7.13]. B-126 HWBUI0010061 Leslie Stayner There is also mechanistic data to support the increased carcinogenecity of long fibers. Davis and others have demonstrated that short-fiber preparations are Cleared more rapidly from rat lungs than long-fiber preparations. As described in this report, a mechanistic hypothesis has been advanced that relates this difference in clearance to the inability of an alveolar macrophage to engulf fibers that are longer than the diameter of the macrophage. However, this mechanistic argument may imply a different choice of cutoffs for the exposure index than what is proposed in this report. The report lists 13.1 pm as the average diameter for a rat alveolar macrophage (AM), versus 21.2 pm fora human AM (p. 4.20). Therefore, based on this one might expect that model should use a fiber size cut-point in the model that would be around 13 pm" for the rat model, and around 21 pm for the human model. Instead, the "optimum' rat model in the paper by Bernstein et al. 1995] uses 40 piti as a fiber see cut-point, arid the "ad hoc' human model uses 10 pm as a fiber size cut-point ; . ... Berman and Crump also cite studies suggesting that long fibers interfere with cellular division, in a way that short fibers do not. There is evidence presented in some of these studies that specifically it is fibers longer than 15 pm that interfere with mitosis [Jensen CG and Watson M. Cell Biology International 23(12): 829-840, 1999, and Jensen GG et al.. Carcinogenesis 17(9): 2013-2021,1996) specifically refer to this as an effect of long fibers - either 15-80 pm long, in the 1999 paper, or 15-55 pm long, in the 1996 paper. Thus based on this mechanistic information one might suggest a cutoff of about 15 pm. B-127 HWBUI0010062 Leslie Stayner C] To what extent do animal studies (e.g., studies by Davis and other researchers) suggest that carcinogenic potency varies with fiber type and fiber length ? There is little if any evidence from animal studies that carcinogenic potency for lung cancer by fiber type. The statistical analyses of the toxicologic data by Berman et al. [1995] failed to demonstrate any significant difference in carcinogenic potency for lung cancer by fiber type. It is suggested in this report [page 7-151] and elsewhere that this may be a reflection of the fact that animals have a much shorter lifespan than humans, and that given the long half-life of amphiboles the difference in potency might only be observable in humans. However, this arguments seems to conflict with the fact that the analysis by Berman et al. [1995] was able to detect a difference in potency by fiber type for mesothelioma. , There is extensive evidence from toxicologic studies that fiber size is an important determinant of carcinogenic potency.- The inhalation studies of Davis and co-workers;[Davis et al. 1986; Davis and Jones, 1988] clearly demonstrated the effect of fiber size bn potency. The total exposure concentration was held, constant in these studies, and the preparations that contained a high proportion of long fibers were markedly more potent than the same fiber type with a short fiber length. The long amosite (with fibers up to 100 |im long) produced 11 lung tumors and 3 mesotheliomas in 40 fats; the short-fiber preparation (with fibers only up to 10 pm) produced no lung tumors and 1 mesothelioma in 43 rats. The long and short chrysotile preparations were not as different in lengths as the amosite, but Davis and Jones stated that the long-fiber preparation had over 80 times as many fibers > 30 pm than the short-fiber preparation. In this case the long- fiber preparation produced approximately three times as many pulmonary tumors as the short-fiber , ... - preparation. Similar differences in pathogenicity were seen for mesotheliomas, as well, in intraperitoneal injection studies comparing long and short fibers. There are other studies in the fox literature that also suggest greater pathogenicity for long fibers, but the Davis et al. studies are sufficient to demonstrate the magnitude of the response differences that have been seen. D] Please comment on the extent to which carcinogenic potency is a function of fiber properties (e:g., didrheter, aspect ratio, surface properties) other than fiber type and fiber length. How adequate is information in the epidemiology or toxicology literature for supporting these other properties into dose-response analyses? B-128 HWBUI0010063 Leslie Sfayner There is no epidemiologic data available to address this question. Toxicologic evidence that carcinogenic potency for lung cancer is associated with fibers > 0.15 pm in diameter was reviewed by Uppmann, Environ Res 46: 86-106, 1988. In addition, the analysis of Berman et a!., Risk Anal 15: 181-195, 1995 suggests that fibers as large as 5 pm in diameter may be carcinogenic in the rat In contrast, mesothelioma has primarily been associated with very thin fibers; Stanton et a!., J. Natl Cancer Inst. 67: 965-975, 1981; reviewed by Lippmann, Environ Res 46:86-106,1988 2) For mesothelioma: A]Influence of fiber type: Please comment on the extent to which the epidemiology literature and mechanistic studies suggest that carcinogenic potencyvariesfromone fiber type to the next (e.g., chrysotile versus amphibole fibers). How adequate is the information in the epidemiology literature for supporting dose-response analyses for different fiber typesR Specifically, to whafextent do you think the proposed risk coefficients in Table 6-29 are supported ;by the epidemiology literature? I believe that the hypothesis that the risk of mesothelioma varies by fiber type is pretty well established. The epidemiologic literature clearly demonstrates much higher incidence of mesothelioma among workers exposed to amphiboles than to chrysotile. For example the percentage of deaths in South African miners exposed to crocidolite is approximately 4.7% [Sluis- Cremer, 1992J, and 2.4% among vermiculite miners [McDonald et al. 1986]; whereas, the percentage of deaths from mesothelioma among Quebec chrysotile miners and millers was only 0.4% [McDonald et al. 1993] and only 0.2% among South Carolina textile workers exposed to chrysotile [Dement et al. 1983], In contrast to lung cancer, the meta-analysis performed in the report of the K,,,s for mesothelioma indicated that the ratio of potencies for chrysotile and amphiboles was highly statistically different (p < 0.001) than 1 (See Table 6-21). Although there are clear differences in mesothelioma risk by fiber type, the actual values of the risk coefficients presented in Table 6-29 have limited support from the epidemiologic literature. Exposure-response information for estimating slopes (S^s ) was generally not available in these studies, and the l^,s could only be crudely estimated with assumptions about the average B-129 HWBUI0010064 Leslie Stayner exposures for most of these cohorts. True exposure-response relationships could only be determined from the studies by Liddell et at. {1997] and Dement et al. [1994], since these investigators made their data available to the authors of this report. I am not aware of mechanistic data that indicates carcinogenic potency for mesothelioma varies by fiber type, although I must confess here that I am not totally up to date on my reading of this literature. B]Influence of fiber lengthz Please comment on the extent to which the epidemiology literature and .mechanistic studies suggest that carcinogenic potency varies with fiber length. How adequate is information in the epidemiology literature for supporting doseresponse anaiysesfor different fiber lengths? In general, Is it appropriate to assess cancer risks using an exposure index (see Equation 7.13) that Is weighed heavily by fibers longer than 10 micrometers (pm)? (Note: Topic area 2 includes more detailed questions on the proposed exposure index.) There is virtually no data available in the epidemiologic literature to evaluate how the carcinogenic potency for mesothelioma varies by fiber length. It is interesting to note, however, that the K,,js (0.013 for Asbestos, and 0.021 for Thedford) derived in this report from the analysis of raw data from the Quebec study of miners and millers [Liddell et al. 1997], was nearly an order of magnitude lower ten the K,, (0.11) derived from analysis of the raw data from the South Carolina textile cohort. This may be consistent with the argument that the exposures in'South' Carolina had a larger percentage oflong fibers, than in the Quebec mines and mills [Dement and Wallingford 1990), and thus with the hypothesis that longer fibers have higher cardnogeriic potency formesothelioma. On the other hand, the fact that the !<,,, for the cement plant study by Hughes et al. [i987] was higher than the South Carolina textile plant would seem tocontradict this hypothesis, since Dement and'Wallingford [1990] also suggested that the exposures at'the South Carolina textile facility had a higher percentage of long fibers than the exposures at the cement factory. There is no epidemiologic evidence to support the choice of the specific exposure index that is proposed in this report [Equation .7.13]. C] To what extent do.animal studies (e.g., studies by Davisand otherresearchers) suggest that carcinogenic potency varies with fiber type and fiber length 7 B-130 HWBUI0010065 Leslie Stayner The toxicological evidence to suggest that the carcinogenic potency for mesothelioma varies by fiber type is limited. There is considerable evidence from the toxicologic studies using fiber implantaion that fiber length is an important determinant of carcinogenic potency for mesothelioma, but there is very limited data from inhalation studies. Part of the problem with answering this question is that very few mesotheliomas are produced in rodent studies where the route of exposure Is via inhalation. The inhalation studies by Wagner et al. [1974] and the studies by Davis et al. produced small numbers of tumors, and overall provide little evidence [see review by Stayner et al. 1996], The analysis by Berman et al. [1995] does suggest that chrysolite is approximately 3 limes less potent than amphibotes. However, there too few cases (n=13) to perform a direct evaluation ofthis questionand it was evaluated by testing whether a direct constant of proportionality could be applied to the probability oflung cancer and mesothelioma. It wasfound that this proportionality constant was weakly significantly (p=0.032) forchrysotile and amphiboles. It should be noted that this analysis does not take into account differences in the fiber size distributions, and only indirectly the exposure level. .. D] Please comment on the extent to which carcinogenic potency is a function of fiber properties (e.g., diameter, aspect ratio, surface properties) other than fibertype and fiber length: How adequate is information in the epidemiology or toxicology literature for supporting these other properties into dose*response analyses? There Is no. data.from,epidemiologic studies to evaluate these questions. 