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A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles (2009)

Chapter: 3 Major Scientific Issues: State of the Science and Future Research Directions

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Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
×

3
Major Scientific Issues: State of the Science and Future Research Directions

The NIOSH Roadmap (NIOSH, 2009) proposes a set of studies to improve knowledge on the potential health effects of elongate mineral particles and the ways in which human exposures can best be studied. The proposed studies are founded upon a broad span of scientific literature on these topics that has been well summarized in the draft Roadmap. This chapter provides the committee’s review of the major scientific issues discussed in the Roadmap.

TERMINOLOGY AND NOMENCLATURE

The NIOSH Roadmap devotes considerable attention to mineralogical terminology and nomenclature. In the last several years it has become increasingly clear that the terminology historically used to describe asbestos in workplace or environmental exposures is inadequate and is often applied incorrectly or inconsistently. Examples include minerals not currently listed in regulatory language, such as winchite and richterite asbestos. This is not to say that the proper mineralogical terminology does not exist. Rather, the terminology used by mineralogists is very specific and covers the full range of minerals and properties that are identified for study in the NIOSH Roadmap, but this terminology is not consistently applied in the Roadmap document. One problem is that mineralogical terminology has frequently been misinterpreted in the scientific literature, commercial publications, and regulatory language, resulting in confusion regarding the exact meaning of mineralogical terms, including those used in describing the physical characteristics of minerals.

Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
×

The Roadmap includes a glossary to attempt to clarify for the reader the ambiguities in meanings and concepts. However, the glossary presently contains many words that are not scientifically or technically valid, as well as definitions of scientific terms that are incorrect or need greater detail.1 The committee emphasizes the need to establish and maintain scientific rigor in the glossary definitions and use of terminology in the Roadmap. The committee strongly endorses the use of correct mineralogical terminology and believes that using accepted and scientifically rigorous terminology and nomenclature throughout the Roadmap, including the Roadmap glossary and in subsequent research activities, is the best means to ensure an accurate understanding of proposed research directions and, ultimately, research outcomes. A complementary goal is that this rigor in terminology may eventually be applied consistently in the regulatory setting. In creating a new acceptable paradigm for risk assessment in this area, the Roadmap should not continue the historical use of ambiguous terminology occasionally found in some existing standards and guidelines. To ensure proper scientific terms, a modern technical glossary or other standard reference text, appropriate for the field of study, should be used and cited. For example, the American Geological Institute Glossary of Geology may be appropriate for many of the mineralogical or geological terms (Neuendorf et al., 2005). Other reference texts should be consulted for words not found in the AGI glossary or for toxicological or epidemiological terms. Words or terms that are not scientifically or technically valid should be removed from the glossary and the text.

NIOSH has also recognized a problem with or deficiency in existing terminology that has caused confusion and concern for researchers, policy makers, and others involved in these issues. NIOSH has introduced the term elongated mineral particle to encompass the broad range of mineral particles that are the primary focus of the proposed research. The committee urges the use of the descriptive term elongate, rather than elongated so as to describe the physical appearance of the particles as opposed to implying that they have been actively lengthened (see also

1

Suggestions for terms that need well-referenced definitions include acicular, actinolite, amphibole, anthophyllite, asbestiform, asbestos, chrysotile, cleavage fragment, crocidolite, fiber, fibril, fibrous, solid solution series, and tremolite. Note that the terms asbestiform and asbestos are not equivalent to fibrous or fiber; nonasbestiform minerals and synthetic materials can also be fibrous. Suggestions for terms to consider removing from the glossary include countable particle, covered mineral, and fragility. Terms to consider adding to the glossary include crystal and petrographic thin section.

Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
×

Chapter 1). The committee does not believe that the acronym EMP should be used. Use of the acronym could impart more rigor and homogeneity to a term that actually describes a diverse group of mineral particles of a certain length and aspect ratio.

An elongate mineral particle is defined as “any fiber or fragment of a mineral longer than 5 μm with a minimum aspect ratio of 3:1 when viewed microscopically using NIOSH Analytical Method #7400 (‘A’ rules) or its equivalent” (NIOSH, 2009, p. 61). This term as introduced in the Roadmap is all-encompassing and includes not only asbestos and nonasbestiform mineral particles but also those minerals or particles that are defined, for example, as acicular or prismatic or as cleavage fragments. Nonetheless, the committee considers the dimensions described in the definition (“longer than 5 μm with a minimum aspect ratio of 3:1”) as a good starting point for research since this encompasses the respirable size range. The committee believes that as knowledge of these mineral particles and their potential for health effects accumulates, the definition of these dimensions should be periodically revisited and refined with the goal of providing a more evidence-based justification. However, this definition used by NIOSH also applies to non-respirable mineral particles as it does not place an upper bound on diameter. For example, a fiber with a diameter of 6 μm and an aspect ratio of 3:1 would likely not be respirable but would be counted under the 7400A rules. While this may not be a problem with most traditional asbestos samples, as more elongate particles are evaluated, this lack of differentiation may prove problematic. Additionally, while this definition has been adopted by NIOSH in rulemaking, it is not consistent with other recognized fiber counting schemes such as the World Health Organization method which does place an upper bound on fiber diameter as do the NIOSH 7400B counting rules. It is also important for the Roadmap to acknowledge that the term elongate mineral particle is not a rigorous mineralogical classification or one to which regulatory significance is assigned, but rather serves a useful purpose in encompassing the full continuum of minerals from asbestiform through nonasbestiform, within specified dimensions. As such, the term elongate mineral particle is a convenient, neutral, and uniform means for the disciplines of mineralogy, toxicology, and epidemiology to discuss broad categories of mineral particles with potentially widely varying potency for causing cancer and other health effects. In the NIOSH Roadmap and in this report, the focus is on minerals, which are naturally occurring substances; discussions of research on synthetic materials are included to provide examples of potential research direc-

Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
×

tions or to provide information within the broader context of airborne particulates.

Regarding other terminology issues, the committee highlights a few terms in this chapter that require attention. The term asbestos is a commercial term generally referring to the Occupational Safety and Health Administration (OSHA) and Mine Safety and Health Administration (MSHA) regulatory definitions that specify six minerals: chrysotile, cummingtonite-grunerite asbestos (commercially termed amosite), anthophyllite asbestos, riebeckite asbestos (crocidolite), tremolite asbestos, and actinolite asbestos (29 CFR 1910.1001(b); 29 CFR 1926.1101(b); 30 CFR 56.5001(b)(1); 30 CFR 57.5001(b)(1); 30 CFR 71.702(a); Ampian, 1976). Other authors have used the term more broadly to include minerals that occur in the asbestiform habit, but usage is usually restricted to minerals of the amphibole group and the mineral chrysotile (Lowers and Meeker, 2002). Importantly, nonasbestiform analogs of these six minerals also exist and often occur in similar sizes and shapes as specified in the various regulations and definitions.

The term cleavage fragment, a fragment of a crystal that is bounded by cleavage faces (Neuendorf et al., 2005), has often been used incorrectly in describing both asbestos and nonasbestiform analogs. This is significant because several toxicity studies appear to suggest that cleavage fragments, which are not regulated currently by OSHA or MSHA, are less toxic than asbestiform particles of the same mineral (Addison and McConnell, 2008). While more research is needed to address this issue, the existing research does not support extending these findings beyond cleavage fragments to the broader class of prismatic to fibrous particles. Conversely, the term asbestos has often been used inappropriately to describe any particle that meets the counting criteria of a particular analytical method (e.g., 3:1 aspect ratio and greater than 5 μm length). The potential health effects of some nonasbestiform mineral particles have not been studied, and the potency of respirable prismatic, acicular, and fibrous particles that do not meet the definitions of commercial asbestos is not known. NIOSH has identified in the Roadmap some research that may help to clarify these issues and to resolve questions now being debated.

Another consideration with regard to terminology is the naming or identification of specific minerals. Mineral names in the geological community are endorsed by the International Mineralogical Association (IMA) Commission on New Minerals, Nomenclature, and Classification (CNMNC), which is charged with approving, defining, and occasionally

Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
×

redefining or reassigning mineral names (IMA, 2009). The CNMNC recognizes that its nomenclature serves only as a recommendation to the mineralogical community (Nickel and Grice, 1998). Although the IMA nomenclature is accepted by the primary mineralogical research journals, and therefore its use is generally required for publication in those journals, the IMA nomenclature carries no actual statutory authority in the United States.

An issue encountered in the application of IMA terminology to asbestos outside the mineralogical community is that the IMA CNMNC continues to refine and redefine mineral names for mineralogical research purposes based on new data and understanding of minerals. An example is the redefinition of amphibole names by the IMA Committee on Amphibole Nomenclature, which has revised the amphibole nomenclature three times since 1978. An additional proposal for another major reorganization of amphibole nomenclature has recently been proposed to the mineralogical community (Hawthorne and Oberti, 2007). These changes in mineral names far outpace the ability of the rulemaking and legislative processes in the United States and have caused considerable confusion and misunderstanding, as is evident in recent legal actions relating to asbestos contamination in Libby, Montana. Finally, the correct application of IMA amphibole nomenclature (Leake et al., 1997, 2004) requires analytical precision and accuracy that is generally beyond the capability of the standard asbestos analysis methods used for exposure assessment purposes. This presents difficulties for the comparison of analytical results between, and even within, laboratories.

Within the chemical community, the Chemical Abstracts Service (CAS) Registry provides definitions of chemical substances including asbestos. Unlike the IMA, the CAS Registry does carry some statutory authority. However, CAS Registry definitions can often be vague. An example is the general definition of asbestos (CAS 1332-21-4) from the online Chemical Abstracts Registry database as a grayish, noncombustible fibrous material” consisting “primarily of impure magnesium silicate minerals”—a definition that could apply to several hundred silicate minerals. The CAS definition for asbestos was ruled applicable by the U.S. Ninth Circuit Court of Appeals for the Clean Air Act (U.S. Court of Appeals, 2007). This dichotomy between the generally precise IMA definitions and the less detailed and less precise CAS definitions presents significant difficulties for those involved in work on asbestos and other elongate minerals.

Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
×

The committee believes that the rigor of established mineralogical terminology is critical to the research process and the ultimate understanding of the mechanisms of toxicity. Therefore, the committee suggests that the Roadmap remain consistent in its use of referenced mineralogical nomenclature rather than commercial names (e.g., amosite). It must also be recognized that mineralogical definitions and nomenclature have changed and may change in the future. It is therefore important that the specific mineral nomenclature scheme used in any publications, such as the Leake et al. (1997, 2004) nomenclature for amphiboles, always be referenced so as to make clear the specific definitions being applied.

Issues of terminology also arise in other relevant research disciplines. The problem of the incorrect use and corruption of terminology extends beyond the question of misunderstanding and unintentional misuse in that it provides an opportunity for exploitation of the terminology to achieve an expedient outcome. It is therefore extremely important that researchers, policy makers, regulatory staff, and others working on these issues take great care in using terminology that is precise and fully developed so that the intent is totally clear. Clear and consistent use of conventional terminology in the Roadmap is thus essential.

