Asbestos Fibers and Other Elongate Mineral Particles: State of the Science and Roadmap for Research

Home , Acicular (crystal habit), Richterite

CURRENT INTELLIGENCE BULLETIN 62

Revised Edition

DEPARTMENT OF HEALTH AND HUMAN SERVICES Centers for Disease Control and Prevention National Institute for Occupational Safety and Health Cover Photograph: Transitional particle from upstate New York identified by the United States Geological Survey (USGS) as anthophyllite asbestos altering to talc. Photograph courtesy of USGS. CURRENT INTELLIGENCE BULLETIN 62

Asbestos Fibers and Other Elongate Mineral Particles: State of the Science and Roadmap for Research

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DHHS (NIOSH) Publication No. 2011–159 (Revised for clarification; no changes in substance or new science presented)

April 2011

Safer • Healthier • PeopleTM

ii Foreword

Asbestos has been a highly visible issue in public health for over three decades. During the mid- to late-20th century, many advances were made in the scientific understanding of worker health effects from exposure to asbestos fibers and other elongate mineral particles (EMPs). It is now well documented that asbestos fibers, when inhaled, can cause serious diseases in exposed workers. However, many questions and areas of confusion and scientific uncertainty remain.

The National Institute for Occupational Safety and Health (NIOSH) has determined that exposure to asbestos fibers causes cancer and asbestosis in humans on the basis of evidence of respiratory disease observed in workers exposed to asbestos, and recommends that exposures be reduced to the lowest feasible concentration. As the federal agency responsible for conducting research and making recommendations for the prevention of worker injury and illness, NIOSH has undertaken a reappraisal of how to ensure optimal protection of workers from exposure to asbestos fibers and other EMPs. As a first step in this effort, NIOSH convened an internal work group to develop a framework for future scientific research and policy development. The NIOSH Mineral Fibers Work Group prepared a first draft of thisState of the Science and Roadmap for Scientific Research herein( referred to as the Roadmap), summariz- ing NIOSH’s understanding of occupational exposure and toxicity issues concerning asbestos fibers and other EMPs.

NIOSH invited comments on the occupational health issues identified and the framework for research suggested in the first draft Roadmap. NIOSH sought other views about additional key issues that should be identified, additional research that should be conducted, and methods for conducting the research. In particular, NIOSH sought input from stakeholders concerning study designs, techniques for generating size-selected fibers, analytic approaches, sources of particular types of EMPs suitable for experimental studies, and worker populations suitable for epidemiological study. On the basis of comments received during the public and expert peer review process, NIOSH revised the Roadmap and invited public review of the revised version by stakeholders. After further revision and public comment, a revised draftRoadmap was submitted for review by the National Academies of Science in early 2009. Based on the National Academies assessment of the draft Roadmap, revisions were made, and NIOSH disseminated a fourth draft version of the document for final public comment in early 2010. After considering these comments, NIOSH has developed this final revision of theRoadmap .

The purpose of this Roadmap is to outline a research agenda that will guide the development of specific research programs and projects that will lead to a broader and

iii clearer understanding of the important determinants of toxicity for asbestos fibers and other EMPs. NIOSH recognizes that results from such research may impact environmental as well as occupational health policies and practices. Many of the issues that are important in the workplace are also important to communities and to the general population. Therefore, NIOSH envisions that the planning and conduct of the research will be a collaborative effort involving active participation of multiple federal agencies, including the Agency for Toxic Substances and Disease Registry (ATSDR), the Consumer Product Safety Commission (CPSC), the Environmental Protection Agency (EPA), the Mine Safety and Health Administration (MSHA), the National Institute of Environmental Health Sciences (NIEHS), the National Institute of Standards and Technology (NIST), the National Toxicology Program (NTP), the Occupational Safety and Health Administration (OSHA), and the United States Geo- logical Survey (USGS), as well as labor, industry, academia, health and safety practitioners, and other interested parties, including international groups. This collabora- tion will help to focus the scope of the research, to fund and conduct the research, and to develop and disseminate informational materials describing research results and their implications for establishing new occupational and public health policies.

This Roadmap also includes a clarified rewording of the NIOSH recommended exposure limit (REL) for airborne asbestos fibers. This clarification is not intended to establish a new NIOSH occupational health policy for asbestos, and no regulatory response by OSHA or MSHA is requested or expected.

John Howard, MD Director, National Institute for Occupational Safety and Health Centers for Disease Control and Prevention

iv Executive Summary

In the 1970s, NIOSH determined that exposure to asbestos fibers causes cancer and asbestosis in humans on the basis of evidence of respiratory disease observed in workers exposed to asbestos. Consequently, it made recommendations to the federal enforcement agencies on how to reduce workplace exposures. The enforcement agencies developed occupational regulatory definitions and standards for exposure to airborne asbestos fibers based on these recommendations. Since the promulga- tion of these standards, which apply to occupational exposures to the six commercially used asbestos minerals—the serpentine mineral chrysotile, and the amphibole minerals cummingtonite-grunerite asbestos (amosite), riebeckite asbestos (crocidolite), actinolite asbestos, anthophyllite asbestos, and tremolite asbestos—the use of asbestos in the United States has declined substantially and mining of asbestos in the United States ceased in 2002. Nevertheless, many asbestos products remain in use and new asbestos-containing products continue to be manufactured in or imported into the United States.

As more information became available on the relationship between the dimensions of asbestos fibers and their ability to cause nonmalignant respiratory disease and cancer, interest increased in exposure to other “mineral fibers.” The term “mineral fiber” has been frequently used by nonmineralogists to encompass thoracic-size elongate mineral particles (EMPs) occurring either in an asbestiform habit (e.g., asbestos fibers) or in a nonasbestiform habit (e.g., as needle-like [acicular] or prismatic crystals), as well as EMPs that result from the crushing or fracturing of nonfibrous minerals (e.g., cleavage fragments). Asbestos fibers are clearly of substantial health concern. Further research is needed to better understand health risks associated with exposure to other thoracic-size EMPs, including those with mineralogical compositions identical or similar to the asbestos minerals and those that have already been documented to cause asbestos-like disease, as well as the physicochemical characteristics that determine their toxicity.

Imprecise terminology and mineralogical complexity have affected progress in research. “Asbestos” and “asbestiform” are two commonly used terms that lack mineralogical precision. “Asbestos” is a term used for certain minerals that have crystallized in a particular macroscopic habit with certain commercially useful properties. These properties are less obvious on microscopic scales, and so a different definition of -as bestos may be necessary at the scale of the light microscope or electron microscope, involving characteristics such as chemical composition and crystallography. “Asbesti- form” is a term applied to minerals with a macroscopic habit similar to that of asbestos. The lack of precision in these terms and the difficulty in translating macroscopic

v properties to microscopically identifiable characteristics contribute to miscommunication and uncertainty in identifying toxicity associated with various forms of minerals. Deposits may have more than one mineral habit and transitional minerals may be present, which make it difficult to clearly and simply describe the mineralogy.

In 1990, NIOSH revised its recommendation concerning occupational exposure to airborne asbestos fibers. At issue were concerns about potential health risks associated with worker exposures to the analogs of the asbestos minerals that occur in a different habit—so-called cleavage fragments—and the inability of the analytical method routinely used for characterizing airborne exposures (i.e., phase contrast microscopy [PCM]) to differentiate nonasbestiform analogs from asbestos fibers on the basis of physical appearance. This problem was further compounded by the lack of more sensitive analytical methods that could distinguish asbestos fibers from other EMPs having the same elemental composition. To address these concerns and ensure that workers are protected, NIOSH defined “airborne asbestos fibers” to encompass not only fibers from the six previously listed asbestos minerals (chrysotile, crocidolite, amosite, anthophyllite asbestos, tremolite asbestos, and actinolite asbestos) but also EMPs from their nonasbestiform analogs. NIOSH retained the use of PCM for measuring airborne fiber concentrations and counting those EMPs having: (1) an aspect ratio of 3:1 or greater and (2) a length greater than 5 µm. NIOSH also retained its recommended exposure limit (REL) of 0.1 airborne asbestos fiber per cubic centimeter (f/cm3).

Since 1990, several persistent concerns have been raised about the revised NIOSH recommendation. These concerns include the following:

•• NIOSH’s explicit inclusion of EMPs from nonasbestiform amphiboles in its 1990 revised definition of airborne asbestos fibers is based on inconclusive science and contrasts with the regulatory approach subsequently taken by OSHA and by MSHA. •• The revised definition of airborne asbestos fibers does not explicitly encompass EMPs from asbestiform amphiboles that formerly had been mineralogically defined as tremolite (e.g., winchite and richterite) or other asbestiform minerals that are known to be (e.g., erionite and fluoro-edenite) or may be (e.g., some forms of talc) associated with health effects similar to those caused by asbestos. •• The specified dimensional criteria (length and aspect ratio) for EMPs covered by the revised definition of airborne asbestos fibers may not be optimal for protecting the health of exposed workers because they are not based solely on health concerns. •• Other physicochemical parameters, such as durability and surface activity, may be important toxicological parameters but are not reflected in the revised definition of airborne asbestos fibers. •• NIOSH’s use of the term “airborne asbestos fibers” to describe all airborne EMPs covered by the REL differs from the way mineralogists use the term and this inconsistency leads to confusion about the toxicity of EMPs. vi NIOSH recognizes that its 1990 description of the particles covered by the REL for airborne asbestos fibers has created confusion, causing many to infer that the nonasbestiform minerals included in the NIOSH definition are “asbestos.” Therefore, in this Roadmap, NIOSH makes clear that such nonasbestiform minerals are not “asbestos” or “asbestos minerals,” and clarifies which particles are included in the REL. This clarification also provides a basis for a better understanding of the need for the proposed research. Clarification of the REL in this way does not change the existing NIOSH occupational health policy for asbestos, and no regulatory response by OSHA or MSHA is requested or expected. The REL remains subject to revision based on findings of ongoing and future research.

PCM, the primary method specified by NIOSH, OSHA, and MSHA for analysis of air samples for asbestos fibers, has several limitations, including limited ability to resolve very thin fibers and to differentiate various types of EMPs. Occupational exposure limits for asbestos derive from lung cancer risk estimates from exposure of workers to airborne asbestos fibers in commercial processes. These risk assessments are based on fiber concentrations determined from a combination of PCM-based fiber counts on membrane filter samples and fiber counts estimated from impinger samples. The standard PCM method counts only fibers longer than 5 µm. Moreover, some fibers longer than 5 µm may be too thin to be detected by PCM. Thus, an undetermined number of fibers collected on each sample remain uncounted by PCM. More sensitive analytical methods are currently available, but standardization and validation of these methods will be required before they can be recommended for routine analysis. However, unlike PCM, these methods are substantially more ex- pensive, and field instruments are not available. In addition, any substantive change in analytical techniques used to evaluate exposures to asbestos and/or the criteria for determining exposure concentrations will necessitate a reassessment of current risk estimates, which are based on PCM-derived fiber concentrations.

Epidemiological evidence clearly indicates a causal relationship between exposure to fibers from the asbestos minerals and various adverse health outcomes, including asbestosis, lung cancer, and mesothelioma. However, NIOSH has viewed as inconclusive the results from epidemiological studies of workers exposed to EMPs from the nonasbestiform analogs of the asbestos minerals. Populations of interest for possible epidemiological studies include workers at talc mines in upstate New York and workers at taconite mines in northeastern Minnesota. Others include populations exposed to other EMPs, such as winchite and richterite fibers (asbestiform EMPs identified in vermiculite from a former mine near Libby, Montana), zeolites (such as asbestiform erionite), and other minerals (such as fluoro-edenite). Future studies should include detailed characterizations of the particles to which workers are or have been exposed.

There is considerable potential for experimental animal andin vitro studies to address specific scientific questions relating to the toxicity of EMPs. Short-termin vivo animal studies and in vitro studies have been conducted to examine cellular and tissue responses to EMPs, identify pathogenic mechanisms involved in those

vii responses, and understand morphological and/or physicochemical EMP properties controlling those mechanisms. Long-term studies of animals exposed to EMPs have been conducted to assess the risk for adverse health outcomes (primarily lung cancer, mesothelioma, and lung fibrosis) associated with various types and dimensions of EMPs. Such studies have produced evidence demonstrating the importance of dimensional characteristics of mineral particles for determining carcinogenic potential of durable EMPs. Although in vitro studies and animal studies are subject to uncertainties with respect to how their findings apply to humans, such studies are warranted to systematically assess and better understand the impacts of dimension, morphology, chemistry, and biopersistence of EMPs on malignant and nonmalignant respiratory disease outcomes. To reduce existing scientific uncertainties and to help resolve current policy controversies, a strategic research program is needed that encompasses endeavors in toxicology, exposure assessment, epidemiology, mineralogy, and analytical methods. The findings of such research can contribute to the development of new policies for exposures to airborne asbestos fibers and other EMPs with recommendations for exposure indices that are not only more effective in protecting workers’ health but firmly based on quantitative estimates of health risk. To bridge existing scientific uncertainties, this Roadmap proposes that interdisciplinary research address the following three strategic goals: (1) develop a broader and clearer understanding of the important determinants of toxicity for EMPs, (2) develop information on occupational exposures to various EMPs and health risks associated with such exposures, and (3) develop improved sampling and analytical methods for asbestos fibers and other EMPs. Developing a broader and clearer understanding of the important determinants of toxicity for EMPs will involve building on what is known by systematically conducting in vitro studies and in vivo animal studies to ascertain which physical and chemical properties of EMPs influence their toxicity and their underlying mechanisms of action in causing disease. Thein vitro studies could provide information on membranolytic, cytotoxic, and genotoxic activities as well as signaling mechanisms. Thein vivo animal studies should involve a multispecies testing approach for short- term assays to develop information for designing chronic inhalation studies and to develop information on biomarkers and mechanisms of disease. Chronic animal inhalation studies are required to address the impacts of dimension, morphology, chemistry, and biopersistence on critical disease endpoints, including cancer and nonmalignant respiratory disease. Chronic inhalation studies should be designed to provide solid scientific evidence on which to base human risk assessments for a variety of EMPs. The results of toxicity studies should be assessed in the context of results of epidemiologic studies to provide a basis for understanding the human health effects of exposure to EMPs for which epidemiologic studies are not available.

Developing information and knowledge on occupational exposures to various EMPs and potential health outcomes will involve (1) collecting and analyzing available occupational exposure information to ascertain the characteristics and extent viii of exposure to various types of EMPs; (2) collecting and analyzing available information on health outcomes associated with exposures to various types of EMPs; (3) conducting epidemiological studies of workers exposed to various types of EMPs to better define the association between exposure and health effects; and (4) developing and validating methods for screening, diagnosis, and secondary prevention for diseases caused by exposure to asbestos fibers and other EMPs.

Developing improved sampling and analytical methods for EMPs will involve (1) re- ducing interoperator and interlaboratory variability of currently used analytical methods; (2) developing a practical analytical method that will permit the counting, sizing, and identification of EMPs; (3) developing a practical analytical method that can assess the potential durability of EMPs as one determinant of biopersistence in the lung; and (4) developing and validating size-selective sampling methods for collecting and quantifying airborne thoracic-size asbestos fibers and other EMPs.

A primary anticipated outcome of the research that is broadly outlined in this Road- map will be the identification of the physicochemical parameters such as chemical composition, dimensional attributes (e.g., ranges of length, width, and aspect ratio), and durability as predictors of biopersistence, as well as particle surface characteristics or activities (e.g., generation reactive oxygen species [ROS]) as determinants of toxicity of asbestos fibers and other EMPs. The results of the research will also help define the sampling and analytical methods that closely measure the important toxic characteristics and need to be developed. These results can then inform development of appropriate recommendations for worker protection.

Another outcome of the research that is broadly outlined in this Roadmap might be the development of criteria that could be used to predict, on the basis of results of in vitro testing and/or short-term in vivo testing, the potential risk associated with exposure to any particular type of EMP. This could reduce the need for comprehensive toxicity testing with long-term in vivo animal studies and/or epidemiological evaluation of each type of EMP. Ultimately, the results from such studies could be used to fill in knowledge gaps beyond EMPs to encompass predictions of relative toxicities and adverse health outcomes associated with exposure to other elongate particles (EPs), including inorganic and organic manufactured particles. A coherent risk management approach that fully incorporates an understanding of the toxicity of particles could then be developed to minimize the potential for disease in exposed individuals and populations.

This Roadmap is intended to outline the scientific and technical research issues that need to be addressed to ensure that workers are optimally protected from health risks posed by exposures to asbestos fibers and other EMPs. Achievement of the research goals framed in this Roadmap will require a significant investment of time, scientific talent, and resources by NIOSH and others. This investment, however, can result in a sound scientific basis for better occupational health protection policies for asbestos fibers and other EMPs.

Contents

Foreword...... iii Executive Summary...... v List of Figures...... xiv List of Tables...... xiv Abbreviations ...... xv Acknowledgments...... xvii 1 Introduction ...... 1 2 Overview of Current Issues...... 5 2.1 Background...... 5 2.2 Minerals and Mineral Morphology...... 6 2.3 Terminology...... 7 2.3.1 Mineralogical Definitions ...... 8 2.3.2 Other Terms and Definitions...... 9 2.4 Trends in Asbestos Use, Occupational Exposures, and Disease . . . . 9 2.4.1 Trends in Asbestos Use...... 9 2.4.2 Trends in Occupational Exposure...... 10 2.4.3 Trends in Asbestos-related Disease...... 12 2.5 Workers’ Home Contamination...... 14 2.6 Clinical Issues...... 15 2.7 The NIOSH Recommendation for Occupational Exposure to Asbestos...... 17 2.7.1 The NIOSH REL as Revised in 1990...... 18 2.7.2 Clarification of the Current NIOSH REL...... 33 2.8 EMPs Other than Cleavage Fragments...... 34 2.8.1 Chrysotile...... 34 2.8.2 Asbestiform Amphibole Minerals...... 36 2.8.3 Other Minerals of Potential Concern...... 38 2.9 Determinants of Particle Toxicity and Health Effects...... 39 2.9.1 Deposition...... 39 2.9.2 Clearance and Retention ...... 40

xi 2.9.3 Biopersistence and other Potentially Important Particle Characteristics...... 42 2.9.4 Animal and In Vitro Toxicity Studies...... 46 2.9.5 Thresholds ...... 58 2.10 Analytical Methods...... 60 2.10.1 NIOSH Sampling and Analytical Methods for Standardized Industrial Hygiene Surveys...... 62 2.10.2 Analytical Methods for Research ...... 63 2.10.3 Differential Counting and Other Proposed Analytical Approaches for Differentiating EMPs...... 65 2.11 Summary of Key Issues...... 66 3 Framework for Research...... 69 3.1 Strategic Research Goals and Objectives...... 70 3.2 An Approach to Conducting Interdisciplinary Research...... 70 3.3 National Reference Repository of Minerals and Information System...... 70 3.4 Develop a Broader Understanding of the Important Determinants of Toxicity for Asbestos Fibers and Other EMPs...... 71 3.4.1 Conduct In Vitro Studies to Ascertain the Physical and Chemical Properties that Influence the Toxicity of Asbestos Fibers and Other EMPs...... 76 3.4.2 Conduct Animal Studies to Ascertain the Physical and Chemical Properties that Influence the Toxicity of Asbestos Fibers and Other EMPs...... 78 3.4.3 Evaluate Toxicological Mechanisms to Develop Early Biomarkers of Human Health Effects...... 81 3.5 Develop Information and Knowledge on Occupational Exposures to Asbestos Fibers and Other EMPs and Related Health Outcomes . . . 81 3.5.1 Assess Available Information on Occupational Exposures to Asbestos Fibers and Other EMPs ...... 82 3.5.2 Collect and Analyze Available Information on Health Outcomes Associated with Exposures to Asbestos Fibers and Other EMPs...... 83 3.5.3 Conduct Selective Epidemiological Studies of Workers Exposed to Asbestos Fibers and Other EMPs...... 84 3.5.4 Improve Clinical Tools and Practices for Screening, Diagnosis, Treatment, and Secondary Prevention of Diseases Caused by Asbestos Fibers and Other EMPs. . . . 87 xii 3.6 Develop Improved Sampling and Analytical Methods for Asbestos Fibers and Other EMPs...... 88 3.6.1 Reduce Inter-operator and Inter-laboratory Variability of the Current Analytical Methods Used for Asbestos Fibers. . 90 3.6.2 Develop Analytical Methods with Improved Sensitivity to Visualize Thinner EMPs to Ensure a More Complete Evaluation of Airborne Exposures...... 91 3.6.3 Develop a Practical Analytical Method for Air Samples to Differentiate Asbestiform Fibers from the Asbestos Minerals and EMPs from Their Nonasbestiform Analogs . . 92 3.6.4 Develop Analytical Methods to Assess Durability of EMPs...... 93 3.6.5 Develop and Validate Size-selective Sampling Methods for EMPs...... 93 3.7 From Research to Improved Public Health Policies for Asbestos Fibers and Other EMPs ...... 94 4 The Path Forward...... 99 4.1 Organization of the Research Program...... 99 4.2 Research Priorities...... 100 4.3 Outcomes...... 101 5 References...... 103 6 Glossary...... 131 6.1 NIOSH Definition of Potential Occupational Carcinogen...... 131 6.2 Definitions of New Terms Used in this Roadmap...... 131 6.3 Definitions of Inhalational Terms ...... 131 6.4 Definitions of General Mineralogical Terms and Specific Minerals. . 132 6.5 References for Definitions of General Mineralogical Terms, Specific Mineral and Inhalation Terms...... 132

xiii List of Figures

Figure 1. U.S. asbestos production and imports, 1991–2007

Figure 2. Asbestos: Annual geometric mean exposure concentrations by major industry division, MSHA and OSHA samples, 1979–2003

Figure 3. Number of asbestosis deaths, U.S. residents aged ≥ 15 years, 1968–2004

Figure 4. Number of deaths due to malignant mesothelioma, U.S. residents aged ≥ 15 years, 1999–2005

List of Tables

Table 1. Definitions of general mineralogical terms.

Table 2. Definitions of specific minerals.

xiv Abbreviations

8-OHdG 8-hydroxydeoxyguanosine AED aerodynamic equivalent diameter AIHA American Industrial Hygiene Association AP-1 activator protein-1 ASTM ASTM International [previously American Society for Testing and Materials] ATSDR Agency for Toxic Substances Disease Registry BAL bronchoalveolar lavage BrdU bromodeoxyuridine CI confidence interval COX-2 cyclooxygenase-2 CPSC Consumer Product Safety Commission DM dark-medium microscopy DNA deoxyribonucleic acid DPPC dipalmitoyl phosphatidylcholine ED electron diffraction EDS energy dispersive X-ray spectroscopy EGFR epidermal growth factor receptor EM electron microscopy EMP elongate mineral particle EP elongate particle EPA U.S. Environmental Protection Agency ERK extracellular signal-regulated kinase ESR electron spin resonance f/cm3 fibers per cubic centimeter f/mL-yr fibers per milliliter-year HSL/ULO Health and Safety Laboratory/UL Optics ICD International Classification of Diseases IgG immunoglobulin G IL interleukin IMA International Mineralogical Association IMIS Integrated Management Information System IP intraperitoneal ISO International Organization for Standardization L liter LDH lactate dehydrogenase LOQ limit of quantification MDH Minnesota Department of Health mg/m3-d milligrams per cubic meter-days

xv MAPK mitogen-activated protein kinase MMAD mass median aerodynamic diameter MMMF man-made mineral fiber MMVF man-made vitreous fiber mppcf million particles per cubic foot MSHA Mine Safety and Health Administration mRNA messenger ribonucleic acid NADPH nicotinamide adenine dinucleotide phosphate NFκB nuclear factor kappa beta NIEHS National Institute of Environmental Health Sciences NMRD nonmalignant respiratory disease NIOSH National Institute for Occupational Safety and Health NIST National Institute of Standards and Technology NORA National Occupational Research Agenda NORMS National Occupational Respiratory Mortality System NTP National Toxicology Program OSHA Occupational Safety and Health Administration PCMe phase contrast microscopy equivalent PCM phase contrast microscopy PEL permissible exposure limit RCF refractory ceramic fiber REL recommended exposure limit ROS reactive oxygen species RTV RT Vanderbilt Company, Inc. SAED selected area X-ray diffraction SEM scanning electron microscopy SMR standardized mortality ratio SO superoxide anion SOD superoxide dismutase SV40 simian virus 40 SVF synthetic vitreous fiber SWCNT single-walled carbon nanotubes TEM transmission electron microscopy TF tissue factor TGF transforming growth factor TNF-α tumor necrosis factor-alpha TWA time-weighted average USGS United States Geological Survey WHO World Health Organization XPS X-ray photoelectron spectroscopy xvi Acknowledgments

This document was prepared under the aegis of the NIOSH Mineral Fibers Work Group by members of the NIOSH staff. Many internal NIOSH reviewers not listed also provided critical feedback important to the preparation of this Roadmap.