3)To what extent are the exposure estimates documented in the asbestos epidemiology literature reliable? The potential for exposure misclassitication in many of the epidemiologic studies is extremely large, and possibly introduces far more uncertainty than.the adjustments used by the authors of. this report. Exposure intensity and even duration of exposure had to be estimated for many ... qf. the studies included in this anafysis. For example, the study by Selikoff and Seidman of U.S. insulators did not include information on duration of exposure, and the US ERA (and this report) simply assumed that all workers in this study were exposed for 25 years, and to 15 f/rni in order to calculate a K,. There are also large uncertainties in the exposure estimates for studies that included analyses by cumulative or average asbestos exposure. One of the key issues is the conversion of measurements from impingers (mpcf) to the more modern methods based on PCM or TEM. B-131 HWBUI0010066 Leslie Stayner This may in fact be an explanation for the differences in potency between the South Carolina chrysotile textile cohort, and the Quebec chrysotile miners and millers study, .which is a critical issue in this risk assessment The SoulfvCarolina textile worker study included extensive side by side measurements for the conversion. It is noted in the report (page. 5.3) that the conversion factors for the Quebec.study came from studies at other facilities. It is also noted in this report (page 6.43) that in the mining environment there is a large potential for. interference in using the . impinger method and even the PCM method from non-asbestos dust and cleavage fragments. This suggests the possibility that fiber counts may have been over estimated in the Quebec study, which ,may explain-in part the lower carcinogenic potency observed in this facility relative to the South Carolina cohort . . .; . ...... Topic Area 2: The proposed exposure index. 4) The proposed exposure index does not Include contributions from fibers'shorter than 5 pm. Please comment on whetherthe epidemiology and,toxicolqgy|iterature support the conclusion that asbestos fibers shorter than 5 pm present little or no carcinogenic risk. . The epidemiologic literature does not have any information to contribute to this question. The toxicologic literature does, and it does strongly indicates that fibers shorter than 5 pm have little if any carcinogenic risk. For example, the multivariate analyses by Berman et al. (1995) indicated zero potency for fibers shorter than 5 pm. However, I think we peed to be somewhat cautious here about overinterpreting these findings. It is still possible that short fibers (<5 pm) have a very low carcinogenic potency, and that the toxicologic studies did not have adequate statistical power to detect the level of risk associated with.exposures to. these.fibers... One might expect short fibers to have similar carcinogenic potency as has been observed for other particles such as titanium dioxide or carbon black. 5) The proposed exposure index is weighed heavily by fibers longer than 10 pm. Specifically, Equation 7.13 suggests that the carcinogenic potency of fibers longer than 10 pm is more than 300 times greater than that of fibers with lengths between 5 and 10 pm. How consistent is this difference in carcinogenic potency with the epidemiology and toxicology literature? B-132 HWBUI0010067 Leslie Stayner There is virtually no information in the epidemiologic literature to address this question. There is also very'limited information from the toxicological literature with the exception of the paper ' by Berman et al. {1995], and even this paper does not clearly support the factor of 300, which appears to have been chosen somewhat arbitrarily (i.e., using an "ad hoc method"). Unfortunately, the Berman et at; paper did not present a model comparable to the proposed index. The closest model shown is the "intermediate" analysis, and in this analysis the potency of fibers that are 5 to 10 pm long is only approximately 1/4* less than 10-20,1/10*' less than 20' 40, and 900 times less than >40 pm: Based on this model it would seem that assuming a factor of 300 in potency between fiber 5 and 10 pm; and >10 pm would only make sense if a very larger percentage of the fibers > 10 pm were > 40 pm. It wduld be very informative if the analysis by Berman et al. could be repeated using the proposed exposure index. One also must be concerned that this formula is based solely on the analysis of toxicological data. One-might expect -that humans might show, a very different pattern in. risk related, to fiber ' size, given species difference in respiratory anatomy arid th'e size' of human' and rat macrophages. The site of lung tumors is also different with rats developing tumors in the alveoli, and humans in the bronchus. Given these species differences, one would strongly suspect that the relationships between fiber size and carcinogenic potency could be species specific.' ` ' 6) Please explain whether the proposed exposure index will allow meaningful comparisons between .current environmental exposures to asbestos and historical exposures to asbestos that pccurred.in the work place. At this time, it is not possible to use the exposure index to make meaningful comparisons between current environmental exposures and workplace because the workplace studies have not included the exposure measurements needed to use the index. Topic Area 3: General questions. 7) The proposedrisk assessment approach assigns carcinogenic potency to individual fibers and to cleavage fragments (or "bun dies that are components of more complex B-133 HWBUI0010068 Leslie Stayner structures"). Please comment on whether cleavage fragments of asbestos are as toxicplogically significant as fibers of the same size range. I am unaware of any epidemiologic or toxicologic studies that have direct bearing on this question. It is interesting to note the concern raised in this report that studies of miners may have included counting ofcleavage fragments, and that this might account for the very low lung cancer risk detected in these studies. 7) Please comment on whetherthe proposed cancer assessment approach is relevant 1 to all amphibole fibers or only to the five types of amphibole-fibers (actiriolite, amosrte, anthophyllite, crocidolite, tremolite) designated in federal regulations. I am not convinced that the proved methodology is even relevant for the arriphiboies designated in federal regulation let alone for other fiber types. 8) The review document recommends that asbestos samples be analyzed by transmission electron microscopy (TEM) and count dnly tHose fibefs-(br bundles) longer than S pm. Such counting practices will provide no information on the amount of asbestos fibers shorter than 5 pm. To what extent would data on shorter fjb.ers in samples be useful for future evaluations (e.g,, validation of the capper risk assessment methodology, assessment of non-cancer endpoints)? I think its obvious that if we ever want to be able in the future to answer the, question a to whether or not fibers. < 5 pm are carcinogenic, than we will need to have; studies in .which these fibers are measured. 9) The proposed risk assessment methodology suggests that exposure estimates should be based only on fibers longerthan 5 pm and thinner than 0,5 pm. Is this cut off for fiber diameter appropriate? in the "optimum" model in the paper by Berman et at., fibers longerthan 40. pm, and > 5 pm in diameter showed a relatively high carcinogenic, potency. This would suggest that 0.5.. pm is not an appropriate cutoff, particularly when you have long fibers. 11) Discuss whether the proposed cancer assessment approach, as a whole, is a reasonable evaluation of the available health effects data. What aspects of the proposed cancer assessment approach, if any, are inconsistent with the epidemiology or toxicology literature for asbestos? B-134 HWBUI0010069 Leslie Stayner z' !) I believe what this report has done is clearly identity weaknesses in the current methodology using for measuring asbestos exposure, and for assessing risk. The choice of a 5 pm cutoff with a 3 to 1 aspect ratio was clearly arbitrary, and not batsed on biologic principles as much as on the available sampling methodology. However, l am afraid the proposed methodology is also quite arbitrary, and lacks a solid scientific basis. I am most concerned that lower index for chrysotile and lung cancer risk is not supported by the analysis of the epidemiologic data. I am also concerned that while the proposed exposure metric may have more plausibility than the current one, that it still needs farther evaluation, before.being adopted. . In particular, I think that there is a real need to reanalyze sofhe of the key epidemiologic studies using this index arid other possible indices based on THM analysis to determine what an appropriate index is. 12) Section 8.2 of the review document presents three options for assessing cancer risks from asbestos exposure. Please comment on the technical merit of the proposed risk assessment options.. Obviously the' first option (using the dose-response: model and a life table) is the most accurate, but the second (estimating risk from a life table) Should be reasonably accurate under most circumstances (i.e., excess risks less than 1 per 100). As far as ease of use, of course the 3rd option is the easiest although the feast reliable. All three methods may be useful for different audiences. EPA officials would probably want in most cases to use the firstoption since it is the most accurate. On the other hand, the unit risk option might be most appropriate for the lay public and this is what EPA might want to continue to use in Us IRIS database. Other-Comments^; ` ' This document is in serious need of editing, and iri many ways is a very rough draft. following editorial arid other minor comments'to offer. : 1 have the 1) Page 4.21 - It seems that a bullet should be added stated that there are important species differences in the morphology, of the lung and pleura, and these differences may have important implications for. risk assessment, . 2) Page 5.7, next to last paragraph - There is a missing reference (F?EF). B-I35 HWBUI0010070 3) Page 6.17, last paragraph -- it is stated that the animal data suggests that tumorigenecity is a function of in-vivo durability. However, this statement seems to be inconsistent with the fact that the animal studies have generally failed to demonstrate a difference carcinogenic potency between chrysotile and the amphiboles. The section 7.2.4 that is referred to is merely a discussion of differences in dissolution rates and does not provide any evidence to support this statement 4} Chesson et .al 1989, which is a critical reference cited several times in this document (e.g. page 6.46), is listed in the references as "Submitted for Publication 1989"? 5) In the meta-analyses of Kt and K,,, I hope that they have not included both the McDonald and Dement analyses of the South Carolina cohort This would obviously be a mistake. 6) Page 6.61 -The improvement in (he range of K L from when adjustments were made is not very impressive and seems to be due to improvements solely in the agreement between the South Carolina textile and Quebec miners studies. I am not sure that this can be interpreted as providing justification for the new index as the report does. 7) Page 6.65, formula 6-12 - the symbols for this formula need to be defined. 8) Page 6.69, last paragraph - It should be noted that the differences in mesothelioma risk was not statistically significant, which is dear in the presentation in the appendix. 9) Page 6.70 - It should be noted that the model does not fit locations 2 or 3&4 very well. 10) Page 6.90 -- For the conservative risk coefficients why not use the largest value for chrysotile rather than only using the largest values for crocidolite and then scaling chrysotile? B-I36 HWBUI0010071 Kyle Steenland ) B-137 HWBUI0010072 Kyle Steenland Professor Rollins School of Public Health ., . - V". . ''EmoiylMyen^ 1518 Clifton Road f,, . . Atlanta, GA 30322 '* ' 464-712^8277 ______________ __________________________________________________ Email: nsteenl@sph.enfiory.edu Or. Steenland is a Professor in the.