With the terminology considerations suggested above, this chapter subsequently highlights a mineral characterization scheme for establishing and using mineral standards that have been well-characterized physically and chemically for use in toxicological research.

MINERAL CHARACTERIZATION AND STANDARDIZED REFERENCE MINERALS

Mineralogy is a fundamental science relating an enormous number of naturally occurring solid materials. A robust, systematic classification scheme for minerals exists based on rigid compositional and structural (crystallographic) criteria. These criteria are well defined and can be quantified. The Roadmap would benefit from further emphasis on the mineralogical research needed and from discussion of the development of standardized reference mineral samples that could be used in toxicological studies to assess the variability in the toxicity of different types of elongate mineral particles. Major issues faced in research in this area include (1) that the bulk rock or ore may contain a complex suite of minerals and that this complexity, although relevant to the toxicological

Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
×

properties of the dust, may not be detectable in the respirable dust derived from the bulk because of analytical limitations, (2) the relative percentage of different minerals present, and (3) the physical characteristics, which may vary with the size fraction after attrition. For these reasons, characterizing the fundamental properties of elongate mineral particles is essential.

Mineral Characterization

Minerals have fundamental properties that can be defined in terms of physical (e.g., growth habit, hardness, cleavage), chemical (e.g., chemical composition, surface reactivity, solubility), optical (e.g., translucence, refractive indices), and electrical (e.g., conductivity, resistivity) characteristics, among others. A degree of variability in the compositional and structural makeup of specific minerals in nature also exists, reflecting differences in petrogenesis and mineral source (natural conditions of formation). Therefore, minerals exhibit a range of physical and chemical properties that result in varied responses to conditions imposed during extraction, processing, and experimentation. Research on the degree of variability between mineral species and within mineral groups, due to their natural conditions of formation, and the extent to which these varying characteristics influence toxicity is largely absent from the Roadmap and more detail is needed.

Key variables of relevance in studying minerals include surface crystal structure and chemistry, size and shape characteristics, and mineral habit—all of which will vary depending on the composition, environment of growth, and response to physical and chemical processing of mineral samples. Essential to the consistent rigorous characterization of minerals is the consideration of mineralogical properties in a similar way throughout the mineral “life cycle”—from extraction or liberation at the source to processing for use in manufactured products or as research materials. Modern methods of mineral characterization can also provide a statistical representation of the range of minerals and their physical characteristics. This form of minerals characterization is used routinely by the mineral industry to identify and quantify mineral samples in terms of their variability in composition, size, and shape.

Whether establishing a new reference mineral sample for eventual use in health-related research or characterizing an unknown suite of elongate mineral particles from an air sample filter, a basic set of mineral

Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
×

characterization techniques can be employed in a tiered fashion. Additional characterization techniques can then be employed if required. The level of analytical detail will depend upon the goal of the research. Table 3-1 outlines a basic characterization sequence and suggests potential outcomes of the research that can be used to plan further research in a systematic way. Such an approach to mineral characterization is currently absent from the Roadmap.

The committee believes that a fundamental problem with the proposed research in the Roadmap is the reliance on limited and outdated analytical methods such as phase contrast microscopy (PCM). Other methods such as transmission electron microscopy (TEM) or scanning electron microscopy (SEM) are not recommended for use exclusively or as “stand-alone” analytical methods. Rather, TEM or SEM can be used most effectively in conjunction, if possible, with the petrographic techniques listed in Table 3-1. The need to develop new methods based on electron microbeam analysis techniques is critical and should not be limited by existing regulatory constraints or existing policy. The committee strongly believes that the science should drive the policy and regulation, not the reverse.

Prediction and prevention are linked to having well-characterized sample sets for experimental work and analysis. The Roadmap recognizes that workers may be exposed to any number of crushed and ground and/or contaminant particles introduced during mining, milling, manufacturing, and demolition of the materials. In these cases, the size and shape criteria used to describe elongate mineral particles encompass many mineral groups in addition to asbestos and analogous minerals. Mineral source and petrogenetic studies can be used to help characterize mineralogical materials in terms of source (original geological source for the mineral and formation conditions). By using statistically reasonable sample populations from diverse natural sources and rock localities (e.g., mines), including historical data sets, minerals from an air sample filter may be classified not only by mineral composition, optical properties, size, and shape, but also by petrogenetic history. This type of approach also has the potential to aid in the design of tailored toxicological studies linked specifically to a particular mineral source and could provide predictive assessment for materials derived from similar geological settings.

Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
×

TABLE 3-1 Tiered Approach to Mineral Characterization

Characterization Step

Purpose

Further Application

1. Examine original rock from source and determine mineral content, mineral habits, textures, and chemistry in situ (petrographic analysis of thin sections and hand specimen analysis [polarized light microscopy, PLM]; electron probe microanalysis [EPMA]).

Establishes mineral characteristics, mineral chemical variations, basic growth habit of single crystals and aggregates of minerals (e.g., equant, granular, acicular, radiated growth habits). Yields a quantitative appreciation of the distribution of minerals in situ and their growth relationships. Note that cleavage fragments are fragments of single crystals and are not regulated by MSHA and OSHA.

This step creates the initial data set of relevant mineralogy and mineralogical associations that will be further developed through subsequent stages.

2. Comminute the sample to different, relevant size fractions and characterize the minerals optically in terms of shape, habit, texture, size, and chemistry using optical mineralogy and/or electron beam techniques. These characteristics may also be applied to an unknown mineral set from an air sample filter.

Establishes the range of habits—from fibrous to acicular to prismatic, etc.—that may be present in a mixed mineral sample that has undergone various degrees of processing and the degree to which specific minerals may persist through greater levels of processing.

This step identifies and refines the list of relevant criteria related to potential health impacts.

Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
×

Characterization Step

Purpose

Further Application

3. Analyze the thin sections, or crushed samples, in controlled size fractions by EPMA, XRD, XRF, PLM, SEM, and TEM.

In combination with PLM, SEM provides an option for larger data sets that are more representative of the sample population. TEM measurements can provide diffraction information to help distinguish the crystallographic differences among various asbestos minerals. New technologies in quantitative mineralogy and image analysis aid with size distribution and counting statistics.

Mineralogically characterized samples can be used further in controlled toxicological research.

4. Detailed analysis of individual grains, such as that offered by surface analysis provides information on oxidation-reduction state, electrostatic behavior, and other potentially relevant properties.

Methods include EXAFS, Auger, AFM, Mössbauer spectroscopy, EBSD, synchrotron, and threedimensional analysis combined with knowledge of biodurability and length of residency of particles with specific characteristics.

Further understanding of the surface characteristics of specific grain populations can be useful for toxicological studies of human tissue and fluids.

NOTES: AFM = atomic force microscopy; EBSD = electron backscattered diffraction; EPMA = electron probe microanalysis; EXAFS = extended X-ray absorption fine structure; PLM = polarized light microscopy; SEM = scanning electron microscopy; TEM = transmission electron microscopy; XRD = X-ray diffraction; XRF = X-ray fluorescence. When analyzing natural materials for basic mineralogical research and characterization, data from steps 1 and 2 are required, whether from historical sources or newly collected by the analyst. Steps 3 and 4 involve progressively more sophisticated types of analysis for mineralogical and, eventually, toxicological research purposes. For rapid identification and characterization of unknown samples from worker air sample filters for regulatory purposes, steps 2 and 3 are the relevant actions to employ.

Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
×

Research is also needed into the potentially toxicological responses of exposure to mixtures of elongate mineral particles. The complexities of this research underscore the need to have well-characterized mineral samples in the context of their natural sources and petrogenesis in order to understand the controlling variables in the toxicological experiments.

Standardized Reference Minerals

Well-characterized reference mineral samples are important for research on the potential health effects of elongate mineral particles, and the need for a well-managed repository should be emphasized. The identification, classification, and characterization of unknown mineral particles from workplace or environmental exposures require comparison to rock-forming minerals that have been characterized mineralogically by conventional petrographic techniques. Similarly, designing and conducting meaningful toxicological experiments require well-characterized reference mineral samples to allow systematic intra- and interlaboratory comparisons of results. The Roadmap notes the need for standardized reference mineral samples but should include more details on an approach to developing a central repository for systematically characterizing and standardizing the samples. This type of repository provides better precursor material for research of the sort proposed in the Roadmap.

Ideally, all minerals studied by laboratory inhalation exposures should either be obtained from the repository or be matched with smaller samples that are well characterized and included in the repository. It should be noted that substantial quantities of minerals would be necessary if the repository intends to support long-term whole-body inhalation studies. (Smaller quantities are needed for nose-only inhalation studies.) For example, tens of kilograms of respirable minerals would be required to conduct a multi-dose inhalation study of sufficient magnitude to test carcinogenic potential. This does not obviate the need for a repository of smaller samples of standardized minerals. A few grams could support comparative in vitro tests that would help place the effects of inhaled minerals into context, even if the study sample did not come from the repository.

Several sets of standardized reference minerals have been developed in laboratories of the National Institute of Environmental Health Sciences (NIEHS) and the former U.S. Bureau of Mines (USBM), as well as other groups, and could be included in a central repository.

Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
×

During the mid-1970s, approximately 500 pounds of respirable crocidolite (from South Africa), chrysotile (from Canada and California), grunerite (from South Africa), and tremolite (from a New York State tremolitic talc deposit) were prepared and mineralogically characterized in conjunction with asbestos-related research conducted by the USBM (Campbell et al., 1980). The existing mineral samples vary in the extent to which they have been characterized, and all existing samples and new mineral samples would eventually have to be examined and represented by the same types of basic analytical data, generated using viable modern techniques (see Table 3-1). Most respirable particle size ranges can be classified or developed from these types of standard minerals. Modest initial studies could, for example, be undertaken using the USBM’s well-characterized asbestos and tremolitic talc samples, as available. The samples originally characterized by the USBM could serve as precursor material. These studies could include petrographic thin sections made from drill cores and/or initial primary crushing samples from the mine, mine run, or crushing runs. Petrographic analysis of thin sections and particle analysis of crushed materials could be augmented by X-ray diffraction, TEM, and SEM. These petrographic analyses could make use of the <2 μm limit of the optics of the petrographic microscope. This type of work could also characterize the minerals needed for future research, including biological testing. Concurrent studies for discriminating asbestos from cleavage fragments and other particle types using samples from personal monitors worn in mines could also be conducted. Once samples are well characterized by these initial studies, the results could be applied to non-mine-related OSHA and Environmental Protection Agency (EPA) monitor samples. This is an example of a tiered approach to the NIOSH research plan (Table 3-1).