The NIOSH Mineral Fibers Work Group acknowledges the contributions of Jimmy Stephens, PhD, former NIOSH Associate Director for Science, who initiated work on this document and articulated many of its most critical issues in an early draft.

The NIOSH Mineral Fibers Work Group also acknowledges the contributions of Gregory Meeker, USGS, who participated in discussions of the pertinent mineralogy and mineralogical nomenclature.

NIOSH Mineral Fibers Work Group Paul Baron, PhD Jeffrey Kohler, PhD John Breslin, PhD Paul Middendorf, PhD, Chair Robert Castellan, MD, MPH Teresa Schnorr, PhD Vincent Castranova, PhD Paul Schulte, PhD Joseph Fernback, BS Patricia Sullivan, ScD Frank Hearl, SMChE David Weissman, MD Martin Harper, PhD Ralph Zumwalde, MS

Major Contributors Paul Middendorf, PhD Leslie Stayner, PhD Ralph Zumwalde, MS Vincent Castranova, PhD Robert Castellan, MD, MPH Frank Hearl, SMChE Martin Harper, PhD Patricia Sullivan, ScD William Wallace, PhD

Peer Reviewers NIOSH greatly appreciates the time and efforts of expert peer reviewers who provided comments and suggestions on the initial publicly disseminated draft of the Roadmap (February 7, 2007 version).

William Eschenbacher, MD David Michaels, PhD, MPH Group Health Associates George Washington University

Morton Lippmann, PhD Franklin Mirer, PhD New York University Hunter College

xvii Brooke Mossman, PhD Brad Van Gosen, MS University of Vermont U.S. Geological Survey

L. Christine Oliver, MD, MPH Ann Wylie, PhD Harvard School of Medicine University of Maryland

William N. Rom, MD, MPH New York University

Institutes of Medicine and National Research Council of the National Academy of Sciences NIOSH appreciates the time and efforts of the National Academy of Sciences (NAS) committee members, consultant, and study staff who contributed to the development of the NAS report A Review of the NIOSH Roadmap for Research on Asbestos Fibers and Other Elongate Mineral Particles on the January 2009 version of the draft Road- map. The individuals contributing to the report are identified in the NAS document.

Document History Throughout its development, this Roadmap has undergone substantial public comment and scientific peer review with subsequent revision. All external input has been considered and addressed, as appropriate, to ultimately produce this final version of the Roadmap. A listing of the various draft versions disseminated for public comment and/or scientific peer review is presented here.

February 2007—Draft entitled Asbestos and Other Mineral Fibers: A Roadmap for Scientific Research was disseminated for public comment and scientific peer review.

June 2008—Draft entitledRevised Draft NIOSH Current Intelligence Bulletin— Asbestos Fibers and Other Elongate Mineral Particles: State of the Science and Road- map for Research was disseminated for public comment.

January 2009—Draft entitledRevised Draft NIOSH Current Intelligence Bulletin— Asbestos Fibers and Other Elongated Mineral Particles: State of the Science and Road- map for Research was submitted to the Institute of Medicine and the National Re- search Council of the National Academies of Science for scientific review.

January 2010—Draft entitledDraft NIOSH Current Intelligence Bulletin—Asbestos Fibers and Other Elongate Mineral Particles: State of the Science and Roadmap for Research—Version 4 was disseminated for public comment.

March 2011—Final Version of NIOSH Current Intelligence Bulletin—Asbestos Fibers and Other Elongate Mineral Particles: State of the Science and Roadmap for Research was published. xviii 1 Introduction

Many workers are exposed to a broad spec- been in existence for decades. Current regula- trum of inhalable particles in their places tions have been based on studies of the health of work. These particles vary in origin, size, effects of exposures encountered in the com- shape, chemistry, and surface properties. Con- mercial exploitation and use of asbestos fibers. siderable research over many years has been Nevertheless, important uncertainties remain undertaken to understand the potential health to be resolved to fully inform possible revision effects of these particles and the particle char- of existing federal policies and/or development acteristics that are most important in confer- of new federal policies to protect workers from ring their toxicity. Elongate particles* (EPs) health effects caused by occupational exposure have been the subject of much research, and to airborne asbestos fibers. the major focus of research on EPs has related to asbestos fibers, a group of elongate miner- Health effects caused by other exposures to al particles (EMPs) that have long been known EMPs have not been studied as thoroughly as to cause serious disease when inhaled. Because health effects caused by exposures in the com- of the demonstrated health effects of asbestos, mercial exploitation and use of asbestos fibers. research attention has also been extended not Miners and others exposed to asbestiform am- only to other EMPs, but also to synthetic vitre- phibole fibers associated with vermiculite from ous fibers which have dimensions similar to as- a mine near Libby, Montana, may not have bestos fibers and, more recently, to engineered been exposed to commercial asbestos fibers, carbon nanotubes and carbon nanofibers. Al- but the adverse health outcomes they have ex- though nonmineral EPs are of interest, they are perienced as a result of their exposure have in- not the subject of this Roadmap, which focus- dicated that those EMPs are similarly toxic. es on EMPs. Other hardrock miner populations face uncertain but potential risk associated with ex- Occupational health policies and associat- posures to EMPs that could be generated dur- ed federal regulations controlling occupation- ing mining and processing of nonasbestiform al exposure to airborne asbestos fibers have amphiboles. Studies of human populations exposed to airborne fibers of erionite, a fibrous * A glossary of technical terms is provided in Section 6. It in- mineral that is neither asbestos nor amphibole, cludes definitions of terms from several standard sources have documented high rates of malignant me- in Tables 1 and 2. In general, where a term is used in this Roadmap the definitions in Tables 1 and 2 under the col- sothelioma (a cancer most commonly asso- umn “NIOSH 1990” are intended unless otherwise spec- ciated with exposure to asbestos fibers). Fur- ified. Readers should be aware that, in reviewing publi- ther research is warranted to understand how cations cited in this Roadmap, it was not always possible properties of EMPs determine toxicity so that to know the meaning of technical terms as used by the authors of those publications. Thus, some imprecision of the nature and magnitude of any potential tox- terminology carries over into the literature review con- icity associated with an EMP to which work- tained in this Roadmap. ers are exposed can be readily predicted and

1 controlled, even when exhaustive long-term below which workers would incur no demon- studies of that particular EMP have not been strable risk of material health impairment. The carried out. large number of potentially exposed workers and these changed exposure scenarios also give This Roadmap has been prepared and is be- rise to the need to better understand whether ing disseminated with the intent of motivating appropriate protection is provided by the cur- eventual development and implementation of rent occupational exposure recommendations a coordinated, interdisciplinary research pro- and regulations. In addition, limited informa- gram that can effectively address key remaining tion is currently available on exposures to, and issues relating to health hazards associated with health effects of, other EMPs. exposure to asbestos fibers and other EMPs. Section 3, Framework for Research, provides a Section 2, Overview of Current Issues, provides general framework for research needed to ad- an overview of available scientific information dress the key issues. NIOSH envisions that this and identifies important issues that need to be general framework will serve as a basis for a resolved before recommendations for occupa- future interdisciplinary research program car- tional exposure to airborne asbestos fibers and ried out by a variety of organizations to (1) elu- related EMPs can be improved and before rec- cidate exposures to EMPs, (2) identify any ad- ommendations for occupational exposure to verse health effects caused by these exposures, other EMPs can be developed. The nature of oc- and (3) determine the influence of size, shape, cupational exposures to asbestos has changed and other physical and chemical characteris- over the last several decades. Once dominated tics of EMPs on human health. Findings from by chronic exposures in asbestos textile mills, this research would provide a basis for deter- friction product manufacturing, cement pipe mining which EMPs should be included in fabrication, and insulation manufacture and recommendations to protect workers from installation, occupational exposures to asbestos hazardous occupational exposures along with in the United States now primarily occur dur- appropriate exposure limits. A fully informed ing maintenance activities or remediation of strategy for prioritizing research on EMPs will buildings containing asbestos. OSHA has esti- be based on a systematic collection and evalu- mated that 1.3 million workers in general ination of available information on occupational dustry continue to be exposed to asbestos. In exposures to EMPs. 2002 NIOSH estimated that about 44,000 mine workers might be exposed to asbestos fibers or Section 4, The Path Forward, broadly outlines a amphibole cleavage fragments during the min- proposed structure for development and over- ing of some mineral commodities. These cur- sight of a comprehensive, interdisciplinary re- rent occupational exposure scenarios frequent- search program. Key to this approach will be ly involve short-term, intermittent exposures, (1) the active involvement of stakeholders rep- and proportionately fewer long fibers than resenting parties with differing views, (2) ex- workers were exposed to in the past. The gen- pert study groups specifying and guiding vari- erally lower current exposures and predomi- ous components of the research program, and nance of short fibers give added significance to (3) a multidisciplinary group providing care- the question of whether or not there are thresh- ful ongoing review and oversight to ensure rel- olds for EMP exposure level and EMP length evance, coordination, and impact of the overall

2 NIOSH CIB 62 • Asbestos research program. NIOSH does not intend this is expected that these more detailed aspects of (or any other) section of this Roadmap to be the program will be most effectively developed prescriptive, so detailed research aims, specific with collaborative input from scientists, policy research priorities, and funding considerations experts, and managers from various agencies, have intentionally not been specified. Rather, it as well as from other interested stakeholders.

NIOSH CIB 62 • Asbestos 3

2 Overview of Current Issues

2.1 Background The complex and evolving terminology used to name and describe the various minerals from Prior to the 1970s, concern about the health ef- which airborne EMPs are generated has led to fects of occupational exposure to airborne fi- much confusion and uncertainty in scientif- bers was focused on six commercially exploit- ic and lay discourse related to asbestos fibers ed minerals termed “asbestos:” the serpentine and other EMPs. To help reduce such confu- mineral chrysotile and the amphibole minerals sion and uncertainty about the content of this cummingtonite-grunerite asbestos (amosite), Roadmap, several new terms are used in this riebeckite asbestos (crocidolite), actinolite as- Roadmap and defined in the Glossary (Sec- bestos, anthophyllite asbestos, and tremolite as- tion 6). The Glossary also lists definitions from bestos. The realization that dimensional char- a variety of sources for many other mineral- acteristics of asbestos fibers were important ogical and other scientific terms used in this physical parameters in the initiation of respiratory disease led to studies of other elongate Roadmap. Definitions from these sources of- mineral particles (EMPs) of similar dimensions ten vary, and many demonstrate a lack of stan- [Stanton et al. 1981]. dardization and sometimes rigor that should be addressed by the scientific community. To date, occupational health interest in EMPs other than asbestos fibers has been focused pri- To address current controversies and uncer- marily on fibrous minerals exploited commer- tainties concerning exposure assessment and cially (e.g., wollastonite, sepiolite, and attapulgite) health effects relating to asbestos fibers and and mineral commodities that contain (e.g., other EMPs, strategic research endeavors are Libby vermiculite) or may contain (e.g., upstate needed in toxicology, exposure assessment, ep- New York talc) asbestiform minerals. Exposure idemiology, mineralogy, and analytical meth- to airborne thoracic-size EMPs generated from ods. The results of such research might inform the crushing and fracturing of nonasbestiform new risk assessments and the potential devel- amphibole minerals has also garnered sub- opment of new policies for asbestos fibers and stantial interest. The asbestos minerals, as well other EMPs, with recommendations for ex- as other types of fibrous minerals, are typical- posure limits that are firmly based on well- ly associated with other minerals in geologic established risk estimates and that effectively formations at various locations in the United protect workers’ health. To support the devel- States [Van Gosen 2007]. The biological sig- opment of these policies, efforts are needed to nificance of occupational exposure to airborne establish a common set of mineral terms that particles remains unknown for some of these unambiguously describe EMPs and are rele- minerals and can be difficult to ascertain, given vant for toxicological assessments. What fol- the mixed and sporadic nature of exposure in lows in the remainder of Section 2 is an over- many work environments and the general lack view of (1) definitions and terms relevant to of well-characterized exposure information. asbestos fibers and other EMPs; (2) trends in

NIOSH CIB 62 • Asbestos 5 production and use of asbestos; (3) occupa- the specific identification of minerals reported tional exposures to asbestos and asbestos-relat- in the literature. Over the past 50 years, several ed diseases; (4) sampling and analytical issues; systems for naming amphibole minerals have and (5) physicochemical properties associated been used. The current mineralogical nomen- with EMP toxicity. clature was unified by the International Miner- alogical Association (IMA) under a single system in 1978 [Leake 1978] and later modified in 2.2 Minerals and Mineral 1997 [Leake et al. 1997]. For some amphibole Morphology minerals, the name assigned under the 1997 IMA system is different than the name used Minerals are naturally occurring inorganic prior to 1978, but the mineral names specified compounds with a specific crystalline struc- in regulations have not been updated to corre- ture and elemental composition. Asbestos is a late with the new IMA system names. term applied to several silicate minerals from the serpentine and amphibole groups that oc- Adding to the complexity of the nomencla- cur in a particular type of fibrous habit and ture, serpentine and amphibole minerals typ- have properties that have made them commer- ically develop through the alteration of other cially valuable. The fibers of all varieties of as- minerals. Consequently, they may exist as par- bestos are long, thin, and usually flexible when tially altered minerals having variations in el- separated. One variety of asbestos, chrysotile, emental compositions. For example, the mi- is a mineral in the serpentine group of sheet croscopic analysis of an elongate amphibole silicates. Five varieties of asbestos are miner- particle using energy dispersive X-ray spec- als in the amphibole group of double-chain troscopy (EDS) can reveal variations in ele- silicates—riebeckite asbestos (crocidolite), mental composition along the particle’s length, cummingtonite-grunerite asbestos (amosite), making it difficult to identify the particle as a anthophyllite asbestos, tremolite asbestos, and single specific amphibole mineral. In addition, actinolite asbestos [Virta 2002]. a mineral may occur in different growth forms, or “habits,” so different particles may have dif- Although a large amount of health informa- ferent morphologies. However, because they tion has been generated on workers occupa- share the same range of elemental composition tionally exposed to asbestos, limited miner- and chemical structure and belong to the same al characterization information and the use of crystal system, they are the same mineral. Dif- nonmineralogical names for asbestos have referent habits are not recognized as having dif- sulted in uncertainty and confusion about the ferent mineral names. specific nature of exposures described in many published studies. Trade names for mined as- Mineral habit results from the environmental bestos minerals predated the development of conditions present during a mineral’s formation. rigorous scientific nomenclature. For exam- The mineralogical terms applied to habits are ple, amosite is the trade name for asbestiform generally descriptive (e.g., fibrous, asbestiform, cummingtonite-grunerite and crocidolite is massive, prismatic, acicular, asbestiform, tab- the trade name for asbestiform riebeckite. A ular, and platy). Both asbestiform (a specif- changing mineralogical nomenclature for am- ic fibrous type) and nonasbestiform versions phiboles has also contributed to uncertainty in (i.e., analogs) of the same mineral can occur in

6 NIOSH CIB 62 • Asbestos juxtaposition or matrixed together, so that both 2.3 Terminology analogs of the same mineral can occur within a The use of nonstandard terminology or terms narrow geological formation. with imprecise definitions when reporting The habits of amphibole minerals vary, from studies makes it difficult to fully understand prismatic crystals of hornblende through pris- the implications of these studies or to compare matic or acicular crystals of riebeckite, actinolite, the results to those of other studies. For the health community, this ultimately hampers re- tremolite, and others, to asbestiform habits of search efforts, leads to ambiguity in exposure- grunerite (amosite), anthophyllite, tremolite- response relationships, and could also lead to actinolite, and riebeckite (crocidolite). The pris- imprecise recommendations to protect human matic and acicular crystal habits occur more health. Terms are often interpreted differently commonly, and asbestiform habit is rela- between disciplines. The situation is complicat- tively rare. Some of the amphiboles, such as ed by further different usage of the same terms hornblendes, are not known to occur in an by stakeholders outside of the scientific com- asbestiform habit. The asbestiform varieties munity. NIOSH has carefully reviewed numer- range from finer (flexible) to coarser (more ous resources and has not found any current brittle) and often are found in a mixture of fine reference for standard terminology and defi- and coarse fibrils. In addition, properties vary— nitions in several disciplines that is complete e.g., density of (010) defects—even within an and unambiguous. An earlier tabulation of as- apparently homogeneous specimen [Dorling bestos-related terminology by the USGS dem- and Zussman 1987]. onstrated similar issues [Lowers and Meeker 2002]. The terms “asbestos” and “asbestiform” In the scientific literature, the term “miner- exemplify this issue. They are commonly used al fibers” has often been used to refer not only terms but lack mineralogical precision. “As- to particles that occur in an asbestiform habit bestos” is a term used for certain minerals that but also to particles that occur in other fibrous have crystallized in a particular macroscopic habits or as needle-like (acicular) single crys- habit with certain commercially useful proper- tals. The term “mineral fibers” has sometimes ties. These properties are less obvious on mi- also encompassed other prismatic crystals and croscopic scales, and so a different definition of cleavage fragments that meet specified dimen- “asbestos” may be necessary at the scale of the light microscope or electron microscope, in- sional criteria. Cleavage fragments are gener- volving characteristics such as chemical com- ated by crushing and fracturing minerals, in- position and crystallography. “Asbestiform” is cluding the nonasbestiform analogs of the a term applied to minerals with a macroscopic asbestos minerals. Although the substantial habit similar to that of asbestos. The lack of pre- hazards of inhalational exposure to airborne cision in these terms and the difficulty in trans- asbestos fibers have been well documented, lating macroscopic properties to microscopi- there is ongoing debate about whether expo- cally identifiable characteristics contribute to sure to thoracic-size EMPs (EMPs of a size that miscommunication and uncertainty in iden- can enter the thoracic airways when inhaled) tifying toxicity associated with various forms from nonasbestiform analogs of the asbestos of minerals. Some deposits may contain more minerals is also hazardous. than one habit or transitional particles may be

NIOSH CIB 62 • Asbestos 7 present, which make it difficult to clearly and or fragments of the nonasbestiform analogs of simply describe the mineralogy. Furthermore, asbestos minerals. Minerals are precisely de- the minerals included in the term asbestos fined by their chemical composition and crys- vary between federal agencies and sometimes tallography. Ionic substitutions occur in miner- within an agency. als, especially for metal cations of similar ionic charge or size. Such substitution can result in NIOSH supports the development of standard an isomorphous series (also referred to as solid- terminology and definitions relevant to the is- solution or mixed crystal) consisting of miner- sues of asbestos and other EMPs that are based als of varying composition between end-mem- on objective criteria and are acceptable to the bers with a specific chemical composition. The majority of scientists. NIOSH also supports differences in chemical composition within an the dissemination of standard terminology isomorphous series can result in different prop- and definitions to the community of interest- erties such as color and hardness, as well as dif- ed nonscientists and encourages adoption and ferences in crystal properties by alteration of use by this community. The need for the devel- unit-cell dimensions. It is sometimes possible opment and standardization of unambiguous to differentiate mineral species on the basis of terminology and definitions warrants a prior- distinctive changes through an isomorphous se- ity effort of the greater scientific community ries. However, in general, classification occurs that should precede, or at least be concurrent by an arbitrary division based on chemistry, with, further research efforts. and this can be complicated by having multiple sites of possible substitution (e.g., in a specific 2.3.1 Mineralogical Definitions mineral, calcium may exchange for magnesium in one position whereas sodium and potassium The minerals of primary concern are the may be exchanged in another position). These asbestiform minerals that have been regulated allocations are open to reevaluation and re- as asbestos (chrysotile, amosite,† crocidolite,‡ classification over time (e.g., the mineral now tremolite asbestos, actinolite asbestos, and named richterite was called soda-tremolite in anthophyllite asbestos). In addition, there is in- pre-1978 IMA nomenclature). terest in closely related minerals to which workers might be exposed that (1) were not commer- When certain minerals were marketed or regu- cially used but would have been mineralogically lated as asbestos, the mineral names had defini- identified as regulated asbestos minerals at the tions that might have been imprecise at the time time the asbestos regulations were promulgat- and might have changed over time. In particu- ed (e.g., asbestiform winchite and richterite); lar, the mineral name amosite was a commercial (2) are other asbestiform amphiboles (e.g., term for a mineral that was not well defined at fluoro-edenite); (3) might resemble asbes- first. The definitions of amosite in theDictionary tos (e.g., fibrous antigorite); (4) are unrelated of Mining, Mineral, and Related Terms [USBOM EMPs (e.g., the zeolites erionite and mordenite, 1996] and in the Glossary of Geology [American fibrous talc, and the clay minerals sepiolite and Geological Institute 2005] allow for the possibil- palygorskite); and (5) are individual particles ity that amosite might be anthophyllite asbestos, although it is now known to be a mineral in †Amosite is not recognized as a proper mineral name. the cummingtonite-grunerite series. This is one ‡Crocidolite is not recognized as a proper mineral name. source of confusion in the literature.

8 NIOSH CIB 62 • Asbestos A further source of confusion comes from the 2.3.2 Other Terms and Definitions use of the geological terms for a mineral habit. Health-related professions also employ termi- Minerals of the same chemistry differing only nology that can be used imprecisely. For exam- in the expression of their crystallinity (e.g., mas- ple, the terms “inhalable” and “respirable” have sive, fibrous, asbestiform, or prismatic) are not different meanings but are sometimes used in- differentiated in geology as independent spe- terchangeably. Also, each of these terms is de- cies. Thus, tremolite in an asbestiform crystal fined somewhat differently by various profes- habit is not given a separate name (either chem- sional organizations and agencies. Particles can ical or common) from tremolite in a massive enter the human airways, but the aspiration ef- habit. It has been suggested that crystals grown ficiency, the degree of penetration to different in an “asbestiform” habit can be distinguished parts of the airways, and the extent of deposi- by certain characteristics, such as parallel or ra- tion depend on particle aerodynamics, as well diating growth of very thin and elongate crys- as on the geometry and flow dynamics within tals that are to some degree flexible, the pres- the airways. In addition to obvious differences ence of bundles of fibrils, and, for amphiboles, between species (e.g., mouse, rat, dog, primate, a particular combination of twinning, stacking human), there is a significant range of variation faults, and defects [Chisholm 1973]. The geo- within a species based on, for example, age, sex, logical conditions necessary for the formation body mass, and work-rate. Thus, these terms of asbestiform crystals are not as common as may mean different things to a toxicologist en- those that produce other crystal habits. These gaging in animal inhalation experiments, an other habits may occur without any accompa- environmental specialist concerned with child- nying asbestiform crystals. However, amphi- hood exposure, and an industrial hygienist bole asbestos may also include additional am- concerned with adult, mostly male, workers. phiboles that, if separated, are not asbestiform [Brown and Gunter 2003]. The mineralogical community uses many terms, including fi- 2.4 Trends in Asbestos Use, bril, fiber, fibrous, acicular, needlelike, prismat- Occupational Exposures, ic, and columnar, to denote crystals that are and Disease elongate. In contrast, in sedimentology, similar terms have been more narrowly defined with 2.4.1 Trends in Asbestos Use specific axial ratios. Over recent decades, mining and use of as- Thus it is not clear, even from a single reference bestos have declined in the United States. The source, exactly what range of morphologies are mining of asbestos in the United States ceased described by these terms and the degree of in 2002. Consumption of raw asbestos contin- overlap, if any. For example, the Dictionary of ues to decline from a peak of 803,000 metric Mining, Mineral, and Related Terms defines fi- tons in 1973 [USGS 2006]. In 2006, 2000 met- bril as “a single fiber, which cannot be separat- ric tons of raw asbestos were imported, down ed into smaller components without losing its from an estimated 35,000 metric tons in 1991 fibrous properties or appearance,” but also de- (see Figure 1) and a peak of 718,000 metric fines a fiber as “the smallest single strand of -as tons in 1973. Unlike information on the im- bestos or other fibrous material.” portation of raw asbestos, information is not

NIOSH CIB 62 • Asbestos 9 Figure 1. U.S. asbestos production and imports, 1991–2007. Source of data: USGS [2008]. readily available on the importation of asbestos- of all mined asbestos is used in Eastern Europe containing products. The primary recent uses and Asia [Tossavainen 2005]. for asbestos materials in the United States are estimated as 55% for roofing products, 26% for Historically, chrysotile accounted for more than 90% of the world’s mined asbestos; it coatings and compounds, and 19% for other presently accounts for over 99% [Ross and applications [USGS 2007], and more recently Virta 2001; USGS 2008]. Mining of crocidolite as 84% for roofing products and 16% for other (asbestiform riebeckite) and amosite (asbesti applications [USGS 2008]. form cummingtonite-grunerite) deposits have Worldwide, the use of asbestos has declined. accounted for most of the remaining asbestos. Using the amount of asbestos mined as a sur- Mining of amosite is thought to have ceased in 1992 and mining of crocidolite is thought to rogate for the amount used, worldwide annu- have ended in 1997, although it is not possible al use has declined from about 5 million met- to be certain. Small amounts of anthophyllite ric tons in 1975 to about 2 million metric tons asbestos have been mined in Finland [Ross and since 1999 [Taylor et al. 2006]. The European Virta 2001] and are currently being mined in Union has banned imports and the use of as- India [Ansari et al. 2007]. bestos with very limited exceptions. In other regions of the world, there is a continued demand for inexpensive, durable construc- 2.4.2 Trends in Occupational Exposure tion materials. Consequently, markets remain Since 1986, the annual geometric mean concen- strong in some countries for asbestos-cement trations of occupational exposures to asbestos in products, such as asbestos-cement panels for the United States, as reported in the Integrated construction of buildings and asbestos-cement Management Information System (IMIS) of the pipe for water-supply lines. Currently over 70% Occupational Safety and Health Administration

10 NIOSH CIB 62 • Asbestos Figure 2. Asbestos: Annual geometric mean exposure concentrations by major industry division, MSHA and OSHA samples, 1979–2003. Source of data: NIOSH [2007a]. Note: the MSHA PEL for this time period was 2 f/cm3.