-Department of Environmental and. Occupational Health afethe-Rollirts School of Public Health at Emory University, He has a Ph.D. in Epidemiolfjgy from the University of Pennsylvania and a Masters in Mathematics (statistics) from the University'of.Cmdnna8.. prior to going to Emory last August; Dr. Steenland sj5rtt 20 years at Rational Institute of OccupaVonai SMfety and Health (NIOSH). At NIOSH he worked primarily in occupational cancer epidemiology, as well as the development of epidemiologic methods. He has edited 2 textbooks, one on occupational and the olhf on environmental epidemiology. ..... i, ; < . ,. n B-138 HWBUI0010073 Kyle Steenland EPA asbestos document (Berman and Krump), comments by Kyle Steenland, 2/10/03 Summary of approach Exposure-response estimates based on a linear relative risk model for lung cancer, and an absolute risk model for mesothelioma, were re-calculated on summary data from the 15-20 epidemiologic studies in the literature with exposure-response data. For limg cancer, these analyses were.based on SMRs comparing exposed populations to large noh-exposed populations with background rates, and in the recalculation an additional parameter was estimated as a multiplier of background rates. Using the results of these analyses^ meta-analysis ofexposures response coefficients was then conducted, for both lung cancer and mesothelioma. A correction was applied to exposure-response coefficients for lung cancer and mesothelioma based on fiber size (more weight on long than fibers) and on fiber type (more weight on amphiboles vs ehiysotiie). Hie fiber size correction was taken a priori from animal data tempered by limitations in available exposure data, while the adjustment for fiber type was estimated from the data. The fiber type adjustment results in separate exposure-response estimates for ehiysotiie and amphiboles, a major difference from the current EPA approach. The fiber size correction has fewer implications. The authors have done a thorough and competentjob synthesizing a large body of literature and data, and have taken inventive approaches to old questions. Nonetheless, I have some questions and disagreements as outlined below. My comments are focused on epidemiologic issues, which is my area ofexpertise. General comments ; I. Style of the document It is actually quite difficult to de-cipher the text, the heart ofwhat was done is contained in a few pages ofa very long document This document could be simplified. For example, pages 6.1-630 could be put in an appendix, as their results are essentially never used by the authors. I have put my comments on page 6.1-6.30 at the end of this document Similarly, the animal data in section 7 seems to be summarized at the end on pages 7.148 through 7.158, and it is not clear to me that the preceding pages could not be reduced in size. II. Meta-analysis of exposure response coefficients. The meta-analysis differed from customary meta-analyses (DerSimonian and Laird, 1986) in which a random effects model is used (in the presence ofheterogeneity) and an inversevariance weighted average ofstudy-specific exposure-coefficients is calculated (with the variance reflected in the confidence interval of each study-specific estimate), along with the addition of a variance component for between study heterogeneity. Here, in contrast, the between-study B-139 HWBUI0010074 Kyle Steenland variance component was estimated via a likelihood approach, a parameter for weighting fibertype was also estimated via likelihood, and the individual study variance (confidence interval) was inflated in a way described in the Appendix, This approaches not unreasonable, and is of importance in the estimation of the fiber-type weighting parameter from the data. One thing not clear, however, is the inflating of confidence intervals for each study as indicated in the Appendix.. First, it should be made dear in the text that these inflated confidence intervals are used uniformly throughout the text, which I believe is the case - it would be better to consistently give them a different name altogether (eg, `reasonable range' which is used sometimes). More importantly. Appendix A is not clear on how these inflated confidence are in fact calculated. They seem rather arbitrary. There appears to be an assumed rvalue of LO for up to 4 factors. This yalue would not appear to make sense as the formula in-Appendix A has the logarithm ofthese factors, which would then be 0. 1 must be . trussing something here. , .. A different and more traditional approach, perhaps more transparent, would be estimate the weighting factor for fiber type from the data and then use it in a traditional meta-analysis, in which the traditional study-specific variances (CIs) are used, and an additional variance . component (which would cover all tire factors in Appendix A) was taken as the between study variance. : HI. Why SMRs in the lung cancer re-analysis? For lung cancer, why were internal analyses not considered, rather than SMRs?. Use of SMRs leads to correction of.background rates (estimation of`alpha') for background rates, which in turn changes the estimated exposure-response coefficients. The raw data for the meta-analysis given in the Appendix uses a Poisson-SMR. model in which background rates are incorporated It is not dear why a Poisson model could not be used;hr internal analyses without recourse to ;. national rates, which would get rid of the need to estimate the extra parameter alpha (background correction). . .: IV. Why these models (the usual EPA models for lung cancer and mesothelioma)?. Given that the authors have re-calculated exposure-response data for each study, why were models restricted largely to the usual EPA models? Why not the more common statistical models, such as the usual log-linear relative risk model ,for lung cancer? For mesothelioma, the usual EPA model was originally based on animal data and mechanistic considerations. It is not a model used for any other disease, to my knowledge. The model, which is based on absolute risk rather than relative risk, is based on an average intensity B-140 HWBUI0010075 Kyle Steenland and time since first exposure* with no consideration of cumulative exposure. Cumulative exposure is the metric ofinterest in most occupational cancer studies. For example, it is tire metric of interest used here for lung cancer (and lung cancer models do not include time since first exposure). This discrepancy between these two models could be mentioned. Ifthere is a reason to accept the EPA models a priori for historical reasons this should be stated. Ofcourse, otie reason is to simplify the task. V. Throw out the outliers? Another suggestion would be to throw-out outliers, such as'any plant where there is no exposure-response for lung cancer (tins contradicts the great bulkoftire evidence) and perhaps the Ontario plant for mesothelioma, where mesothelioma deaths were almost as numerous as lung cancer deaths. Comments on adjustment for fiber size and fiber type. The charge for peer reviewers primarily relate to these two questions. The authors claim that `by adjusting for fiber type arid fiber size, the existing data base of studies can be reconciled adequately to reasonably support risk assessment'. The basis of this statement is not dear. Adjusting for fiber type and fiber size reduces somewhat the heterogeneity ofthe data; nonetheless, the heterogeneity remaining within the categories ofamphibole and chrysotile studies remains very large, and any decision to accept a common risk coefficient across such heterogenous data is more a policy flan a statistical decision (the authors do not do any tests for heterogeneity, referring rather to non-overiapping confidence limits, but tests are somewhat superfluous in the face of large and apparent heterogeneity.) Adjustment for fiber type. Mesothelioma. It would appear that there is reasonable evidence that adjustment for fiber type is worthwhile for mesothelioma, in that the amphibole cohorts appear to have considerably higher risks than the chrysotile cohorts. However, there is great heterogeneity within the amphibole cohorts, making prediction within them quite difficult (the controversy over Whitenoom exposure estimates further increases uncertainty here, see below under `minor points'). Furthermore, the chrysotile cohorts are also quite different, ie, between Quebec and S. Oarolina/N. Orleans. The Carolina axid'New Orleans cohorts show high risk, and approach the lower bounds of some ofthe amphibole cohorts. Nonetheless, given the general increase in risk for all the amphibole cohorts vs the chrysotile cohorts, some adjustment for fiber type appears justified. B-I41 ) ) HWBUI0010076 Kyle Steenland Animal data also apparently tends to support an increased risk of mesothelioma for amphiboles. Adjustment for fiber type. Lung caner. The evidence for adjustment for fiber type for lung cancer is more problematic* in that it relies almost exclusively on the low risk among Quebec chiysotile miners* or conversely on the high risk for Carolina textile workers and New Orleans cement workers exposed to chiysotile. The discrepancy of results these results for these 3 cohorts is unresolved, and yet upon it rests the conclusion that the lung cancer risk as substantially different.between amphiboles and chrysolite. The evidence is weak, in ray view, to make an adjustment for fiber type for lung cancer risk. The animal data,do not.dearly indicate that lung cancer risk is higher for amphiboles vs chrysotiie, further weakening the case for adjustment for fibertype for lung cancer. Theories about the short life ofrats and die ovpr-whelming ofclearance mechanisms have been proposed to explain the lack ofdifference in rats-by fiber type, but these explanations do: not appear to have explained away die issue. Adjustment for fiber size. The adjustment for fiber size on page 6.50 (a re-weighting of traditional exposure measures used in the current standards, which are based on fibers longer than 5 um and witha 3:1 aspect ratio and greater than OJ25 um diameter) is. taken from the animal data in which long thin fibers (>40 um) appear to be more carcinogenic, plus an ad hoc recognition that the epidemiologic studies permit exposure measures only based on a dichotomy of greater or less than 10- um in length (so that a re-weighting, using .40 um cannot be done). The data supporting the carcinogenicity of long and thin fibers appear reasonably uncontroversiaL Theapplication of this adjustment in fact does not change much the observed heterogeneity in the-data, Another possible approach to adjusting for fiber size is to pick the weighting (cunentlyjOJ%;for <10 um, 97/7%. for >10 um) such that heterogeneity in the data is maximally reduced, hi practice so little weight is given to fibers <10 um that their weighting could simply be 0. B-142 HWBUI0010077 o Kyle Steenland More minor points a) Specific comments on pages 6.1-630., While fiiey are interesting exercises, it is not dear to me why the analyses ofraw data for two specific cohorts was done, given the limited inferences which can be drawn about the universe of asbestos studies (a pooled analysis ofall existing data, as opposed to amet-analysis, would he ideal but very time-consuming and possfoly impractical). Tentative conclusions aboutthe current EPA model are drawn based on these two studies, based on sparse data, which do not Strike me as valid. In particular inferences about the pattern of rate ratios after employment termination strike me as unwarranted, as they are based on. very sparse data. Time-related patterns of RRs, eg, stratified by time since termination^ are affected-by other variables involving die healthy: worker survivor-effect, independent ofcumulative dose. Estimation ofmodels using various. . assumptions about internal dose vs external dose are focused on patterns for time-since- termination. It mi$it be more interesting to first evaluate dose-response by cumulative dose. using estimates of internal dose vs external dose. But in any case, ifonly two cohorts can be studied using raw data, it does not seem worth