Important descriptive and quantitative parameters needed in a unified characterization of standards include the following:

  • Mineralogy of all phases of the sample including quantification of all accessory minerals

  • Chemical compositional variability of the mineral of interest

  • Size, shape, and degree of mineral fabric and texture, including the habit and single-crystal development

  • Source (including, if available, the geological and petrogenetic history of the deposit from which the samples are derived and the mineralogy of the source material)

  • Industrial or manufacturing history

Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
×
  • Characterization of the aerodynamic properties of the minerals, and the composition of the other materials for toxicological studies

  • Surface chemistry, surface structure, and charge

One of the fundamental parameters for reference and testing materials is particle dimension. However, the Roadmap does not deal with the issue of particle dimension, except obliquely as may be inherent to the different source materials. The importance of particle dimension to health cannot be conclusively determined on the basis of comparing results of studies that contrast two different mineral assemblages, each of which varies in particle size and surface area. A few studies have investigated the degree to which particle dimension in samples of the same mineral is a determinant of toxicity (Davis et al., 1991; Berman et al., 1995; Bernstein and Hoskins, 2006; Bernstein et al., 2006). To expand on these studies, researchers will need samples of the same mineral type (whether from the same source or from well-characterized standards) differentiated by size, shape, dimension, and growth habit. A national mineral repository could meet this need. While not trivial to establish, particularly with the need for processing, characterization, storage, and curatorial facilities, such a repository could include suites of minerals with varying size fractions and growth habits as well as suites of minerals with varying chemistry for use as benchmark samples. Without such a repository, much of the proposed Roadmap research will have diminished value. Given likely developments in instrumentation and classification, the standards should be assessed to allow for future enhancements in the data set.

TOXICITY SCREENING AND TESTING

State of Science and Future Directions

As discussed in Chapter 2, the Roadmap needs to explicitly outline a standardized approach to screening for the potential hazards of elongate mineral particles whose biological effects have not yet been characterized. A systematic, tiered structure of increasingly complex in vitro and in vivo assays would be useful not only for screening for toxicity, but also for placing the nature and extent of the hazard of the new material in the context of what is known about the hazards of previously tested mineral particles. The screening process would begin with the assessment of the physical and chemical nature of the mineral particles that would pro-

Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
×

vide information to begin to assess where the different types of elongate mineral particles fall along the spectrum of materials for which some information on biological hazard exists. In this and subsequent steps, it is important to ensure that the mineral particles being evaluated represent the physical and chemical characteristics of the respirable material to which humans are, or may be, exposed. If exposures involve mixtures of minerals, the tested samples should represent those mixtures. Separation of mixed exposures into different types would only be appropriate at later stages to assess the components that may impact toxicity.

Careful consideration should be given to selecting the screening tests. The assumption must be that the tests reflect types of responses and perturbations of biological response pathways that are most likely to be caused by elongate mineral particles. It is possible that important responses may not be probed by the selected tests. As knowledge of response mechanisms and critical pathways improves, the selection of tests may evolve (NRC, 2007).

After a series of intermediate steps, the screening may, in certain cases, have to be carried through to long-term inhalation studies of animals. However, an underlying goal would be to establish a screening process and knowledge base where extension to chronic animal studies would rarely be needed to assess the extent to which human exposures should be limited (that is, to establish a regulatory categorization). The following steps (tiers) comprise the proposed framework. This framework is similar to the tiered testing system for natural and synthetic fibers proposed by the International Life Sciences Institute (ILSI, 2005). The intent of the committee’s framework is for research needs to flow from present limitations in addressing each of the steps (Figure 3-1).

FIGURE 3-1 Overview of a possible testing strategy for elongate mineral particles.

FIGURE 3-1 Overview of a possible testing strategy for elongate mineral particles.

NOTE: If at any point, human data are available, those data should have priority in assessing toxicity and the potential for health impacts.

Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
×

Physical and Chemical Characteristics

First the Roadmap should identify the types of studies needed to better understand the biologically relevant physical and chemical characteristics of elongate mineral particles. As noted above, a thorough mineralogical characterization of the mineral particles, particularly their chemical structure, physical dimensions, and biopersistence, is needed for meaningful comparisons of toxicological responses. Regard must be given to the several technical issues related to sampling and characterization, noted in subsequent sections, to ensure that the mineral samples studied accurately reflect the minerals to which humans are exposed. By relating biological responses to standardized mineralogical nomenclature, a knowledge base can be developed that progressively reduces the range of mineralogical particle types that need to be tested de novo in order to classify their hazard potential. The following stepwise approach could be undertaken to examine and categorize the mineral particles. It is possible that having addressed these steps, further investigation of some mineral particles may not be needed.

  1. What are the physical dimensions of the mineral particles to which people are exposed? What is the aerodynamic size distribution of the airborne mineral particles? What is the distribution of the dimensions of the bulk particles?

    If the particle is respirable or of a thoracic size fraction, it should be considered potentially hazardous and warrants further evaluation. Concern is heightened if the inhaled particles include dimensions that are consistent with other known harmful elongate mineral particles.

  2. What are the mineralogical characteristics of the respirable and thoracic size fractions of particles to which people are exposed? Is this homogeneous or a mixture of particles? Is the particle similar to those for which health hazards are already known?

    If the particle is analogous to previously studied particles, its toxicity should be considered comparable until proven otherwise. The confidence in the assessment should be proportional to the degree of similarity between the particles.

Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
×
  1. What are the potential exposure concentrations? Specifically, what are the exposure concentrations of the thoracic fraction of the particles? What is the duration of the exposure?

    If exposures to the particles meet or exceed accepted exposure limits for the general class of particle, the exposure scenario should be considered problematic. If the exposure is below accepted limits for a new elongate mineral particle, some preliminary toxicity testing may still be needed to evaluate the need for a more extensive effort if the particle has characteristics that suggest the potential for toxicity. The magnitude of exposure must be considered in making this decision.

In Vitro Solubility

Elongate mineral particles must reside in the lung for extended times to produce disease beyond the transient inflammation that might be associated with the deposition of any poorly soluble material. Because in vivo solubility is one of the characteristics that determine the persistence of elongate mineral particles, the next step is to assess the solubility of the particle in biological media using state-of-the-art methodologies. A current approach for assessing in vitro solubility uses a lung fluid stimulant, such as Gamble’s solution (de Meringo et al., 1994; Zoitos et al., 1997), to provide a rapid and inexpensive approximation of likely in vivo solubility. Existing data on the relative solubility of several types of elongate mineral particles in this assay (Hesterberg and Hart, 2001; Hesterberg et al., 2002) helps place the results in context; this is particularly valuable when toxicity data may also be available for these other elongate mineral particles. Although solubility assays are reproducible using the same type of elongate mineral particles, the assay should include concurrent control particles with known solubility. Extreme acid, base, or enzymatic solutions should be avoided at this step; solubility in an already-accepted lung fluid stimulant has proven to adequately mirror in vivo biopersistence. It is recommended that solubility studies be conducted at two pHs—one slightly acidic, reflecting the pH inside macrophage phagolysosomes, and the other neutral, reflecting the pH on the surface of the alveoli (Christensen et al., 1994; Sebastian et al., 2002; Maxim et al., 2006).

Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
×

Elongate mineral particles have a range of solubility and biopersistence, and there is not a well-established cut-off point below which a mineral particle would not be of concern. Developing a quantitative database of how well-characterized minerals respond to dissolution experiments in human and animal tissues and fluids will provide valuable information in deciding what mineral particles should undergo further toxicological testing. Mineral surface structure, chemistry, and electrostatic charge behavior are additional important parameters and require accurate characterization of the test particles used. At present such a description of this type of research is missing from the Roadmap.

Decision point: If the solubility of the elongate mineral particle falls within the range of similar particles known to be biopersistent and to cause disease, it should be considered potentially pathogenic.

In Vitro Toxicity Assays

As noted in the Roadmap, numerous in vitro methods have been developed for exploring the mechanisms of toxicity produced by elongate mineral particles. The appeal of these cellular and tissue assays is that they are more rapid and less costly than in vivo assays, and apart from primary embryo fibroblasts, most do not require live animals. The in vitro studies provide useful information on dose-response toxicity of the mineral particles. The studies also can be used to assess the effects of dimension, chemical composition, and interaction of particles with other environmental toxicants such as chemical carcinogens, viruses, or radiation (radon) in modulating the biological behaviors of the elongate mineral particles. Taking advantage of advances in toxicogenomics, bioinformatics, and computational toxicology as applicable, the goal should be improvement in the utility of in vitro assays for classifying the potential hazard of newly encountered particles and ultimately predicting in vivo health outcomes of exposure without the need for in vivo studies. However, considerable advancement will be necessary before in vivo studies can be discarded; thus, the primary purpose of in vitro tests in the near term will be to screen materials for further investigation. In vitro toxicity studies using single cell types do not reflect complex interactions among tissues and organs, do not include the modifying effects of deposition patterns and clearance by mucociliary actions and macrophages, and cannot be used to ascertain the contribution from biopersistence. In

Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
×

vitro assays have the potential for indicating false positives for causing disease, particularly at the very high concentrations used in some of these studies. For example, vitreous fibers and wools, although positive in many short-term toxicity assays, including cell killing, apoptosis, and generation of reactive radical species (for example, reactive oxygen and reactive nitrogen species), have low potential for causing disease in vivo. At this time, none of the in vitro assays have been validated as predictors of disease in animals or humans to provide the confidence for their use as the sole determinant to predict health hazards of new elongate mineral particles.

In vitro assays have provided rankings of the relative inflammatory and carcinogenic potential of varieties of asbestos having known in vitro toxicity and have also provided insights into the cellular mechanisms of response. Further research and validation may enable in vitro assays to fill a similar role for certain classes of elongate mineral particles. A clearly positive response in vitro would signal the need for further testing and might suggest the longer-term health outcomes to be investigated. A very low or negative response on multiple in vitro assays might be useful for assigning the particle to a low-risk category. Because asbestosis, lung cancer, and mesothelioma likely have different mechanisms of pathogenesis, attention must be given to selecting an array of in vitro assays capable of detecting cellular events thought to be involved in pathways leading to each outcome of concern.

The goal would be to establish an efficient testing approach that uses a small number of assays to estimate in vivo toxicity based on in vitro responses. More than one type of assay would be necessary to explore the range of potential toxicity responses (e.g., genotoxicity, inflammogenicity). The thoracic or respirable fraction of the elongate mineral particles would be tested using a range of doses reflecting those that may occur during human exposure, depending on the choice of the in vitro target cell, in parallel with control particles having extremes of responses in each assay.

Decision points: A tentative assignment of hazard level would result from ranking in vitro toxicity relative to those of elongate mineral particles having known in vivo toxicity. A benign ranking in combination with evidence from existing tiers of low potential toxicity might result in no further testing. Otherwise, the nature of in vitro toxicity would help focus subsequent in vivo assessment on the most likely health outcomes.

Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
×

In terms of the state of scientific understanding of the toxicity of elongate mineral particles, several opportunities exist to improve the Roadmap. Most carcinogenic asbestos and glass fibers can morphologically transform rodent fibroblast cell lines (Hesterberg and Barrett, 1984; Mikalsen et al., 1988) but not primary human epithelial cells (see Hei et al., 2000, for review). This has been attributed to the extremely low transformation frequency observed in primary cells. As a result, virally immortalized human epithelial cells have been used successfully in morphologic transformation studies with certain types of asbestos (Hei et al., 1997; Wang et al., 2004; Bertino et al., 2007). The results are consistent with the observation that SV40 may act as a co-carcinogen with asbestos in the pathogenesis of mesothelioma (Bocchetta et al., 2000). However, because of the cost and long lag time required for the transformation of human epithelial cells in culture, no dose-response data are available and most of the studies lack adequate asbestos controls. Nevertheless, these studies provide a platform for mechanistic analyses of the neoplastic transforming process (Zhao et al., 2000; Piao et al., 2001; Cacciotti et al., 2005). In the future, a focus on the molecular mechanisms of compensatory cell proliferation and transformation to malignancy will prove to be useful in understanding the disease process.

The description of genetic toxicology studies in the Roadmap needs to be improved. Although various types of asbestos have been shown to induce chromosomal aberrations and sister chromatid exchanges in human mesotheliomas and lung cancers and in cultured human and mammalian cells, mutagenic studies at most mammalian genetic loci have largely been negative (Jaurand, 1996; Hei et al., 2000; Schins and Hei, 2006, for review). This has been attributed to the findings that asbestos induces, either directly or indirectly2 through the production of reactive radical species, multilocus deletions that are not easily recoverable at the hprt and oua loci.3 The observation is consistent with data obtained using other mutagenic assays that are proficient in detecting either large deletions, homologous recombinations, or score mutants located on a nonessential gene (Both et al., 1994; Park and Aust, 1998). These findings provide a direct link between chromosomal abnormalities that have frequently been demonstrated in human and rodent cell lines exposed to

2

Directly through either surface chemistry or phagocytosis or indirectly through secondary lipid peroxication, NADPH oxidase, or mitochondrial membrane damage.

3

The hprt loci encodes enzyme hypoxanthine phosphoribosyltransferase, while the oua loci encodes the enzyme that is the receptor for ouabain, a cardiac glycoside, which is a potent inhibitor of the sodium pump.

Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
×

asbestos and carcinogenicity in vivo. If an elongated mineral particle type is found to be mutagenic in any in vitro genotoxic endpoint, it needs to be further evaluated.

The Roadmap describes in detail the cell-signaling pathways including nuclear factor kappa B, mitogen-activated protein kinase, and c-Jun-N-terminal kinase, that are activated in murine mesothelial cells and immortalized human bronchial epithelial cells treated with either asbestos or nonasbestiform analogs. However, what is missing is a statement on the specificity of these signaling end points for asbestos toxicology. The observation that antioxidants such as vitamin E and catalase can ameliorate the response indicate that this is a general response to oxidative damage. As such, glass fibers, for example, of similar aspect ratio as asbestos that are noncarcinogenic in vivo are likely to be positive in the activation of these signaling end points.

Recent studies on gene expression profile in human mesothelial cells treated with asbestos suggest that the activating transcription factor-3 (ATF3), which modulates the production of inflammatory cytokines (Shukla et al., 2009), is an important marker in asbestos-treated cultures. In addition, there is evidence that extranuclear targets, including mitochondria, are relevant to asbestos toxicology (Xu et al., 2007). These recent findings provide a conceptual link from frustrated phagocytosis of asbestos to reactive radical species, to cytokine production, to tissue inflammation, and ultimately to fibrosis or carcinogenesis.

In Vivo Toxicity Assays

Elongate mineral particles ranked as likely hazardous based on their mineralogical characteristics or having characteristics that prevent close correspondence to particles of known toxicity would be tested in vivo. It should be acknowledged that the three general types of responses of greatest concern, based on experience with asbestos, are fibrosis, mesothelioma, and lung cancer. Moreover, the most important physical and chemical characteristics probably differ among the three outcomes (Lippmann, 1988). The highest standard for in vivo assessment would be repeated inhalation exposures of animals, by which these outcomes could be revealed. Other routes of administration (e.g., intrapleural, intraperitoneal injection) might be useful for certain types of mechanistic studies, but their relevance to human exposure conditions is considerably less certain. Intracavitary injection is not an acceptable substitute for deposi-

Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
×

tion via the respiratory tract. Although results of animal studies can rarely be extrapolated to estimates of human risks with absolute confidence (a point that the Roadmap should make more clearly), reliance on animal inhalation studies as a basis for regulatory classification is a well-established practice.

The Roadmap reviews the testing of elongate mineral particles in animals, but does not indicate which animal models have been validated. Although the Roadmap states that “it remains uncertain which species of animal(s) best predict(s) …” (NIOSH, 2009, p. 74), there are publications addressing this issue. For example, the European Union has adopted the in vivo biopersistence protocol ECB/TM/27 rev.7 which is a well-validated 90-day intratracheal test for respirable fibers and particles (European Commission Joint Research Centre, 1999). The Roadmap would benefit from including summary tables, such as those presented by Hesterberg (2009), showing the correlation between disease in animals and humans with various elongate mineral particles known to be nonhazardous. Indeed, the data presented in the Roadmap appear adequate to provide such a correlation. If the correlations were adequately reviewed, it might become clear which types of animal studies would or would not be useful to predict the relative toxicity of an unknown elongate mineral particle with a reasonable degree of certainty. The committee considers that existing data may be sufficient to provide guidance on the design of animal studies. In that context, the following points are presented.

  • The particles to be used in toxicological studies need to be well characterized and to the extent possible, the exposure should be designed to achieve target-tissue dosing that simulates dosing in human exposures. A positive control may be warranted if comparative toxicity is an important issue. A negative control may not be necessary if the model has been adequately validated.

  • Inhalation appears to be the most relevant route of exposure as proposed by the International Life Sciences Institute (ILSI, 2005) for the study of manufactured vitreous fibers. Other routes can be considered depending on the characteristics of the unknown mineral.

  • The rat appears to be the most appropriate rodent species, based on past experience (Mauderly, 1997). Syrian hamsters are known to be less useful in chronic studies because of their susceptibility to infection, and studies of mice may not add significantly to the findings in rats.

Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
×
  • Both genders of rats may not be required because very few studies of asbestos have shown a gender difference (Wagner et al., 1973, 1974, 1982). However, females have demonstrated greater responses than males to some nonelongate particles (Nikula et al., 1995). The potential for gender-based differences in response to elongate mineral particles is unknown.

  • Animals should be exposed to multiple concentrations. Exposure levels should be selected based on several considerations, such as maximum tolerated dose, number of thoracic elongate mineral particles in the aerosol having the length range of concern (e.g., >20 μm long), and levels relevant to human exposure. The spacing of dose levels should be chosen to provide the best data for risk assessment. Caution should be exercised to avoid exposures that deposit unrealistically large doses of mineral particles, in order to avoid nonspecific fibrotic and proliferative responses to overloading, such as have occurred with some non-fibrous particles (Oberdörster, 1995).

  • Differences in the aerodynamic sizes of particles that are respirable by humans and rats (thoracic size fraction) should be considered. Aerodynamically larger particles can be inhaled and deposited in the thorax of humans in comparison to rats. Accordingly, only a portion of a highly polydisperse population of elongate mineral particles may actually deposit in the lungs of rats. Characterization of the aerodynamic particle size range of the aerosol is necessary to determine whether or not the full range of human exposure is being tested. Dogs and nonhuman primates more accurately model the initial deposition of highly polydisperse elongate particles in humans and could be used for acute studies of initial deposition.

  • Subchronic (90-day) exposures may be adequate. ILSI (2005) suggests that a 90-day exposure followed by a 90-day recovery period should be adequate to determine the relative toxicity of elongate mineral particles if subchronic data are available for other materials for comparison. In some cases, lifetime exposures may be warranted. As part of this study, it would be valuable to conduct lung burden evaluations to determine biopersistence, changes in elongate mineral particle morphology, (e.g., splitting and breaking), and changes in the distribution of the elongate mineral particles in the respiratory tract over time.

Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
×
  • Pulmonary fibrosis is a useful predictive end point. ILSI (2005) concluded that pulmonary fibrosis was a useful screening end point for subsequent outcomes such as interstitial fibrosis, COPD (chronic obstructive pulmonary disease), lung cancer, and mesothelioma. In the rat, pulmonary fibrosis has consistently preceded the development of lung cancer and mesothelioma from inhaled elongate mineral particles. However, pulmonary fibrosis is not always followed by the other diseases. In this sense, pulmonary fibrosis in the rat represents a conservative end point for estimating longer-term hazards. In some cases, the longer-term outcomes may have to be explored by lifetime inhalation studies.

    Decision point: If pulmonary fibrosis is observed, the material in question should be considered likely to be hazardous. Because not all fibrosis leads to cancer, the development of fibrosis does not confirm a carcinogenic hazard.

It must be stressed that adequate human data should always take priority over animal data in characterizing the risk from elongate mineral particles. Robust positive data from humans are sufficient for regulatory action. However, negative data from humans may not be adequate to discount long-term risks from exposures to elongate mineral particles because of the relatively long latency period in humans for some diseases. Toxicological testing, both in vitro and in vivo, is appropriate in the absence of data, or the absence of robust data, from humans.

EXPERIMENTAL DESIGN ISSUES

For toxicological experiments involving multiple characteristics of the mineral particles of interest (e.g., length-to-width ratio, biopersistence) it is often not possible to study all combinations of all characteristics as would be done in a full factorial design. In many cases, however, this may not be necessary because the focus is less on estimating and testing high-order interactions and more on screening the many potentially important characteristics to determine which do and which do not impact a toxicological outcome of interest. In this case, a fractional factorial design should be considered because it will greatly reduce the number of required experimental conditions and provide the ability to

Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
×

screen large numbers of potentially important risk variables and estimate their direct (main) effects and in some cases even obtain unconfounded tests of their two-way interactions.

When the factors or characteristics of interest are continuous variables and cannot be readily dichotomized to fit within the context of a 2k design, a reasonable alternative strategy is response-surface methodology. The basic idea is to look at a more limited number of combinations of a variety of factors and to identify areas in the high-dimensional response surface that are associated with maximal biological activity. Related methods for further exploration of the response surface (e.g., steepest ascent methods) can then be used to more carefully explore the areas of higher biological activity. Appendix C provides a more detailed overview of these potentially useful experimental design tools.

EPIDEMIOLOGY

Assessment of the State of the Science

The Roadmap discusses epidemiological studies of workers with mining and/or milling exposures to mineral particles that have been reported to be nonasbestiform from three different regions: the talc mining region of upstate New York, the Homestake gold mine in South Dakota, and the taconite iron ore mines in northeastern Minnesota. The Roadmap section reviews in sufficient detail the published reports of the epidemiological studies of these occupational cohorts through 2007.