(OSHA) and the database of the Mine Safety the NIOSH REL decreased from 11.1% in 1987– and Health Administration (MSHA), have been 1994 to 2.6% in 1995–1999, but it increased to consistently below the NIOSH recommend- 9.8% in 2000–2003 [NIOSH 2007a]. ed exposure limit (REL) of 0.1 fibers per cubic centimeter of air (f/cm3) for all major indus- The preceding summary of occupational ex- try divisions (Figure 2). The number of occu- posures to asbestos is based on the OSHA and pational asbestos exposures that were measured MSHA regulatory definitions relating to asbestos. and reported in IMIS decreased from an aver- Because NIOSH includes nonasbestiform ana- age of 890 per year during the 8-year period of logs of the asbestos minerals in the REL that may 1987–1994 to 241 per year during the 5-year pe- have, at least from some samples, been excluded riod of 1995–1999 and 135 for the 4-year peri- by OSHA and MSHA in performing differential od of 2000–2003. The percentage exceeding the counting, the reported percentages of exposures NIOSH REL decreased from 6.3% in 1987–1994 exceeding the REL should be interpreted as low- to 0.9% in 1995–1999, but it increased to 4.3% in er limits. Because of analytical limitations of the 2000–2003. During the same three periods, the phase contrast microscopy (PCM) method and number of exposures measured and reported in the variety of workplaces from which the data MSHA’s database decreased from an average of were obtained, it is unclear what portions of these 47 per year during 1987–1994 to an average of exposures were to EMPs from nonasbestiform 23 per year during 1995–1999, but it increased analogs of the asbestos minerals, which have to 84 during 2000–2003 (most of which were been explicitly encompassed by the NIOSH REL collected in 2000). The percentage exceeding for airborne asbestos fibers since 1990.

NIOSH CIB 62 • Asbestos 11 Very limited information is available on the increase in risk of several nonmalignant respi- number of workers still exposed to asbestos. ratory diseases, including diffuse fibrosis of the On the basis of mine employment data [MSHA lung (i.e., asbestosis) and nonmalignant pleu- 2002], NIOSH estimated that 44,000 miners ral abnormalities including acute pleuritis and and other mine workers may be exposed to as- chronic diffuse and localized thickening of the bestos or amphibole cleavage fragments dur- pleura [ATS 2004]. In addition, it has been de- ing the mining of some mineral commodities termined that laryngeal cancer [IOM 2006] and [NIOSH 2002]. OSHA estimated in 1990 that ovarian cancer [Straif et al. 2009] can be caused about 568,000 workers in production and ser- by exposure to asbestos, and evidence suggests vices industries and 114,000 in construction that asbestos may also cause other diseases (e.g., industries may be exposed to asbestos in the pharyngeal, stomach, and colorectal cancers workplace [OSHA 1990]. More recently, OSHA [IOM 2006] and immune disorders [ATSDR has estimated that 1.3 million employees in con- 2001]). struction and general industry face significant asbestos exposure on the job [OSHA 2008]. National surveillance data, showing trends over time, are available for two diseases with rather In addition to evidence from OSHA and MSHA specific mineral fiber etiologies—asbestosis and that indicates a reduction in occupational ex- malignant mesothelioma (see following subsec- posures in the United States over the last sev- tions). Lung cancer is known to be caused in eral decades of the 1900s, other information part by asbestos fiber exposure but has multi- compiled on workplace exposures to asbes- ple etiologies. Ongoing national surveillance for tos indicates that the nature of occupational lung cancer caused by asbestos exposure has not exposures to asbestos has changed [Rice and been done. However, using various assumptions Heineman 2003]. Once dominated by chron- and methods, several researchers have projected ic exposures in manufacturing processes such the number of U.S. lung cancer deaths caused by as those used in textile mills, friction product asbestos. Examples of the projected number of manufacturing, and cement pipe fabrication, asbestos-caused lung cancer deaths in the Unit- current occupational exposures to asbestos in ed States include 55,100 [Walker et al. 1983] and the United States primarily occur during main- 76,700 [Lilienfeld et al. 1988]; each of these pro- tenance activities or remediation of buildings jections represent the 30-year period from 1980 containing asbestos. These current occupa- through 2009. However, in the absence of spe- tional exposure scenarios frequently involve cific diagnostic criteria and a specific disease short-term, intermittent exposures. code for the subset of lung cancers caused by asbestos, ongoing surveillance cannot be done for 2.4.3 Trends in Asbestos-related lung cancer caused by asbestos. Disease 2.4.3.1 Asbestosis Evidence that asbestos causes lung cancer and mesothelioma in humans is well documented NIOSH has annually tracked U.S. deaths due to [NIOSH 1976; IARC 1977, 1987a,b; EPA 1986; asbestosis since 1968 and deaths due to malig- ATSDR 2001; HHS 2005a]. Epidemiological nant mesothelioma since 1999, using death cer- studies of workers occupationally exposed to tificate data in the National Occupational Re- asbestos have clearly documented a substantial spiratory Mortality System (NORMS). NORMS

12 NIOSH CIB 62 • Asbestos Figure 3. Number of asbestosis deaths, U.S. residents aged ≥15 years, 1968–2004. Source of data: NIOSH [2007b]. data, representing all deaths among U.S. resi- asbestosis deaths in the United States are antici- dents, show that asbestosis deaths increased al- pated to continue for several decades. most 20-fold from the late 1960s to the late 1990s (Figure 3) [NIOSH 2007b]. Asbestosis mortality 2.4.3.2 Malignant Mesothelioma trends are expected to substantially trail trends in asbestos exposures (see Section 2.4.2) for two Malignant mesothelioma, an aggressive disease primary reasons: (1) the latency period between that is nearly always fatal, is known to be caused asbestos exposure and asbestosis onset is typi- by exposure to asbestos and some other min- cally long, commonly one or two decades or eral fibers [IOM 2006]. The occurrence of more; and (2) asbestosis is a chronic disease, so mesothelioma has been strongly linked with affected individuals can live for many years with occupational exposures to asbestos [Bang et the disease before succumbing. In fact, asbesto- al. 2006]. There had been no discrete Interna- sis deaths have apparently plateaued (at nearly tional Classification of Disease (ICD) code for 1,500 per year) since 2000 (Figure 3) [NIOSH mesothelioma until its most recent 10th revision. 2007b]. Ultimately, it is anticipated that the an- Thus, only seven years of NORMS data are avail- nual number of asbestosis deaths in the United able with a specific ICD code for mesothelioma States will decrease substantially as a result of (Figure 4); during this period, there was a 9% documented reductions in exposure. However, increase in annual mesothelioma deaths, from asbestos use has not been completely eliminat- 2,484 in 1999 to 2,704 in 2005 [NIOSH 2007b]. ed, and because asbestos-containing materials A later peak for mesothelioma deaths than remain in structural materials and machinery, for asbestosis deaths would be entirely expect- the potential for exposure continues. Thus, ed, given the longer latency for mesothelioma

NIOSH CIB 62 • Asbestos 13 Figure 4. Number of deaths due to malignant mesothelioma, U.S. residents aged ≥15 years, 1999– 2005. Source of data: NIOSH [2007b].

[Järvholm et al. 1999]. One analysis of malig- [NIOSH 1995]. Families have been exposed to nant mesothelioma incidence based on the Na- asbestos when workers were engaged in min- tional Cancer Institute’s Surveillance, Epidemi- ing, shipbuilding, insulating, maintenance and ology, and End Results (SEER) Program data repair of boilers and vehicles, and asbestos re- found that an earlier steep increase in inci- moval operations. Occupants of homes where dence had moderated and that mesothelioma asbestos workers live may be exposed while incidence may have actually peaked sometime house cleaning and laundering; these activities in the 1990s in SEER-covered areas [Weill et al. can result in hazardous exposure for the per- 2004]. In contrast to NORMS data, which rep- son performing the tasks, as well as for others resents a census of all deaths in the entire Unit- in the household. ed States, the analyzed SEER data were from ar- As the understanding of the effects of second- eas in which a total of only about 15% of the U.S. hand exposure to asbestos has increased, health population resides. effects among families of asbestos-exposed workers have been identified. Most document- 2.5 Workers’ Home ed cases of asbestos-related disease among Contamination workers’ family members have occurred in households where women were exposed during In addition to workers’ exposures, their families home laundering of contaminated work cloth- also have the potential for exposure to asbestos ing. In addition, children have been exposed

14 NIOSH CIB 62 • Asbestos at home by playing in areas where asbestos- who remain at risk due to past exposures, the contaminated shoes and work clothes were lo- disease currently is essentially incurable [British cated, or where asbestos-containing materials Thoracic Society Standards of Care Committee were stored [NIOSH 1995]. As a result of these 2001]. Diagnosis may be relatively straightfor- exposures, family members have been found to ward but can be difficult because of a challeng- be at increased risk of malignant mesothelioma, ing differential diagnosis [Lee et al. 2002]. Ad- lung cancer, cancer of the gastrointestinal tract, vances have been made to improve diagnostic asbestosis, and nonmalignant pleural abnor- testing for malignant mesothelioma with use of malities [NIOSH 1995]. immunochemical markers and other more so- phisticated histopathological analyses, and ad- Because of the long latency periods between ditional research is aimed at improving treat- exposure and manifestation of asbestos-relat- ment of the disease [Robinson and Lake 2005]. ed disease, identification and intervention are Notable recent research efforts have been direct- difficult. Home contamination may pose a -se ed toward the development of biomarkers for rious public health problem; however, the ex- mesothelioma that can be assessed by noninva- tent to which these health effects occur is not sive means. A long-term goal of the biomarker fully known because there are no information research is to enable screening of high-risk in- systems to track them [NIOSH 1995]. dividuals with sufficiently sensitive and specific noninvasive biomarkers to identify disease 2.6 Clinical Issues at an early stage, when therapeutic intervention might have a greater potential to slow the A thorough review of how asbestos-related dis- progression of the disease or be curative. Oth- eases are diagnosed is beyond the scope of this er goals are to use noninvasive biomarkers for document, and authoritative guidance on the monitoring the disease in patients treated for diagnosis and attribution of asbestos-caused mesothelioma and for diagnosing the disease. diseases has been published elsewhere [Anon- Noninvasive biomarkers, including osteopontin ymous 1997; British Thoracic Society Stan- and soluble mesothelin-related peptide, have dards of Care Committee 2001; Henderson et been and continue to be evaluated, but none are al. 2004; ATS 2004]. considered ready for routine clinical application [Cullen 2005; Scherpereel and Lee 2007]. The diagnosis of asbestos-caused malignancies (e.g., lung cancer and malignant mesothelioma) Nonmalignant asbestos-related diseases are di- is almost always based on characteristic histol- agnosed by considering three major necessary ogy (or abnormal cytology in some cases). De- criteria: (1) evidence of structural change con- spite research on other possible etiologies, genet- sistent with asbestos-caused effect (e.g., ab- ic susceptibilities, and hypothesized cofactors normality on chest image and/or tissue his- such as simian virus 40, it is generally accepted tology); (2) evidence of exposure to asbestos that most cases of malignant mesothelioma are (e.g., history of occupational or environmen- caused by exposure to asbestos or other min- tal exposure with appropriate latency, and/ eral (e.g., erionite) fibers [Robinson and Lake or higher than normal numbers of asbes- 2005; Carbone and Bedrossian 2006]. Of par- tos bodies identified in lung tissue, sputum, ticular concern to patients diagnosed with ma- or bronchoalveolar lavage; and/or other con- lignant mesothelioma, as well as to individuals current marker of asbestos exposure, such as

NIOSH CIB 62 • Asbestos 15 pleural plaques as evidence of exposure when In developed countries, conventional film ra- diagnosing asbestosis); and (3) exclusion of al- diography is rapidly giving way to digital ra- ternative diagnoses [ATS 2004]. The specific- diography, and work is currently under way to ity of an asbestosis diagnosis increases as the develop digital standards and validate their use number of consistent clinical abnormalities inin classifying digital chest radiographs under creases [ATS 2004]. In practice, only a small the ILO system [Franzblau et al. 2009; NIOSH proportion of cases are diagnosed on the ba- 2008a]. Progress on developing technical stan- sis of tissue histopathology, as lung biopsy is an dards for digital radiography done for pneu- invasive procedure with inherent risks for the moconiosis and ILO classification is under patient. Thus, following reasonable efforts to way [NIOSH 2008a]. In a validation study involving 107 subjects with a range of chest pa- exclude other possible diagnoses, the diagnosis renchymal and pleural abnormalities typical of of asbestosis usually rests on chest imaging ab- dust-induced diseases, Franzblau et al. [2009] normalities that are consistent with asbestosis compared ILO classifications based on digital in an individual judged to have sufficient expo- radiographic images and corresponding con- sure and latency since first exposure. ventional chest X-ray films. The investigators found no difference in classification of small Chest radiography remains the most com- parenchymal opacities. Minor differences were monly used imaging method for screening ex- observed in the classification of large paren- posed individuals for asbestosis and for eval- chymal opacities, though more substantial dif- uating symptomatic patients. Nevertheless, as ferences were observed in the classification of with any screening tool, the predictive value of pleural abnormalities typical of asbestos expo- a positive chest radiograph alone depends upon sure [Franzblau et al. 2009]. the underlying prevalence of asbestosis in the screened population [Ross 2003]. A widely ac- Computerized tomography, especially high- cepted system for classifying radiographic ab- resolution computed tomography (HRCT), normalities of the pneumoconioses was initial- has proven more sensitive and more specif- ly intended primarily for epidemiological use ic than chest radiography for the diagnosis of but has long been widely used for other purpos- asbestosis and is frequently used to help rule es (e.g., to determine eligibility for compensa- out other conditions [DeVuyst and Gevenois tion and for medicolegal purposes) [ILO 2002]. 2002]. Standardized systems for classifying A NIOSH-administered “B Reader” Program pneumoconiotic abnormalities have been pro- trains and tests physicians for proficiency in posed for computed tomography but have not the application of this system [NIOSH 2007c]. yet been widely adopted [Kraus et al. 1996; Huuskonen et al. 2001]. Some problems with the use of chest radiography for pneumoconioses have long been rec- In addition to documenting structural tis- ognized [Wagner et al. 1993] and recent abus- sue changes consistent with asbestos-caused es have garnered substantial attention [Miller disease, usually assessed radiographically 2007]. In response, NIOSH recently published as discussed above, the diagnosis of asbes- guidance for B Readers [NIOSH 2007d] and for tosis relies on documentation of exposure the use of B Readers and ILO classifications in [ATS 2004]. In clinical practice, exposure various settings [NIOSH 2007e]. is most often ascertained by the diagnosing

16 NIOSH CIB 62 • Asbestos physician from an occupational and environ- fibers and are less likely to produce asbestos mental history, assessed with respect to in- bodies [De Vuyst et al. 1998; ATS 2004]. tensity and duration. Such a history enables a judgment about whether the observed clin- 2.7 The NIOSH ical abnormalities can be reasonably attributed to past asbestos exposure, recognizing Recommendation for that severity of lung fibrosis is related to dose Occupational Exposure and latency [ATS 2004]. The presence of to Asbestos otherwise unexplained characteristic pleural plaques, especially if calcified, can also be NIOSH has determined that exposure to as- used as evidence of past asbestos exposure bestos fibers causes cancer and asbestosis in [ATS 2004]. As explained by the ATS [2004], humans and recommends that exposures be “the specificity of the diagnosis of asbesto- reduced to the lowest feasible concentration. sis increases with the number of consistent NIOSH has designated asbestos to be a “Poten- findings on chest film, the number of clin- tial Occupational Carcinogen”§. Currently, the ical features present (e.g., symptoms, signs, designation “Potential Occupational Carcino- and pulmonary function changes), and the gen” is based on the classification system ad- significance and strength of the history of opted by OSHA in the 1980s and is the only exposure.” In a small minority of cases, par- designation NIOSH uses for occupational car- ticularly when the exposure history is uncer- cinogens. After initially setting an REL at 2 as- tain or vague or when additional clinical asbestos fibers per cubic meter of air (f/cm3) in sessment is required to resolve a challenging 1972, NIOSH later reduced its REL to 0.1 f/cm3, differential diagnosis, past asbestos exposure measured as an 8-hour time-weighted average is documented through mineralogical analy- (TWA)¶ [NIOSH 1976]. The REL was set at a sis of sputum, bronchoalveolar lavage fluid, or lung tissue. Light microscopy can be used §NIOSH’s use of the term “Potential Occupational Car- to detect and count asbestos bodies (i.e., as- cinogen” dates to the OSHA classification outlined in 29 CFR 1990.103, and, unlike other agencies, is the bestos fibers that have become coated with only classification for carcinogens that NIOSH uses. iron-containing hemosiderin during resi- See Section 6.1 for the definition of “Potential Occu- dence in the body, more generically referred pational Carcinogen.” The National Toxicology Pro- to as ferruginous bodies) in clinical sam- gram [NTP 2005], of which NIOSH is a member, has determined that asbestos and all commercial forms of ples. Electron microscopy (EM) can be used asbestos are known to be human carcinogens based on to detect and count uncoated asbestos fibers sufficient evidence of carcinogenicity in humans. The in clinical samples. Methods for such clinical International Agency for Research on Cancer (IARC) mineralogical analyses often vary, and valid concluded that there was sufficient evidence for the carcinogenicity of asbestos in humans [IARC 1987b]. background levels are difficult to establish. ¶The averaging time for the REL was later changed to 100 The absence of asbestos bodies cannot be minutes in accordance with NIOSH Analytical Meth- used to rule out past exposure with certain- od #7400 [NIOSH 1994a]. This change in sampling ty, particularly chrysotile exposure, because time was first mentioned in comments and testimony presented by NIOSH to OSHA [NIOSH 1990a,b] and chrysotile fibers are known to be less per- was reaffirmed in comments to MSHA in 2002, with sistent in the lungs than amphibole asbestos the explanation that the 100-minute averaging time

NIOSH CIB 62 • Asbestos 17 level intended to (1) protect against the non- then Method 7400 can be supplemented carcinogenic effects of asbestos; (2) materi- with electron microscopy, using electron dif- ally reduce the risk of asbestos-induced can- fraction and microchemical analyses to im- cer (only a ban can ensure protection against prove specificity of the fiber determination. carcinogenic effects of asbestos); and (3) be NIOSH Method 7402 … provides a qualita- measured by techniques that are valid, repro- tive technique for assisting in the asbestos fi- ducible, and available to industry and official ber determinations. Using these NIOSH mi- agencies [NIOSH 1976]. This REL was set at croscopic methods, or equivalent, airborne the limit of quantification (LOQ) for the phase asbestos fibers are defined, by reference, as contrast microscopy (PCM) analytical method those particles having (1) an aspect ratio of for a 400-L sample, but risk estimates indicated 3 to 1 or greater; and (2) the mineralogic that exposure at 0.1 f/cm3 throughout a work- charz elemental composition) of the asbes- ing lifetime would be associated with a residu- tos minerals and their nonasbestiform anal risk for lung cancer. A risk-free level of ex- alogs. The asbestos minerals are defined as posure to airborne asbestos fibers has not been chrysotile, crocidolite, amosite (cumming established [NIOSH 1976, 1984]. tonite-grunerite), anthophyllite, tremolite, and actinolite. In addition, airborne cleavage fragments from the nonasbestiform hab- 2.7.1 The NIOSH REL as Revised its of the serpentine minerals antigorite and in 1990 lizardite, and the amphibole minerals con- In 1990, NIOSH [1990b] revised its REL, retain- tained in the series cummingtonite-grunerite, ing the 0.1 f/cm3 limit but explicitly encompass- tremolite-ferroactinolite, and glaucophane- ing EMPs from the nonasbestiform analogs of riebeckite shall also be counted as fibers pro- the asbestos minerals: vided they meet the criteria for a fiber when viewed microscopically. NIOSH has attempted to incorporate the appropriate mineralogic nomenclature in The NIOSH REL for asbestos has been de- its recommended standard for asbestos and scribed in NIOSH publications and in formal recommends the following to be adopted comments and testimony submitted to the De- for regulating exposures to asbestos: partment of Labor. The recommendation was based on the Institute’s understanding in 1990 The current NIOSH asbestos recommend- of potential hazards, the ability of the analyt- ed exposure limit is 100,000 fibers greater ical methods to distinguish and count fibers, than 5 micrometers in length per cubic me- and the prevailing mineral definitions used to ter of air, as determined in a sample collect- describe covered minerals. ed over any 100-minute period at a flow rate of 4 L/min using NIOSH Method 7400, or 2.7.1.1 Rationale for Encompassing equivalent. In those cases when mixed fi- Nonasbestiform Analogs of ber types occur in the same environment, Asbestos Varieties Within the REL

would help “to identify and control sporadic exposures NIOSH’s rationale for recommending that non- to asbestos and contribute to the overall reduction of asbestiform analogs of the asbestos minerals exposure throughout the workshift” [NIOSH 2002]. be encompassed within the policy definition

18 NIOSH CIB 62 • Asbestos of airborne asbestos fibers was first articulated for some mining operations and down- in comments and testimony to OSHA [NIOSH stream users of their mined commodities. 1990a,b]. According to the 1990 testimony, NIOSH based its recommendation on three Given the inconclusive epidemiological evidence elements: for lung cancer risk associated with exposure to cleavage fragments (first bullet, above), NIOSH •• The first element comprised results of took a precautionary approach and relied upon epidemiological studies of worker popula- the other two elements to recommend that the tions exposed to EMPs from nonasbesti- 0.1 f/cm3 REL for airborne asbestos fibers also form mineral analogs of the asbestos va- encompass EMPs from the nonasbestiform an- rieties (e.g., cleavage fragments). The 1990 alogs of the asbestos minerals. In fact, the 1990 testimony characterized the existing ev- NIOSH testimony included an explicit asser- idence as equivocal for excess lung can- tion that the potential risk of lung cancer from cer risk attributable to exposure to such exposure to EMPs (of the nonasbestiform asbes- nonasbestiform EMPs. tos analog minerals) warranted limiting such exposures. However, even if such EMPs were not •• The second element comprised results of hazardous, the inability of analytical methods to animal carcinogenicity studies involving accurately distinguish countable particles as ei- experimental intrapleural or intraperitoneal ther asbestos fibers or cleavage fragments (of administration of various mineral particles. the nonasbestiform analog minerals) presents a The 1990 testimony characterized the re- problem in the context of potentially mixed ex- sults of the studies as providing strong ev- posures (i.e., asbestos fibers together with EMPs idence that carcinogenic potential depends from the nonasbestiform analogs). NIOSH’s 1990 on a mineral particle’s length and width and recommendation provided a prudent approach reasonable evidence that neither chemical to mixed dust environments with potential expo- composition nor mineralogical origin is a sure to asbestos; limiting the concentration of all critical factor in determining a mineral par- countable particles that could be asbestos fibers ticle’s carcinogenic potential. to below the REL would ensure that the asbestos fiber component of that exposure would not ex- •• The third element comprised the lack of ceed the REL. routine analytical methods to accurately Some scientists and others have questioned and consistently distinguish between as- NIOSH’s rationale for including EMPs from bestos fibers and nonasbestiform EMPs nonasbestiform amphibole minerals in its in samples of airborne fibers. The 1990 definition of “airborne asbestos fibers.” Miner- testimony argued that asbestiform and alogists argue that these EMPs do not have the nonasbestiform minerals can occur in morphological characteristics required to meet the same area and that determining the the mineralogical definition of “fibers”; acicular location and identification of tremolite and prismatic amphibole crystals and cleav- asbestos, actinolite asbestos, and antho age fragments generated from the massive hab- phyllite asbestos within deposits of their its of the nonasbestiform analogs of the asbestos nonasbestiform mineral analogs can be minerals are not true mineralogical fibers. Oth- difficult, resulting in mixed exposures ers have opined that the scientific literature does

NIOSH CIB 62 • Asbestos 19 not demonstrate any clear health risks associated ATA which, based on mechanistic and tox- with exposure to the nonasbestiform EMPs cov- icological data, may be associated with a ered by the NIOSH “airborne asbestos fiber” def- carcinogenic effect, do not appear to pres- inition. ent an occupational risk. Their presence in the workplace is not apparent from the re- Whether or not to include EMPs from non cord evidence. asbestiform analogs of the asbestos minerals in federal regulatory asbestos policies has been In its 2005 proposed rule for asbestos, MSHA the subject of long-standing debate. The expo- stated that substantive changes to its asbestos sure-related toxicity and health effects associat- definition were beyond the scope of the pro- ed with the various morphologies (e.g., acicular, posed rule and chose to retain its definition of prismatic) of the nonasbestiform analogs of asbestos, which “does not include nonfibrous the asbestos minerals continue to be a central or nonasbestiform minerals” [MSHA 2005]. point in the debate. In 1986, OSHA revised its These decisions are reflected in MSHA’s final asbestos standard and included nonasbestiform rule published in 2008 [MSHA 2008]. In for- anthophyllite, tremolite, and actinolite (ATA) mal comments during the rulemaking pro- as covered minerals within the scope of the re- cess, NIOSH agreed with MSHA’s decision not vised standard [OSHA 1986]. OSHA’s decision to modify its asbestos definition in the current to include nonasbestiform ATA proved contro- rulemaking, stating that “NIOSH is present- versial. In a 1990 proposal to reverse this revi- ly re-evaluating its definition of asbestos and sion, OSHA [1990] noted that there were “a nonasbestiform minerals, and will work with number of studies which raise serious questions other agencies to assure consistency to the ex- about the potential health hazard from occu- tent possible” [NIOSH 2005]. In the interim, pational exposure to nonasbestiform tremolite, the following subsections provide more detail anthophyllite and actinolite,” but that the “current on the three elements comprising NIOSH’s ra- evidence is not sufficiently adequate for OSHA to tionale for recommending in 1990 that nonas- conclude that these mineral types pose a health bestiform analogs of the asbestos minerals be risk similar in magnitude or type to asbestos.” encompassed by the REL.