the effort, as no generalizations can be extrapolated to other studies. Similarly, it was not clear to me why the multi-stage model was included in the analysis oftwo cohorts. Again, while this was an interesting exercise, it could have been predicted that this model - which has not been adopted by epidemiologist conducting occupational studies is complex and involves estimating a large number ofparameters based on biological assumptions. It is difficult to interpret these parameters b) There is a dispute about exposure levels in Whitenoom which is not reflected in this document, whereby exposure levels may have been overestimated by 4-10 times (see Hodgson and Damton, 2000). This becomes relevant (see below), given the large weight of this study (large numbers of cases). c) Asa general comment, it would be worthwhile ifthe authors were to add the observed numbers of cancers to Table 6.12. These would enable an immediate appreciation ofthe strength ofevidence provided by each study. B-143 '.J HWBUI0010078 HWBUI0010079 Mary Jane Teta B-145 HWBUI0010080 _________________________ - ' Mary Jane Teta Principal Epidemiologist Exponent, Inc. 234 Old Woodbury Road Southbury, CT 06488 203-262-6441 Fax: 203-262-6443 Email: Keta@exbbnent.cQm Dr. Teta specializes in chronic disease epidemiology, particularly occupational and environmental epidemiology studies; regulatory risk assessment, particularly for cancer endpoints; and risk commuriicaligh to the media and public; She has served on numerous scientific advisory boards including those of ATSDR, EPA, The Mickey Letand Center and'ttie Harvard Cehtfer-fbr Risk Analysis. She is an Adjunct Associate Professor ofEpidemiology in the Department of Bibstatistics and Epidemiology at the University of Massachusetts. She received her Doctorate of Public Health from Yale Universiity and her MPH in Biostatistics from Yale University. She is a Fellow of the Arrieffcan ColtegeofEpidemiology; a consultant to EPA's Science Advisory Board; a consultant to several task groups at the American Chemistry Council; former Chair, of the Scientific Committee of the American Industrial Health Council; a member of NIOSH's Risk Assessment Task.Group; and an NIH consultant for the National Children's Study. Her publications include,' "The Influence dFOccupaMofial and Environmental Asbestos Exposure on the Incidence of Mesothelioma in Connecticut" and "Mesothelioma in Connecticut 1955-1977: Occupational and Environmental Associations." : . .. B-J46 HWBUI0010081 M. Jane Teta. Dr.PH CHARGE QUESTIONS Topic Areal: Interpretations of the epidemiology and toxicology literature. 1) For lung cancer A] Influence of fiber type: Please comment on Hi extent to which, the.epidemiojogy literature and mechanistic studies suggest that carcinogenic potency varies from one fiber type to the next (e.g., chrysotile versus, amphibole fibers).-.How adequate is the.information in the epidemiology literature for.supporting dose-response-analyses, for different fiber types! Specifically, to what extent do you think the proposed risk coefficients in. Table 6-29 are supported by Ihe epidemiology literature? There is compelling evidence from epidemiologic and mechanistic studies that .carcinogenic potency varies by fiber type with chrysotile being a less potent lung, carcinogen than the amphiboles. The formal analysis ofthe cohort studies included in the Berman/Qump report illustrates this fact, even after adjustment for fiber size. There are 16 cohort studies with quantitative data upon which to base these analyses and published studies wife average TEM fiber size distributions relevant to all but two of them. This is adequate information. While uncertainties remain related to some ofthe assumptions and adjustments made in this methodology, the end result is much greater homogeneity among fee studies within each fiber type and a clear distinction in risk between chrysotile and the amphiboles. The analysis of relative risk (RR) wife time, using raw data from Wittenoom (croddolite) and SC (primarily chrysotile), is also informative with respect to potency variability. The RR remains constant after exposure for fee Wittenoom miners but diminishes wife time since last exposure for the textile workers. This is consistent with fee findings of Finkelstein and Dufrensne (1999) that chrysotile splits both longitudinally arid transversely in the human lung and that lung burdens decrease substantially with cessation ofexposure. The breakdown ofchrysotile and its greater solubility has an inverse relationship with tumorgenicity. Although fiber size is fee stronger influence on biopersistence, both rodent and human pathology studies indicate that in vivo durability (solubility) is a predictor ofclearance and it is dependent on fiber rtuneralogy. B-147 HWBUI0010082 M. Jane Teta. Dr.PH While unable jto distinguish the effects pf fiber size and type, the large body of asbestos epidemiologic studies* not included in this report because of inadequate exposure data for exposure-response modeling, is very consistent with die lesser potency of chrysotiie. For example, Camus et al , (New England Journal of Medicine 1998; 338: 1565-71) reported no excess risk of lungcaneer in a population ofwomen with relatively high levels of nonoccupational asbestos exposure from two chrysotiie asbestos mining regions. However,ffi?reare,numerous examples ofbystander and domestic amphibole exposures [e.g, shipyard, a^bestcs cement] linked with increased lung cancer rates. There is no . clear evidence, ofincreased tang cancer risk amopg .vehicle mechanics despite potential exposure to chrysotiie in brake dust and little or no risk associated with manufacture of (chrysotiie) friction products. Similar fiber type risk differences have etfen been observed within the same cohort (e.g.,.J&blson et ai. 1984 Mortality among asb^tds-exposerf. workers in a railroad Workshop. Scand J WorkEnviron Health 10; 283*291) or industrial . . <t*' .. ' . ... e s ' .; f group (chrysotiie v. arnosite cement cohorts). The contrast, in lung cancer risk atnong female gas mask workers follows a similar clear pattern of lower risk among those exposed to chrysotiie than crocidolite. The exception.ofjcourse is the textile manufacturing studies, where fiber size and the extent of mixed exposures to arnphiboles confound the ability to address variability in risk due to mineralogy. As Berman and Crump point out, the existing EPA model provides an adequate description of lung cancer mortality for the Wittenoon cohort but may not be adequate for the SC cohort These findings, in addition to the differences observed in the optimized coefficients upon adjustment for fiber size (Table 6-29) and the consistent mechanistic data, provide compelling evidence that the dose-response curves for chrysotiie .and the arnphiboles are too disparate.to be represented by one curve or model.. The optimized coefficients for pure fiber types with a ratio of 5.3:1 (arnphiboles to chrysotiie) in Table 6-29 successfully reduce study potency variability (33% from a factor of 90 (based on 18 studies) to 60 (based on 16 studies)). Since the coefficients have been M. Jane Teta, Dr.PH adjusted for fiber type and size, a straightforward quantitative assessment of consistency with epidemiology studies may not be feasible. Furthermore, since the most informative epidemiology studies have been used to derive these values, they cannot be used as an independent test ofconsistency! this might have been possible, had some studies been excluded from the derivation ofthe coefficients. In this case, predictions based on: the coefficients could have been compared to what was observed in the study cohorts, the disadvantage, ofcourse, would be the reduction hi the number ofstudies and the associated increased uncertainty in the optimization procedure. Would it be possible, however, to examine thefobserved number of lung cancer cases in each study against predicted, using the optimized odefficienfeto evaluate the goodness offit? B] Influence o(fiber length Please comment on the extent to which the epidemiology literature and mechanistic studies suggest that carcinogenic potency varies withfiber lengthHow adequate is Informatiodin the epidemiology Mterahire for supporting dose- -response analyses for dififerent/Mrer.lengths! In general, is it appropriate to assess cancer risks using an exposure index (see Equation 7.13) that is weighed heavily by fibers longer than 10 micrometers (pm)? (Bote: Topic area 2 includes more detailed questions on the proposed exposure index.) i. . .. : Epidemiology and mechanistic stiidies provide convincing evidence that fiber size and shape (length and diameter) are important predictors ofcarcinogenic risk. Mechanistically, fiber dimension is related to respirability, deposition, degradation, clearance and translocation, and, therefore, is a major determinant of cumulative dose to the lung. Attempts to relate potency to asbestos air concentrations or worse, measures of dust containing asbestos, results in extreme variability in potencies, both among different fiber types and within thesame fiber type. The detailed review of experimental ifeta from rodents and humans in the Berman/Crump report show that: shod fibers (<d 6 urn) are cleared much more quickly than long (>20 um) insoluble fibers, short fibers do not induce fibrosis, long fibers produce substantial inflammation, and deposition and translocation depend predominately on fiber size, while durability depends mostly on fiber type. Even longer fibers may be cleared efficiently if B-149 HWBUI0010084 ML Jane Teta. Dr.PH they arc soluble. Studies were examined that included varying fiber lengths within the same fiber type to enable distinctions to be made, free ofconfounding. Both the epidemiology: and mechanistic data support using a weighted exposure index that recognizes the predominant influence of fibers longer than lOum. The analysis ofthe lung cancer crude potencies (not adjusted for fiber size) based on the Quebec miners and SC textile worker studies, together with a re-analysis of the lung pathology results ofworkers from these two locations ate very informative. Higher measured concentrations in Quebec do not translate to higher lung cancer potency; in feet the epidemiology studies confirm higher lung cancer risks in. the textile workers. Hie Bennan/Crump analyses show that airborne concentration ratios between the tWo work settings are not predictors of lung butderi (relative ratios of fiber types [chrysotile or tremolitej); More importantly; size distribution comparisons indicate that textile dust in SC may have been highly enriched with long tremolite fibers (>20 uni). The published;' size distributions in these environments (Gibbs and Hwang, 1975,1980) and knowledge of the raw fiber purchased by the textile plant further support these findings. The absence ofa clear increase in lung cancer in epidemiology studies ofauto and brake mechanics, after adjustment for smoking, may be explained in part by the potential exposure to short fiber chrysotile, in contrast with the long fiber types in textile settings needed to facilitate weaving of the fibers. Table 6-15 shows a clear correlation between fiber length and lung cancer potency coefficients. Wittenoom, however, seems to be an exception, with a predominance of shorter fibers and one ofthe higher potencies. Potencies adjusted for fiber size (by using the new exposure metric) are presented in Table 6-15. All coefficients increase by factors of2 to 7, with the exception of Wittenoom, whose increase is less than 2, dropping it down to 9th most potent (of 20 cohorts). The Wittenoom results merit some discussion and clarification. B-I50 HWBUI0010085 M. JaneTeta. Dr.PH Hie Benitan/Crarnp approach to adjusting the lung cancer potencies