The subsection on studies of the New York talc miners and millers concludes with a summary indicating that an excess of pneumoconiosis and pleural plaques is “well recognized to have occurred among workers exposed to talc” (NIOSH, 2009, p. 22). The dust from these talc mines has been reported to contain nonasbestiform tremolite, asbestos anthophyllite altering to talc at the nanometer scale (considered as unregulated by OSHA), and antigorite-lizardite particles (NIOSH, 1980; Kelse, 2005). However, the NIOSH study and others document the presence of asbestos. Mesothelioma rates have been reported to have been elevated in Jefferson County, the site of much of the talc industry in New York (Vianna et al., 1981; Enterline and Henderson, 1987; Hull et al., 2002), but these studies used a nonspecific International Classification of Diseases (ICD) code for malignant neoplasms of the pleura that may have included cancers metastatic to the pleura. Data from 1999 to 2004

Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
×

using a specific ICD-10 code for malignant mesothelioma show no excess of mesothelioma in Jefferson and St. Lawrence counties (NIOSH, 2009). The most controversial aspect of the published epidemiological studies from the New York talc industry is excess lung cancer mortality. While this finding has been consistently reported, so has the lack of an exposure-response relationship.

The subsection on studies of Homestake gold miners notes that three different groups of investigators have reported on lung cancer risk among these workers (Gilliam et al., 1976; McDonald et al., 1978; Brown et al., 1986, which was updated by Steenland and Brown, 1995). The dust from this mine has been reported to contain nonasbestiform mineral particles that are mostly cummingtonite-grunerite, along with accessory tremoliteactinolite and other amphibole varieties. No excess of mesothelioma has been documented among these gold miners. Although small excesses of lung cancer deaths were found in the most recent study (Steenland and Brown, 1995), there was again a lack of a cumulative dust exposure response. However, the subsection also notes that total dust is likely a poor surrogate for exposure to nonasbestiform mineral particles, making this study largely uninformative about the risk of lung cancer associated with such exposure. This subsection concludes that the studies of the Homestake gold miners provide at best weak evidence of an excess risk of lung cancer, and there are inadequate data on worker exposures to nonasbestiform minerals.

The subsection on studies of taconite iron ore miners and millers in northeastern Minnesota indicates that recent sampling and analysis of the ores from the taconite iron ore mines reported no asbestos, but did find ferroactinolite, ferrian sepiolite, grunerite-ferroactinolite, and actinolite, some of which was fibrous. The subsection concludes with a summary noting that cohort mortality studies (Higgins et al., 1983; Cooper et al., 1988, 1992) have not provided any evidence of an increased risk of respiratory cancer or mesothelioma. In contrast, recent reports from the Minnesota Department of Health (MDH, 2007; Brunner et al., 2008) have documented an excess of mesotheliomas among males, but not females, in this region of Minnesota and many of these cases had been workers in the taconite industry. There is evidence that at least some of the cases may have had exposures to asbestos, but further research to resolve this issue is ongoing.

The summary of the section states that the results from these studies of workers reportedly exposed to nonasbestiform mineral particles “do not provide clear answers regarding the toxicity” (NIOSH, 2009, p. 26)

Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
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because of a number of limitations. First, all three populations of workers studied were exposed to complex mixtures of particles that included only a relatively small percentage of nonasbestiform mineral particles. Second, data on past exposures to those particles are inadequate, and exposure to total dust is likely a poor surrogate for such exposure. Third, the reliability of death certificate information for mesothelioma diagnosis prior to 1999 may be poor. Fourth, the lack of individual smoking data is another major limitation for interpretation of any lung cancer risk among these populations. Because of these limitations, the section concludes that “the findings from these studies should best be viewed as providing inconclusive as opposed to negative evidence regarding the health hazards associated with exposures to nonasbestiform elongated mineral particles” (NIOSH, 2009, p. 27). This conclusion is judged by the committee to be appropriate. To be useful for causal inference, epidemiological studies require sufficient data on the relevant exposures, health outcomes, and confounding factors. Unfortunately, sufficient data on exposures, outcomes, and confounders do not appear to be available for any of the three U.S. populations. Information or research needs on the potential for synergistic interactions between smoking and elongate mineral particle exposure should be detailed.

The section further concludes that additional studies of these three populations would need improved characterization of exposures to elongate mineral particles, diagnosis of mesothelioma, information on smoking, and information about exposures in other employment; additional studies should be attempted only if “these improvements are deemed feasible” (NIOSH, 2009, p. 27). The committee agrees with this conclusion. Although improved exposure assessment may be possible through reanalysis of archived samples from the three mining sources, it is unclear that improved information on smoking and other employment can be obtained for the New York talc and the Homestake mining populations. Perhaps adequate additional information on mesothelioma diagnosis, smoking, and other employment can be obtained through the ongoing study of the Minnesota taconite-exposed population.

The committee agrees with the Roadmap’s assessment of the results of the epidemiological studies on elongate mineral particles as inconclusive.

Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
×

Gaps in the Roadmap and Research Directions

The epidemiological studies discussed in the Roadmap reflect NIOSH’s concern with the potential toxicity of elongate mineral particles, and the committee appreciates this concern. The Roadmap however, as currently titled and configured, is intended to outline a research framework for asbestos as well as other elongate mineral particles. In this light, attention to epidemiological studies of workers and nonworkers exposed to vermiculite from the mine in Libby, Montana, is important. NIOSH investigators have been involved in the study of Libby miners and millers for many years (Amandus and Wheeler, 1987; Sullivan, 2007). Because the amphiboles in the Libby ore have been recently reclassified using 1997 IMA amphibole nomenclature to be predominantly winchite and richerite rather than tremolite, it behooves the Roadmap to specify the ongoing research efforts to better understand the exposure-response relationships for various health outcomes (pleural plaques, pulmonary fibrosis, mesothelioma, lung cancer) among both workers and residents. The risk of asbestosis from exposure to elongate mineral particles in nonoccupational settings has not been studied adequately. Significant excess mortality from nonmalignant respiratory disease has been reported by NIOSH among Libby workers with relatively low cumulative lifetime exposures (i.e., at a level allowable by the current OSHA standard over a 45-year working life) (Sullivan, 2007). Such an exposure-response is striking and deserves further investigation. In addition to discussions of occupational exposures, further attention to environmental exposures is needed in keeping with the goal of setting out a research plan that could be used by multiple federal agencies and other organizations to address the range of potential exposures. In examining the impact of environmental exposures it will be important for researchers to explore the effects of childhood exposures as well as exposures in other potentially vulnerable populations.

Further, the document discusses only U.S. epidemiological studies. Multiple international studies of exposure to amphibole particles have not been included. While the committee understands that the Roadmap was not intended to be a comprehensive review of the asbestos epidemiological literature, some attention to these studies seems relevant for planning future research on the health effects of exposure to elongate mineral particles. Several studies have shown risk of pleural plaques and/or mesothelioma to be associated with exposure to amphibole particles in either soil or whitewash derived from soil in some Mediterranean countries and in New Caledonia (Sakellariou et al., 1996; Luce et al.,

Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
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2000, 2004; Senyiğit et al., 2000; Menvielle et al., 2003). It is important to determine to what extent it is possible to extrapolate from exposures and health outcomes recognized in these studies to populations with occupational exposures.

Scientific Rationale and Research Directions

As noted in discussions in Chapter 2, efforts are needed to clarify the goals of the roadmap and to lay out the research hypotheses. The Roadmap states that “research is needed to assess and quantify potential human health risks associated with occupational exposures to other mineral fibers and elongated mineral particles, as well as to better understand and quantify the epidemiology of asbestos-related diseases using more refined indices of exposure” (NIOSH, 2009, p. 76). The committee agrees with both aspects of this statement.

The Roadmap recommends that “it would be reasonable to thoroughly review, assess, and summarize the available information on asbestiform amphiboles that have not been commercially exploited as asbestos” (NIOSH, 2009, p.77). The committee agrees that such a review could be informative. The Roadmap specifically indicates that it is not meant to be a comprehensive review of the scientific literature. However, such a review (with the literature search methodology thoroughly detailed) would provide NIOSH with a foundation on which to build a focused research program by identifying specific data gaps that are relevant to worker protection as well as potential opportunities for collaboration with partners in the United States (e.g., EPA, Agency for Toxic Substances and Disease Registry [ATSDR]) regarding issues in Libby, Montana, and in other countries where populations have been exposed to amphiboles that have not been commercially exploited.

The Roadmap also notes the need to determine whether elongate amphibole particles pose a risk to human health and recommends that an expert panel be assembled to evaluate whether the existing epidemiological evidence could support development of a likely maximum risk estimate associated with exposure to these elongate mineral particles. Based on the review of the epidemiological literature contained in this document, it does not appear that the epidemiological evidence is sufficiently robust for such an endeavor.

Section 2.3.2 of the Roadmap briefly discusses the possibility of using new tools for the diagnosis of asbestos-related health effects at earlier stages of disease such as “modern medical pulmonary imaging tech-

Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
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niques” (positron emission tomography [PET] scanning is specifically mentioned) or “bioassays of circulating levels of cytokines or other biochemical factors associated with disease processes” (NIOSH, 2009, p. 78). The committee notes that although the development of sensitive bioassays for intermediate end points on the pathways from exposure to asbestos and other elongate mineral particles to pulmonary fibrosis, lung cancer, and mesothelioma is a laudable research goal, the application of such bioassays to medical surveillance of exposed workers would require a major and lengthy validation effort given the long latency of these health outcomes. Research is needed on radiographic changes induced by elongate mineral particles other than asbestos to determine if these differ from asbestos-induced changes. Because chest computed tomography (CT) scanning is a better tool than the standard chest X-ray to detect fiber-induced change, it would play a major role in such research.

Modern chest imaging techniques such as high-resolution CT or PET scanning are not likely to be useful in medical surveillance of asbestosor other related disease in the near term due to the level of radiation exposure, lack of portable equipment, and expense. More details are needed in the Roadmap on NIOSH’s effort to advance the International Labour Organization’s (ILO’s) pneumoconiosis radiographic classification scheme and the NIOSH B-reader certification program into the modern era of digital chest radiographic imaging. This effort is vitally important to the ability to sustain asbestos medical surveillance programs as well as conduct epidemiological research in populations exposed to asbestos or other elongate mineral particles. The committee encourages NIOSH to continue to support its program to develop digital images of the ILO standard films and software to project these images correctly.

