Seven expert panelists reviewed and discussed the state of the science on how fiber length relates to toxicity of asbestos and synthetic vitreous fibers (SVFs)—an issue relevant to the Agency for Toxic Substances and Disease Registry's (ATSDR's) ongoing work at several sites where fiber contamination is found in or near residential neighborhoods. The expert panelists included epidemiologists, pathologists, physicians, hygienists, pulmonologists, and toxicologists. During a 2-day meeting in October 2002 in New York City, the panelists thoroughly discussed the physiological fate of structures less than 5 micrometers (µm) in length having aspect ratios greater than 3:1, health effects of asbestos and SVFs of the same dimensions, and research needs.
The panelists' main findings and recommendations are listed below. The remainder of this report summarizes the discussions and observations that led to these findings, and reviews the panelists' comments on many topics not listed in this executive summary. This report provides insights and advice on how to interpret exposures to asbestos and SVFs less than 5 µm in length based on panelist discussions; however, the contents of this report should not be considered ATSDR policy.
Factors that influence toxicity. Health effects from asbestos and SVFs ultimately are functions of fiber dose, fiber dimension (length and diameter), and fiber durability or persistence in the lung (as determined by the mineral type, the amorphous or crystalline structure, and the surface chemistry).
Fibers or particles? Some panelists questioned why structures less than 5 µm long, regardless of their aspect ratio, were referred to as "fibers." This report refers to structures less than 5 µm long as "fibers," while acknowledging that some expert panelists have reservations about this terminology.
Deposition and retention of short fibers. The lung depositional patterns of fibers less than 5 µm long have been well established and depend almost entirely on fiber width. For short fibers with diameters between 0.1 and 1.6 µm, total lung deposition in healthy people will be between 10% and 20% of what is inhaled, with most of that deposition occurring in the deep lung; the fibers that do not deposit will be exhaled. For short fibers with diameters less than 0.1 µm, a greater proportion will deposit and there will be a somewhat greater proportion of deposition in the proximal airways.
The short fibers can be cleared from the lung by various mechanisms, depending on where the fibers deposit. Fibers depositing on the surface of conductive airways (i.e., the tracheobronchial region) are efficiently cleared by the mucociliary escalator, generally within 24 hours. Many of the short fibers that reach the gas exchange region of the lung are cleared by alveolar macrophages, and the rate of clearance by phagocytosis has been found to vary with fiber length and to differ across mammalian species. One panelist, for instance, cited studies of mice and rats suggesting that phagocytosis clears short fibers from the alveolar regions of the lung within a few weeks following exposure. On the other hand, another panelist noted that researchers have established that alveolar macrophage mediated clearance in human lungs takes considerably longer (retention half-times of 400 to 700 days). Overall, panelists noted that rodents clear short fibers from their lungs approximately 10 times faster than do humans. Deposition and retention patterns may differ in people with impaired capacities to clear foreign material from their lungs. The extent to which short fibers preferentially translocate from the gas exchange region to the pleura is not well known.
Cancer effects of short fibers. Given findings from epidemiologic studies, laboratory animal studies, and in vitro genotoxicity studies, combined with the lung's ability to clear short fibers, the panelists agreed that there is a strong weight of evidence that asbestos and SVFs shorter than 5 µm are unlikely to cause cancer in humans.
Noncancer effects of short fibers. The laboratory animal studies, epidemiologic studies, and in vitro studies generally suggest that asbestos and SVF pathogenicity increases with fiber length, but there are several notable exceptions. In laboratory animals, for example, short asbestos and SVFs at sufficiently high doses have been shown to cause inflammation, pulmonary interstitial fibrosis, and pleural reactions; however, the doses needed to cause these effects in humans may not be relevant to environmental exposures. In humans, four epidemiologic studies (Churg et al. 1989, 1990; Nayebzadeh et al. 2001; Case 2002b) involving highly exposed workers found that pulmonary interstitial fibrosis is correlated with the amount of short fibers in the lung at death; some researchers have hypothesized that this apparent association is explained by long fibers breaking down into shorter fibers between exposure and the time at which lung samples were collected. Finally, at least two in vitro studies (Ye et al. 1999, 2001) have found that short fibers are at least as active as, if not more active than, long fibers on a surface area or mass basis for multiple endpoints (e.g., tumor necrosis factor-alpha [TNF-a] production, activation of TNF-a gene promoter activity); however, the relevance of these in vitro findings to health effects in vivo is not known. Taken together, the findings from the laboratory animal, epidemiologic, and in vitro studies suggest that short fibers may be pathogenic for pulmonary fibrosis, and further research is needed to clarify this issue.
Research needs and recommendations. Throughout the meeting, the panelists identified data gaps and made recommendations for filling them. Some recommendations addressed issues specific to sites (e.g., Libby, Montana; Lower Manhattan) with concerns about short fibers in residential communities. These recommendations are listed in Section 4.1. The panelists' recommendations for general research projects follow, in no particular order:
Encourage increased use of sampling human lung tissue or other biological indices, such as sputum collection, in known or suspected human exposure situations to improve both qualitative and quantitative exposure assessment.
Conduct a laboratory animal study to characterize the extent to which fibers of all lengths translocate into the pleura, and whether the translocation preferentially occurs for fibers of any dimension or type. Some panelists noted that translocation of fibers into the pleura does not necessarily imply causation of pleural disease, the mechanisms and site of action of these mechanisms being unknown (Kane et al. 1996). One panelist indicated that some studies (e.g., Gelzeichter et al. 1996; McConnell et al. 1999) have already examined this issue, to a certain extent, for refractory ceramic fibers; and a follow-up study has recently been completed, but not yet published, for amphibole fibers.
Develop and adopt standardized environmental and biologic sampling and analytical protocols to ensure that samples collected from different sites for different purposes can be compared.
Perform personal exposure sampling, or an equivalent, to quantify what exposures result when household surfaces are contaminated with asbestos or SVFs; analyze samples using conventional fiber counting methods (i.e., counting only fibers longer than 5 µm), but archive a subset of filter samples for further analysis.
Further investigate the possible association between short fibers and pulmonary interstitial fibrosis in humans and the impact of short fibers in regard to pleural changes, such as pleural plaques and diffuse pleural fibrosis.
Design and conduct an in vitro study to characterize the influence of fiber length on cell proliferation, DNA damage, and cytotoxicity endpoints that can then be confirmed in animal studies.