for fiber size (length and width) is very effective in reconciling the variability in the unadjusted estimates. This body ofepidemiological data is adequate for supporting these dose-response analyses. The approach ofusing relevant THEM size distributions from the published literature to implement the size adjustment is both rational and innovative. The uncertainty values assigned, however, need to be more clearly explained andjustified The range ofuncertainty values should be described for each consideration and the >. criteria used clarified CJ To what extent do animal studies (e;g., studies by'Davis and other researchers) suggest that carcinogenic potency varies with fiber type and fiber length? As an epidemiologist, I will defer to the toxicologists on this issue. D] Please comment pn the. exteqt to which carcinogenic potency, a function of fiber properties (e.g., diameter, aspect ratio, surface properties) other than fiber type and' fiber length. How adequate is information in ttielepidemiology or toxicology literature forsupporting these other properties into doseresponse analyses? Fiber diameter is a more important characteristic with respect to respirability (0.02-2um) than fiber length. In addition, experimental studies clearly show that long, thin fibers have the greatest potency. Few fibers thicker than 0.7 um appear to reach the deep lung. Berman and Cramp make a persuasive ease that maximum diameter is more important than aspect ratio as a criteria for an exposure metric; I dp not thank epidemiology informs this issue. B-151 HWBUI0010086 M Jane Teta, Dr.PH 2) For mesothelioma: A] Influence of fiber type: Please comment on the extent to which the epidemiology literature and mechanistic studies suggest that carcinogenic potency varies from one fiber type to the next (e.g.. chrysolite versus araphibofe fibers). How adequate is the information in the epidemiology literature for supporting dose-response analyses for different fiber types! Specifically, to what extent do you think the proposed risk coefficients in Table 6-29 are supported by the epidemiology iiteratdre? The evidence from epidemiologic and mechanistic studies that carcinogenic potency varies by fiber type with chiysotile being less potent than the amphiboles is even more dramatic for mesothelioma than for Sung cancer. The formal analysis of foe cohort studies included in foe Berman/Crump report illustrates this fact, even after adjustment for fiber size. There arc 12 cohort studies with quantitative data upon which to base these analyses and published studies with average TEM fiber size distributions relevant to all but one ofthem. This is adequate information. (See 1A for comments regarding foe mechanistic evidence.) While uncertainties remain related to some offoe assumptions and adjustments included in this methodology, foe end result is much greater homogeneity among foe studies within each fiber type and a clear distinction in mesothelioma risk between chiysotile and the amphiboles (about 600 times more potent). The percentages ofdeaths from mesothelioma in amphibole-exposed cohorts greatly exceed what is seen among workers primarily exposed to chiysotile. Paraoccupational and bystander mesothelioma excesses examined in formal epidemiology sfodies have been associated with amphibole exposures. In a recent publication. Case et al. identified six mesothelioma cases among women in' foe Quebec chiysotile mining region. AUresided in TThetfoni, where the mines have a higher tremolite concentration arid none in Asbestos. The ubiquitous uses ofcrocidolite in Australia have led to foe highest rates ofmesothelioma in foe world The clear increased rate of lung cancer in foe SC textile cohort contrasts with foe few observed suspect deaths from mesothelioma. The cases ofmesothelioma identified in the Quebec miners and millers study track with foe crocidolite exposure at location 2 and foe higher tremolite content at Thetford In a mostly chiysotile friction products plant, the 11 cases of mesothelioma were attributable to uses of crocidolite at the plant or other employment (e.g., Berry and Newhouse, 1983). The contrast in B-152 HWBUI0010087 M. Jane Teta, Dr.PH lung cancer risk among female gas mask workers follows a similar dear pattern of lower risk among (hose exposed to chrysolite than crocidolite. In addition, the current EPA model, which applies potency derived from cohorts heavily exposed to amphiboles, has beenshown to overpredict mesothelioma in a chrysotile-exposed population (Camus et at, 2002). The CT friction product plant studied by McDonald et al. (1984) with no reported deaths due to mesothelioma based on death certificates is worthy ofcomment, since it has had special treatment in this report There were 3 deaths due to mesothelioma that were employed at this location, identified from the CT Tumor Registry as part ofa case/control study (Teta et aL, 1983; Letters to the editor, TOM 1986 28: 808-809). One man worked at an asbestos textile plant, 1921-32, which was tire parent company to the friction products plant studied by McDonald. His hire date proceeded the start of her cohort, 1938, and involved amphibole exposure. There were two women whose cause ofdeath on their death certificates did riot list mesothelioma. One was classified as probably pleural mesothelioma and the other as a confirmed case of peritoneal mesothelioma during a pathological review. There were issues related to possible domestic exposures and possible involvement of otherjobs, so it is not known whether these cases are attributable to exposure at the friction products plant Peritoneal mesothelioma is virtually unheard ofdue to chrysotile exposure. The Bernian/Crump report included in their analyses suspected mesothelioma cases from the SC textile cohort and cases in other studies for which there was possible involvement ofother employment This seems reaspnable, given the under reporting ofcases in the past on death certificates. In this same spirit, perhaps the two women might be included in the analysis of the McDonald cohort The treatment, in general, ofuncertain mesothelioma cases should be evaluated for consistency in computing Km values. For example, in Hughes, 1987, Kins were derived for chrysotile and amphibole cohorts separately. However, no Kms were calculated for Berry and Newhouse (1983), although the study had 0 cases exposed to chrysotile and 8-11 for crocidolite. Neither study permitted CIs to be computed directly. B-153 o ' ) HWBUI0010088 M Jane Teta. Dr.PH The optimized coefficients for pure fiber types with a ratio of600:1 (amphiboies to chrysotile) in Table 6-29 successfully reduce study potency variability, a remarkable reconciliation from a factor of. 1000 to about 26. Since the coefficients have been adjusted for fiber size, a straightforward quantitative assessment ofconsistency with epidemiology studies may not be feasible. Furthermore, since the most informative epidemiology studies have been used to derive these values, feeycanpot be used as an independent test of consistency. This might have been .. possible, had some studies been excluded from the derivation ofthe coefficients. In this case, predictions based on the coefficients could have been compared to what was observed in the study cohorts. The disadvantage, ofcourse, would be the reduction in the number ofstudies and the associated increased uncertainty in the optimization procedure. Would it be possible, however, to examine the number of observed mesothelioma cases in each study against, predicted, using the optimized coefficients to evaluate foe goodness of fit? BJ Influence of. fiber length: Please comment on the extent to which the epidemiology literature and mechanistic studies suggest that carcinogenic potency varies with fiber length. How adequate is information in the epidemiology literature for supporting dos&response analyses for different fiber lengths? In general, is it appropriate to assess cancer risks using an exposure index (see Equation 7.13) that is weighed heavily by fibers longer than. 10 micrometers (pm)? (Note: Topic area 2 includes more detailed questions on the proposed exposure index.) Epidemiology and mechanistic studies provide convincing evidence that fiber size.and shape (length and.diameter) are important predictors of carcinogenic risk. h/Iechanistically, fiber dimension is related to respirabiiity, deposition, degradation, clearance and translocation and, therefore, is a major determinant of cumulative dose to the lung. Attempts to relate potency to asbestos air concentrations or worse, measures of dust containing asbestos, results in extreme variability in potencies, both among different fiber types and within the same fiber type. As wife lung cancer,.itis evident from Table 6-15 that the unadjusted mesothelioma potencies for fee 12 cohort studies correlate with fiber size, with the exception^ Wittenoom, which ranks #2 in potency but #10 in total fibers > lOum. The most dramatic changes after adjustment are in the insulating manufacturing and insulator cohorts, whose potencies dramatically increased, due to the highest proportion of long fibers. The smallest change occurred for Wittenoom, consistent B-154 HWBUI0010089 M. Jane Teta, Dr.PH with a distribution favoring short fibers (crocidolite). (Note: the KL values for Wittenoom and SC in Table 6-16 don't seem to agree to the values in Tables 6-1 and 6-2.) The Berman/Crump approach to adjusting the mesothelioma potencies for fiber size (length and width) is very effective in reconciling the variability in die unadjusted estimates. This body of epidemiological data is adequate for supporting these dose-response analyses. The approach of using relevant TEM size distributions from the published literature to implement die size adjustment is both rational and innovative. The uncertainty values assigned, however, need to be more clearly explained aridjustified. The range ofuncertainty values should be described for each consideration and the criteria used clarified. The authors might consider a section describing each decision in the process that was made to account foruncertainty, in both the use ofTEM values from other studies and the F1-F4 factors related to exposure and othbr uncertainties. C] To what extent do animal studies (e.g., studies by Davis and other researchers) suggest that carcinogenic potency varies withfiber type andfiber length*? As an epidemiologist, I will defer to the toxicologists on this issue. D] Please comment on the extent to which carcinogenic potency is a function of fiber properties (e.g., diameter, aspect ratio, surface properties) other than fiber type and fiber length. How adequate is information in the epidemiology or toxicology literature forsupporting these other properties into doseresponse analyses? I have nothing to add beyond my.briefcomment in 1 D. 3) To what extent are the exposure estimates documented in the asbestos epidemiology literature reliable? Obviously, some studies have more complete and more accurate exposure estimates and the amount oferror and imprecision is a function oftime, with estimates ofhistorical exposures being the most difficult to reconstruct In the past they are more likely, however, to be worst case, with representative sampling becoming routine around the mid to late 1970s, ifthe chemical industry pattern in the U.S. holds. The authors used uncertainty factors (FI-F3) to account for uncertainties in exposure estimates for each of the studies: FI for uncertain recreation B-155 HWBUI0010090 M. Jane Teta, Dr.PH ofpast exposures, F2 for conversion and F3 for use of a crude estimate ofaverage exposure. F4 was used for other types ofuncertainties. While these issues capture the key exposure factors, the choice of F values ("at least 1.5 and is at least 2 or more in most cases") is inadequately explained and appears arbitrary. Furthermore, the formula for the overall uncertainty factor (A.6), the square root of the exponent of the sum of the logs squared ofthe factors, needs morejustification than the reasonable one that it accounts for errors in different directions. In addition, the factors are only applied to foe confidence intervals (Cl), as ifthe only influence on the coefficients would be related to random variability or precisioa It is unclear how foe Os impact the final coefficients in Tables 6-29 and 6-30. I would disagree with the use ofF3 as an uncertainty: factor and argue.that use ofan overall cohort average exposure is too uncertain and studies with this severe a limitation should not be used for exposure-response. It appears this occurs for only one study, SelikofFand Seidmari, 1991. The limitation of(his study is even greater because the average exposure concentration did not even come directly from foe study itself (A case study by Nicholson, 1976, is cited in the 1986 EPA Health Assessment^ Furthermore, there were no data on duration Ofexposure, requiring another outside average to be used. This was a very important study with respect to identification ofasbestos hazards, but the available information is not adequate for use in exposure-response analyses. Another study I would reconsider including in the exposure- response is Lacquet et al., 1980. The follow up is much to short and the exposure information inadequate. ... Topic Area 2: The proposed exposure index. 