The workshop participants highlighted some overarching issues that were considered obstacles to progress in asbestos research. These include inconsistency in the use of the definition of asbestos fibers, a lack of standard size-selected reference materials, and an inadequate understanding of appropriate dose metric(s). Further, there is a need to better understand a) the potential for fiber-induced mutations that influence cancer, b) relevant mechanisms of translocation of different fiber types to extrapulmonary sites, c) health effects outside of the respiratory tract and pleural tissue, and d) the role of population variability and sensitivity to asbestos-induced adverse health end points. The variability in approach to each of these areas impairs the ability to compare results across studies. Each overarching issue discussed is briefly described below and includes broad recommendations for future research in fiber toxicity.
Standardized terminology. The need for standardized terminology is paramount. There is no consensus on how to define terms as basic as “asbestos” and “fiber.” Agreement between the many disciplines and researchers interested in understanding the environmental (human and ecologic) effects of asbestos exposure would greatly facilitate progress, because inconsistent use of terminology currently makes it difficult to compare results across the many existing studies. Recommendations from this workshop include that until standardized definitions are in place, researchers should at a minimum be encouraged to explicitly state their definitions and provide full fiber size distributions for the materials used in experimental studies. The recent NIOSH Roadmap report (NIOSH 2011), in response to the NRC review (IOM/National Research Council 2009) of the draft document, discusses issues related to appropriate terminology to be used in describing various types of asbestos fibers.
Sample characterization/measurement methods. Another overarching issue is the need for more explicit reporting of findings with respect to both definition of fiber and the type of sampling methods, including how fibers were quantified. Counting rules need to be well defined for results to be compared consistently and correctly between analytical laboratories. Counting rules include the fiber dimensions selected as the cutoff for inclusion in the fiber count, the total number of objects to be counted, and the methodology used. This is necessary to be able to rigorously compare results across studies, and relates to limits of detection and how these limits may lead to truncation of fiber distributions that may be implicit in different experimental designs. There was a strong general agreement that it is necessary to perform a complete characterization of all samples being compared and to fully describe this information, including counting rules, when publishing the results of a study. There are still some questions as to what constitutes a full characterization and which methods are best suited to use for these purposes.
Standard size-selected reference materials. It was recognized that the use of standard reference materials is also needed to assist in comparing research from multiple laboratories and test conditions. However, even if standard reference materials were made available for research, standard definitions for consistent characterization of materials used in research studies are still needed, as mentioned above. Size-selected test materials also are needed to disaggregate the influence of fiber dimension, morphology, and mineral form on specific toxic actions of fibers observed in both in vitro and in vivo experimental systems.
Defining the appropriate dose metric. Another key issue discussed by the workshop participants was related to identifying the appropriate dose metric to be used in asbestos studies. As discussed above, there are key knowledge gaps regarding the role of physicochemical characteristics in asbestos-induced health effects. This makes the choice of a dose metric for any response analysis extremely important. Even though it is not clear which characteristics are important for understanding relative differences between fiber types, it is clear that the standard use of mass alone is probably not sufficient. Comparisons between fiber types based solely on an equal mass basis do not take into account differences in fiber number, surface area, reactivity, or fiber dimensions in each sample. This can lead to erroneous conclusions about the relative potencies of fiber types, which can have serious ramifications. Rather than prescribe the definition of a dose metric a priori, studies should explore various dose metrics to ascertain which one best describes the exposure–response relationship for internal burdens at the organ or cellular levels as well as the exposure–response relationship for the given end point or outcome measure under evaluation.
Development of novel experimental systems. One of the primary reasons that uncertainties exist in understanding the mechanistic response to asbestos is the lack of appropriate in vivo and in vitro test systems. There is a continued need for experimental systems that better reflect the MOAs for asbestos-induced disease in humans, specifically for pleural effects and translocation of fibers to the pleural space, as well as tissue-specific mutagenicity assays. More research is needed with appropriate target cells (i.e., mesothelioma cells, Clara cells, alveolar epithelial cells) that is focused on the biological role those cells may have on the pathology of disease.
Genotoxicity of asbestos. The role of genotoxicity in asbestos-related diseases is unknown. Further, although existing data suggest that alterations in gene expression and epigenetic effects may contribute to some types of asbestos fibers inducing disease, more research is needed to fully understand the complex and overlapping signaling pathways involved in these effects, including ROS production, DNA damage and repair and p53 activation, cell death (apoptosis or necrosis), and inflammation. The interaction of these and other alterations leading to fiber-induced mutagenicity is unclear. Another key issue related to cancer risk assessment of asbestos is whether there is a possible threshold exposure level (duration and magnitude) below which there is no genotoxic response after fiber exposure. Therefore, well-conducted in vitro and in vivo studies are needed to clarify this controversial issue.
Extrapolation to humans. It was recognized that extrapolation of results from in vitro studies and in vivo laboratory animal studies to human populations is an important knowledge gap and research need. Although well-designed epidemiologic studies examining malignant and nonmalignant health effects of a range of fiber types after multiple routes of contemporary exposure would be ideal for understanding pathogenicity in humans, such populations are fortunately now rare. Furthermore, if identified, it would be unethical even to allow such exposure conditions to persist. In addition, human epidemiology studies are generally hindered by limited exposure information. Therefore, validated laboratory animal models (including primates) will be necessary to better understand the dose response for various asbestos-related disease outcomes. These laboratory animal models must be demonstrated to be relevant to human asbestos-induced adverse health effects to improve our understanding of pathogenesis and develop useful biomarkers.
Population variability and sensitivity.
There is a major gap in understanding individual susceptibility to the various types of asbestos-induced disease and variability in susceptibility across populations. Limited data are available regarding the impact of asbestos exposure in children, and the role of many preexisting health conditions on asbestos-induced disease is unknown. Although the impact of certain coexposures such as smoking has been known for decades (Selikoff et al. 1968
), limited information is available on the role of other coexposures.