In the preamble to the final rule removing nonasbestiform ATA from its asbestos stan- 2.7.1.1.1 Epidemiological Studies dard, OSHA [1992] stated that: The first element of NIOSH’s rationale for rec- …various uncertainties in the data** and ommending in 1990 that nonasbestiform ana- a body of data showing no carcinogenic ef- logs of the asbestos minerals be encompassed fect, do not allow the Agency to perform by the REL related to evidence from epidemi- qualitative or quantitative risk assessments ological studies. concerning occupational exposures. Fur- A number of epidemiological studies have been ther, the subpopulations of nonasbestiform conducted to evaluate the health risk to work- **OSHA was referring to the scientific data on which ers reported to be exposed to EMPs. Epidemi- NIOSH based its own carcinogenic health effect rec- ological studies have been conducted in the ommendation to OSHA. Governeur talc district of upstate New York in

20 NIOSH CIB 62 • Asbestos which the deposits have been reported to con- Excessive rates of mesothelioma have been retain both amphibole cleavage fragments and ported for Jefferson County, which is immedi- transitional mineral fibers [Beard et al. 2001]. ately adjacent to the Balmat, Fowler, and Ed- Differing interpretation of the analysis of these wards talc-mining areas of St. Lawrence County particles has caused considerable disagreement in New York [Vianna et al. 1981; Enterline and over the asbestos content of these talc depos- Henderson 1987; Hull et al. 2002]. In a study its [Van Gosen et al. 2004]. Because of the dis- of all histologically confirmed mesothelioma agreement over the classification of these min- cases reported to New York State’s tumor reg- eral particles, the epidemiological studies of istry from 1973 to 1978, Vianna et al. [1981] talc miners and millers in upstate New York reported six cases from Jefferson County, re- are reviewed here. Additional epidemiological sulting in a mesothelioma rate for that coun- studies of worker populations with exposures ty more than twice that of New York State (ex- to EMPs are also reviewed, including studies cluding New York City). In a national study conducted at the Homestake gold mine in South of pleural cancer mortality (ICD-9 163) from Dakota and the taconite mining region of north- 1966 through 1981, Enterline and Henderson eastern Minnesota. The findings from these -in [1987] reported 4 mesothelioma cases in Jef- vestigations are reviewed in detail below. ferson County females (0.6 expected) and 7 cases in Jefferson County males (1.4 expected), resulting in county mesothelioma rates that were Studies of New York Talc Miners and Millers the second and sixth highest county-specific Workers exposed to talc†† have long been rec- rates in the nation for females and males, re- ognized to have an increased risk of develop- spectively (both p < 0.01). More recently, Hull ing pulmonary fibrosis, often referred to as talc et al. [2002] updated the Enterline and Hen- pneumoconiosis [Siegel et al. 1943; Kleinfeld et derson pleural cancer mortality analysis for al. 1955]. Talc-exposed workers have also been Jefferson County, reporting 5 new male cases reported to have an increased prevalence of (2 expected) and 3 new female cases (0.5 ex- pleural abnormalities, including pleural thick- pected) through 1997 and describing Jeffer- ening and pleural plaques [Siegel et al. 1943; son County mesothelioma death rates as “5–10 Gamble et al. 1982]. times the background rate.” A potential limitation of the Enterline and Henderson [1987] Several more recent epidemiological studies and and Hull et al. [2002] analyses is that they re- reviews have been conducted of workers em- lied on ICD code 163 (“malignant neoplasms ployed in talc mines and mills in upstate New of the pleura, mediastinum, and unspecified York [Brown et al. 1979, 1990; Kleinfeld et al. sites”) as a surrogate identification for malig- 1967, 1974; Lamm and Starr 1988; Lamm et al. nant mesothelioma. That code lacked specifici- 1988; Stille and Tabershaw 1982; Gamble 1993; ty and sensitivity for mesothelioma; in a study of Honda et al. 2002; Gamble and Gibbs 2008]. Massachusetts deaths, many non-mesothelioma malignancies involving the pleura were assigned †† The characteristics of talc deposits vary with location code 163 and most mesotheliomas were not as- [Van Gosen et al. 2004]. Unless otherwise specified, the talc referred to in this section is restricted to the signed code 163 [Davis et al. 1992]. The more re- deposits in New York State which contain talc and cent ICD-10 system, which has been used since other minerals. 1999 to code death certificate data in the United

NIOSH CIB 62 • Asbestos 21 States, includes a discrete code for malignant rate among the workers at the RTV mine and mesothelioma. Based on that new ICD-10 code, mills has been suggested as one possible ex- the age-adjusted death rates (per million pop- planation for the excess lung cancer mortality ulation) for 1999–2004 were 12.9 (based on 5 [Kelse 2005; Gamble 1993]. However, it is gen- mesothelioma deaths) for Jefferson County and erally considered implausible that confound- 10.9 (based on 5 mesothelioma deaths) for St. ing by smoking in occupational cohort studies Lawrence County. These are similar to the over- could explain such a large (i.e., about twofold all U.S. mesothelioma death rates for this same to threefold) increase in lung cancer mortality period (based on a total of 15,379 mesothelioma [Steenland et al. 1984; Axelson and Steenland deaths) of 11.5 per million [NIOSH 2007b]. 1988; Axelson 1989].

An excess of lung cancer has also been report- The most persuasive argument against a caused following several epidemiological studies al interpretation of these findings is that the of New York talc mines and mills [Kleinfeld et lung cancer excess in this study population did al. 1967, 1974; Brown et al. 1990; Lamm and not increase with duration and measures of ex- Starr 1988; Stille and Tabershaw 1982; Lamm posure to dust [Lamm et al. 1988; Stille and et al. 1988; Honda et al. 2002]. The most ex- Tabershaw 1982; Honda et al. 2002]. Also, the tensive research has been conducted on work- excess of lung cancer in this cohort has been ers at the talc mine and mills owned by RT reported to be limited to workers with short Vanderbilt Company, Inc. (RTV), located in St. employment (<1 year) [Lamm et al. 1988] and Lawrence County. A significant excess of mor- to workers who have been employed in oth- tality from nonmalignant respiratory disease er industries where exposure to carcinogens (NMRD) has been consistently noted in these may have occurred prior to their working in studies. These studies have also generally dem- the RTV mine and mills [Lamm et al. 1988; onstrated an approximately twofold to three- Stille and Tabershaw 1982]. The latter obser- fold increase in lung cancer mortality among vation could be explained by there simply be- these workers [Brown et al. 1990; Honda et al. ing too few workers and inadequate follow-up 2002; Lamm et al. 1988]. The lung cancer ex- of workers who have worked only at RTV to cess has been reported to be particularly high provide the statistical power necessary to dem- among workers with more than 20 years since onstrate an increased lung cancer risk. For ex- their first exposure (latency), which is a pat- ample, in one of the studies only 10% of the de- tern consistent with an occupational etiology cedents were reported to have not worked in [Brown et al. 1979, 1990]. Authors of several other industries prior to their employment at studies have questioned whether the excess of RTV [Stille and Tabershaw 1982]. lung cancer observed in these studies is due to employment at the RTV mines and mills or to In the most recent study of RTV miners and other factors [Honda et al. 2002; Lamm et al. Millers, Honda et al. [2002] examined lung can- 1988; Stille and Tabershaw 1982]. Attributing cer mortality in relation to quantitative estimates these findings to employment in the RTV mine of exposure to respirable talc dust [Oestenstad et is difficult because there were numerous mines al. 2002]. As in previous studies, mortality from operating in upstate New York, and the min- lung cancer was found to be significantly elevat- eralogical composition of the ores varied sub- ed (standardized mortality ratio [SMR] = 2.3; stantially [Petersen et al. 1993]. A high smoking 95% confidence interval [95% CI] = 1.6–3.3),

22 NIOSH CIB 62 • Asbestos with the most pronounced excess of lung can- Three controls (n = 66) for each case were se- cer mortality found in short-term workers (<5 lected from members of the cohort who had years). An exposure-response relationship was not died of NMRD or accidents, and they were observed in the study between cumulative ex- matched to cases on the basis of dates of birth posure to respirable dust and NMRD and pul- and hire. Controls were also required to have monary fibrosis. survived for as long as their matched case. In- formation on smoking and work histories was One explanation that has been offered for the obtained by interviewing the case (if alive) or lack of exposure-response in these studies is relatives. An attempt was made to verify infor- that the observed excess of lung cancer was a mation on previous employment by checking result of exposures from employment prior personnel records and by contacting previous to starting work at RTV. It has been suggest- employers. A panel of epidemiologists and ined that many of these workers may have had dustrial hygienists classified previous non-talc prior employment in neighboring talc mines employment with regard to the probability of in upstate New York with similar exposures occupational exposure to a lung cancer risk. to talc [NIOSH 1980]. Not considering exposures at these other mines could have substan- As in previous investigations of the RTV co- tially impacted results of exposure-response hort, Gamble [1993] found that the risk of lung analyses. Exposures to dust may also have been cancer decreased with increasing duration of substantially higher in the neighboring mines employment at RTV. This was true among both than in the RTV mine [Kelse 2005]. Because smokers and nonsmokers, and also when indi- RTV workers may have had exposures to dust viduals with inadequate time since first expo- in other mines, their exposures may have been sure (<20 years) and short duration of employ- underestimated, which could explain the ob- ment were excluded. Lung cancer risk was also served lack of an exposure-response relation- found to decrease with increasing probability ship in the epidemiological studies of RTV of exposure to lung carcinogens from non-talc workers. There is also evidence to suggest that employment. A positive exposure-response re- RTV workers may have been exposed to lung lationship was evident when non-RTV talc ex- carcinogens from prior work in non-talc indus- posures were included in the analysis, although tries [Lamm et al. 1988]. this relationship was not statistically significant.

Gamble [1993] conducted a nested case-con- This study by Gamble [1993] does not provide trol study of lung cancer in the RTV cohort support for the hypothesis that prior employ- to further explore whether factors unrelated ment in non-talc industries was responsible to exposures at RTV, such as smoking and ex- for the excess of lung cancer observed among posures from prior employment, might be re- RTV workers. The author interpreted his find- sponsible for the observed excess of lung can- ings as providing support for the argument cer among RTV workers. Cases and controls that the excess of lung cancer was due to con- were identified from among 710 workers who founding by smoking, on the basis of the fact were employed between 1947 and 1958, and that smoking was strongly associated with lung vital status was ascertained through 1983. All cancer risk and on the observation that the individuals whose underlying cause of death exposure-response relationship with talc was was lung cancer were included as cases (n = 22). more strongly negative (inverse) in analyses

NIOSH CIB 62 • Asbestos 23 restricted to smokers than among all study Van Gosen [2007] has reported that fibrous subjects. However, it is no surprise that an as- varieties of talc, tremolite, and anthophyllite sociation was observed between smoking and occur in the tremolite-talc deposits of the lung cancer, and the fact that the negative (in- Governeur talc mining district of upstate New verse) exposure-response trend was stronger York. It has been debated whether the fibrous among smokers does not explain why the co- amphiboles in those talc ores meet the crite- hort as a whole experienced much higher lung ria of asbestos, with the debate centered on the cancer rates than expected. complex and unusual transitional fibers composed partly of talc and partly of anthophyllite. Only two cases of pleural mesothelioma have NIOSH [1980] and others [Van Gosen 2006; been reported in the cohort studies of RTV Webber 2004] have reported that dust from the miners and millers [Honda et al. 2002], and RTV mine, which is in the Governeur talc min- those authors reported that it was unclear ing district, contains asbestos. In an industri- whether these cases are attributable to exposure al hygiene assessment conducted at RTV mines to talc at the RTV mine and mills. One of the by NIOSH [1980], X-ray diffraction and pe- individuals had worked for only a short time in trographic microscopic analyses of talc prod- a job with minimal talc exposure, had previous- uct samples found them to contain 4.5%–15% ly worked for many years in the construction of anthophyllite (some of which was categorized a talc mine, and had subsequently worked on as asbestos). In contrast, Kelse [2005] report- repairing oil heating systems. The other case ed the percentage by weight of talc from the developed only 15 years after first exposure to RTV mine in upstate New York as 1%–5% RTV talc, although mesothelioma has more nonasbestiform anthophyllite. In airborne sam- typically been observed to develop after much ples collected by NIOSH at the mine and mill longer times from first exposure. NIOSH has and analyzed by TEM, 65% of the EMPs that recently received unpublished reports of ad- were longer than 5 µm were anthophyllite and ditional cases of pleural mesothelioma among 7% were tremolite, and much of the tremolite workers at RTV or its predecessor, Interna- was from a nonfibrous habit [NIOSH 1980]. tional Talc [Abrams 2010; Maimon 2010], and Kelse [2005] reported that up to 1.8% was from a report of at least one worker using products an asbestiform habit, though the asbestiform from the mine who may also have died from component was reported not to be asbestos. mesothelioma [Satterley 2010]. NIOSH has also Serpentine and amphibole minerals typical- received unpublished observations concerning ly develop through the alteration of other min- findings from chest radiographs RTV has ob- erals. Consequently, they may exist as partially tained on its workers semiannually since 1985. altered minerals having variations in elemen- Although pleural plaques were more frequently tal compositions. Minerals undergoing this al- observed, the program has identified only one teration are often called “transitional minerals.” worker with irregular parenchymal opacities Thus the elemental composition of individual consistent with asbestosis-like disease, results mineral particles can vary within a mineral de- that a consulting pulmonologist “did not find posit containing transitional minerals, which … to be consistent with that of a workforce ex- could account for differences in the reported posed to asbestos” [Kelse et al. 2008]. composition of talc from the RTV mine.

24 NIOSH CIB 62 • Asbestos A limitation of the epidemiological studies of companies. The talc in one of the closed mines RTV talc workers is the lack of an exposure-re- was reported to have had “cobblestones” of ser- sponse analysis based on direct measurements pentine rock that were highly tremolitic. In the of airborne EMP concentrations. Most of the mining of this talc, these cobblestones were re- studies used tenure as a surrogate for exposure, ported to have been avoided and/or discard- and the exposure metric used in the Honda et ed. Therefore, miners may have been exposed al. [2002] study was respirable dust, which may to tremolite, but it is unlikely that the mill- not be correlated with exposure to EMPs. Re- ers from this company were exposed [Selevan lationships between health outcomes and ex- 1979]. Van Gosen [2004] described the talc de- posure to an agent of interest can be attenuated posits in this area as “associated spatially with when a nonspecific exposure indicator is used serpentinite masses that in some areas host as a surrogate for exposure to the agent of inter- well-developed chrysotile asbestos [Bain 1942; est [Blair et al. 2007; Friesen et al. 2007]. Thus, Cady et al. 1963]. The alteration zone local- when the exposure index used to assess the ef- ly contains actinolite, tremolite, anthophyllite, fect of EMPs is based on a surrogate measure, and (or) cummingtonite, as described by Cady such as respirable dust, rather than on specif- et al. [1963]. Zodac [1940] described ‘radiating ic measurement of EMP concentrations, the masses of fibrous actinolite, which often have lack of an exposure-response relationship be- to be handled carefully as the needlelike crys- tween the exposure index and the health out- tals may penetrate fingers, are common on the come might not accurately reflect the true risk, dumps’ in a talc quarry near Chester, Vermont. particularly where the composition of a mixed The amphiboles present were not identified as dust exposure varies by work area. asbestiform. Finally, a cohort study of Vermont talc miners A statistically significant excess of NMRD and millers has some relevance for interpreting mortality was observed among the millers the findings from the studies of New York talc workers [Selevan et al. 1979]. Airborne dust (SMR = 4.1; 95% CI = 1.6–8.4), but not among samples and talc bulk samples from all locations the miners (SMR = 1.6; 95% CI = 0.20–9.6), in in the mines and mill studied were analyzed this study [Selevan 1979]. In contrast, respira- by X-ray diffraction or analytical EM, which tory cancer mortality was found to be signifi- showed the talcs to be similar in composition; cantly elevated among the miners (SMR = 4.3; no asbestos was detected in any of the samples. 95% CI = 1.4–10), but not among the millers To determine potential differences between the (SMR = 1.0; 95% CI = 0.12–4.0). The authors talcs mined and milled by a company no lon- suggested that their respiratory cancer findings ger in operation, seven samples of talcs were might be due to non-talc exposures, such as ra- obtained and also analyzed by X-ray diffrac- don progeny, because exposures to talc dust tion or analytical EM. These samples were re- were higher among millers than miners. The ported to be free of asbestos contamination and pattern of excess respiratory cancer observed the mineral composition was within the range in this study is similar to that reported in stud- of samples from then-producing operations. ies of RTV miners and millers. It has been not- The one remaining company, no longer oper- ed [Lamm and Starr 1988] that this provides ating at that time, had been located in the same evidence against the hypothesis that the lung geographic area as two of the then-producing cancer excess among RTV miners is caused

NIOSH CIB 62 • Asbestos 25 by exposure to the EMPs in RTV talc, because at least 5 years in the mine. McDonald et al. these were not identified in Vermont talc. [1978] conducted a retrospective cohort study of 1,321 men who had retired and worked In summary, excesses of pulmonary fibrosis for at least 21 years in the mine as of 1973 and pleural plaques are generally recognized and were followed for vital status until 1974. to have occurred among workers exposed to Brown et al. [1986] conducted a retrospective talc. Pleural cancer mortality rates have been cohort study of 3,328 miners who had worked reported to be significantly elevated in Jeffer- for at least 1 year between 1940 and 1965, with son County, adjacent to St. Lawrence County, follow-up of vital status to 1977. Follow-up of where the New York talc industry has been lo- this same cohort was subsequently updated to cated. However, recent death certificate data 1990 by Steenland and Brown [1995]. Expo- for 1999–2004 do not suggest a particular- sures of potential concern at this mine in- ly high rate of mesothelioma in St. Lawrence clude crystalline silica, radon progeny, arse- County or Jefferson County. Also, aspects of nic, and nonasbestiform EMPs. The longer the few cases of mesothelioma that have been (>5 µm) nonasbestiform EMPs have been re- carefully evaluated in the published studies of ported to be primarily cummingtonite-grunerite New York talc miners make it unclear whether (69%), but tremolite-actinolite (15%) and other the cases are attributable to employment in the nonasbestiform amphibole varieties (16%) were talc industry. Lung cancer mortality has been also detected [Zumwalde et al. 1981]. Most of consistently reported to be elevated in studies the EMPs observed by TEM (70%–80%) were of New York talc miners. However, attribution shorter than 5 µm; for the entire population of of this excess to exposures to dust containing EMPs, the geometric mean length was 3.2 µm talc and other minerals has been questioned, and the geometric mean diameter was 0.4 µm. because the lung cancer excess was generally found to be most pronounced in short-term There is very little evidence of an excess of workers and did not increase with cumula- mesothelioma in the studies of Homestake tive exposure to talc dust. It is highly unlikely gold miners. One case of mesothelioma with that chance or confounding from smoking or “low” dust exposure was noted in the study prior mining exposures fully accounts for the by McDonald et al. [1978]. Slight excesses of lung cancer excess observed in these studies. cancer of the peritoneum (4 cases; SMR = 2.8; These findings may be at least partly explained 95% CI = 0.76–7.2) and other respiratory can- by employment in other industries, including cer (3 cases; SMR = 2.5; 95% CI = 0.52–7.4) other mines in upstate New York. were described in the most recently reported study [Steenland and Brown 1995]. These Studies of Homestake Gold Miners categories might be expected to include cases of mesothelioma; however, mesothelioma Three groups of investigators have conduct- was not mentioned on the death certificates ed retrospective cohort studies of miners at for these cases. the Homestake gold mine in South Dako- ta, with somewhat different and overlapping Significant excesses in mortality from tuber- cohort definitions. Gillam et al. [1976] stud- culosis and pneumoconiosis (mainly silicosis) ied 440 white males who were employed as of were observed in all of the studies. An excess of 1960 and who had worked underground for respiratory cancer (10 cases: SMR = 3.7; 95%

26 NIOSH CIB 62 • Asbestos CI = 1.8–6.7) was noted in the earliest study, by associated with increased risk of respiratory dis- Gillam et al. [1976]. Respiratory cancer mor- eases in this population. tality was not found to be elevated (34 cases; SMR = 1.0; 95% CI = 0.71–1.4), and there was Studies of Taconite Miners only weak evidence that it increased with level of exposure, in the study by McDonald et al. There has been a long history of concern about a [1978]. A slight excess of lung cancer (115 cas- potential association between exposures associ- es; SMR = 1.1; 95% CI = 0.94–1.4) was noted ated with the taconite iron ore industry in north- in the most recent study, in comparison with eastern Minnesota and the potential cancer risk. U.S. mortality rates [Steenland and Brown This concern started in 1973, when amphibole 1995]. This lung cancer excess was more pro- fibers were found in the Duluth water supply nounced when county rates were used as the and were traced to tailings that had been dis- referent (SMR = 1.3; 95% CI = 1.0–1.5), and posed of in Lake Superior by the Reserve Mining even more so when South Dakota state rates Company. Extensive sampling and analysis of ar- were used (SMR = 1.6; 95% CI = 1.3–1.9). The eas of the Peter Mitchell taconite iron ore mines excess was also increased (versus U.S. rates; were recently conducted by Ross et al. [2007], SMR = 1.3; 95% CI = 1.0–1.6) when the anal- who reported finding “no asbestos fibers of any ysis was restricted to individuals with at least type” in the mines. However, they did find and 30 years of time since first exposure (latency). describe fibrous ferroactinolite, fibrous ferrian Lung cancer mortality was not found to in- sepiolite, fibrous grunerite-ferroactinolite, and crease with estimated cumulative exposure to fibrous actinolite in ore samples, some of which dust in this study, though a clear exposure- was very thin (<0.01 μm) with a very high aspect response trend was observed for pneumoco- ratio. They estimated fibrous amphibole material niosis. The limited available data on smok- to represent “a tiny fraction of one percent of the ing habits indicated that miners in this cohort total rock mass of this taconite deposit” [Ross et smoked slightly more than the U.S. general al. 2007]. population in a 1960 survey. Several epidemiological studies have exam- Taken together, the studies of Homestake gold ined mortality of miners working in the taco- miners provide, at best, weak evidence of an ex- nite mines and mills of Minnesota. Higgins et al. cess risk of lung cancer. Although small excesses [1983] published the earliest study, which exam- of lung cancer have been reported in the most re- ined the mortality of approximately 5,700 work- cent studies of the Homestake gold miners, the in- ers employed at the Reserve Mining Company creased mortality has not been found to increase between 1952 and 1976 and followed up to 1976. with measures of cumulative dust exposure. The Overall mortality (SMR = 0.87) and mortality uncertainty of the relationship between contem- from respiratory cancer (15 cases; SMR = 0.84) poraneous dust and EMP exposures hinders the were both less than expected. Respiratory cancer usefulness of historical dust measurement data mortality was not found to be increased among in estimating EMP exposures [Zumwalde et al. workers with at least 15 years since first expo- 1981]. Thus the lack of cancer noted in these sure (latency) and did not increase with estimat- studies is largely uninformative with respect to ed cumulative exposure to dust. The maximum the hypothesis that nonasbestiform EMPs are follow-up of this cohort was 24 years, which is