4) The proposed exposure index does not include contributions from fibers shorter than 5 pm. Please comment on whether the epidemiology and toxicology literature support the conclusion that .asbestos fibers shorter than 5 pm present little or no carcinogenic risk. There is adequate evidence that fibers shorter than 5um present little or no risk. Experimental data confirm that clearance offibers is dependent on fiber length and that short fibers do not produce fibrosis. Mechanistic and other experimental studies show fibers < 5 um clear readily B-156 HWBUI0010091 ) M. Jane Teta. Dr.PH and the small proportion that do not clear are sequestered in alveolar macrophages. Fibers shorter than 10-20 um are almost completely handled by macrophages. The strongest evidence comes from Berman's re-analysis of the toxicological studies of Davis et al. using TEM based fiber length distribution data. None of the epidemiology studies have TEM data and there is no way to identify workers in the studies thdt are exposed only to fibers < 5 um. Therefore, epidemiology cannot specifically address this issue. There is corroborative epidemiology, however, in studies ofvehicle and brake mechanics, who have potential exposure to short fiber asbestos (chrysotUe) and have not been found to be at increased risk ofmesothelioma in numerous studies examining this issue. 5) The proposed exposure index is weighed heavily by fibers longer than 10 pm. Specifically, Equation 7.13 suggests that the carcinogenic potency of fibers longer than 10 pm is more than 300 times greater than that , of fibers with lengths between 5 and 10 pm. How consistent is this difference in carcinogenic potency with the epidemiology and toxicology literature? This difference is based on the re-analysis ofthe Davis et al. studies, using TEM based fiber distributions. Other experimental evidence is comstorafive indicatmg that fiber lengths shorter than 10 to 20 um are readily handled by macrophages. In addition, the optimum exposure index indicates little impact ofexposures as high as 40 um in length. As indicated in #4 above, epidemiology cannot offer specific guidance on this issue. 6) Please explain whether the proposed exposure index will allow meaningful comparisons between current environmental exposures to asbestos and historical exposures to asbestos that occurred in the work place. Current environmental exposures to asbestos can be fully characterized by fiber type and size using TEM. Berman and Crump have characterized the exposures of workers in the cohort studies used for expdsure-response by these same characteristics. Factors have been introduced, however, to address uncertainty in the exposure data from the studies and in the derivation of fiber size distributions from these studies for purposes of potency calculations and their CIs. Therefore, if I understand the question correctly, direct comparisons of exposure would not be a meaningful B-157 HWBUI0010092 M. Jane Teta, Dr.PH exercise. However, use of the models with the new potency estimates can be effectively employed to estimate lifetime risk associated with the particular environmental circumstance. ... Topic Area 3: General questions. 1) The proposed risk assessment approach, assigns carcinogenic potency to individual fibers and to cleavage fragments (or Abiindles that are components of more complex structures). Please comment on whether cleavage fragments of asbestos are as toxicologically significant as .fibers of the same size range. This issue is beyond my area of expertise. 2) Please comment on whether the proposed cancer assessment approach is relevant to at! amphibole fibers or only to the five types of amphibole fibers (actinofife. amosite, anthophyllite, crocidotite, tremolite) designated in federal regulations. I am not familiar with any other amphibole fibers and doubt that there is any epidemiology to inform the issue. ... 3) The review document recommends that asbestos samples be analyzed by transmission electron microscopy (TEM) and count only those fibers (or bundles) longer than 5 pm. Such counting practices wilt provide no information on the amount of asbestos fibers.shorter than 5 pm. To what extent would, data on shorter fibers in samples be useful for future evaluations (e.g.. validation of the cancer risk assessment methodology, assessment of non-cancer endpoints)? , Since fibers shorter than 5 urn do not contribute to fibrosis, there would be no value in collecting these data for non-cancer endpoints. To validate the risk assessment methodology, more research : would be needed. The only circumstance I could think of that would be of interest is where there is an exposure scenario (e.g,, work environment, environmental source) where exposures are : limited to < 5 um and there is an ability to identify increased risk, ifit existed for lung cancer and mesothelioma. It would be extremely difficult, however, to design a valid study with reasonable precision. Power issues and confounding exposures would likely be insurmountable. 4) The proposed risk assessment methodology suggests that exposure estimates should be based only on fibers longer than 5 pm and thinner than 0.5 pm. Is this cut-off for fiber diameter appropriated With the exception ofmouth breathing, few fibers > 0.7 um in diameter reach the deep lung. And not all those that do will adhere to the lung surface. Experimental data also indicate that it is the fibers thinner than 0.7 um and longer than a minimum of 10 um that likely contribute to disease. Timbrell (1982) reported complete clearance of short (< 4 um) fibers with diameter less B-158 HWBUI0010093 M. Jane Teta. Dr.PH than 0.6um. (Berman and Crump make another argument supporting' 05 um as the cut-offrelated to diffusional diameter. This discussion is outside the scope ofmy expertise.) Reliance on the re analyses ofthe Davis et al. toxicology studies using TEM based exposure results in an adequate fit of the data with a cut-offof03 um diameter for structures between I and 40 um in length. Adequate fit was also seen with a 0.4 um cut-off. In light ofthis evidence 0.5 um seems appropriate. 5) Discuss whether the proposed cancer assessment approach, as a whole, is a reasonable evaluation of the available health effects data. What aspects of the proposed cancer assessment approach, if any, are inconsistent with the epidemiotogyof toxjcbtacjy literature for asbestos? This is a very impressive piece ofwork that considers all the evidence and integrates it effectively. The methodological approach is supported by a solid foundation ofscientific evidence and data. Uncertainties in the human data are considered and factored into the method. The experimental data is careftHy scrutinized and reasonably evaluated in a balanced fashion The variability in the results'ofthe epidemiology studies are well described, but no standards are provided tojudge the acceptability of the studies for risk assessment. ' : I found the epidemiology data to be accepted at face value as evidenced by the placement of study summaries in foe Appendix. The information from these studies is fundamental to the methodology. Justification for foe uncertainty factors needs to be clearer (see response to question #3), What criteria were used for acceptability of foe studies for inclusion (see prior discussion of Selikoff and Seidmanand Lacquet et al.)? I support , the . use of human data and the methodology proposed but question whether study quality and foe suitability ofeach study for. exposure-response was measured against any standard. 1 am not convinced that introducing the uncertainty factor, F4, for example, solves all the limitations unrelated to exposure, such as k sizeable proportion of subjects lost to follow up. Would it be more appropriate to exclude the study? I see no substantive inconsistencies with the existing epidemiology and toxicology literature. The extreme variability in estimates of risk from the epidemiology studies has troubled scientists for B-159 HWBUI0010094 M. lane Teta, Dr.PH some time. It is well accepted in the scientific community that asbestos fiber, size and type are key determinants of risk. More specifically, ft is well recognized that the long, thin fibrils are "the most potent and that amphiboles have greater potency than chrysotile. This scientific understanding and a practical approach to applying it has been captured in the Berman/Crump proposed methodology. The result is a vast improvement in reconciling die differences in the. epidemiology studies. I-.. . : i ' This is an innovative piece of work that vastly improves the risk assessment methodology for asbestos and makes excellent use ofall the currently available scientific information. 