The Roadmap discusses the possibility of conducting new studies of (1) worker populations exposed to amphibole cleavage fragments such as the New York talc and Minnesota taconite miners and millers; (2) populations such as Libby workers and residents incidentally exposed to a range of mineral particles from mines; (3) populations exposed to less well-studied elongate mineral particles such as wollastonite and attapulgite; and (4) meta-analyses of data from previous studies of populations exposed to mineral particles with various attributes (NIOSH, 2009). The section specifically lists criteria for selecting and prioritizing such studies, including adequacy of exposure information and work histories, sufficiency of latency and sample size, and availability of data on potential confounding factors such as cigarette smoking. The committee agrees that these criteria should be considered before any new epidemiological

Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
×

study of an exposed population is begun. It is recommended that priority be given to epidemiological studies that will contribute to better understanding of elongate mineral particle characteristics that determine toxicity and to ensuring that rigorous mineralogical characteristics are established. Research should include identifying biomarkers of toxicity that can be studied in human populations as has been discussed at a recent expert panel meeting held by ATSDR (ATSDR, 2008).

Further, the Roadmap states that opportunities for epidemiological studies of workers exposed to asbestos and the other elongate mineral particles are present in other countries. As noted above, the committee urges more discussion of these opportunities in the Roadmap.

EXPOSURE ASSESSMENT

Exposure assessment issues are cross-cutting and are centrally related to all components of the Roadmap. Exposure assessment encompasses issues associated with sampling strategy, exposure characterization, and air sampling and analysis. Issues associated with sampling and analysis are described in the background and the third strategic goal of the Roadmap, while exposure characterization is mentioned only superficially under objective one of the second research goal (see Box 2-1).

Exposure Characterization

The Roadmap contains a thorough discussion of issues associated with sample analytical techniques. There is also recognition of the importance of developing and employing comprehensive sampling strategies to characterize exposures that comprise more than one type of mineral particle (mixed exposures). There is tremendous value in performing comprehensive exposure characterizations in workplaces with mixed exposures regardless of the suitability of these workplaces for health effect studies. Detailed exposure characterizations should be multidimensional and focus on spatial and temporal variability in elongate mineral particle number, size distribution, and other physical and chemical characteristics. The exposure characterization should go beyond analyzing or reanalyzing previously collected samples. Sampling should be task- or activity-based with sufficient power to provide statistically valid estimates of exposure, a detailed description of important physical and

Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
×

chemical properties, and key exposure determinants. In the review section of the Roadmap the need for such an assessment is recognized: “these initial efforts should be supplemented with efforts to systematically identify, sample, and characterize elongated mineral particle exposures throughout U.S. industry” (NIOSH, 2009, p. 76). Roadmap section 2.3.1 recognizes the need to conduct such an assessment. These data will be important for designing, conducting, and interpreting epidemiological and toxicological studies.

Bulk samples of airborne material from selected well-characterized workplaces can be collected as reference samples to be included in the national repository of asbestos and related minerals only after rigorous mineralogical characterization. Attention should be paid to conducting source characterization studies in order to link sources of elongate mineral particles associated with ambient and/or nonoccupational exposure. Similar tools used for bulk-sample characterization in the workplace can also be applied to identifying sources associated with environmental exposures.

Sampling and Analysis

The review of current issues in the Roadmap covers the methods of sampling and analysis for standardized industrial hygiene surveys (e.g., PCM), analytical methods for research, and a short section on differential counting and other proposed methods. One of the strategic goals of the Roadmap is to “develop improved sampling and analytical methods for asbestos fibers and other elongated mineral particles” (NIOSH, 2009, p. 65). Five specific areas of research are listed:

  1. Reduce the inter-operator and inter-laboratory variability of the current analytical methods used for asbestos.

  2. Develop analytical methods with improved sensitivity to visualize thinner elongate mineral particles to ensure a more complete evaluation of airborne exposures.

  3. Develop a practical analytical method for air samples to differentiate between asbestos exposures and exposures to nonasbestiform elongate mineral analogs.

  4. Develop analytical methods to assess the durability of elongate mineral particles.

Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
×
  1. Develop and validate size-selective sampling methods for elongate mineral particles (NIOSH, 2009, p. 65).

A more comprehensive review of all microscopy methods, including SEM, for counting should be presented in the Roadmap’s review of current issues. Modern SEM holds promise as an analytical tool and, as a result, the discussion of SEM capabilities should be expanded. There is little discussion of the variability associated with asbestos counting in the section of the Roadmap that reviews current issues; yet this topic is one of the priority research areas. Additional discussion of this issue will help to justify its importance as a research priority.

Section 1.7 of the Roadmap discusses the use of analytical methods for industrial hygiene surveys as separate from analytical methods for research. The discussion focuses on integrating the use of optical microscopy methods for surveys and electron microscopy for research. The value of maintaining this distinction needs to be reconsidered. The use of drastically different exposure assessment tools for these two cases will magnify uncertainty about exposure and risk. Phase contrast microscopy methods have been used for more than 40 years. Many of the research gaps identified in the Roadmap and in this report are the result of inherent weaknesses of PCM. Advancement of our understanding of the risk associated with elongate mineral particles will not be achieved until we move aggressively to develop new techniques and employ suitable methods (e.g., PLM) already available. The Roadmap and its proposed research provide an important opportunity to make this case. The limitations of electron microscopy mentioned in the Roadmap (Section 2.4) should not be used as an excuse to maintain the status quo. Electron microscopy methods are used routinely for environmental analysis. In addition, occupational hygienists routinely collect samples that require sophisticated analyses that take days to weeks to turnaround. These limitations seem like a reasonable trade-off. Another way to look at the difference between a routine assessment tool and a research tool is that a routine assessment is less comprehensive, not an inferior method.

The document presents a good case for why PCM is an inadequate tool for elongate mineral particle exposure assessment yet falls short of recommending that it be replaced with PLM and electron microscopy techniques. PCM does not provide the detailed exposure characterization needed to conduct the complex risk assessments described in the Roadmap. Research by its nature drives the development of new technology. The Roadmap focuses to too great an extent on current costs and time

Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
×

delays associated with electron microscopy methods. As noted on page 82, “in some workplace situations, such as in construction, increases in the time needed to analyze samples and identify elongated mineral particles could potentially delay the implementation of appropriate control measures to reduce exposures.” The discussion should rather be focused on research to develop new tools.

The committee believes that the Roadmap should place a high priority on developing new electron microscopy-based methods and a lower priority on improving PCM. The Roadmap should also include a recommendation that research be conducted to relate old methods to new methods to maintain a direct link to information determined using PCM.

The Roadmap also needs to emphasize the importance of integrating the development of new and/or improved sampling and analytical methods in parallel with toxicological and epidemiological research. Since sampling and analytical methods are designed for risk assessment purposes, their development should be driven by hazard assessment information produced in these studies. For example, it does not make sense to develop solubility-based methods until toxicology studies better assess the boundaries of dissolution that are risk-based.

The Roadmap emphasizes the need to characterize thoracic elongate mineral particle deposition. The rationale for this choice must be presented. It is not clear that a thoracic-based metric is appropriate for all disease outcomes. Is a respirable elongate mineral particle metric more appropriate for mesothelioma risk? It is conceivable that different size-based exposure metrics may be appropriate for different health outcomes.

Regardless of method used, more discussion of the statistics of elongate mineral particle counting and counting quality control is needed. The advancement of science with respect to elongate mineral particle exposure assessment requires nationally recognized quality control programs. Expectations should be changed so that each count is presented as an estimate with a range of expected variability (see below).

The Roadmap should include a specific recommendation that automated counting methods be explored and compared to human counting with respect to precision and accuracy.

Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
×

Counting Strategies

In reviewing the literature on asbestos counting, there appears to be considerable variability in counts from analyst to analyst within a given laboratory as well as between laboratories. As a consequence, a new observed count from a particular analyst from a particular laboratory may deviate considerably from the true value. In an effort to provide a connection between observed and true counts and characterize the uncertainty in the true count, Dulal Bhaumik and colleagues have extended the ideas of Gibbons and Bhaumik (2001) and Bhaumik and Gibbons (2005) to the case of a Poisson random variable, which is the appropriate distribution for rare-event count data. Appendix B provides a brief sketch of one potential methodology for addressing the variability as well as an illustration of the application of this methodology. Statisticians who are also familiar with exposure data analysis should be actively involved in addressing some of the challenging data analysis issues in this area of research.

Additional Statistical Issues

There is considerable discussion in the NIOSH Roadmap on the effect of fiber counts and fiber dimensions on exposure risk. Thus the distribution of these quantities is of obvious interest. For exposure assessment, it is important to characterize the joint distribution of fiber length and width for a given material. Several researchers (see Cheng, 1986; Baron, 2001; Cheng et al., 2006) have investigated this problem and noticed that fiber length and width typically have a bivariate log-normal distribution. Data analysis based on the bivariate lognormal distribution can be complicated, depending on the parameter or parameters for which inference is desired. Likelihood based results for testing or constructing confidence intervals for one or more parameters of the distribution often produce undesirable results (e.g., inflated type 1 error rates or low coverage probability) when sample sizes are small. In order to overcome this problem one can explore procedures based on the novel concepts of generalized p-values (for hypothesis testing) and generalized confidence intervals (for computing confidence intervals) for univariate and bivariate lognormal distributions (see Krishnamoorthy and Mathew, 2003; Krishnamoorthy et al., 2006; Bebu and Mathew, 2008). Major advantages of such procedures are that they are accurate and are applicable

Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
×

to small samples. The concepts of generalized p-values and generalized confidence intervals also provide accurate methodology for comparing two lognormal distributions (for example, to compare the arithmetic means of fiber lengths obtained from two different sites or materials).

The NIOSH Roadmap also addresses the issue of comparing thoracic samplers. To compare thoracic samplers, the OSHA criterion for establishing the equivalence of a sampling device to a reference device requires that “90 percent of the readings of the sampling device should be within plus or minus 25 percent of the readings obtained by the reference device, or within plus or minus 25 percent of the actual airborne chemical concentration.” In this context one can use rigorous statistical tests developed by Krishnamoorthy and Mathew (2002) for comparing two samplers, and Krishnamoorthy et al. (2009) for comparing several samplers. The OSHA criterion, or a suitable version of it, appears to be the right criterion to compare thoracic samplers. Traditional approaches for comparison of samplers based on geometric means using t-tests are generally inadequate.

SPECIFIC COMMENTS

In addition to the major issues discussed throughout this chapter, the following paragraphs highlight a few specific suggestions for consideration to improve the Roadmap.

Some minor changes to the front matter might help readers understand the full context of the report and the iterations it has gone through. This could include detailing the specific drafts and dates of the drafts and pointing out that the peer reviewers listed on page xii reviewed the February 2007 draft. A timeline (see Table 2-1 of this report) may be helpful since the Roadmap has undergone several iterations. The committee also believes that the goal of the document should be reflected in the title and the cover. If the research is intended to address all elongate mineral particles, not just asbestos or its analogs, a different title might be appropriate. If the Roadmap is expanded at some point to include a larger range of elongate particles, more generally (whether minerals, man-made materials [e.g., ceramics], organic materials [e.g., wool and cotton], or others), the title should reflect that intent. Given the broad spectrum of elongate mineral particles addressed in the Roadmap, the cover photographs and design should also reflect this wide range of particles with

Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
×

captions that are informative regarding the scale bars, labels, and other information.