NIOSH CIB 62 • Asbestos 27 probably too short to be able to detect increased 2008]. The MDH has initiated epidemiologi- mortality from lung cancer or mesothelioma. cal studies of mesothelioma incidence among workers at the Conwed Corporation and at the Cooper et al. [1988, 1992] have reported on the iron mines in northeastern Minnesota. The re- mortality experience of 3,431 miners and mill- cords from a cohort of approximately 72,000 ers who were employed in the Erie or Minntac iron miners and from 5,700 Conwed work- mines and mills for at least 3 months between ers have been linked with a mesothelioma data 1947 and 1958. Follow-up of the cohort, ini- registry. Between 1988 and 2007, a total of 58 tially to 1983 [Cooper et al. 1988], was extend- mesothelioma cases among the miners and 25 ed to 1988 in their more recent update [Coo- cases among the Conwed workers were iden- per et al. 1992]. Comparisons were made with tified. Because only 3 of the 58 mesothelioma white male mortality rates for Minnesota and cases identified in the miner cohort had also for the U.S. population. Mortality from respi- been employed at Conwed, it is unlikely that ratory cancer was found to be slightly less than the mesothelioma excess in miners could be ex- expected in this study (106 cases, based on plained by asbestos exposures during employ- Minnesota rates: SMR = 0.92; 95% CI = 0.75– ment at the Conwed ceiling tile facility [MDH 1.1). Respiratory cancer mortality was close to 2007]. the expected value (46 cases, on the basis of Minnesota rates: SMR = 0.99; 95% CI = 0.72– Brunner et al. [2008] have recently reported 1.3) among workers with more than 20 years findings from an MDH study of mesothelioma since first exposure (latency). cases occurring among iron miners between 1988 and 1996. The job histories of the cas- A statistically significant excess of mesothelioma es were reviewed for evidence of exposure to has been reported in northeastern Minneso- commercial asbestos. Mining jobs were identi- ta, the area in which the taconite mining and fied from company personnel files. Nonmining milling industry is located [MDH 2007]. In employment information was obtained from its most recent report, the Minnesota Depart- worker application files, worker compensation ment of Health (MDH) reported that a to- records, and obituaries. Potential asbestos ex- tal of 159 cases occurred in this region during posures for jobs held in the mining industry the period of 1988 to 2006. The mesothelioma were identified by interviewing 350 workers, rate for males was approximately twice the ex- representing 122 occupations and 7 different pected rate, based on the rest of the state (146 mining companies. To estimate the probabili- cases: rate ratio [RR] = 2.1; 95% CI = 1.8–2.5), ty and intensity of potential exposure to com- whereas the rate for females was less than ex- mercial asbestos in each of the jobs, an expert pected (RR = 0.72; 95% CI = 0.38–1.2). The panel rated the potential for asbestos exposure fact that the excess of mesothelioma was ob- on the basis of these interviews, available job served only among males strongly suggests an descriptions from the relevant time period, occupational etiology. In addition to the taco- and their knowledge of the mining environ- nite industry, a plant producing asbestos ceil- ment. The job histories for 15 of 17 iron mining tiles (Conwed Corporation) was located ers known to have developed mesothelioma in the northeastern Minnesota region. From were considered sufficient for the study. Elev- 1958 to 1965 amosite was used at Conwed, and en of these 15 were reported to have had prob- from 1966 to 1974 chrysotile was used [Mandel able exposure, 3 were reported to have possible

28 NIOSH CIB 62 • Asbestos exposure to commercial asbestos, and 1 did not (but not females) in northeastern Minnesota have an identifiable source of exposure to com- and that a large number of these cases involved mercial asbestos. The asbestos exposures were workers in the Minnesota taconite industry. from nonmining jobs (4 cases), mining jobs (4 There is some evidence that these cases could, cases), or both (6 cases). The findings from this at least in part, be related to exposures to com- study suggest that the excess of mesothelioma mercial asbestos that occurred in or outside of observed among taconite miners might be ex- the taconite mining industry, but further re- plained by exposure to commercial asbestos search on this question is needed. The MDH is rather than from the nonasbestiform amphi- currently working with researchers at the Uni- bole EMPs generated during iron ore process- versity of Minnesota School of Public Health ing. However, this was a case series and it was on a mesothelioma case-control study, a respi- not possible to determine whether commer- ratory morbidity study, and a mortality study cial asbestos exposure was different in the cas- of the iron miners of northeastern Minnesota es than in the cohort as a whole or in a control [MDH 2007]. group. This study also did not include the 41 additional mesothelioma cases that have been Summary of Epidemiological Studies of reported by the MDH since 1996 [MDH 2007]. Cohorts Exposed to Nonasbestiform EMPs The age-adjusted rates of deaths due to malig- The results from studies of populations ex- nant mesothelioma during the period 2000– posed to nonasbestiform EMPs do not provide 2004 for the two counties considered to be clear answers regarding the toxicity of these in the iron range (Itasca and St. Louis Coun- EMPs. A number of features limit their use- ties) are reported as 30.4 and 31.3 per mil- fulness. First, the populations in these stud- lion, respectively, which are 2.6 and 2.7 times ies were exposed to a complex mixture of par- the U.S. average [NIOSH 2009a]. Two coun- ticles. Although an excess of pneumoconiosis ties (Carlton and Koochiching Counties) ad- has been observed in the studies of Homestake jacent to the iron range counties have malig- gold miners and New York talc workers, the nant mesothelioma rates of 55.3 and 77.5 per extent to which these findings are attributable million, which are 4.8 and 6.7 times the U.S. to their exposures to nonasbestiform EMPs average. The age-adjusted asbestosis rates dur- cannot be determined. A potential limitation ing 1995–2004 were reported for only two of of the New York talc studies is that, if the EMPs these counties: St. Louis County (7.9 per mil- do include fibers from asbestiform minerals, as lion, which is 1.3 times the U.S. average) and reported in the literature [NIOSH 1980; Van Carlton County (54.0 per million, or 8.9 times Gosen 2006; Webber 2004], it is difficult to -de the U.S. average) [NIOSH 2009b]. termine whether the observed health effects can be attributed to them, given the heteroge- In summary, the results from cohort mortality neous mineral composition of exposures. studies of taconite miners and millers in Minne- sota have not provided evidence of an increased Another major limitation of these studies is that risk of respiratory cancer or mesothelioma. they lack adequate information on past expo- This appears to be somewhat in conflict with sure to EMPs. An excess of respiratory cancer reports from the MDH that mesothelioma in- was observed in the studies of New York talc cidence is significantly elevated among males workers, and a small excess was observed in the

NIOSH CIB 62 • Asbestos 29 most recent study of Homestake gold miners. explain the apparent contradiction between In both studies, the excess of respiratory can- the lack of an excess of mesothelioma in the co- cer was not found to increase with cumulative hort studies of taconite miners, and the excess exposure to dust. Relationships between health of mesothelioma that has been reported in the outcomes and exposure to an agent of interest more recent studies based on a mesothelioma can be attenuated when a nonspecific expo- registry in northeastern Minnesota. sure indicator is used as a surrogate for exposure to that agent [Blair et al. 2007; Friesen et Finally, the lack of information on cigarette al. 2007]. Thus, when the exposure index used smoking habits of the studied workers is a ma- to assess the effect of EMPs is based on a sur- jor issue in interpreting the findings for respira- rogate measure, such as respirable dust, rather tory cancer in these studies. Concern about cig- than on specific measurement of EMP concen- arette smoking in occupational cohort studies trations, the lack of an exposure-response rela- is generally based on the assumption that blue tionship between the exposure index and the collar workers smoke more than the general health outcome might not accurately reflect population. However, the extent of this bias is the true risk, particularly where the composi- generally not expected to be able to account for tion of a mixed exposure varies by work area. more than a 50% increase in lung cancer risk Interpretation of findings from the New York and is unlikely to explain the twofold to three- talc studies has been further complicated by fold risk reported in the New York talc stud- the employment of the workers elsewhere, in- ies. Confounding by smoking could conceiv- cluding employment at other talc mines in the ably explain the small excess of lung cancer that area. Lack of positive findings from exposure- has been reported in the most recent study of response analyses in the New York talc studies Homestake gold miners [Steenland and Brown of RTV miners and millers could also have re- 1995]. However, smoking may have introduced sulted from exposure misclassification—possible a negative bias in some of these studies. Ciga- under-ascertainment of exposure to talc and rette smoking has been reported to have been other mineral particles caused by not consid- banned in the Homestake gold mines [Brown ering exposures at neighboring talc mines or previous employment in the same mine under et al. 1986] and in the underground taconite different ownership. mines [Lawler et al. 1985]. Preventing workers from smoking at work could have negatively bi- The reliability of death certificate information ased the lung cancer findings in these studies. is another major limitation, particularly for the diagnosis of mesothelioma. Mesothelioma did Because of the study limitations described not have a discrete ICD code until the 10th re- above, the findings from these studies should vision of the ICD, used for U.S. death certifi- best be viewed as providing inconclusive as cate data only since 1999. This likely explains opposed to negative evidence regarding the the discordance between the apparent recent health effects associated with exposures to lack of excess mesothelioma deaths in an up- nonasbestiform EMPs. To be more informative, state New York county adjacent to the county additional studies of these populations would in which talc mines and mills have been locat- need improved characterizations of exposure to ed and the excess “mesothelioma” death rates EMPs, smoking status, and exposures associat- previously reported in that county. This may ed with other employment. Additional studies

30 NIOSH CIB 62 • Asbestos of these populations should be pursued if these nonasbestiform tremolites [Smith et al. 1979]. In improvements are deemed feasible. its rule-making, OSHA noted several limitations of the study, including the small number of animals studied, the early death of many animals, 2.7.1.1.2 Animal Studies and the lack of systematic characterization of fi- The second element of NIOSH’s rationale for ber size and aspect ratio [OSHA 1992]. One of recommending in 1990 that nonasbestiform the nonasbestiform tremolitic talcs was later an- analogs of the asbestos minerals be encom- alyzed and determined to have tremolitic chem- passed by the REL is related to evidence from ical composition and 13% “fibers,” as defined by animal studies. Citing several original studies a 3:1 aspect ratio [Wylie et al. 1993]. and reviews [Stanton et al. 1977, 1981; Wagner et al. 1982; Muhle et al. 1987; Pott et al. 1974, Since 1990, another carcinogenicity study of 1987; Lippmann 1988], NIOSH [1990a] con- nonasbestiform amphibole minerals has been cluded that they provided evidence that fiber published. An IP injection study in rats used six dimension (and not fiber composition) was the samples of tremolite, including three asbestiform major determinant of carcinogenicity for min- samples that induced mesothelioma in 100%, eral fibers, stating that 97%, and 97% of challenged animals [Davis et al. 1991]. Two nonasbestiform tremolite sam- Literature reviews by Lippmann [1988] ples resulted in mesotheliomas in 12% and 5% and Pott et al. [1987] enhance the hypoth- of the animals, and the response rate of 12% was esis that any mineral particle can induce above the expected background rate. Another cancer and mesothelioma if it is sufficient- sample that was predominantly nonasbestiform ly durable to be retained in the lung and if but reported to contain a small amount of it has the appropriate aspect ratio and di- asbestiform tremolite resulted in mesothelioma mensions. Similarly, Wagner [1986] concluded that all mineral particles of a spe- in 67% of animals. Of note, the nonasbestiform cific diameter and length size range may material associated with the 12% mesothelioma be associated with development of diffuse incidence and this latter material contained an pleural and peritoneal mesotheliomas. approximately equal number of EMPs longer than 8 μm and thinner than 0.5 μm. That general conclusion notwithstanding, a study by Smith et al. [1979] that was not cited by Studies of in vitro assays of various biolog- NIOSH in 1990 addressed the specific question ical responses, some published before and of carcinogenicity of EMPs from nonasbestiform some after 1990, have also found relative tox- amphiboles. Pleural tumor induction by intra icities of asbestiform and nonasbestiform pleural (IP) injection challenge in hamsters was minerals that generally parallel the differenc- compared for various challenge materials, in- es observed in the in vivo IP injection stud- cluding two asbestiform tremolites and two ies of tumorigenicity [Wagner et al. 1982; nonasbestiform (prismatic) tremolitic talcs. In Woodworth et al. 1983; Hansen and Mossman contrast to the two asbestiform tremolites, which 1987; Marsh and Mossman 1988; Sesko and induced tumors in 22% and 42% of challenged Mossman 1989; Janssen et al. 1994; Mossman hamsters at the higher dose, no tumors result- and Sesko 1990] A recent review of the litera- ed following challenge with either of the two ture concluded that low-aspect-ratio cleavage

NIOSH CIB 62 • Asbestos 31 fragments of amphiboles are less potent than Two analytical components of the NIOSH REL asbestos fibers [Mossman 2008]. for airborne asbestos fibers are applied to air samples: the microscopic methods and the In summary, there is more literature now than in counting rules. The microscopic methods in- 1990 pertaining to differential animal carcinoge- clude the following: nicity and toxicity of EMPs from nonasbestiform amphiboles (e.g., acicular crystals, prismatic •• Phase contrast microscopy (PCM)—An- alytical Method 7400 “A rules”—Asbes- crystals, and cleavage fragments). The number of tos and Other Fibers by PCM [NIOSH studies is limited and each study has limitations, 1994a] is used to count all particles that but they suggest that nonasbestiform amphiboles are longer than 5 µm and have a length- might pose different risks than asbestos. More to-width ratio equal to or greater than 3:1. detailed discussion of these studies, including discussion of important limitations of the studies, •• Transmission electron microscopy (TEM)— can be found in Section 2.8.4 of this document. Analytical Method 7402—Asbestos by TEM [NIOSH 1994b] is used as a supplement to the PCM method when there 2.7.1.1.3 Analytical Limitations is uncertainty about the identification of elongate particles (EPs) that are count- The third element that served as a basis for ed. When TEM analysis is used for par- NIOSH’s 1990 recommendation that nonasbesti ticle identification, only those EPs that form analogs of the asbestos minerals be encom- are identified as “asbestos” and meet passed by the REL was the inability to accurate- the dimensional criteria used by PCM ly and consistently distinguish asbestos fibers and (>0.25 µm width and >5 µm length) are nonasbestiform EMPs in samples of airborne counted as asbestos fibers. PCM counts particulate. The 1990 NIOSH testimony argued can be adjusted to yield corrected asbes- that asbestiform and nonasbestiform minerals tos fiber counts by multiplying them by can occur in the same geological area and that the proportion of fibers determined by mixed exposures to airborne asbestos fibers and TEM to be asbestos. EMPs from the nonasbestiform analog minerals There are several limitations of the use of PCM can occur at mining operations. The potential for and TEM for asbestos analysis. PCM is stat- mixed exposures can also occur downstream if ed to be limited to observing EPs with widths the mined commodity contains both asbestiform >0.25 µm and is not equipped for particle iden- and nonasbestiform minerals. tification. TEM, although capable of resolving EPs with widths as small as 0.001 µm, frequent- The 1990 NIOSH testimony further pointed ly cannot differentiate nonasbestiform from out the lack of routine analytical methods for asbestiform EMPs when the elemental compo- air samples that can accurately and consistent- sition is the same or when present in a hetero- ly determine whether an individual EMP that geneous mix of unknown particles. A poten- meets the dimensional criteria of a countable tial limitation of TEM is that partial lengths of particle is an asbestos fiber or a nonasbestiform long fibers may not be observed because they EMP (e.g., acicular crystals, prismatic crystals, intersect grid bars or lie partially outside the cleavage fragments). small field of view. However, this is likely to

32 NIOSH CIB 62 • Asbestos affect only a small number of observed parti- as “asbestos fibers.” However, as the following cles, because very few particles are greater than clarified REL makes clear, particles that meet the 15 µm length, as evidenced in air samples from specified dimensional criteria remain countable textile processing [Dement et al. 2009] and min- under the REL for the reasons stated above, even ing and milling operations [Gibbs and Hwang if they are derived from the nonasbestiform ana- 1980]. A more important limitation of TEM is logs of the asbestos minerals. that, because only a small portion of the filter sample is being analyzed, airborne fiber concen- With use of terms defined in this Roadmap, the trations might not be determined with certain- NIOSH REL is now clarified as follows: ty. Another limitation of both methods is that high concentrations of background dust collect- NIOSH has determined that exposure to asbes- ed on samples may interfere with fiber count- tos fibers causes cancer and asbestosis in hu- ing by PCM and particle identification by TEM. mans and recommends that exposures be reduced to the lowest feasible concentration. Thus, the current PCM and TEM methods used for routine exposure assessment lack the NIOSH has designated asbestos to be a “Po- ‡‡ capability to accurately count, size, and iden- tential Occupational Carcinogen” and recom- tify all EMPs collected on airborne samples. mends that exposures be reduced to the lowest Further discussion of the analytical limitations feasible concentration. The NIOSH REL for air- and possible improvements are discussed in borne asbestos fibers and related elongate min- Section 2.8. eral particles (EMPs) is 0.1 countable EMP from one or more covered minerals per cubic centi- 2.7.2 Clarification of the Current meter, averaged over 100 minutes, where NIOSH REL •• a countable elongate mineral particle (EMP) As described in the preceding sections, uncer- is any fiber or fragment of a mineral longer tainty remains concerning the adverse health than 5 µm with a minimum aspect ratio effects that may be caused by nonasbestiform of 3:1 when viewed microscopically with EMPs encompassed by NIOSH since 1990 in use of NIOSH Analytical Method 7400 (‘A’ the REL for asbestos. Also as described in a pre- rules) or its equivalent; and ceding section, current analytical methods still cannot reliably differentiate between asbestos ‡‡NIOSH’s use of the term “Potential Occupational Car- fibers and other EMPs in mixed-dust environ- cinogen” dates to the OSHA classification outlined in ments. NIOSH recognizes that its descriptions of 29 CFR 1990.103, and, unlike other agencies, is the the REL since 1990 have created confusion and only classification for carcinogens that NIOSH uses. See Section 6.1 for the definition of “Potential Occu- caused many to infer that the additional covered pational Carcinogen.” The National Toxicology Pro- minerals were included by NIOSH in its defini- gram [NTP 2005], of which NIOSH is a member, has tion of “asbestos.” NIOSH wishes to make clear determined that asbestos and all commercial forms of that such nonasbestiform minerals are not “as- asbestos are known to be human carcinogens based bestos” or “asbestos minerals.” NIOSH also on sufficient evidence of carcinogenicity in humans. The International Agency for Research on Cancer wishes to minimize any potential future confu- (IARC) concluded that there was sufficient evidence sion by no longer referring to particles from the for the carcinogenicity of asbestos in humans [IARC nonasbestiform analogs of the asbestos minerals 1987b].

NIOSH CIB 62 • Asbestos 33 •• a covered mineral is any mineral having extensive clarification of specific minerals cov- the crystal structure and elemental com- ered by the NIOSH REL may be warranted. position of one of the asbestos variet- That more extensive clarification of covered ies (chrysotile, riebeckite asbestos [croci minerals is beyond the scope of this Roadmap dolite], cummingtonite-grunerite asbestos but will be addressed through additional efforts [amosite], anthophyllite asbestos, tremolite by NIOSH to encompass contemporary miner- asbestos, and actinolite asbestos) or one of alogical terminology within the REL. their nonasbestiform analogs (the serpen tine minerals antigorite and lizardite, and the amphibole minerals contained in the 2.8 EMPs Other than cummingtonite-grunerite mineral series, Cleavage Fragments the tremolite-ferroactinolite mineral series, and the glaucophane-riebeckite min- 2.8.1 Chrysotile eral series). Chrysotile fibers consist of aggregates of long, This clarification of the NIOSH REL for air- thin, flexible fibrils that resemble scrolls or borne asbestos fibers and related EMPs re- cylinders, and the dimensions of individual sults in no change in counts made, as defined chrysotile fibers depend on the extent to which by NIOSH Method 7400 (‘A’ rules). However, the material has been manipulated. Multi-fibril it clarifies definitionally that EMPs included in chrysotile fibers commonly split along the fiber the count are not necessarily asbestos fibers. length and undergo partial dissolution within the lungs [NRC 1984]. Such longitudinal split- The NIOSH REL comprises two components. ting in the lung represents one way that air sam- One component states the agency’s intent about ple counts may underestimate the cumulative what minerals should be covered by the REL; dose of fibers in the lung. the other component describes the sampling and analytical methods to be used for collect- Epidemiological studies of chrysotile in Que- ing, characterizing, and quantifying exposure bec mines [McDonald and McDonald 1997] to airborne particles from the covered miner- and South Carolina textile mills [Dement et al. als. Each of these components of the NIOSH 1994; Hein et al. 2007] have produced very dif- REL is discussed in detail in later subsections ferent estimates of the risk of cancer associat- of this Roadmap. ed with exposure to chrysotile fibers. With the differences in fiber concentrations accounted The NIOSH REL remains subject to change for, the exposure in the textile mills appears to based on research findings that shed light be associated with much higher risk than ex- on the toxicity of nonasbestiform amphibole posure in the mines. Several explanations for EMPs covered by the REL and on the toxic- the difference in lung cancer risks observed in ity of other EMPs outside the range of those these two different workplaces have been pro- minerals currently covered by the REL. In ad- posed. One suggested explanation is that the dition, because of changes by the IMA in 1978 textile workers were exposed to mineral oil. [Meeker et al. 2003] in how minerals (e.g., am- However, this explanation does not satisfacto- phiboles) are identified and classified (opti- rily explain the differences [Stayner et al. 1996]. cal microscopy to chemistry-based), a more Considering that the textile mill workers were

34 NIOSH CIB 62 • Asbestos exposed to fibers considerably longer and thin- amount of crocidolite was processed at one lo- ner than those found in mines [Peto et al. 1982; cation, wet or lubricated with oil or graphite, Dement and Wallingford 1990], a more likely to unite woven tape and braided packing [Mc- explanation is that the difference in risk may Donald et al. 1983]. Since crocidolite was never be due, at least in part, to dimensional differ- carded, spun, or twisted, the predominant expo- ences in the particles to which workers were sure at the plant was to chrysotile asbestos. A re- exposed. It has also been proposed that expo- cent reanalysis by transmission electron micros- sures in the textile mills were almost exclusive- copy (TEM) of archived fiber samples collected ly to chrysotile asbestos, whereas exposures in from the study facility in 1965 and 1968 identi- the mines were to a mixture of chrysotile asbes- fied only two amphibole fibers among 18,840 fi- tos fibers and EMPs of related nonasbestiform ber structures (0.01%) in archived airborne dust minerals (i.e., antigorite and lizardite) [Wylie samples from that textile mill study; the remain- and Bailey 1992]. Stayner et al. [1997] also der were identified as chrysotile [Stayner et al. point out, in comparing a number of epidemi- 2007]. Additionally, in fiber burden studies of ological studies, that the variation in relative malignant mesothelioma in humans, chrysotile risk for lung cancer is often greater within an fibers were often present in mesothelioma tissue, industry (e.g., mining or textile) than between even in the absence of detectable amphibole fi- varieties of asbestos. bers [Suzuki and Yuen 2001], though this alone does not constitute conclusive evidence of a role Some have argued that pure chrysotile may not for chrysotile in the etiology of mesothelioma. be carcinogenic and that increased respirato- In addition to analyses of air samples from epi- ry cancer among chrysotile workers can be ex- demiologic studies, UICC chrysotile B was an- plained by the presence of tremolite asbestos alyzed, with special attention given to identify- as a contaminant of chrysotile [McDonald and ing tremolite contamination. Analysis of more McDonald 1997]. This is referred to as the am- than 20,000 fibers identified only particles with phibole hypothesis. However, several studies of the characteristics of chrysotile, not tremolite workers using chrysotile with very little contam- [Frank et al. 1998]. Additionally, Kohyama et ination by tremolite have demonstrated strong al. [1990] reported no amphibole asbestos was relationships between exposure to chrysotile found in UICC chrysotile B at the detection lev- and lung cancer. A study of chrysotile asbestos el of 0.1%. This material has been used in an in- workers in China [Yano et al. 2001] found an halation experiment that produced lung cancers age- and smoking-adjusted relative risk of 8.1 and mesotheliomas [Wagner et al. 1974] and for lung cancer among highly exposed work- another study reporting mesotheliomas after ers, compared to workers with low exposure to intrapleural inoculation [Wagner et al. 1973]. asbestos. The identified contamination of the chrysotile by tremolite was less than 0.001%. In A possible difference in risk for carcinogenicity the South Carolina textile mill study, a strong re- between chrysotile and amphibole asbestos ex- lationship between lung cancer and chrysotile posures has been investigated in animal mod- exposure has been demonstrated [Dement et el studies. In a one-year rat inhalation study, al. 1994; Hein et al. 2007]. The plant also pro- chrysotile samples were extremely fibrogenic cessed less than 2000 lbs of crocidolite yarn per and carcinogenic. Pulmonary carcinomas de- year from the early 1950s until 1972. This small veloped in approximately 25% of animals,