6) Section 8.2 of the review document presents three options to? assessing cafncer risks from asbestos exposure. Please comment on the technical merit of the proposed risk assessment options. ` ` . -1 i" " V I support options #1 and #2 as appropriate approaches to assessing cancer risks for asbestos ., exposure. They are both, technically correct with option #1 being moire flexibfe (e.gi, can Mndie time-varying exposure), being the more general case; but option #2 being easier to implement ... (only need estimates of long-term exposure). Choosing between these options depends on the circumstances of the population of interest To make a judgment about lifetime risk to an urban: U.S. population with a relatively constant exposure, option #2 would be die easiest to use arid .. would provide the same result, had option #1 been employed. If^demolition project is under consideration in which exposure concentrations might vary by task: arid workers would have various fixed durations ofemployment, then option #2 would not be suitable, but the more general case, option #1 would be. I would not recommend option #3, some sort of combineditnit risk, because it defeats file purpose of taking into account how potencies vary by fiber size and type and introduces an additional weighting procedure. While single unit risk estimates have the advantage of simplicity, the. disadvantages in this case outweigh the advantage, particularly with the ease ofuse of the risk table; Topic Area 4: Development of Conclusions and Recommendations At the end of the workshop, the peer consultants will be asked to draft conclusion statements identifying their most notable findings on the proposed methodology. As a prelude to developing B-160 HWBUI0010095 ML Jane Teta. Dr.PH these statements, the peer consultants are invited to provide any additional comments or concerns, both strengths and weaknesses, on topics not specifically addressed-in the previous charge questions. After completing the discussions the peer consultants will prepare their conclusions, and they will also be asked to develop recommendations for how EPA can improve the methodology. Please note that, although recommendations for future research projects are welcomed, the focus of this workshop is on foe proposed risk assessment methodology and how it may be used to support decisions at asbestos-contaminated sites. Additional comments: It is noted in 6.65 that background cases of mesothelioma are rare in the general population. Is 2 per million, the estimate for foe U:S. smalt enough to not impactthie model? Why are 90% Cl preferred in this document? . Discussion of two-sfoge model may be better placed in the .Appendix, since it didn't turn out to be useful . Very long section on factors governing cellular and tissue response (i.e., mechanism of carcinogenicity) should be substantially shortened (with more detail - in Appendix), since it resulted mostly in hypotheses that were not integral to methodology. Clarify how CIs are incorporated info final coefficients, if in feet they are. If not, how do the uncertaintyfetors make a difference? .. - >: Would incorporation of a maximum latency period into the EPA model improve its performance? There is little discussion of peritoneal mesothelioma - would potency estimates be any different for this endpoint? .: P. 5.6 notes one needs incidence of meso. by "age at first exposure" to implement EPA model Is this correct or should it.be "time since first exposure?? i P. 6.65, description of equation 6-12. "assuming that exposure remains constant" may be incorrect. P. 8.7 notes consistency with Stayner yet he concludes that with respect to lung cancer, epidemiology doesn't support lower potency for chrysotile? . Is there any mechanistic data to understand why chrysotile is closer in potency to amphiboles for king cancer but so much less potent than amphiboles for mesothelioma? .... References ' Berman DW and Crump K. 2001. Technical Support Document for a Protocol to Assess AsbestosRfelated Risk Final Draft. Prepared for U.S: Department of Transportation and U.S: Environmental Protection Agency. September 4,2001. EPA 1986. Airborne Asbestos Health Assessment Update. U S'. Environmental Protection Agency. EPA 600/8-84-003F. 1986. B-16I J HWBUI0010096 Appendix C List of Registered Observers of the Peer Consultation Workshop $*.: -c.-v.-...-/ .vo~r!: fs HWBUI0010097 jg% M United States 3 Environmental Protection Agency ^fci r 11 f Office of Solid Waste and Emergency Response Workshop to Discuss a Proposed Protocol to Assess Asbestos-Related Risk Westin St. Francis San Francisco, CA February 25-27,2003 Final Observer List ; ' s" . ''i-if'-/ Chris Anaya 2056 Portsmouth Drive El Dorado Hills. CA 95762 916-939-7000 Fax: 916-933-1019 Email: anaya@prodigy.net - Elizabeth Anderson Sciences International. Inc. 1800 Diagonal Road Alexandria, VA 22314 703-684-0123 Fax: 703-684-2223 Email: elanderson@sciences.com Jenny Sard Redwood Empire Brandi American Lung Association of California 115 Talbot Avenue Santa Rosa, CA 95404 707-527-5664 Fax: 707-542-6111 Email: jbard@aiac.org D. Wayne Berman President Aeolus, Inc. 751 Taft Street Albany, CA 94706 510-524-7855 Fax: 510-524-7854 Email: bermanw@aol.com : ; V .. Bruce Bishop Attorney Wilcox & Savage 1800 Bank of America Center Norfolk. VA 23510 Email: bbIshop@wilsav.com . Charles Blake Vice President, Director Technical Services Atlanta Region OHS Clayton Group Services, Inc. 3380 Chastain Meadows Parkway - Suite 300 Kennesaw, GA 30144 7704907500 Fax: 770499-7511 Email: cblake@claytongrp.com David Bowen Attorney Wilcox & Savage 1800 Bank of America Center Norfolk, VA 23510 757-628-5507 Fax: 757-628-5566 Email: dbowen@wilsav.com John Budroe Staff Toxicologist Air Toxicology & Epidemiology Section Office of Environmental Health Hazard Assessment California Environmental Protection Agency 1515 Clay Street - 16th Floor Oakland, CA 94612 510-622-3145 Fax: 510-622-3210 Email: jbudroe@oehha.ca.gov 3 *ERG C-l HWBUI0010098 Leonard Burrelli Environmental Profiles, lnp.__ 813Fredricfc'Road.'''': ' . ! . - . Baltimore, MB.'2'ji228 'V,.:"'.' : 410-744-0706' ' ' "r' ; Fax:410-744-2003 Email: burrelli@episetvices.com. .. ... , . :,, Doug Cameron ' Reed Smith 435 Sixth Avenue Pittsburgh. PA 15219 412-2004104 Fax:412-288-3063 Email: dcameron@reedsmith.cdri -ri.5. - - Alex Catalona Attorney 5 :: Morgenstein& Jubeliner,LLP One Market Spear Tower - 32nd Floor San Francisco, CA 94105 415-901-8700 Fax: 415-901-8701 .,, . _,. " " ' r f"` * t .1. ; '** : .'V 'C-s' ! .. , . */' iJ' r . "-i'' :, f Eric Chatfieid' President Chatfieid Technical Consulting Ltd.. 2071 Dickson Road : : " Mississauga.ON L5B. 1Y8 Canada .` 905-896-7611 ' . V' Fax: 905-896-1930 Email: echatfield@ejchatfield.com V-1-* r ` ' w' Deborah Cote [fS* .:.t t " McKenna Long & Aldridge, LLP One Market rv. -K-i Spear Tower - Suite 3500 .... . , . . I'';' 4aa1c5-<2i6fi7744143080 -v., -it . Fax: 415~28?-4198 J Email: cfcote@mckennalong.cpni *!*- . ':vA- ' Kenny Crump Principal ENVIRON 602 East Georgia Avenue Ruston, LA 71270 318-251-6985 Fax:316-255-2040 Email: kcnimp@environcorp.com Stan Dawson Staff Toxicologist `e ' - / Air Toxicology and Epidemiology ; ' Office of Environmental Health' Hazard1Assessment 1001 I Street v!'''' `> ' P.O.Box 4010 Sacramento, CA 95812 ! '- ;\- 916-323-2522 ' Fax: 916-327-7320 Email: sdawson@oehha.ca.gov =' V -J -if: .':A Sandra Dittmar 'v'V. Professional Toxioolagist .. : .. MWH 777 Campus Commons - Suite 175 - " c .. Sacramento. CA 95825 1i m* 916-569-3249 - '.* Fax: 916-569-3258 Email: saixfc^diltfnaii@us.tnw^^ Morton Clubirt. . "''~w. Orrick, Hemfigton S'Sutclij^J.ttP ; v } l~ys"' ` 666 Fifth Avenue . ..sivi New York. NY 10103 Email: tiau@wilsav.com. Mi- f ; ;V;:f rS*-..--ce6' Jacques Dunnigan 380 chemin de North-Hatley Katevale. QC JOB 1W0 Canada 819-847-3177 Fax: 819-847-1931 '' Email; dunnigan@abacom.com ir- v ' ' ' '--I'*' :: - ^ - 1 Gwen Eng Regional Representative 5- : Agency for Toxic Substahees'4nd Disease-Registry (ATSDR) ? ! -' 75 Hawthorne Street (HHS r1)r ' ' :: ; ; San Francisco, CA 94105 415-947-4317 Email: eng.gwen@epa.gov rrv .:>T> : ' v' V-c-:" .. i..'jV*s\ V. ' Richard Flnke c*'-'! .k>. Senior Litigation Counsel ` ' 'v ' WR Grace & Co. 5400 Broken Sound Boulevard NW^S'uite 300 ; Boca Ratdn, FL'33487'';: 561-362-1533 Fax: 561-362-1582 Email: richard.finke@grace.com C-2 HWBUI0010099 Sean Fitzgerald Branch Manager RJ Lee Group, Inc,... v..... SSttM^oo^adk^Slreet-.i-. San Leandro, CA 94577 510-544-8411 Fax; 510-567-0488 Email: sfitzgerald@rjlg.com StefanieFogel .-... Attorney Piper Rudnicfc, LLT - sv. 3400 Two Logan Square !4r<-s,:; ,.-.c, Philadelphia, PA 19103 215-650-3364 . >. ... , .. .. - Fax:215-606-3364 ` ' ..v.-.- :<..* Email: stefanie.fogel@pipemidhick.corij.:-; a .. Steve Foley - - ->cZ -0 X' Attorney Foley & Mansfield /?;*&: vVsrot-;*- . 1333 North California, Boulevard- Suite,9P;. , , Walnut Creek, CA 94596 : 925-930-2866 et-.'.ii V'<L . Fax; 925-930-7335 Email: foleys@foleymansfisld.oom - 1 x -v Jack Foley Attorney Foley & Mansfietd 1108 Nicollet Mall Minneapolis, MN 55403 Fl .h ... Camille Fong McKenna, Long & Aldridge . .. . One Market, Spear Street Tower - 35t|.Rpoc. San Francis,co, CA 4,1.05,. ,, .4 ' . Fax: 415-2674198 .......................... (y<.\v. Email: cfong@mckennalgng,o^njj..: r.;,,-.;.).,.-,. Clifford Franklin 3: Field Investigator . ;.: Liberty Mutual P.O. Box 667 Grove City, PA 16127 ::h':. ,Vi. .....--; 800-344-0213 . Fax: 003-33^8088;..... r,vty>B GW. Email: difford.frankiin@libertyrnyitealrcjqinri r Mary Goldade Chemist Ecosystems Protection & Remediation U.S. Environmental Protection Agency 999 18th Street - Suite 300 (8EPR-PS). Denver, CO 80202 303-312-7024 Fax: 303-312-6065 t' ' Email: goIdade.mary@epa.gov Jessica Greene Senior Scientist Exponent 1970 Broadway - Suite 250 Oakland, CA 94612. 510-208-2000 Fax: 510-208-2039 Email: jgreene@exponenlcom ,, Kimberly Heuer Attorney ` -r . Morgan Lewis & Bockius, LLP V 1701 Market Street Philadelphia, PA 19103 215-9634756 Email: kheuei@morganlewis.com. Gerald Hiatt " -v Senior Regional Tdxiediciglst'''^ ; Superftind .... ..., '.".V r ' U.S. Environmental Proledion'Agehcy 75 Hawthorne Street (SFD-8B) . ,'' .V : San Francisco, CA 94105 ' ' '' 415-972-3064 , Fax:415-947-3518" ' . '^r/r :' Email: hiatt.gerald@epa.gov Lee Hofmann " Senior Science Advisor .. .. , . . . . . . . Office of Solid Waste and'Elnj^fency Response Office of Program Management.... : . . ~, U.S. Environmental Protection Agency V. Ariel Rios Building,{51Q3T) . . ^' ` .". : ;'t;. 1200 Pennsylvania Avr4n8^'NW'',`i"' ` 1 Washington, DC 20460 202-566-1928 Fax: 202-566-1934 ...;;1; Email: hofmann.lee@epa.gov We* -X ' ` Vi5 , ' -I ->96 :.V C-3 ) HWBUI0010100 Jennifer Jinot " - Quantitative Risk Methods Group Office of Research and Devefojrtnent " ' U.S. Environmental Protection Agency. 1200 Pennsylvania Avenue. NW (8622PD) Washington, DC 20460 202-564-3281 Fax:202-565-0079 ' Email: Jinot.jennifer@epa.gov '; ' Shea Jones Remedial Project Manager ... . Superfund Division ;: U.S. Environmental ProtectibnAgehcy 75 Hawthorne Street (SFD-7-2) San'Francisco, CA 94105 415-972-3148 1 - ?; Fax: 415-947-3526 Email: jones.8hea@epa.gov : ` WilliawWSiniry ; - - "A- Attorney " !' ' * Piper Rudnick, LLT................. ' 3400 Two Logan Square ;' = '-_ y ! : Philadelphia, PA 19103 '' 215-656-3340 ! Fax: 215-606-3340 -: Email: wrtlliam.kiniiy@pipernjdnrck.com ^parna Koppikar1 >Wfedical'CMSrJ'--':; Quantitative Risk MethodsGroup ^ National Center for EhtrtmqofenBj'XsseSsnfient U.S. Environmental Proter&wAgency; 1200 Pennsylvania Avenue, NW. (8623 D) Washington, DC 20004'' 202-561-3242 Fax:202-565-0076 Email: koppikar.apma@epa.gov =. = ; ; Eileen Kuempel ~ Senior Health Resarch Scientist : Risk Evaluation _ National Institute for Ctedlipsitiohail Safety and Health 4676 Columbia Parkway (C-15) Cincinnati, OH 45226 513-533-8363 /. Fax:513-533-8224 - -o ; . ,i Email: ekuempel@cdc.gov Chris Laszcz-Davis : - . The Environmental Quality Organfeabon. LLC 3685 ML Diablo Boulevard - Suite 210 1 ' ' Lafayette. CA 94549 925-330-1774 ' ` Fax:925-599-1185 ^' ' Email: chrisld@eq-organizaytm.cbm Richard Lee '-^r' - RJ Lee Group, Inc. ` . -r - 350 Hochberg Road Monroeville, PA 15146 >: 724-325-1776 Fax:724-733-1799 '. . Email: ppolka@ijlg.com *'*'- -.x; Libby Levy :> v: Regional Representative. . . . ! 5 Agency for Toxic Sufcstarices'&rid DisebsevFt^iiiry (ATSDR) 75 Hawthorne Street, (HHS 1} - .-'it aojiiiJ San Francisco, CA 94105 -A % `:>0c 415-947-4319 Fax:415-947-4323 Email: ievy.libby@epa.gov _ :x;, > '%, ::> JjSi.'V James Luey Chief,..Superfund Technical Assistiri^'Uri^55' ProgiiSm'Sti'ppdd* : :*.V Office of Ecbsystems' Protectkrri& Rejnfediiatton; v` U.S. Emironm^talPr<Me'ctidn'Agehcf:' 999 18th Street- Suite 300 (SEPRApS)/; ' Denver, CO 80202 ` : 303-312-6791 - xz'-. Fax: 303-312-6897 vo:- s.-?,V : P ' is Email: luey.jim@epa.gov *--j :&?<*:-o :;A Michael Lumpkin Toxicologist .;-Aj>5.v:?.ev' Clayton Group Services, Inc. ' >' 3380 Chasiane Meadows Partway - Suite^OOww Kennesaw, GA 30144 I -v3'= 770499-7500 Fax:770-499-7511 ?>:y *% **!