Care should be taken to ensure that descriptions of studies written prior to the release of the Roadmap use the same terminology used in the original article. If necessary, a note could be added to clarify or update the terminology. Because elongate mineral particle is a broad descriptive term and not a rigorous mineralogical term, the preference when feasible is for providing the correct mineral names.

REFERENCES

Addison, J., and E. E. McConnell. 2008. A review of carcinogenicity studies of asbestos and non-asbestos tremolite and other amphiboles. Regulatory Toxicology and Pharmacology 52(Suppl 1):S187–S199.

Amandus, H. E., and R. Wheeler. 1987. The morbidity and mortality of vermiculite miners and millers exposed to tremolite–actinolite: Part II. Mortality. American Journal of Industrial Medicine 11:15–26.

Ampian, S. G. 1976. Asbestos minerals and their nonasbestos analogs. Presentation to the Mineral Fibers Session, Electron Microscopy of Microfibers. Pennsylvania Sate University, August 23–25.

ATSDR (Agency for Toxic Substances and Disease Registry). 2008. Biomarkers of asbestos exposure and disease. http://www.atsdr.cdc.gov/asbestos/asbestos/biomarkers_asbestos/index.html (accessed September 9, 2009).

Baron, P. A. 2001. Measurement of airborne fibers: A review. Industrial Health 39:39–50.

Bebu, I., and T. Mathew. 2008. Comparing the means and variances of a bivariate lognormal distribution. Statistics in Medicine 14:2684–2696.

Berman, D. W., K. S. Crump, E. J. Chatfield, J. M. Davis, and A. D. Jones. 1995. The sizes, shapes, and mineralogy of asbestos structures that induce lung tumors or mesothelioma in AF/HAN rats following inhalation. Risk Analysis15(2):181–195.

Bernstein, D. M., and J. A. Hoskins. 2006. The health effects of chrysotile: Current perspective based on recent data. Regulatory Toxicology and Pharmacology45(3):252–264.

Bernstein, D. M., R. Rogers, P. Smith, and J. Chevalier. 2006. The toxicological response of Brazilian asbestos: A multidose subchronic 90-day inhalation toxicology study with 92-day recovery to assess

Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
×

cellular and pathological response. Inhalation Toxicology 18(5):313–332.

Bertino, P., A. Marconi, L. Palumbo, B. M. Bruni, D. Barbone, S. Germano, A. U. Dogan, G. F. Tassi, C. Porta, L. Mutti, G. Gaudino. 2007. Erionite and asbestos differently cause transformation of human mesothelial cells. International Journal of Cancer 121(1):12–20.

Bhaumik, D. K., and R. D. Gibbons. 2005. Confidence regions for random-effects calibration curves with heteroscedastic errors. Technometrics 62:223–230.

Bocchetta, M., I. Di Resta, A. Powers, R. Fresco, A. Tosolini, J. R. Testa, H. I. Pass, P. Rizzo, and M. Carbone. 2000. Human mesothelial cells are unusually susceptible to simian virus 40-mediated transformation and asbestos cocarcinogenicity. Proceedings of the National Academy of Sciences 97(18):10214–10219.

Both, K., D. W. Henderson, and D. R. Turner. 1994. Asbestos and erionite fibers can induce mutations in human lymphocytes that resulted in loss of heterozygosity. International Journal of Cancer 59:538–542.

Brown, D. P., S. D. Kaplan, R. D. Zumwalde, M. Kaplowitz, and V. E. Archer. 1986. Retrospective cohort mortality study of underground gold mine workers. In Silica, Silicosis, and Lung Cancer, edited by D. Goldsmith, D. Winn, and C. Shy. New York: Praeger. Pp. 335–350.

Brunner, W. M., A. N. Williams, and A. P. Bender. 2008. Investigation of exposures to commercial asbestos in northeastern Minnesota iron miners who developed mesothelioma. Regulatory Toxicology and Pharmacology 52(Suppl 1):S116–S120.

Cacciotti P., D. Barbone, C. Porta, D. A. Altomare, J. R. Testa, L. Mutti, and G. Gaudino. 2005. SV40-dependent AKT activity drives mesothelial cell transformation after asbestos exposure. Cancer Research 65(12):5256–5262.

Campbell, W. J., C. W. Huggins, and A. G. Wylie. 1980. Chemical and physical characterization of amosite, chrysotile, crocidolite, and nonfibrous tremolite for oral ingestion studies by the National Institute of Environmental Health Sciences. Washington, DC: U.S. Bureau of Mines. R. I. 8452.

Cheng, Y-S. 1986. Bivariate lognormal distribution for characterizing asbestos fiber aerosols. Aerosol Science and Technology 5:359–368.

Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
×

Cheng, Y-S., T. D. Holmes, and B. Fan. 2006. Evaluation of respirator filters for asbestos fibers. Journal of Occupational and Environmental Hygiene3:26–35.

Christensen, V. R., S. Lund Jensen, M. Guldberg, and O. Kamstrup. 1994. Effect of chemical composition of man-made vitreous fibers on the rate of dissolution in vitro at different pHs. Environmental Health Perspectives 102(Suppl 5):83–86.

Cooper, W. C., O. Wong, and R. Graebner. 1988. Mortality of workers in two Minnesota taconite mining and milling operations. Journal of Occupational Medicine 30:506–511.

Cooper, W. C., O. Wong, L. S. Trent, F. Harris. 1992. An updated study of taconite miners and millers exposed to silica and nonasbestiform amphiboles. Journal of Occupational Medicine 34:1173–1180.

Davis, J. M., J. Addison, C. McIntosh, B. G. Miller, and K. Niven. 1991. Variations in carcinogenicity of tremolite dust samples of differing morphology. Annals of the New York Academy of Sciences 643:473–490.

de Meringo, A., C. Morscheidt, S. Thélohan, and H. Tiesler. 1994. In vitro assessment of biodurability: Acellular systems. Environmental Health Perspectives 102(Suppl 5):47–53.

Enterline, P. E., and V. L. Henderson. 1987. Geographic patterns for pleural mesothelioma deaths in the United States, 1968–81. Journal of the National Cancer Institute 79:31–37.

European Commission Joint Research Centre. 1999. Methods for the determination of the hazardous properties for human health of man made mineral fibres (MMMF), edited by D. M. Bernstein and J. M. Riego Sintes. http://tsar.jrc.ec.europa.eu/documents/Testing-Methods/mmmfweb.pdf (accessed October 5, 2009).

Gibbons, R. D., and D. Bhaumik. 2001. Weighted random-effects regression models with application to inter-laboratory calibration. Technometrics 43:192–198.

Gillam, J., J. Dement, R. Lemen, J. Wagoner, V. Archer, and H. Blejer. 1976. Mortality patterns among hard rock gold miners exposed to an asbestiform mineral. Annals of the New York Academy of Sciences 271:336–344.

Hawthorne, F. C., and R. Oberti. 2007. Classification of the amphiboles. Reviews in Mineralogy and Geochemistry 67:55–88.

Hei, T. K., L. J. Wu, and C. Q. Piao. 1997. Malignant transformation of immortalized human bronchial epithelial cells by asbestos fibers. Environmental Health Perspectives 105:1085–1088.

Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
×

Hei, T. K., A. Xu, D. Louie, and Y. L. Zhao. 2000. Genotoxicity versus carcinogenicity: Implications from fiber toxicity studies. Inhalation Toxicology 12:141–147.

Hesterberg, T. 2009. Comments on Asbestos Roadmap—Animal Bioassays. Presentation to the Committee for the Review of the NIOSH Roadmap on Asbestos and Other Elongate Mineral Particles. Washington, DC, March 30.

Hesterberg, T. W., and J. C. Barrett. 1984. Dependence of asbestos- and mineral dust-induced transformation of mammalian cells in culture on fiber dimension. Cancer Research 44(5):2170–2180.

Hesterberg, T. W., and G. A. Hart. 2001. Synthetic vitreous fibers: A review of toxicology research and its impact on hazards classification. Critical Reviews of Toxicology 1:1–53.

Hesterberg, T. W., G. A. Hart, W. C. Miiller, G. Chase, R. A. Rogers, J. B. Mangum, and J. I. Everitt. 2002. Use of short-term assays to evaluate the potential toxicity of two new biosoluble glasswool fibers. Inhalation Toxicology 14:217–246.

Higgins, I. T. T., J. H. Glassman, M. S. Oh, and R. G. Cornell. 1983. Mortality of Reserve Mining Company employees in relation to taconite dust exposure. American Journal of Epidemiology 118:710–719.

Hull, M. J., J. L. Abraham, and B. W. Case. 2002. Mesothelioma among workers in asbestiform fiber-bearing talc mines in New York State. Annals of Occupational Hygiene 46(Suppl 1):132–135.

ILSI (International Life Sciences Institute). 2005. Testing of fibrous particles: Short-term assays and strategies. Report of an ILSI Risk Science Institute Working Group. Inhalation Toxicology 17(10):497–537.

IMA (International Mineralogical Association). 2009. Commission on New Minerals, Nomenclature and Classification. http://www.imamineralogy.org (accessed June 22, 2009).

Jaurand, M. C. 1996. Use of in vitro genotoxicity and cell transformation assays to evaluate the potential carcinogenicity of fibres. In Mechanisms of fibre carcinogenesis, edited by A. B. Kane, P. Boffetta, R. Saracci, and J. D. Wilbourn. IARC 140. Lyon: IARC. Pp. 55–72.

Kelse, J. W. 2005. White Paper: Asbestos, health risk and tremolitic talc. Norwalk, CT: RT Vanderbilt Co. Inc. As cited in NIOSH, 2009.

Krishnamoorthy, K., and T. Mathew. 2002. Statistical methods for establishing equivalency of a sampling device to the OSHA standard. American Industrial Hygiene Association Journal 63:567–571.

Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
×

Krishnamoorthy, K., and T. Mathew. 2003. Inferences on the means of lognormal distributions using generalized p-values and generalized confidence intervals. Journal of Statistical Planning and Inference 115:103–121.

Krishnamoorthy, K., T. Mathew, and G. Ramachandran. 2006. Generalized p-values and confidence intervals: A novel approach for analyzing lognormally distributed exposure data. Journal of Occupational and Environmental Hygiene 3:642–650.

Krishnamoorthy, K., A. Mallick, and T. Mathew. 2009. Model based imputation approach for data analysis in the presence of non-detectable values: Normal and related distributions. Annals of Occupational Hygiene 59:249–268.