NIOSH CIB 62 • Asbestos 35 and advanced interstitial fibrosis developed in Darnton [2000]. Based on the findings of Loo- lung tissue in 10% of all older animals, where- mis et al. [2009], Hodgson and Darnton [2010] as intrapleural injection studies produced reanalyzed their data. They found that cumu- mesotheliomas in over 90% of animals [Da- lative risk of mesothelioma for chrysotile-ex- vis et al. 1986]. It was noted that very little posed asbestos workers in processing plants chrysotile remained in the lungs of the animals was approximately an order of magnitude that survived longest following dust inhala- greater than the risk they had previously re- tion. From this it was suggested that chrysotile ported for mines and processing plants com- is very potent in rodents but, except where ex- bined, and commented that this risk is still at posure levels are very high and of long dura- least an order of magnitude lower than that as- tion, may be less hazardous to man because sociated with exposure to amphibole asbestos chrysotile fibers are removed from lung tis- [Hodgson and Darnton 2010]. sue more rapidly than are amphibole fibers. In A recent analysis of potency factors of vari- a further analysis of the data, using regenerat- ous minerals estimated that the relative poten- ed dusts, Berman et al. [1995] found that al- cy of chrysotile for producing mesothelioma though chrysotile and amphiboles do not differ ranged between zero and 1/200th that of am- in potency for lung tumor induction, mineral- phibole asbestos and that amphibole asbes- ogy is a determinant of the relative potency of tos and chrysotile were not equally potent in inhaled dusts for mesothelioma induction, and producing lung cancer [Berman and Crump chrysotile is less potent than amphiboles. 2008b]. However, the Asbestos Committee of EPA’s Science Advisory Board expressed sub- Hodgson and Darnton [2000] reviewed the lit- stantial concern that the scientific basis for a erature and estimated that, at exposure levels similar modeling approach being considered seen in occupational cohorts, the exposure- by EPA for risk assessment was weak and inad- specific risk of mesothelioma from the three equate, and specifically cited the lack of avail- principal commercial asbestos types is broad- able data to estimate TEM-specific levels of ex- ly in the ratio 1:100:500 for chrysotile, amosite, posure for epidemiological studies used in the and crocidolite, respectively, and the risk differ- analysis [EPA 2008a]. Subsequently, EPA chose ential for lung cancer between chrysotile fibers not to pursue this approach [EPA 2008b]. and the two varieties of amphibole asbestos fibers is between 1:10 and 1:50. In 2009, Loo- mis et al. [2009] reported the results of a mor- 2.8.2 Asbestiform Amphibole tality study of chrysotile textile workers which Minerals found increased risks of both mesothelioma Asbestiform amphibole fibers consist of ag- and lung cancer. The increase in mesothelioma gregates of long, thin, flexible fibrils that sep- and pleural cancer in this cohort was consis- arate along grain boundaries between the fi- tent with the average of 0.3% mesothelioma brils. Because the fibril diameter of crocidolite deaths in the cohorts that previously had been is less than that of anthophyllite asbestos but reported by Stayner et al. [1996] based on the flexibility is greater, there is an indication 12 studies of workers exposed to chrysotile that flexibility is a function of fibril diame- in mining and processing plants, but higher ter. As with chrysotile, the dimensions of in- than the estimates reported by Hodgson and dividual amphibole asbestos fibers depend on

36 NIOSH CIB 62 • Asbestos the extent to which the material has been ma- amphiboles winchite and richterite, as well as nipulated. There are conflicting reports on the tremolite asbestos [Meeker et al. 2003]. splitting of amphibole fibers in vivo. Following intrapleural inoculation in rats, ferroactinolite The recently updated NIOSH cohort study of and amosite have been reported to split lon- Libby workers found elevated SMRs for asbes- gitudinally in the lung, resulting in increased tosis (SMR 165.8; 95% CI 103.9–251.1), lung numbers of thinner fibers with increased as- cancer (SMR 1.7; 95% CI 1.4–2.1), cancer of pect ratio [Coffin et al. 1982, 1992; Cook et al. the pleura (SMR 23.3; 95% CI 6.3–59.5), and 1982], and crocidolite has also been observed mesothelioma [Sullivan 2007]. An exposure- to split longitudinally [Coffin et al. 1992]. In response relationship with duration of employ- other studies, crocidolite splitting was not ob- ment and total fiber-years cumulative exposure served, even after several years [Bellman et al. was demonstrated for both asbestosis and lung 1987]. Longitudinal splitting of fiber bundles cancer. Significant excess mortality from non- after entering the lung represents one way that malignant respiratory disease was observed air sample counts may underestimate the cu- even among workers with cumulative expo- mulative dose of fibers in the lung. sure <4.5 fibers/cc-years (i.e., a worker’s cumulative lifetime exposure, if exposed to asbestos There is little scientific debate that the asbestiform fibers at the current OSHA standard of 0.1 f/cm3 varieties of the five commercially important am- over a 45-year working life). IARC stated min- phibole asbestos minerals are carcinogenic and eral substances (e.g., vermiculite) that contain should be covered by regulations to protect asbestos should also be regarded as “carcino- workers. However, concerns have been raised genic to humans” (Group 1) [IARC 2009]. Ver- that the current OSHA and MSHA asbestos reg- miculite from the Libby mine was used to pro- ulations and even the current NIOSH REL for duce loose-fill attic insulation, which remains in airborne asbestos fibers, which explicitly cover millions of homes around the United States, and the asbestiform varieties of the six commercially homeowners and/or construction renovation important asbestos minerals, should be expand- workers (e.g., plumbers, cable installers, elec- ed to provide worker protection from exposure tricians, telephone repair personnel, and insu- to EMPs from asbestiform minerals. lators) are potentially exposed when this loose- fill attic insulation is disturbed. This concern is exemplified by exposures to winchite and richterite fibers at a vermiculite Because winchite and richterite are not explic- mine near Libby, Montana, where exposures to itly listed among the six commercial asbestos the these fibers have resulted in high rates of minerals, it is sometimes assumed that they lung fibrosis and cancer among exposed work- are not included in the regulatory definition ers, similar to the occurrence of asbestos-related for asbestos. However, some of what is now re- diseases among asbestos-exposed workers in ferred to as asbestiform winchite and richterite other industries [Amandus and Wheeler 1987; in the 1997 IMA nomenclature would have Amandus et al. 1987a,b; McDonald et al. 2004; been accurately referred to as tremolite asbes- Sullivan 2007; Rohs et al. 2008]. Workers at the tos according to the analytical criteria (opti- mine and residents of Libby were exposed to cal methods of identification) specified in the EMPs identified (on the basis of the 1997 IMA 1978 IMA nomenclature [Meeker et al. 2003]. amphibole nomenclature) as the asbestiform Furthermore, an even greater portion of this

NIOSH CIB 62 • Asbestos 37 richterite and winchite would have been iden- mesothelioma affecting several villages in Cen- tified as tremolite asbestos according to the tral Turkey has been studied for several decades optical methods of identification used prior to [Baris et al. 1981]. Homes and other buildings in 1978. In fact, over the years, amphibole miner- those villages were traditionally constructed of als from the Libby mine that are now referred blocks of local volcanic stone containing erionite, to as winchite and richterite were identified by a fibrous zeolite mineral. A recently published mineralogists using then-current terminolo- prospective mortality study has document- gy as soda tremolite [Larsen 1942], soda-rich ed that mesothelioma accounts for over 40% of tremolite [Boettcher 1966], and tremolite as- deaths among those residing in the affected vil- bestos and richterite asbestos [Langer et al. lages [Baris and Grandjean 2006]. This localized 1991; Nolan et al. 1991]; NIOSH identified ex- epidemic of malignant mesothelioma produced posures to workers as tremolite in reports of an opportunity for a pedigree study that found the Libby mine epidemiological studies in the a strong genetic influence on erionite-caused 1980s [Amandus and Wheeler 1987; Amandus mesothelioma [Dogan et al. 2006]. As with ex- et al. 1987a,b]. posure to asbestos, there is evidence that exposure to erionite causes other malignant tumors Similar to the situation in Libby, a study of a [Baris et al. 1996] and pleural plaques [Karakoca cluster of malignant mesothelioma cases in east- et al. 1997] in addition to mesothelioma. Like- ern Sicily has implicated an etiological role for wise, as with amphiboles, the mineralogy of zeo- an asbestiform amphibole in the fluoro-edenite lites, including erionite, appears to be compli- series, initially identified as a mineral in the cated and subject to misclassification [Dogan tremolite-actinolite series [Comba et al. 2003]. and Dogan 2008]. Although no clear epidemic of erionite-caused disease has been documented In the face of past and future nomenclature elsewhere, the mineral occurs in the intermoun- changes in the mineralogical sciences, work- tain west of the United States and a recent publi- ers need to be protected against exposures to cation purports to be the first to report a case of pathogenic asbestiform minerals. The health erionite-associated malignant mesothelioma in and regulatory communities will need to care- North America [Kliment et al. 2009]. fully define the minerals covered by their policies and monitor the nomenclature chang- The International Agency for Research on Can- es to minimize the impact of these changes on cer (IARC) has considered evidence relevant to worker protections. carcinogenicity for several EMPs [IARC 1977, 1987a, 1997]. In addition to the traditional commercial asbestos, IARC has made assess- 2.8.3 Other Minerals of ments that the evidence is sufficient to deter- Potential Concern mine that both erionite and talc containing By analogy to asbestiform amphiboles, there asbestiform fibers are human carcinogens (i.e., is reason to be concerned about potential for Group 1) [IARC 2009]; the evidence for carci- health risks associated with inhalational expo- nogenicity of nonasbestiform talc was judged sure to EMPs not covered by asbestos policies. to be insufficient to determine human carcinogenicity (i.e., Group 3) [IARC 1987a]. A Group Erionite is perhaps the most worrisome known 3 determination means that “the available example [HHS 2005b]. An epidemic of malignant studies are of insufficient quality, consistency

38 NIOSH CIB 62 • Asbestos or statistical power to permit a conclusion re- particles by diverse processes over time, where- garding the presence or absence of a causal as- as retention is the temporal persistence of parti- sociation, or no data on cancer in humans are cles within the respiratory system [Morrow 1985]. available” [IARC 1997]. On the basis of studies The deposition of inhaled particles in the respi- in rats, palygorskite (attapulgite) fibers longer ratory tract is a function of their physical charac- than 5 mm were determined to be possibly car- teristics (dimension and density), the anatomical cinogenic to humans (Group 2B) [IARC 1997]. and physiological parameters of the airways, and In experimental animals the evidence was limit- the rate and depth of respiration [Yu et al. 1986]. ed for the carcinogenicity of long sepiolite fibers Although particle chemical composition does (>5 µm) and inadequate to assess carcinoge- not play a role in deposition, respiratory clearance nicity of nonerionite fibrous zeolites (includ- of all particle types is dependent on both physi- ing clinoptilolite, mordenite, and phillipsite) cal and chemical characteristics of the particle. and wollastonite (Group 3) [IARC 1997]. These In addition, surface charge and hydrophilicity, as Group 3 determinations highlight the need for well as adsorbed materials (e.g., coatings on syn- additional research on nonasbestiform EMPs. thetic fibers) and other physical and chemical factors, determine whether small particles and fibers will agglomerate into larger, nonrespirable mass- 2.9 Determinants of Particle es [ILSI 2005]. Toxicity and Health Effects Depending on their physical characteristics, in- Current recommendations for assessing occu- haled particles are differentially deposited in one pational and environmental exposures to as- of the following three respiratory system com- bestos fibers rely primarily on dimensional partments: the extrathoracic region, consisting and mineralogical characteristics. Dimension, of the anterior and posterior nose, mouth, phar- which influences the deposition of EMPs in the ynx, and larynx; the bronchial region, consisting lung, lung clearance mechanisms, and retention of the trachea, bronchi, and bronchioles down time in the lung, is an important determinant to and including the terminal bronchioles; and of toxicity. However, other particle character- the alveolar-interstitial region, consisting of the istics, such as durability in lung fluids, chemi- respiratory bronchioles, alveolar ducts, and al- cal composition, and surface activity, may also veolar sacs. play important roles in causing respiratory diseases. Research to elucidate what roles these Important parameters for the deposition of EMP characteristics play in causing biologi- airborne particles are their aerodynamic and cal responses may help to provide better evi- thermodynamic properties. Below a particle dence-based recommendations for asbestos fi- size of 0.5 µm aerodynamic equivalent diam- bers and other EMPs. eter (AED), thermodynamic properties pre- vail. The AED of EPs is mostly determined by 2.9.1 Deposition their geometric diameter and density. Deposi- tion of EPs in an airway is strongly related to Deposition of airborne particles in the respi- the orientation of the particles with respect ratory system is defined as the loss of parti- to the direction of the air flow and is affected cles from the inspired air during respiration. by the interrelationship of four major depo- Clearance pertains to the removal of deposited sition mechanisms: impaction, interception,

NIOSH CIB 62 • Asbestos 39 sedimentation, and diffusion [Asgharian and Clearance depends upon the physicochemical Yu 1988]. In a study to assess EP deposition in properties of the inhaled particles, the sites of the tracheobronchial region, Zhou et al. [2007] deposition, and respiratory anatomy and phys- evaluated the deposition efficiencies of carbon iology. For example, inhaled insoluble parti- fibers (3.66 µm diameter), using two human cles with larger AEDs tend to deposit on the airway replicas that consisted of the oral cavity, nasopharyngeal mucus and are generally cleared pharynx, larynx, trachea, and three to four gen- by sneezing or nose blowing or by flow into the erations of bronchi. Carbon fiber deposition oropharynx, where they are swallowed. Insolu- was found to increase with the Stokes number, ble particles with smaller AEDs tend to depos- indicating that inertial impaction is the domi- it lower in the respiratory tract, with associated nant mechanism. Also, fiber deposition in the longer retention times. Those deposited in the tracheobronchial region was lower than that of alveolar region are subject to longer retention spherical particles at a given Stokes number, times than those deposited on the bronchial re- indicating a greater likelihood for small-width gion [Lippmann and Esch 1988]. EPs to move past the upper respiratory tract The most important process for removal of in- and reach the lower airways where diffusion- soluble particles from the airways is mucociliary al deposition predominates [Yu et al.1986]. clearance, which involves a layer of mucus pro- These results were confirmed by results of lat- pelled by the action of ciliated airway cells er studies evaluating the deposition of asbes- that line the trachea, bronchi, and terminal tos, using a similar tracheobronchial cast mod- bronchioles [Warheit 1989]. The mucociliary el [Sussman et al. 1991a, b]. The probability of transport system is sensitive to a variety of deposition of a particle in a specific location in agents, including cigarette smoke and ozone the airways is not the same as the probability [Vastag et al. 1985]. These toxicants affect the of penetration to that region, and for particles speed of mucus flow and consequent particle in a certain range of AEDs, the difference be- clearance by altering ciliary action and/or mod- tween penetration and deposition may be sub- ifying the properties and/or amount of mucus. stantial [ICRP 1994]. Chronic exposure to cigarette smoke has been shown to cause a prolonged impairment of par- 2.9.2 Clearance and Retention ticulate clearance from the bronchial region. This impaired clearance is associated with in- A variety of mechanisms are associated with the creased retention of asbestos fibers in the bron- removal of deposited particles from the respi- chi, where they stimulate inflammatory pro- ratory tract [Warheit 1989]. Physical clearance cesses in the bronchial epithelium [Churg and of insoluble particles deposited in the lung is Stevens 1995; Churg et al. 1992]. an important physiological defense mechanism that usually serves to moderate any risk that Because the alveolar region of the lung does might otherwise be associated with exposure to not possess mucociliary clearance capabili- particles. Inhaled particles that deposit on respi- ty, particles (generally <2 µm AED) deposit- ratory tract surfaces may be physically cleared ed in this region are cleared at a much slower by the tracheobronchial mucociliary escala- rate than particles deposited in the bronchi- tor or nasal mucus flow to the throat, and then al region. Particles that are soluble may dis- they may be either expectorated or swallowed. solve and be absorbed into the pulmonary

40 NIOSH CIB 62 • Asbestos capillaries, whereas insoluble particles may and lysosomal contents are released into the al- physically translocate from the alveolar air- veolar space. Frustrated phagocytosis can initi- space [Lippmann et al. 1980; Lippmann and ate a process in which reactive oxygen species Schlesinger 1984; Schlesinger 1985]. Most in- (ROS) are generated, stimulating the induction soluble EPs that deposit in the alveolar regions of tumor necrosis factor-alpha (TNF-α). TNF-α are phagocytized (i.e., engulfed) by alveolar is considered an inflammatory and fibrogenic macrophages. Macrophages contain lysosomes cytokine that plays an important role in the patho- packed with digestive enzymes, such as acid genesis of pulmonary fibrosis [Blake et al. 1998]. hydrolases, at acidic pH levels. Lysosomal contents are capable of digesting many—though not All three types of disruption of normal mac- all—types of phagocytized particles. Alveolar rophage function contribute to decreased par- macrophages that have phagocytized particles ticle clearance rates and can result in inflam- tend to migrate to the bronchoalveolar junc- mation of the alveolar spaces. In addition, tions, where they enter onto the mucociliary particles that are not phagocytized in the al- escalator for subsequent removal from the veoli can translocate to the lung interstitium, lung [Green 1973]. It has been postulated by where they may be phagocytized by intersti- some investigators that dissolution of parti- tial macrophages or transported through the cles within macrophages is a more important lymphatic system to pulmonary lymph nodes determinant of long-term clearance kinetics [Lippmann et al. 1980; Lippmann and Schlesinger for many mineral dusts than is mucociliary 1984; Schlesinger 1985; Oberdorster et al. 1988]. transport and the migratory potential of lung Tran and Buchanan [2000] have reported find- macrophages [Brain et al. 1994]. However, ings suggesting that sequestration of particles certain circumstances can disrupt the normal in the interstitial compartment is more promi- phagosomal function of alveolar macrophages. nent in exposed humans than is the observed One such circumstance involves the toxic retention of particles due to overload in animal death of macrophages initiated by highly re- studies. The importance of interstitialization in active particle surfaces (e.g., crystalline silica particles). Another such circumstance involves humans is consistent with the kinetic differ- overwhelming the capacity of macrophages ences observed in lung clearance rates in hu- by an extreme burden of deposited particles, mans and rats. The first-order rate coefficient sometimes referred to as “overload,” even by for alveolar clearance is approximately 1 or- particles that would be considered “inert” at der of magnitude faster in rats than in humans lower doses. A third type of circumstance, typ- [Snipes 1996], which may allow for greater ified by asbestos fibers, involves EPs that, even interstitialization of particles in humans at all though having a small enough AED (defined levels of lung dust burden. These findings -in primarily by particle width) to permit depo- dicate that adjustment of kinetic differences sition in the alveolar region, cannot be read- in particle clearance and retention is required ily phagocytized because particle length ex- when using rodent data to predict lung disease ceeds macrophage capacity. When alveolar risks in humans and that current human lung macrophages attempt to phagocytize such EPs, models underestimate working lifetime lung they cannot completely engulf them (some- dust burdens in certain occupational popula- times referred to as “frustrated phagocytosis”), tions [Kuempel et al. 2001].

NIOSH CIB 62 • Asbestos 41 Evidence from in vivo studies in rodents and in fragments than for asbestos fibers. Asbestos -fi vitro studies indicates that EPs (vitreous glass bers also tend to separate longitudinally once and EMPs) with a length equal to or greater deposited in the lung, thus increasing the total than the diameter of rodent lung macrophages number of retained fibers without an accom- (about 15 µm) are most closely linked to bio- panying reduction in lengths of the retained logical effects observed in rodent lungs [Blake fibers [NRC 1984]. In contrast, cleavage frag- et al. 1998]. Alveolar macrophages appear to ments tend to break transversely because of be capable of phagocytizing and removing EPs dissolution of their weaker crystalline struc- shorter than approximately 15 µm, either by ture, resulting in shorter particles that can be transport to the mucociliary system or to local more easily cleared through phagocytosis and lymph channels. With increasing length above mucociliary clearance [Zoltai 1981]. The im- approximately 15 µm, alveolar macrophages ap- pact of these structural differences on solubil- pear to be increasingly ineffective at physical re- ity in lung fluids warrants study, because sub- moval, resulting in differential removal rates for stantial differences in solubility in lung fluids EPs of different lengths. Although EP lengths between asbestos fibers and other EMPs (in- greater than 15 µm appear to be associated with cluding amphibole cleavage fragments) could toxicity in experimental studies with rodents, a translate into differences in toxicity. “critical” length for toxicity in humans is probably greater than 15 µm [Zeidler-Erdely et al. 2.9.3.1 Biopersistence 2006]. For long EPs that cannot be easily cleared by macrophages, biopersistence in the lung is Dissolution of EPs in the lung is a poorly un- influenced by the ease with which the EPs break derstood process that is dependent on particle into shorter lengths. characteristics, biological processes, and concomitant exposure to other particulates. The 2.9.3 Biopersistence and Other ability of an EP to be retained and remain intact in the lung is considered an important factor in Potentially Important Particle the process of an adverse biological response. Characteristics EPs of sufficient length that remain intact and It has been hypothesized that the differenc- are retained in the lung are thought to pose the es in crystalline structure between amphibole greatest risk for respiratory disease. The ability asbestos fibers and amphibole cleavage frag- of an EP to reside long-term in the lung is gener- ments account for apparent differences in tox- ally referred to as biopersistence. Biopersistence icological response to these particles. Cleavage of EPs in the lung is a function of site and rate fragments that meet the dimensional crite- of deposition, rates of clearance by alveolar ria for countable particles under federal reg- macrophages and mucociliary transport, solu- ulatory policies for asbestos fibers are gen- bility in lung fluids, breakage rate and breakage erally shorter and wider than asbestos fibers pattern (longitudinal or transverse), and rates [Siegrist and Wylie 1980; Wylie 1988]. This of translocation across biological membranes. dimensional difference between populations The rates of some of these processes can affect of asbestos fibers and populations of cleav- the rates of other processes. For example, a high age fragments might contribute to generally rate of deposition in the alveolar region could shorter biopersistence in the lung for cleavage potentially overwhelm macrophage clearance