#<&$*. Email: mlumpkin@ciaytongrp.com HWBUI0010101 Patricia Maravilla RegionalAsbestos Coordinator Toxics Office Cross-Media Division U.S. Environmental Protection Agency 75 Hawthorne Street (CMD-4) San Franciscc!, |GA 94)1P5 415-947-4177 Fax; 415-947-3583 Email: maravitla.pat@epa.gov . , ./ Laura McIntosh Scientist Exponent, tnc. 149 Commonwealth Drive Menlo Park, CA 64025 850-688-6734 . Fax:650-688-1799 . ..... . .E(^jb.z^dptosh@^xpprien|i.a)m. . (Lance McMahan 9450 Oak Avenue ; Orangevate, CA 95662 916-989-0559 Fax: 916-989-0559 Email; jancem@directcon.riet . . -. . ABbraKMgier; ;, Senior Medicai Officer & Regional .Towcoic^ist U.SrEnyironmentai;Piptction Agepcy 99918th StfeetrrSuite;09.(EPg-rP5j Denver, CQ,602^; i.-:: ; 303-312-7023 Fax:303-312-6065 > , Emaii: milier.aubrey@epa.gov - Eric Moeller President Vermicufite Association P.O.Box687 ,oj ' .*,!-. tnvane^riCA .94937'-.;; . . .. - - 415-669-1489 Fax; 415669-1489 Email: emoeiIer@horizoncabie.com ifr.y.-.ir'-yi - -r : ' , -V." Lawrence Motion 5191 Abbeywood Drive Castro Valiey, CA 94552 510-538-7113 Fax: 510-538-3699 Email: lmolton@aol.com .... Suresh Moolgavkar Professor Fred Hutchinson Cancer Research Center 9005 NorthEast 21st Place c , : Bellevue, WA . 206-667-4273 . Fax:425-637-1978 Email: moolgavkar@earthlink.net Fiona Mowat Sdentist Exponent, Inc. .. ... . 149 Commonwealth Drive ..... Menlo Park,CA 94025,, 650-688-1782 ` VV. .'V. , Fax: 650-688-1799 ' i;T-- . , Email: fmowat@exponent.com ' : .r . .. , ... .... . ... ,f ' ] ; Deirdre Murphy w. * Risk & Exposure Assessment Office of Air Quality Planning and Standards,. t U.S. Environmental Protection Agency .... (C404-01) ; Research Triangle Park, NC.Z7JI1. .,., ,y_ 919-541-0729 ' `-'.vb* Fax: 919-541-0840 . , ; .. Email:murphy.deirdre@epa.gov , ... r. ........ ' O->' "***. `' -J iiiii.--' : William Nelson Senior Regional Representative ... . ., Agency for Toxic Substances and Disease: Registry (atsdr) 75 Hawthc^.sbfpt.oHH^i.): ...; San Framdsco^X^i 9*I0,'. . . .. 415-947-43lfe-v . Email: nelson.biil@epa.gbv ,. :.... O' LlsaOberg /.. McKenna, Long &.^!dridgp , , ... .;,}n .... One Market, Spear Street Tower - 35th Floor San Francisco, CA 94105 415-267-4175 ... '"X-I .''7 " Fax: 415-267-4198 " ' rJ:., ... .X;. . Email: lobergpmckenpalpng.c^m^j:,;..:...;: i Howard Ory :r- V.- ; Adjunct Professor of Epidemiology ; Emory School of Public Health ; v my-- 882 Barton Woods Road Atlanta. GA 30307 989-636-1934 Email: hwo@bellsouth.net <-:. .. HWBUI0010102 Dennis Paustenbach . Corporate Vice President,r!- t!i' - Exponent, Inc. _ - .= 149Commonweatttt'Dnve : Merto Park, CA 94025 650-588-1756 Fax: 650-688-1799 Email: dpaustenbadi^e><pb'nen(,corfi Karen Prena Attorney 190 South LaSalle Street Chicago, IL 60610 312-701-7008 jV!.. v- -: David Rizzolo Asbestos Program Manager11 ... San Francisco Department of Public 1390 Market Street - Suite 910 grefp*-' -v San Francisco, 415-252-3951 CA941;0;.v2 l= Fax: 415-252-3959 Email: davrid.rizzolo@sfdph.org David Shaw ..... .. t ' L '-lift <!:. Williams, Kastner &'Gibbs.' Two Union Square 601 Union Street - Suite 4100 Seattle, WA 98111 206-628-6621 Fax:2063285611 i; Email: dshaw@wkg.com 'iatiQ.'r&s:'' y, i-V .. ' : - . j '!. v TXiOi' .1 \) Catherine Sinwridnsi'r ' Senior Industrial Hygenfet Bolter & Yates 1300 Higgins Road - Suite 301 " t > .: r J.. V. Park Ridge, IL 60068 847-685-9226 ' Fax: 847-692-3127 ....,.. ... .., .... Email: csimmons@bo!ter-yates.cbiri"" - *<.*. v! ^nVr.c'O":. >:-r- Froere and Org''a' nbi.cs Brgnfh-.;,,, , -, v \ . A:. NaSonal Pfogram CIrenilcials'Divrisipn. U.S. Environmental Protection /$$&#/**' ;,'0^.. 1200 Pennsylvania Avenue, Washington, DC 20460 2025665512 , ' " ,*r' ' . Fax: 202-566-0473 Email: smith.john@epa.gov Terry Smith v*.: Program Manager i.pc.o: ... Analytical Operation Center Office of Eiriefgericy 'a^' Rert^ial Response U.S. Environmental Protedticiri Agency' 1200 PenrfeufvarSa^Ayeriue^NW (5204 G) '`~; r- f Washington, DC 20460 ' - .> 703-603-8849 "V -W- - Fax: 703-603-9112 ' - i: ^ : Email: smith.teny@epa.gov _ , John Spencer Environmental Profiles. Inc. ' > 813 Fredrick Road - '* Baltimore. MD21228 410-744-0700 '5 - Fane 410-744-2003 ! ' >* Email: jspencer@episervices.com -w : '.-"`fc Robert Thackston'. ...v.ivni Partner'--i;vr-'? =V . . V-. Hawkins, Pa'melLSThrickstoh.'liLP ..0 4514 Cote Avenue -%uite'550'v> ' Q&; Dallas.TX75205 r i .. -xr!>: ?. 214-7805100 2-Vi>U,Za--- .T Fax:214-780-5200 Email: rthackston@hplegal.com v..:;T Dan Thornton s!--afx.-vr Environmental Sdenfisl ' ' ' : r v ' Accelerated Respdrise'Genter :: <i <' Office of Emergency and Rerriediai'Rbspons# ; U.S. Environmental Prot4@&6fr 1200 Pennslyvania Avenue, NW (5204G)'1-V': ; * Washington, DC 20460 703-603-8811 Fax: 703-603-9100 Email: lhomton.dan@epa.gov . jU sT r -4 . . .-.vt' ?.'.: =' Lang Tran : V: Toxicology Research -1 i^orrrv^K Institute of Occupatfonal'.-Mefllcihe 8 Roxburg.Place Edinburgh, EH8 9SV '; ? United Kingdom ^ bv-j -d 0131 667 5131 Email: lang.tran@iomhg.org.uk HWBUI0010103 0 AnnaTreinies Toxicologist . ...ft. Science Team ... Office of Solid,Waste apd Emergency. Response. U.S. Environmental Protection Agency, 12SX5 Perwsylyania.Avenue, NW.CS103T). Washington. DC 20460 v, 202-566-1039 Fax: 202-566-1034 ; Email: troinies.anna@epa.gov . ,. >. : Terry Trent 6185 Barbara Lane Auburn, CA 95602 916-745-2073 Fax:916-745-1050 Email: ttrenti@juno.com r.. ................. * , .; : Richard Troast Senior Environmental Scientist . . Office erf Emergency and Remedial Response. . U.S. Environmental Protection Agej)cy/ .. ,.H 1200 Pennsylvania Avenue, NW (5204G) ; Washington, DC 20460 . :^r 703-603-8805 Email: troasLrichard@epa.gov . y Pam Tsai Toxicologist ' Office of Radiation and Compliance Assurance U.S. Environmental Protection Agpncy 75 Ha.wtt}tpj0!Sjrest.(^jr-6).;, San Francispo;43A 94165..,. 415-947-419NBU .f ; .... . j : Fax: 415-947-3583 Emaii: tsai.pam@epa.gov y Ron Tsuchiya . : > Toxics Program Officer Cross Media U.S. Environmental Protection Agency 75 Hawthorne Street (CMD-4) San Francisco, CA941Q5. 415-947-4168 Fax: 415-947-3583 .. Emaifctsuchiya.ron@epa.gov ;; . Jay Turim Executive Vice President,... . Sciences International, Inc. 1800 Diagonal Road - Suite 500 Alexandria. VA 22314 .0 703-684-0123 Fax: 703-684-2223 Email: jturim@scierices;cpm .. ,. Drew Van Orden Senior Scientist RJ Lee Group, Inc. 350 Hochberg Road Monroeville, PA 15146 i . i' " i~. ... - '"i: -_iv ry i; - 724-325-1776 Fax: 724-733-1799 Emaii: drew@rjlg.com. 'j-- C->! :-. Francis Weir 0 . 0 s r;. President <:> Frands W. Weir, Ph.D., Inc. 14334 Schroeder Road Houston,TX77070.,... . ' 832-237-7502 Fax: 832-237-7504 Email: toxte1@houst*m.rr,qqm ,v Chris Weis Toxicologist National Enforcement lnvesti_ Office of Criminal Enforcement, and Training y... k:; - - ./a5..v;: U.S. Environmental Protection Building 53 - Denver Federal Ce P.O.Box25227 n' Denver, CO80225 *' ;' `. " 303-236-6393 . Fax: 303-236-5199 '^^' v Email: weis.diris@epa.gov lohn Wheeler. .v3?> Senior Toxicologist' Exposure Investigation and Consultation Brpndy -lealth Assessment and Consultation'< '0 ' . Agency for Toxic Substances and Disease* Rfedistr 1600 Clifton Ropd, NE`(MS<E-29r:-'` 0*' AuttlAannttae, dGAA aBferfr- 404-496-0504.:.. ' J A-Jp-smn. ,v:: '; :; Fax: 404496^420'v jzwt@cdc.gov : i ""-' }. V-:- ) C-7 HWBUI0010104 &EPA United States Environmental Protection Agency. Office of Solid Waste and Emergency Response Workshop to Discuss a Proposed. Protocolto'Assess Asbestos-Related Risk .... Westin St. Francis San Francisco, CA February 25-27, 2003 Agenda.. _ . .. ; . ., . ' Workshop Co-Chairs: Roger McClellan, Toxicology & Human Health Risk Analysis Leslie Stayner, Natima! InstjMe'fw &cdariation 'ai Safety arid Health Facilitator: Jan Connery, Eastern Research Group,..inc. TUESDAY, FEBRUARY 25, 2 0 03 8:00AM : >Registration/Check-ln V-y 8:30AM 8:35AM 8:45AM 9:00AM Welcome and Announcements..................... . Opening Remarks .......................................... ........ Richard Troast , U.S. Environmental Protection Agency (U.S. ERA) . Offic&of Solid-Waste and Emergency Response (OSWER) Office of Emergency and Remedial Response (OERR) *- 'I-5** :V. *.`l ,v . ' >'. .. Peer Consultant Introductions and ConfSict-of-interesiDiselosure .,. .,.. . * . ----- -.. ... . Facilitated by Jan Connery r*nak Pfirnncpi anH OrAiind RulAft 9:10AM Background on the Proposed Protocol to Assess Asbesios-Reidted Risk*.. k ..... . >: 10:10AM B REAK ;. i. , . Aeolus, Inc. and Kepny Crump, ENVIRON ' 10:30AM Charge to the Peer Consultants flpj. Hva'iV.ecVaM.'jr'/** ^ERG HWBUI0010105 TUESDAY, FEBRUARY 2 5, 2 0 0 3 (conti n u e d ) *.r &-. 10:40AM Topic Area 1: Interpretations of the Epidemiology and Toxicology Literature Discussions,facilitated by.Roger McClellan (Animal Toxicology and Mechanistic studies) sandVe^fe'^ayner(EpideMbiogy):- / " ' 0/ v LUNG CANCER : ' ? O. n (1) Fiber Type a. Epidemiology (b) Animal Toxicology and Mechanistic Studies i; `ri ,_ !2:00Noon 1:00PM 2:00PM LUNCH (onown) :! ' 1 Observer Comment Period ....................................................... Facilitated by Jan Connery s. i Topic Area 1: Interpretations of the Epidemiology and Toxicology Literature- U. Fiber Dimensions and Surface Properties (length and other conslderaffons) a. Epidemiology ' ~'c ' : v` - b. Animal Toxicology and Mechanistic Studies ' 3:30PM BREAK * 0 3 / 1' - r> U 3:45PM Topic Area 1: Interpretations of the Epidemiology and Toxicology Literature MESOTHELIOMA ......... AV ' ;: 0`: : II. - Fiber Type " - - a. Epidemiology A : * Animal Toxicology and Mechanistic Studies '`..Vj-.- ...s":.1,.; II. Fiber Dimensions and Surface Properties (length and otherconsiderations) a. Epidemiology v-" 'b. Animal Toxicology and Mechanistic Studies uml 1 -5:30PM ADJOURN * W:E:D NESDAY, FEBRUARY 2-6 , 2 00 3 . ;v 8:00AM1' Observer Comment Period 9:00AM Review of Day One Discussions and Day Two Charge to Peer Consultants D-2 HWBUI0010106 WEDNESDAY, FEBRUARY 2 6, 2 0 0 3 (continued) 9:10AM Topic Area 1: Interpretations of the Epidemiology and Toxicology Literature EXPOSURE ESTIMATES..............................................................Facilitated by Leslie Stayner 9:40AM Topic Area 2: The Proposed Exposure Index Question #4.....................................................................................Facilitated by Roger McClellan 10:10AM BREAK 10:30AM Topic Area 2: The Proposed Exposure Index Question #5...................................................................................... Facilitated by Leslie Stayner 11:15AM Topic Area 2: The Proposed Exposure Index Question #6.....................................................................................Facilitated by Roger McClellan 12:00Noon i;oopm LUNCH Topic Area 3: General Questions Question 7 ............................................................................................................Roger McClellan Question 8...........;...........................................................................:.................... Leslie Stayner Questions 9............................................................................................................Roger McClellan Question 10..............................................................................................................Leslie Stayner Question 12..............................................................................................................Leslie Stayner Questions 11 ..........................................................................................................Roger McClellan 3:15PM 3:30PM BREAK Discussion of Other Key Issues ....................................................................Facilitated by Roger McClellan and Leslie SLayner 4:50PM Wrap Up of Day Two Discussions and Review of Goals for Thursday 5:00PM ADJOURN THURSDAY, FEBRUARY 27, 2 0 0 3 8:00AM 10:15AM Topic Area 4: Development of Conclusions and Recommendations BREAK 10:30AM Topic Area 4: Development of Conclusions and Recommendations 11:35AM Closing Remarks 11:45AM ADJOURN D-3 HWBUI0010107