Leake, B.E., A. R. Woolley, C. E. S. Arps, W. D. Birch, M. C. Gilbert, J. D. Grice, F. C. Hawthorne, A. Kato, H. J. Kisch, V. G. Krivovichev, K. Linthout, J. Laird, J. A. Mandarino, W. V. Maresch, E. H. Nickel, N. M. S. Rock, J. C. Schumacher, D. C. Smith, N. C. N. Stephenson, L. Ungaretti, E. J. W. Whittaker, and G. Youshi. 1997. Nomenclature of amphiboles: Report of the subcommittee on amphiboles of the International Mineralogical Association, Commission on New Minerals and Mineral Names. American Mineralogist 82:1019–1037.

Leake, B. E., A. R. Woolley, W. D. Birch, E. A. J. Burke, G. Ferraris, J. D. Grice, F. C. Hawthorne, H. J. Kisch, V. G. Krivovichev, J. C. Schumacher, N. C. N. Stephenson, and E. J. W. Whittaker. 2004. Nomenclature of amphiboles: Additions and revisions to the International Mineralogical Association’s amphibole nomenclature. American Mineralogist 89:883–887.

Lippmann, M. 1988. Asbestos exposure indices. Environmental Research 46:86–106.

Lowers, H., and G. Meeker. 2002. Tabulation of asbestos-related terminology. U.S. Geological Survey Open-File Report 02-0458. http://pubs.usgs.gov/of/2002/ofr-02-458 (accessed October 5, 2009).

Luce, D., I. Bugel, P. Goldberg, M. Goldberg, C. Salomon, M. A. Billon-Galland, J. Nicolau, P. Quénel, J. Fevotte, P. Brochard. 2000. Environmental exposure to tremolite and respiratory cancer in New Caledonia: A case-control study. American Journal of Epidemiology 151(3): 259–265.

Luce, D., M. A. Billon-Galland, I. Bugel, P. Goldberg, C. Salomon, J. Févotte, and M. Goldberg. 2004. Assessment of environmental and

Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
×

domestic exposure to tremolite in New Caledonia. Archives of Environmental Health 59(2):91–100.

Mauderly, J. L. 1997. Relevance of particle-induced rat lung tumors for assessing lung carcinogenic hazard and human lung cancer risk. Environmental Health Perspectives105(Suppl 5):1337–1346.

Maxim, L. D., J. G. Hadley, R. M. Potter, and R. Niebo. 2006. The role of fiber durability/biopersistence of silica-based synthetic vitreous fibers and their influence on toxicology. Regulatory Toxicology and Pharmacology 46:42–62.

McDonald, J. C., G. W. Gibbs, F. D. K. Liddel, and A. D. McDonald. 1978. Mortality after long exposure to cummingtonite-grunerite. American Review of Respiratory Disease 118:271–277.

MDH (Minnesota Department of Health). 2007. Mesothelioma in north-eastern Minnesota and two occupational cohorts: 2007 update. St. Paul, MN: Minnesota Department of Health. http://www.health.state.mn.us/divs/hpcd/cdee/mcss/documents/nemeso1207.pdf (accessed June 30, 2008).

Menvielle, G., D. Luce, J. Févotte, I. Bugel, C. Salomon, P. Goldberg, M. A. Billon-Galland, M. Goldberg. 2003. Occupational exposures and lung cancer in New Caledonia. Occupational and Environmental Medicine 60(8):584–589.

Mikalsen, S. O., E. Rivedal, and T. Sanner. 1988. Morphological transformation of Syrian hamster embryo cells induced by mineral fibres and the alleged enhancement of benzo[a]pyrene. Carcinogenesis 9(6):891–899.

Neuendorf, K. K. E., J. P. Mehl, Jr., and J. A. Jackson, eds. 2005. Glossary of geology, 5th edition. Alexandria, VA: American Geological Institute.

Nickel, E. H., and J. D. Grice. 1998. The IMA Commission on New Minerals and Mineral Names: Procedures and guidelines on mineral nomenclature, 1998. Canadian Mineralogist 36:1–16.

Nikula, K. J., M. B. Snipes, E. B. Barr, W. C. Griffith, R. F. Henderson, and J. L. Mauderly. 1995. Comparative pulmonary toxicities and carcinogenicities of chronically inhaled diesel exhaust and carbon black in F344 rats. Fundamental and Applied Toxicology 25:80–94.

NIOSH (National Institute for Occupational Safety and Health). 1980. Occupational exposure to talc containing asbestos. Cincinatti: NIOSH. DHEW (NIOSH) Publication No. 80-115. http://www.cdc.gov/niosh/review/public/099/pdfs/TalcContainingAsbestosTR.pdf (accessed September 16, 2009).

Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
×

NIOSH. 2009. Revised draft. NIOSH current intelligence bulletin. Asbestos fibers and other elongated mineral particles: State of the science and roadmap for research. January 2009. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health. http://www.cdc.gov/niosh/docket/pdfs/NIOSH-099b/099B-040109AsbestosNAReviewDoc.pdf (accessed September 18, 2009).

NRC (National Research Council). 2007. Toxicity testing in the twenty-first century: A vision and a strategy. Washington, DC: The National Academies Press.

Oberdörster G. 1995. Lung particle overload: Implications for occupational exposures to particles. Regulatory Toxicology and Pharmacology 21(1):123–135.

Park, S.H., and A. E. Aust. 1998. Participation of iron and nitric oxide in the mutagenicity of asbestos in hgprt-, gpt+ Chinese hamster V79 cells. Cancer Research 58:1144–1148.

Piao, C. Q., Y. L. Zhao, and T. K. Hei. 2001. Analysis of p16 and p21(Cip1) expression in tumorigenic human bronchial epithelial cells induced by asbestos. Oncogene 20(50):7301–7306.

Sakellariou, K., V. Malamou-Mitsi, A. Haritou, C. Koumpaniou, C. Stachouli, I. D. Dimoliatis, S. H. Constantopoulos. 1996. Malignant pleural mesothelioma from nonoccupational asbestos exposure in Metsovo (north-west Greece): Slow end of an epidemic? European Respiratory Journal 9(6):1206–1210.

Schins, R., and T. K. Hei. 2006. Genotoxic effects of particles. In Particle toxicology, edited by K. Donaldson and P. Borm. London: CRC Press. Pp. 287–300.

Sebastian, K., J. Fellman, R. Potter, et al. 2002. EURIMA test guideline: In-vitro acellular dissolution of manmade vitreous silicate fibres. Technical report. Glastechnische Berichte—Glass Science and Technology 75(5):263–270.

Senyiğit, A., C. Babayiğit, M. Gökirmak, F. Topçu, E. Asan, M. Coşkunsel, R. Işik, and M. Ertem. 2000. Incidence of malignant pleural mesothelioma due to environmental asbestos fiber exposure in the southeast of Turkey. Respiration 67(6):610–614.

Shukla, A., M. B. MacPherson, J. Hillegass, M. E. Ramos-Ning, V. Alexeeva, P. M. Vacek, J. P. Bond, H. I. Pass, C. Steele, and B. T. Mossman. 2009. Alterations in gene expression in human mesothelial cells correlated with mineral pathogenicity. American Journal of Respiratory Cell Molecular Biology 41:114–123.

Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
×

Steenland, K., and D. Brown. 1995. Mortality study of gold miners exposed to silica and nonasbestiform amphibole minerals: An update with 14 more years of followup. American Journal of Industrial Medicine 27:217–229.

Sullivan, P. 2007. Vermiculite, respiratory disease and asbestos exposure in Libby, Montana: Update of a cohort mortality study. Environmental Health Perspectives 115:579–585.

U.S. Court of Appeals Ninth Circuit. 2007. U.S. v. W. R. Grace. http://www.ca9.uscourts.gov/datastore/opinions/2007/09/20/0630472.pdf (accessed July 9, 2009).

Vianna, N. J., J. Maslowsky, S. Robert, G. Spellman, and B. Patton. 1981. Malignant mesothelioma: Epidemiologic patterns in New York State. New York State Journal of Medicine 81:735–738.

Wagner, J. C., G. Berry, V. Timbrell. 1973. Mesothelioma in rats after inoculation with asbestos and other materials. British Journal of Cancer 28(2):173–185.

Wagner, J. C., G. Berry, J. W. Skidmore, V. Timbrell. 1974. The effects of the inhalation of asbestos in rats. British Journal of Cancer 29(3):252–269.

Wagner, J. C., G. B. Berry, R. J. Hill, D. E. Munday, et al. 1982. Animal experiments with MMM(V)F — Effects of inhalation and intrapleural inoculation in rats. In: Biological effects on man-made mineral fibers. Vol. 2. WHO/IARC Conference, Copenhagen, April 20–22, 1982. Pp. 209–233.

Wang, Y., S. P. Faux, G. Hallden, D. H. Kirn, C. E. Houghton, N. R. Lemoine, and G. Patrick. 2004. Interleukin-1 beta and tumor necrosis factor alpha promotes the transformation of human immortalized mesothelial cells by erionite. International Journal of Oncology 25:173–178.

Xu, A., S. Huang, Y. Lien, D. Yu, and T. K. Hei. 2007. Genotoxic mechanisms of asbestos fibers: Role of extranuclear targets. Chemical Research in Toxicology 20:724–733.

Zhao, Y. L., C. Q. Piao, L. J. Wu, M. Suzuki, and T. K Hei.2000. Differentially expressed genes in asbestos-induced tumorigenic human bronchial epithelial cells: Implications for mechanism. Carcinogenesis 21:2005–2010.

Zoitos, B. K., A. de Meringo, E. Rouyer, S. Thélohan, J. Bauer, B. Law, P. M. Boymel, R. Olson, V. R. Christensen, M. Guldberg, A. R. Koenig, and M. Perander. 1997. In vitro measurement of fiber dis-

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solution rate relevant to biopersistence at neutral pH: An interlaboratory round robin. Inhalation Toxicology 9(6):525–540.

Suggested Citation:"3 Major Scientific Issues: State of the Science and Future Research Directions." Institute of Medicine and National Research Council. 2009. A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles. Washington, DC: The National Academies Press. doi: 10.17226/12697.
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Although asbestos is no longer mined in the United States, prior and ongoing exposures to asbestos continue to contribute to respiratory diseases, including mesothelioma, lung cancer, and asbestosis. To examine ongoing issues and concerns in this field, the National Institute for Occupational Safety and Health (NIOSH) drafted a research roadmap, Asbestos Fibers and Other Elongated Mineral Particles: State of the Science and Roadmap for Research, that provides an overview of the state of the science and a plan for future research in areas including toxicology, mineralogy, epidemiology, and exposure assessment.

The focus of the proposed research is on clarifying the relationship between human health effects and the physical and chemical characteristics of a wide range of elongate mineral particles. In 2008, NIOSH asked the Institute of Medicine and the National Research Council to form a committee to provide a review of the scientific and technical quality of the January 2009 draft NIOSH Roadmap document. The present volume provides the committee's assessment of the Roadmap and recommendations for strengthening its utility for NIOSH, other federal agencies, the private sector, and other stakeholders.

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