42 NIOSH CIB 62 • Asbestos mechanisms and increase the rate of transloca- and epigenetic changes that may lead to can- tion to the lung interstitium. cer [Barrett 1994]. Although some evidence indicates that durability may be a determinant The persistence of an EP in the lung is influenced of toxicity for various synthetic vitreous fibers by changes that may occur in its dimension, sur- (SVFs), EMPs need to be evaluated to deter- face area, chemical composition, and surface mine whether they conform to this paradigm chemistry. Differences in any of these charac- [ILSI 2005]. teristics can potentially result in differences in clearance and retention and affect toxic poten- Measurement of the biopersistence of various tial. For example, EPs too long to be effectively EMPs has been suggested as a means for estimat- phagocytized by alveolar macrophages will tend ing their relative potential hazard. Short-term to remain in the alveolar compartment and be inhalation and intratracheal instillation studies subjected to other clearance mechanisms, in- have been used to determine the biopersistence cluding dissolution, breakage, and translocation of various SVFs and asbestos fibers. Animal in- to interstitial sites and subsequently to pleural halation studies are preferred over animal tra- and other sites. cheal instillation studies to assess biopersistence because they more closely mimic typical hu- The durability of EPs residing in the lung is an man exposure. The European Commission has important characteristic influencing biopersis- adopted specific testing criteria that permit the tence. An EP’s durability is generally measured results from either short-term biopersistence by its ability to resist dissolution and mechani- studies or chronic animal studies to be used as a cal disintegration after being subjected to lung basis for determining carcinogenicity [Europe- extracellular fluid (approximate pH of 7) and an Commission 1997]. lysosomal fluids (approximate pH of 5). EPs that are more soluble will be less biopersistent, Several animal inhalation studies have indicat- and thicker EPs may take longer to dissolve ed that oncogenic potential of long SVFs can than thinner EPs, all else being equal. For ex- be determined by their biopersistence [Mast ample, long, thin EPs that are not very dura- et al. 2000; Bernstein et al. 2001; Moolgavkar ble could dissolve and/or fragment into short- et al. 2001]. It has been suggested that a cer- er EPs, increasing their probability of being tain minimum persistence of long EPs is nec- cleared from the lung and thus potentially de- essary before even minute changes appear in creasing lung retention time and risk for fibrot- the lungs of exposed animals [Bernstein et al. ic or neoplastic effects. Some EPs, such as cer- 2001]. Furthermore, Moolgavkar et al. [2001] tain types of glass fibers, are fairly soluble in have suggested that EP-induced cancer risk, lung fluid and are cleared from the lung in a in addition to being a linear function of expo- matter of days or months. Other EPs, such as sure concentration, is also a linear function of amphibole asbestos, can remain in the lung for the weighted half-life of EPs observed in inha- decades. It has been suggested that some types lation studies with rats. Also, dosimetry mod- of EPs may alter the mobility of macrophages els for rodents and humans indicate that, on a and the translocation of EPs to the pleura or normalized basis, EP clearance rates are lower lymph nodes [Davis 1994]. No relationship has in humans than in rats [Maxim and McConnell been established between biopersistence of EPs 2001] and that EPs frequently sequester in the in the lung and the risk of induction of genetic interstitial compartment of humans [Snipes

NIOSH CIB 62 • Asbestos 43 1996; Tran and Buchanan 2000]. Thus, results different pH conditions were used. Fluid pH from chronic inhalation studies with rodents appears to influence the creation of complexes exposed to EPs may underestimate risks for from the leached elements of the EP, which in humans, and adjustment for kinetic differences turn alters the rate of solubility. Chrysotile fibers in particle clearance and retention in rats is re- tend to dissolve readily in acids because of the quired to predict lung disease risks in humans preferential leaching of magnesium (Mg) from [Kuempel et al. 2001]. the fiber. The leaching of Mg from tremolite and anthophyllite and of sodium from crocidolite Studies using in vitro assays have been con- also occurs more readily in acid conditions. ducted with various SVFs and silicate minerals to determine the dissolution rate in simulated The rate of EP dissolution has also been ob- lung and lysosomal fluids [Hume and Rimstidt served to be affected by differing internal and 1992; Werner et al. 1995; Hesterberg and Hart surface structures. EPs with porous or rough 2000; Jurinski and Rimstidt 2001]. In vitro dis- surfaces have larger surface areas than smooth solution studies can provide a rapid and more EPs with the same gross dimensions. These controlled alternative to classic long-term tox- larger surface areas interact more readily with icity testing in animals and could provide use- the surrounding medium because of the great- ful information when performed as companion er number of sites where solute molecules can experiments with in vivo studies if conditions be absorbed. EMPs with cleavage plane sur- of exposure and test agent can be made simi- faces will contain varying degrees of defects; lar. The design ofin vitro assays is intended to the higher the number of surface defects, the mimic the biological conditions that exist in the greater the potential instability of the particle. lung once the EP comes into contact with lung Dissolution of these types of EMPs is typical- tissue or macrophages. Although uncertainties ly initiated where surface vacancies or impuri- exist about the specific physiological processes ties are present [Searl 1994]. Chrysotile asbes- that occur in the lung, results from in vitro as- tos is an example of a sheet silicate made up says can provide some insight into the chemi- of numerous fibrils composed of tightly bound cal reactions that influence EP dissolution. For rolled layers of Mg hydroxide. These Mg hy- example, it appears that EP (e.g., glass fiber) droxide layers are readily leached by acid so- dissolution occurs more readily when the EP lutions within human tissues [Spurny 1983], is in contact with a fluid that is undersaturated causing disintegration of the fibril’s crystal- with respect to the EP’s composition. The con- line structure. In contrast, the amphibole as- dition of undersaturation must be maintained bestos minerals are chain silicates with a crys- at the EP’s surface for dissolution to continue. talline structure comprising alkali and alkali If an EP is surrounded by a saturated or super- earth metals that are tightly bound, making saturated solution (compared to the EP com- the fibers less susceptible to dissolution. In position), then no further dissolution occurs. contrast to the crystalline structure of the asbestos fibers, some high-temperature glass -fi The results from manyin vitro experiments bers are more stable than chrysotile fibers be- demonstrate different patterns of dissolution cause they are composed of silicate chains, for most of the tested EP types (i.e., glass, asbes- sheets, and frameworks [Searl 1994]. The ab- tos) under various test conditions. This effect sence of cleavage planes or structural defects was most notable in those experiments where in glass fibers limits the degree to which fluids

44 NIOSH CIB 62 • Asbestos can penetrate their interior to promote disso- to incorporate into occupational safety and health lution. Chrysotile fibers were found to be less policies concerning exposures to EMPs. durable in rat lungs than some high-temperature SVFs [Bellmann et al. 1987; Muhle et al. 2.9.3.2 Other Potentially Important 1987] but more durable in physiological so- Particle Characteristics lutions than some refractory ceramic fibers Surface composition and surface-associated ac- (RCFs) [Scholze and Conradt 1987]. tivities have been suggested as factors affect- EP surface characteristics (e.g., structural de- ing the potential for disease induction by EMPs fects, porosity) and composition affect not (e.g., asbestos) [Bonneau et al. 1986; Kane 1991; Jaurand 1991; Fubini 1993]. For nonelongate re- only the rate of dissolution but also the manner spirable mineral particles (e.g., crystalline silica), in which dissolution occurs. In some instanc- surface composition and surface interactions can es, surface dissolution will cause alterations in directly and profoundly affectin vitro toxicities internal structure sufficient to cause mechan- and in vivo pathogenicity; they can also direct- ical breakage. In some studies, slagwools and ly cause membranolytic, cytotoxic, mutagenic, or rockwools exposed to water developed irreg- clastogenic damage to cells and have been shown ular surfaces, creating stress fractures that to induce fibrogenic activities in animals and hu- caused transverse breakage [Bellmann et al. mans. Investigation is warranted to confirm that 1987]. Similar occurrences of glass fiber break- these effects of surface composition and surface age have been observed when there was leach- interactions also apply to EMPs. One strategy ing of alkaline elements [Searl 1994]. is to determine the effects of well-characterized surface modification of different types of EMPs Results from in vitro and short-term in vivo on cell-free interactions with biological materials, studies conducted with various EMPs and in vitro cellular cytotoxicities or genotoxicities, SVFs provide some confirmation that persis- and pathology in animal models. tence of EPs in the lung is influenced by particle durability [Bernstein et al. 1996]. However, Surface properties of mineral fibers and oth- other evidence suggests that, because of the rela- er EMPs may have direct impact on cytotoxic tively short biodurability of chrysotile fibers, any or genotoxic mechanisms responsible for damage to the lung tissue caused by chrysotile fi- fibrogenic or carcinogenic activity. Chemical bers must be initiated soon after exposure [Hume surface modification of asbestos fibers has been and Rimstidt 1992], suggesting that biopersistence shown to affect their cytotoxicity [Light and of EPs in the lung may be only one of many factors Wei 1977a,b; Jaurand et al. 1983; Vallyathan that contribute to biological response. A better un- et al. 1985]. Although asbestos fibers clearly derstanding of the factors that determine the bio- can be carcinogenic, they are not consistently logical fate of EMPs deposited in the lung is criti- positive in genotoxicity assays; their principal cal to understanding the mechanisms underlying damage is chromosomal rather than gene mu- differences in toxic potential of various EMPs of tation or DNA damage [Jaurand 1991]. One different dimensions and compositions. Because study linked cytotoxicity with in vitro mam- biopersistence of EMPs is thought to play an im- malian cell transformation [Hesterberg and portant role in the development of disease, it may Barrett 1984]; thus, surface factors affecting eventually prove to be an important characteristic cytotoxicity might affect potential for inducing

NIOSH CIB 62 • Asbestos 45 some genotoxic activities. However, modify- •• the general question of extrapolating hu- ing the surface of a well-characterized sam- man health effects from in vivo animal ple of chrysotile fibers by depleting surface Mg model studies; while retaining fiber length did not result in a •• the physiological relevance of in vitro cel- significant quantitative difference forin vitro lular studies of EMP toxicities; micronucleus induction between the native and surface-modified materials, both of which •• the association of EMP dimensions with were positive in the assay [Keane et al. 1999]. pathology demonstrated in animal model studies; The surface of mineral fibers and other EMPs •• the potential mechanisms and associated also might be an indirect but critical factor in EMP properties responsible for initiating the manifestation of pathogenic activity. EMP cell damage; surfaces may be principal determinants of EMP durability under conditions of in vivo dissolu- •• the extensive information now available on a tion in biological fluids. As such, they would “central dogma” of subsequent intracellular be a controlling factor in biopersistence, criti- biochemical pathway stimulation leading to cal to the suggested mechanisms of continuing toxicity or intercellular signaling in disease irritation or inflammatory response in causing promotion; and fibrosis or neoplastic transformation. •• the use of these mechanistic paradigms to explain specific questions of 2.9.4 Animal and In Vitro ȣȣ differences between the activities of as- Toxicity Studies bestiform and nonasbestiform EMPs, including seemingly anomalous differ- Over the last half-century, in vivo animal ences between some in vitro and in vivo model studies have explored induction of lung EMP activities; cancer, mesothelioma, and pulmonary fibrosis by asbestos fibers and other EMPs following ȣȣ differences between the activities of intrapleural, intraperitoneal, or inhalation chal- erionite fibers and amphibole asbes- lenge. Numerous cell-free, in vitro cellular, and tos fibers; and in vivo short-term animal model studies have ȣȣ the possibility of EMP-viral co-carcino been pursued, attempting to (1) examine tissue genesis. and cellular responses to EMPs and impact of EMP conditioning on these responses; (2) iden- Several reviews and recommendations for ani- tify and evaluate interactions and mechanisms mal model and cellular studies on these issues involved in pathogenesis; and (3) seek morpho- have been developed by expert workshops and logical or physicochemical EMP properties con- committees. Early studies on the carcinoge- trolling those mechanisms. These short-term nicity of asbestos and erionite fibers were re- studies provide an evolving basis for design or viewed by IARC [1977, 1987a,b], and SVFs interpretation of higher-tier chronic exposure were reviewed more recently [IARC 2002]. studies of selected EMPs. Short-term in vivo and in vitro studies to elucidate mechanisms of fiber-induced genotoxicity Some of the short-term studies have addressed and genetic mechanisms affecting fiber-induced the following: lung fibrosis have been extensively reviewed.

46 NIOSH CIB 62 • Asbestos A review for the EPA by an international work- humans and that adjustment for kinetic differing group assembled in 2003 provides an up- ences in particle clearance and retention in rats date on short-term assay systems for fiber tox- is required to predict lung disease risks in hu- icity and carcinogenic potential [ILSI 2005], mans [Kuempel et al. 2001]. and two additional reviews discuss the fiber genotoxicity literature up to the current decade How the results of in vitro tests that use cells or [Jaurand 1997; Schins 2002]. organ cultures apply to humans has been questioned because of differences in cell types and species-specific responses. It is difficult to iso- 2.9.4.1 Model Systems Used to Study late and maintain epithelial or mesothelial cells EMP Toxicity for use as models. Interpretation of in vitro test The paucity of information on human health results may be limited because in vitro models effects of some new synthetic EPs has led to re- may not consider all processes, such as clear- newed considerations of the value and limita- ance or surface conditioning, which occur in tions of animal model studies, as well as the in- vivo. A major deficiency of in vitro systems is terpretability of intrapleural, intraperitoneal, or that biopersistence is not easily addressed. In inhalation challenge methods of animal mod- addition to the usual exposure metric of mass, el tests to make predictions of human health experimental designs should also include ex- effects [IARC 2002]. One analysis conclud- posure metrics of EMP number and surface ed that rat inhalation is not sufficiently sen- area [Mossman 2008; Wylie et al. 1997]. sitive for prediction of human carcinogenicity by EMPs other than asbestos fibers [Muhle As frequently performed, in vitro assays of min- and Pott 2000]. Another review concluded that eral particle-induced damage, measured by cell there are significant interspecies differenc- death or cytosolic or lysosomal enzyme release, es between the mouse, hamster, rat, and hu- do not adequately model or predict the results man, with the available evidence suggesting of in vivo challenge or epidemiological findings. that the rat is preferable as a model for the hu- For example, respirable aluminosilicate clay man, noting that rats develop fibrosis at com- dust is as cytotoxic as quartz dust in such in vitro parable lung burdens, in fibers per gram of dry assays, whereas quartz, but not clay, is strongly lung, to those that are associated with fibro- fibrogenicin vivo [Vallyathan et al. 1988]. sis in humans. The review suggested that, on a weight-of-evidence basis, there is no reason to 2.9.4.2 Studies on Effects of conclude that humans are more sensitive to fi- Fiber Dimension bers than rats with respect to the development of lung cancer [Maxim and McConnell 2001]. Early animal inhalation studies showed that However, others suggest that, because inhaled chrysotile fibers induced fibrosis, hyperplasia particles frequently sequester in the interstitial of lung epithelial cells, and carcinomas in mice compartment of humans, alveolar clearance is [Nordman and Sorge 1941] and tumors in rats approximately one order of magnitude slow- [Gross et al. 1967]. Another study revealed er in humans than in rats [Snipes 1996; Tran lung carcinomas and mesotheliomas in rats af- and Buchanan 2000]. Those comparisons im- ter inhalation exposure to asbestos fiber sam- ply that results of inhalation studies with rats ples of amosite, anthophyllite, crocidolite, and exposed to particles underestimate the risk for chrysotile [Wagner et al. 1974]. The effects of

NIOSH CIB 62 • Asbestos 47 fiber length, width, and aspect ratio on carci- of retained EMPs; (2) mesothelioma is most nogenicity were addressed in a seminal study closely associated with numbers of EMPs lon- using a pleural surface implantation meth- ger than about 5 µm and thinner than about od of challenge in the rat [Stanton et al. 1977, 0.1 µm; and (3) lung cancer is most closely as- 1981]. Tests were performed on 72 durable sociated with EMPs longer than about 10 µm EPs: 13 crocidolites; 22 glasses; 8 aluminum ox- and thicker than about 0.15 µm. Lippmann ide sapphire whiskers; 7 talcs; 7 dawsonites; 4 [1988] also stated that the risk of lung cancer is wollastonites; 2 asbestos tremolites; 1 amosite; associated with a substantial number of fibers 2 attapulgites; 2 halloysites; 1 silicon carbide longer than 10 µm with widths between 0.3 µm whisker; and 3 titanates. The incidence of ma- and 0.8 µm. A more recent review of the re- lignant mesenchymal neoplasms a year after sponse to asbestos fibers of various lengths in implantation correlated best with EPs that were animal models, along with data from studies of longer than 8 µm and no wider than 0.25 µm, human materials, concluded that asbestos fi- with relatively high correlations with EPs lon- bers of all lengths induce pathological respons- ger than 4 µm and no wider than 1.5 µm. This es; it suggested caution when attempting to ex- suggested that carcinogenicity of durable EPs clude any subpopulation of inhaled asbestos depends on dimension and durability, rather fibers, on the basis of length, from being con- than physicochemical properties. This is some- sidered contributors to the development of as- times referred to as the Stanton hypothesis and bestos-related diseases [Dodson et al. 2003]. has been the subject of continuing research. Reanalysis of the dimensions of seven of the crocidolite samples used in the 1981 study 2.9.4.3 Initiation of Toxic Interactions found that tumor probability was significant- A first question in seeking a full understanding ly correlated with the number of index parti- of EMP properties and mechanisms responsi- cles (defined as particles longer than 8 µm and ble for fibrosis, lung cancer, or mesothelioma no wider than 0.25 µm), but the coefficient was risks is the identity of initiating toxic interac- low enough to suggest that factors other than tions and the morphological, physical, and/or size and shape play a role in carcinogenic ef- chemical properties of EMPs controlling them. fects of durable EPs [Wylie et al. 1987]. Further Among proposed initiating mechanisms are analysis confirmed the number of such index these: (1) EMP surfaces generate ROS (even in particles as the primary dimensional predictor vitro in the absence of cells), which are the pri- of tumor incidence, but the correlation was in- mary toxicants to cells; (2) EMP surfaces are creased when the data were analyzed by sepa- directly membranolytic or otherwise direct- rate mineral types [Oehlert 1991]. These anal- ly cytotoxic or genotoxic to components of the yses suggested that mineral type is important, cell, as are some nonelongate mineral particles, which is counter to the Stanton hypothesis. and that damage can cause necrosis, apoptosis, Lippmann [1988] reviewed data from animal mutation, or transformation directly or by re- models exposed by instillation or inhalation of sponsive cellular production of secondary re- EMPs of defined size distributions, along with active intermediates; and (3) EMP morpholo- data on human lung fiber burden and associ- gy itself can result in frustrated phagocytosis ated effects, and concluded that (1) asbestosis with an anomalous stimulation or release of is most closely associated with the surface area ROS or other toxic reactive species.

48 NIOSH CIB 62 • Asbestos 2.9.4.3.1 Reactive Oxygen Species prevented DNA strand breakage in cells in vitro Asbestos fibers can generate ROS or reactive by crocidolite fibers [Mossman and Marsh 1989]. nitrogen species in in vitro systems through In a cell-free study of five natural and two syn- direct aqueous-phase surface chemical reac- thetic fibers, erionite, JM code 100 glass fibers, tions, as well as by stimulating secondary re- and glass wool were the most effective initia- lease of reactive species from cells. Electron tors of hydroxyl radical formation, followed spin resonance with use of spin-trapping tech- by crocidolite, amosite, and chrysotile fibers. niques showed that crocidolite, chrysotile, and Hydroxyl radical formation activity showed amosite asbestos fibers were all able to catalyze positive correlations with tumor rates in rats the generation of toxic hydroxyl radicals in a challenged by intrapleural injection and with cell-free system containing hydrogen peroxide, human mesothelioma mortality rates, but a normal byproduct of tissue metabolism, and not with tumor rates in rats challenged by that the iron chelator desferroxamine inhibited intraperitoneal injection [Maples and John- the reaction, indicating a major role for iron in son 1992]. SO-produced ROS then might in- the catalytic process [Weitzman and Graceffa duce DNA oxidative damage, measured as el- 1984]. ROS generated by some EMP surfaces evated 8-hydroxydeoxyguanosine (8-OHdG). in cell-free media may provide toxicants to ini- In cell-free systems, the crocidolite-induced tiate cell structural or functional damage, in- increase of 8-OHdG in isolated DNA was en- cluding chromosomal or DNA genetic damage hanced by addition of H2O2 and diminished by or aneuploidy from spindle apparatus damage. addition of desferroxamine [Faux et al. 1994]. They also may activate cellular signaling path- However, de-ironized crocidolite fibers incu- ways that promote cell proliferation or trans- bated in a cell-free system induced twice the formation. Research has investigated the possi- 8-OHdG oxidative damage to DNA as untreat- ble roles of iron in this reactivity and the roles ed crocidolite fibers. In parallel rat exposures, of released versus surface-borne iron. the combination of de-ironized crocidolite fi-

bers plus Fe2O3 resulted in mesothelioma in all Asbestos fibers can cause lipid peroxidation animals, whereas mesothelioma developed in in mammalian cells and artificial membranes only half the animals injected with crocidolite that can be prevented by removal of catalyt- fibers alone and none of the animals injected ic iron. Reduction of crocidolite cytotoxicity with Fe2O3 alone [Adachi et al. 1994]. Other re- by certain antioxidants (including superoxide search suggested that unreleased fiber-surface- dismutase [SOD], a depletor of superoxide an- bound iron is important to the reactivity; ion [SO]; catalase, a scavenger of hydrogen per- long fibers of amosite and crocidolite both oxide [H2O2]; dimethylthiourea [DMTU], a caused significant dose-dependent free radi- scavenger of the hydroxyl radical [•OH]; and cal damage to cell-free phage DNA, suppress- desferroxamine, an iron chelator) suggested ible by the hydroxyl radical scavenger mannitol that iron is involved in the generation of ROS and by desferroxamine, but short RCFs and through a modified Haber-Weiss Fenton-type man-made vitreous fibers (MMVFs) did not, reaction resulting in the production of hydroxyl while releasing large quantities of Fe(III) iron radical (e.g., from SO and H2O2 generated dur- [Gilmour et al. 1995]. Crocidolite fibers in- ing phagocytosis) [Goodglick and Kane 1986; duced mutations in peritoneal tissue in vivo in Shatos et al. 1987]. Such scavenging or chelation rats, most prominently guanine-to-thymine

NIOSH CIB 62 • Asbestos 49 (G-to-T) trans-versions known to be in- by cell membrane glycoproteins [Brody and Hill duced by 8-OHdG; this was interpreted as 1983]. However, chrysotile and crocidolite fi- strong evidence for the involvement of ROS bers both induced increased membrane rigidi- or reactive nitrogen species in crocidolite- ty in model unilamellar vesicles made of satu- induced mutagenesis in vivo, consistent with rated dipalmitoyl phosphatidylcholine (DPPC), in vitro and cell-free studies [Unfried et al. suggesting that lipid peroxidation is not in- 2002]. In contrast to glass fiber, crocidolite fi- volved in membrane rigidity induced by asbes- ber intratracheal instillation in rats increased tos [Gendek and Brody 1990]. Silicate slate dust 8-OHdG levels in DNA at one day and in its and chrysotile fibers both induced hemolysis repair enzyme activity at seven days. Thisin in vitro and peroxidation of polyunsaturat- vivo activity is consistent with asbestos- and ed membrane lipids. However, poly(2-vinyl- MMVF-induced increases of 8-OHdG oxida- pyridine N-oxide) (PVPNO) and DPPC sur- tive damage in vitro [Yamaguchi et al. 1999]. face prophylactic agents suppressed lysis but not peroxidation, whereas SOD and catalase 2.9.4.3.2 Membrane Interactions did the reverse; and lysis was much faster than peroxidation. This suggested that membrane ly- Many mineral particles, elongate or not, can di- sis and peroxidation are independent process- rectly cause membranolysis or other cytotoxic es [Singh and Rahman 1987]. However, either responses without necessarily invoking extra- mechanism may be involved in membrane dam- cellular generation of ROS. Mechanisms of cell age by EMPs; and seemingly disparate findings damage by EMPs, independent of ROS forma- suggest uncharacterized details of EMP proper- tion, have been proposed to involve direct in- ties or of cellular or mineral conditioning under teractions of particle surface functional groups test conditions may be important. (e.g., silicon or aluminum or magnesium) with lipoproteins or glycoproteins of the cell mem- In in vitro studies, quartz dust and chrysotile brane. It has been suggested that silica particle fibers induced loss of viability and release of lactate cytotoxicity to macrophages is due to distortion dehydrogenase (LDH) from alveolar macrophages. and disruption of secondary lysosomal mem- DPPC reduced these activities of the quartz but branes by phagocytosed particles whose surface not of the asbestos [Schimmelpfeng et al. 1992]. silanol groups hydrogen-bond to membrane DPPC is adsorbed from aqueous dispersion lipid phosphates, but that chrysotile-induced in approximately equal amounts on a surface cellular release of hydrolytic enzymes is due to area basis, about 5 mg phospholipid per square surface magnesium interacting ionically with meter, by asbestos fibers [Jaurand et al. 1980] sialic acid residues of membrane glycoproteins, and by nonfibrous silicate particles [Wallace inducing cation leakage and osmotic lysis [Alli- et al. 1992]; this is close to the value predicted son and Ferluga 1977]. Chrysotile fibers cause by mathematical modeling of an adsorbed bi- lysis of red blood cells. EM indicates that cell layer [Nagle 1993]. In the case of silica or clay membranes become wrapped around the fi- membranolytic dusts, this adsorption fully sup- bers and that cell distortion and membrane presses their activity until toxicity is manifested deformation correlate with an increase in the as the prophylactic surfactant is digested from intracellular ratio of sodium to potassium ions. the particle surface by lysosomal phospholipase Cell pretreatment with neuraminidase pre- enzyme; mineral-specific rates of the process vents fiber-cell binding, suggesting mediation suggest a basis for differing fibrogenic potentials

50 NIOSH CIB 62 • Asbestos of different types of mineral particles [Wallace of frustrated phagocytosis is suggested by the et al. 1992]. Stanton hypothesis of an overriding significance of particle dimension for disease induction by Samples of intermediate-length and short- durable EPs. A general concept is that EMPs length NIEHS chrysotile were compared, with longer than a phagocytic cell’s linear dimen- and without DPPC lung surfactant pretreat- sions cannot be completely incorporated in a ment, for micronucleus induction in Chinese phagosome. Recruitment of membrane from the hamster lung V79 cells in vitro. Increase in Golgi apparatus or endoplasmic reticulum may micronuclei frequency and multinuclear cell provide extensive addition to the plasma mem- frequency were induced by all samples, with brane for a cell’s attempted invagination to ac- the greatest micronucleus induction by un- commodate a long EMP in a phagosomal mem- treated intermediate-length chrysotile fibers brane [Aderem 2002]. However, because of the and with greater activity for untreated versus length of the EMP relative to the dimensions of treated short chrysotile fibers. Cell viability the cell, the final phagosomal structure is topo- was greater for treated fibers [Lu et al. 1994]. logically an annulus extending fully through the NIEHS intermediate-length chrysotile was cell, rather than an enclosed vacuole fully with- mildly acid-treated to deplete surface-borne in the cell. Following uptake of nonelongate par- magnesium while only slightly affecting fiber ticles, there is a maturation of the phagosomal length. Challenge of Chinese hamster lung fi- membrane; the initial phagosomal membrane is broblast cells in vitro for micronucleus induc- that of the cell’s external plasmalemma, which tion found no significant difference between cannot kill or digest phagocytosed material. Af- the treated and untreated samples, support- ter sealing of the fully invaginated phagosomal ing a model of chemically nonspecific chro- vesicle in the interior of the cell, there is a rap- mosomal and spindle damage effects [Keane et id and extensive change in the membrane com- al. 1999]. Chrysotile fiber induction of mucin position [Scott et al. 2003]. This involves, in secretion in a tracheal cell culture was inhib- part, an association with lysosomal vesicles ited by using lectins to block specific carbo- and exposure of particles within the secondary hydrate residues on the cell surface; leached phagosome or phagolysosome to lytic enzymes chrysotile was inactive, suggesting that the sur- and adjusted pH conditions. It is speculated face cationic magnesium of chrysotile was re- that failure of the phagosome to close, as occurs sponsible for interaction with cell surface in frustrated phagocytosis, induces dysfunc- glycolipids and glycoproteins [Mossman et al. tion of the system. Conventional phagocytosis 1983]. However, complete removal of accessible of nonelongate particles can lead to a respira- sialic acid residues from erythrocytes did not tory or oxidative burst of membrane-localized inhibit hemolysis by chrysotile fibers, suggest- NADPH oxidase of SO radicals, which may be ing that chrysotile fibers can induce lysis by in- converted to H2O2, hydroxyl radicals, and oth- teraction with some other component of the cell er toxic reactive products of oxygen. If these are [Pelé and Calvert 1983]. released extracellularly in connection with frustrated phagocytosis, they are potentially harm- 2.9.4.3.3 Morphology-mediated Effects ful to the tissue [Bergstrand 1990]. A third possible mechanism for damage by EMP Failure of normal phagocytosis to be com- principally involves morphology. The possibility pleted may affect the duration or intensity

NIOSH CIB 62 • Asbestos 51 of the phagocytic response. It may also affect in the nucleus such as activator protein (AP)-1 or the generation or release of reactive species nuclear factor kappa beta (NF-κB), which in turn or membranolytic digestive enzymes into the regulate the transcription of mRNA from genes still-exterior annulus. Another possible effect for TNF-α or other cytokines involved in cell pro- is to alter the maturation of the annular frus- liferation or inflammation. trated phagocytic membrane from the normal structural and functional evolution of a Fibers of the six asbestos minerals generate closed phagolysosomal vesicle fully interior to MAPK in lung epithelium in vitro and in vivo, the cell. Even in the response to such a frustrat- increasing AP-1 transcription activation, cell ed phagocytosis, there might be some mineral proliferation, death, differentiation, or inflam- specificity beyond morphology alone for EMP- mation. This is synergistic with cigarette smoke induced release of reactive species. Amosite fi- [Mossman et al. 2006]. Macrophage release of bers, MMVF, silicon carbide fibers, and RCF-1 oxidants or mitogenic factors through such a fibers all stimulated modest release of SO that pathway could then cause cell proliferation or was not dose-dependent in isolated rat alveo- DNA damage [Driscoll et al. 1998]. In contrast lar macrophages. However, when IgG, a normal to MMVF-10 and RCF-4, amosite and two other component of lung lining fluid, was adsorbed carcinogenic fibers (silicon carbide and RCF-1) onto the fiber surfaces, SO release was strong- produced significant dose-dependent transloca- ly enhanced for all but the silicon carbide fibers. tion of NF-κB to the nucleus in A549 lung epi- SO release correlated with fibers’ IgG-adsorptive thelial cells. It was hypothesized that carcinogen- capacity, except for the amosite, which required ic fibers have greater free radical activity, which only poorly adsorbed IgG for strong activi- produces greater oxidative stress and results in ty, suggesting some mineral specificity beyond greater translocation of NF-κB to the nucleus morphology alone for the EMP-induced cellu- for the transcription of pro-inflammatory genes lar respiratory burst [Hill et al. 1996]. (e.g., cytokines) [Brown et al. 1999]. Crocidolite induced AP-1 in vitro in JB6 cells and induced 2.9.4.3.4 Cellular Responses to Initiation AP-1 transactivation in pulmonary and bronchi- of Toxicity al tissue after intratracheal instillation in transgenic mice, apparently mediated by activation of Subsequent to initiating damage by direct or in- MAPK [Ding et al. 1999]. Chrysotile challenge duced ROS generation—by direct membranolysis to blood monocytes co-cultured with bronchi- generated by interactions of mineral surface al epithelial cells resulted in elevated levels in ep- sites with membrane lipids or glycoproteins, ithelial cells of protein-tyrosine kinase activity, or by not-fully-defined toxic response to mor- NF-κB activity, and mRNA levels for interleukin phology-based frustrated phagocytosis—a stan- (IL)-1β, IL-6, and TNF-α. Protein-tyrosine ki- dard model for consequent complex cellular re- nase activity, NF-κB activity, and mRNA syn- sponse has evolved and has been the subject of thesis were inhibited by antioxidants, suggesting extensive and detailed analyses [Mossman et ROS-dependent NF-κB-mediated transcription al. 1997]. EMP-generated primary toxic stimu- of inflammatory cytokines in bronchial epitheli- li to the cell are subject to signal transduction by al cells [Drumm et al. 1999]. mitogen-activated protein kinase (MAPK), be- ginning an intracellular multiple kinase signal Chemokines known to be associated with par- cascade, which then induces transcription factors ticle-induced inflammation were found to be

52 NIOSH CIB 62 • Asbestos secreted by mesothelial cells after amosite chal- to EGFR, suggesting initiation of a cell-sig- lenge to cultured rat pleural mesothelial cells, naling cascade to cell proliferation and can- and they were found in pleural lavage of rats cer [Faux et al. 2000]. “Long” amosite fibers challenged in vivo [Hill et al. 2003]. were more active than “short” amosite fibers in causing (1) damage to nude DNA; (2) in vitro Fibers from crocidolite (asbestiform riebeckite) cytotoxicity in a human lung epithelial cell and EMPs from nonfibrous milled riebeckite line; (3) free radical reactions; (4) inhibition increased phosphorylation and activity of a of glycerol-6-phosphate dehydrogenase and MAPK cascade in association with induction of pentose phosphate pathways; (5) decrease in an inflammatory state of rat pleural mesothelial intracellular reduced glutathione; (6) increase cells and progenitor cells of malignant meso in thiobarbituric acid reaction substances; and thelioma. Amelioration by preincubation with (7) leaking of LDH [Riganti et al. 2003]. vitamin E indicated this to be an oxidative stress effect [Swain et al. 2004]. Lung lysate, An important paradox or seeming failure of cells from bronchoalveolar lavage, and alve- in vitro studies concerns mesothelioma. Al- olar macrophages and bronchiolar epitheli- though chrysotile and amphibole asbestos fibers al cells from lung sections from rats exposed each clearly induce malignant mesothelioma to crocidolite or chrysotile fibers contained in vivo, they do not transform primary human nitrotyrosine and phosphorylated extracellular mesothelial cells in vitro, whereas erionite fibers signal-regulated kinases (ERKs); nitrotyrosine do. Asbestos fibers can induce some genotoxic is a marker for peroxynitrile that activates changes; crocidolite fibers induced cytogenotoxic ERK signaling pathways, altering protein func- effects, including increased polynucleated cells tion [Iwagaki 2003]. In vitro challenge of hu- and formation of 8-OHdG in a phagocytic human bronchiolar epithelial cells with crocidolite man mesothelial cell line, but did not induce or chrysotile fibers induced tissue factor (TF) cytogenotoxic effects in a nonphagocytic hu- mRNA expression and induced NF-κB and man promyelocytic leukemia cell line [Takeuchi other transcription factors that bind the TF gene et al. 1999]. Tremolite, erionite, RCF-1, and promoter. TF in vivo is involved in blood coag- chrysotile fiber challenges of human-hamster ulation with inflammation and tissue remodel- hybrid A(L) cells showed chrysotile fibers to ing [Iakhiaev et al. 2004]. Asbestos fibers acti- be significantly more cytotoxic. Mutagenic- vate an ERK pathway in vitro in mesothelial and ity was not seen at the hypoxanthine-guanine epithelial cells. Crocidolite challenge to mice re- phosphoribosyltransferase (HPRT) locus for sults in phosphorylation of ERK in bronchiolar any of the fibers. Erionite and tremolite fibers and alveolar type II epithelial cells, epithelial cell induced dose-dependent mutations at the gene hyperplasia, and fibrotic lesions. Epithelial cell marker on the only human chromosome in the signals through the ERK pathway lead to tissue hybrid cell. Erionite was the most mutagenic remodeling and fibrosis [Cummins et al. 2003]. type of fiber. RFC-1 fibers were not mutagenic, in seeming contrast to their known induction Crocidolite and erionite fibers, but not non of mesothelioma in hamsters [Okayasu et al. fibrous milled riebeckite, upregulated the ex- 1999]. Crocidolite fibers induced significant but pression of epidermal growth factor receptor reversible DNA single-strand breaks in trans- (EGFR) in rat pleural mesothelial cells in vitro. formed human pleural mesothelial cells, and Cell proliferation was co-localized subsequent TNF-α induced marginal increases; co-exposure

NIOSH CIB 62 • Asbestos 53 to crocidolite fibers and TNF-α caused greater been suggested that simian virus 40 (SV40) and damage than fibers alone. Antioxidant enzymes asbestos fibers may be co-carcinogens. SV40 is did not reduce the DNA damage, suggesting a a DNA tumor virus that causes mesothelioma mechanism of damage other than by free radi- in hamsters and has been detected in sever- cals [Ollikainen et al. 1999]. Crocidolite fibers al human mesotheliomas. Asbestos fibers ap- were also very cytotoxic to the cells; presumably, pear to increase SV40-mediated transformation cell death may prevent the observation of cell of human mesothelial cells in vitro [Carbone transformation. In vitro challenge to mesothelial et al. 2002]. In an in vivo demonstration of cells and to fibroblast cells by crocidolite fibers, co-carcinogenicity of SV40 and asbestos fibers, but not by glass wool, induced dose-dependent mice containing high copy numbers of SV40 cytotoxicity and increased DNA synthesis activi- viral oncogene rapidly developed fast-growing ty [Cardinali et al. 2006]. Crocidolite fibers were mesothelioma following asbestos challenge. found to induce TNF-α secretion and receptors Transgenic copy number was proportional to in human mesothelial cells, and TNF-α reduced cell survival and in vitro proliferation [Robin- cytotoxicity of crocidolite fibers by activating son et al. 2006]. NF-κB and thus improving cell survival and per- mitting expression of cytogenetic activity [Yang Various mechanisms protect cells and tissues et al. 2006]. Erionite fibers transformed immor- against oxidants, and it is conceivable that ge- talized nontumorigenic human mesothelial cells netic and acquired variations in these sys- in vitro only when exposed in combination with tems may account for individual variation in IL-1β or TNF-α [Wang et al. 2004]. Erionite fi- the response to oxidative stress [Driscoll et al. bers were poorly cytotoxic but induced prolifer- 2002]. Similarly, species differences in antiox- ation signals and a high growth rate in hamster idant defenses or the capacity of various de- mesothelial cells. Long-term exposure to erionite fenses may underlie differences in response to fibers resulted in transformation of human xenobiotics that act, in whole or part, through mesothelial cells in vitro, but exposure to asbes- oxidative mechanisms. Oxidative mechanisms tos fibers did not transform those cells [Bertino of response to xenobiotics are especially rel- et al. 2007]. In vitro challenge of mesothelial cells evant to the respiratory tract, which is direct- to asbestos fibers induced cytotoxicity and apop- ly and continually exposed to an external en- tosis but not transformation. In vitro challenge vironment containing oxidant pollutants (e.g., of human mesothelial cells to asbestos fibers in- ozone, oxides of nitrogen) and particles that duced the ferritin heavy chain of iron-binding may generate oxidants as a result of chemi- protein, an anti-apoptotic protein, with decrease cal properties or by stimulating production of cell-derived oxidants. In addition, exposure to in H2O2 and other ROS and resistance to apoptosis [Aung et al. 2007]. This was seen also in a hu- particles or other pollutants may produce ox- man malignant mesothelial cell line. idative stress in the lung by stimulating the recruitment of inflammatory cells. For example, The question of a co-carcinogenic effect of as- the toxicity of asbestos fibers likely involves the bestos fibers with a virus has been raised. Most production of oxidants, such as hydroxyl radi- malignant mesotheliomas are associated with cal, SO, and H2O2. Studies have also shown that asbestos exposures, but only a fraction of ex- asbestos fibers and other mineral particles may posed individuals develop mesothelioma, indi- act by stimulating cellular production of ROS cating that other factors may play a role. It has and reactive nitrogen species. In addition to

54 NIOSH CIB 62 • Asbestos direct oxidant production, exposure to asbes- had an aspect ratio greater than 10:1. Analysis of tos and SVFs used in high-dose animal stud- 200 particles of the prismatic tremolite showed ies stimulates the recruitment and activation of that 2.5% (five EMPs) had an aspect ratio of 3:1 macrophages and polymorphonuclear leuko- or greater and 0.5% (one EMP) had an aspect ra- cytes that can produce ROS through the activi- tio greater than 10:1. ty of NADPH oxidase on their cell membranes. Developing an understanding of the oxidative Wagner et al. [1982] challenged rats by IP in- stress/NF-ĸB pathway for EMP-mediated injection of tremolite asbestos, a prismatic non flammation and the interplay among exposure- asbestiform tremolite, or a tremolitic talc con- induced oxidant production, host antioxidant sidered nonasbestiform containing a limited defenses, and interindividual or species vari- number of long fibers. Only the tremolite asbes- ability in defenses may be very important for tos produced tumors; mesothelioma was found appropriate risk assessments of inhaled EMPs in 14 of 37 animals. The authors speculated that [Donaldson and Tran 2002]. tumor rate may have risen further if the testing period had not been shortened due to infection- induced mortality. Per microgram of injected 2.9.4.4 Studies Comparing EMPs from dose, the asbestiform sample contained 3.3 × Amphiboles with Asbestiform 104 nonfibrous particles, 15.5 × 104 fibers, and versus Nonasbestiform Habits 56.1 × 103 fibers >8 µm long and <1.5 µm wide. Smith et al. [1979] compared tumor induction Corresponding values for the prismatic amphi- after IP injection in hamsters of two asbestiform bole were 20.7 × 104, 4.8 × 104, and 0. Tremolitic tremolites, two nonasbestiform prismatic tre talc values were 6.9 × 104, 5.1 × 104, and 1.7 × molitic talcs, and one tremolitic talc of uncer- 103. Infection-reduced survival prevented eval- tain asbestiform status. No tumors were ob- uation of a crocidolite-exposed positive control. served following the nonasbestiform tremolite challenge, in contrast to the asbestiform tre Another IP injection study with the rat used six molites. However, tumors were observed from samples of tremolite of different morphological the tremolitic talc of uncertain amphibole sta- types [Davis et al. 1991]. For three asbestiform tus. In rule-making, OSHA [1992] noted the samples, mesothelioma occurred in 100%, 97%, small number of animals in the study, the ear- and 97% of exposed animals, at correspond- ly death of many animals, and the lack of sys- ing doses of 13.4 × 109 fibers with aspect ra- tematic characterization of particle size and as- tio >3:1 per 121 × 106 fibers with length >8 µm pect ratio. Subsequent analyses (by chemical and diameter <0.25 µm (100% of exposed ani- composition) performed on the nonasbestiform mals); 2.1 × 109 per 8 × 106 (97% of exposed an- tremolitic talc from the study, which was not as- imals); and 7.8 × 109 per 48 × 106 (97% of ex- sociated with mesothelioma, found 13% of par- posed animals). For an Italian tremolite from ticles had at least a 3:1 aspect ratio [Wylie et al. a nonasbestos source and containing relative- 1993]. A prismatic, nonasbestiform tremolitic ly few asbestiform fibers (1.0 × 109 per 1 × talc and an asbestiform tremolite from the study 106), mesothelioma was found in two-thirds of were analyzed for aspect ratio [Campbell et al. the animals, with delayed expression. For two 1979]. The researchers analyzed 200 particles of nonasbestiform tremolites (0.9 × 109 per 0; 0.4 the asbestiform tremolite sample and found 17% × 109 per 0), tumors were found in 12% and had an aspect ratio of 3:1 or greater and 9.5% 5% of the animals, respectively; of these, and

NIOSH CIB 62 • Asbestos 55 the response rate of 12% was above the expect- a view that shorter, thicker cleavage fragments ed background rate. The Italian sample result- of the nonasbestiform amphiboles are less haz- ing in 67% mesothelioma incidence contained ardous than the thinner asbestos fibers [Addi- only one-third the number of EMPs >8 µm son and McConnell 2008]. long, in comparison with the nonasbestiform sample associated with 12% mesothelioma, and In summary, several types of animal studies have those two samples contained an approximate- been conducted to assess the carcinogenicity and ly equal number of fibers with length >8 µm fibrogenicity of asbestiform and nonasbestiform and width <0.5 µm. The preparations of the tremolite fibers and other EMPs. Tremolite as- three asbestiform samples and the Italian sam- bestos was found to be both fibrogenic and carci- ple were essentially identical. However, the two nogenic in rats by inhalation. However, the data nonasbestiform samples associated with low for other particle forms of tremolite and for oth- mesothelioma incidence required significantly er amphiboles in general are much more limited different pretreatment: the first required mul- and are based primarily on mesotheliomas pro- tiple washings and sedimentation, and the sec- duced by intrapleural administration studies in ond, grinding under water in a micronizing rats. Although these tests can be highly sensitive mill. It was noted that those two nonasbestiform for specific material-tissue interactions, these samples and the Italian sample contained minor studies bypass the lung entirely and thus pro- components of long, thin asbestiform tremolite vide no information on the test material’s po- fibers. This study suggested that carcinogenic- tential for causing lung tumors. In addition, ity may not depend simply on the number of they have often been criticized for employing EMPs, and the researchers called for methods a nonphysiological route of administration. of distinguishing “carcinogenic tremolite fi- Some of the older studies [Smith et al. 1979; bers” from nonfibrous tremolite dusts that con- Wagner et al. 1982] are difficult to interpret tain similar numbers of EMPs of similar aspect because of inadequate characterization of the ratios [Davis et al. 1991]. It has been suggest- tremolite preparation that was used, although ed that the response observed for the Italian the studies do show fewer or no tumors from tremolite is of a pattern expected for a low dose prismatic tremolite than from asbestiform of highly carcinogenic asbestos tremolite [Ad- tremolite when tested similarly. Unfortunately, dison 2007]. doses used in most animal studies are generally reported in terms of mass (e.g., 10, 25, or 40 A recent review of past studies of varieties of mg/rat). Unless the test preparations are well tremolite and the limitations of earlier studies characterized in terms of fiber counts and fi- (e.g., their use of injection or implantation ver- ber size distributions, it is difficult to relate the sus inhalation) suggested that, on the basis of mass-based dose in the animals to fiber count observed differences in the carcinogenicity of concentrations used to assess human occupa- tremolite asbestos and nonasbestiform prismat- tional exposures. Where semiquantitative fiber ic tremolite, differences in carcinogenicity of count and size distribution data are provided, as amphibole asbestos fibers and nonasbestiform in the study report by Davis et al. [1991], it is evi- amphibole cleavage fragments are sufficiently dent that the prismatic tremolite samples contain large to be discernable, even with the study lim- fewer particles >5 µm in length with an aspect itations [Addison and McConnell 2008]. The ratio of >3:1 per 10-mg dose than the asbestiform authors also concluded the evidence supports tremolite samples, and the median particle

56 NIOSH CIB 62 • Asbestos widths are greater for the prismatic tremolite A recent review concludes that a large body of samples. Although the prismatic tremolite sam- work shows that cleavage fragments of amphi- ples clearly generated fewer mesotheliomas than boles are less potent than asbestos fibers in a the asbestiform tremolite samples, it is not appar- number of in vitro bioassays [Mossman 2008]. ent whether the tumorigenic potency per EMP is lower for the nonasbestiform tremolites. Several studies have investigated induction of molecular pathways in cells exposed to EMPs. In a comparison of one asbestiform and two The goals of such studies were to elucidate nonasbestiform tremolites, cellular in vitro as- mechanisms involved in fiber-induced patho- says for LDH release, beta-glucuronidase release, genicity and to compare the relative potency of cytotoxicity, and giant cell formation showed rel- asbestiform and nonasbestiform EMPs. How- ative toxicities that parallel the differences seen in ever, seemingly contradictory findings between an in vivo rat IP injection study of tumorigenicity some experiments suggest that improved meth- using the same samples [Wagner et al. 1982]. ods for preparation of size-selected test parti- In vitro cellular or organ tissue culture stud- cles and more extensive characterization of ies showed squamous metaplasia and increased EMPs are needed. DNA synthesis in tracheal explant cultures treat- Although few animal studies of nonasbestiform ed with long glass fibers or with crocidolite or amphibole dusts have been conducted, this re- chrysotile fibers, whereas cleavage fragments search has revealed generally significant differ- from their nonasbestiform analogues, riebeckite ences in pathogenicity between nonasbestiform and antigorite, were not active [Woodworth and asbestiform amphiboles. There are few find- et al. 1983]. For alveolar macrophages in vitro, ings of biological effects or tumorigenicity in- crocidolite fibers induced the release of ROS duced by samples classified as nonasbestiform, at an order of magnitude greater than cleav- and there are rational hypotheses as to the age fragments from nonasbestiform riebeckite cause of those effects. There are general funda- [Hansen and Mossman 1987]. Similar differenc- mental uncertainties concerning EMP proper- es were observed in hamster tracheal cells for ties and biological mechanisms that determine mineral particle toxicities and pathogenicities, •• induction of ornithine decarboxylase, an specifically concerning the similarities or dif- enzyme associated with mouse skin cell ferences in disease mechanisms between EMPs proliferation and tumor promotion [Marsh from asbestiform versus nonasbestiform am- and Mossman 1988]; phiboles. In vitro studies have generally shown •• stimulating survival or proliferation in a differences in specific toxic activities between colony-forming assay using those ham- some asbestiform and nonasbestiform am- ster tracheal epithelial cells [Sesko and phibole EMPs, although in vitro systems are Mossman 1989]; not yet able to predict relative pathogenic risk for mineral fibers and other EMPs. This sug- •• activation of proto-oncogenes in tracheal gests a focus of research to determine if and epithelial and pleural mesothelial cells in when nonasbestiform amphibole EMPs are ac- vitro [Janssen et al. 1994]; and tive for tumorigenicity or other pathology, if •• cytotoxicity [Mossman and Sesko 1990]. there is a threshold for those activities, and if

NIOSH CIB 62 • Asbestos 57 distinguishing conditions or properties that Berman et al. [1995] statistically analyzed ag- determine such pathogenicity can be found. gregate data from 13 inhalation studies in which rats were exposed to 9 types of asbestos 2.9.5 Thresholds (4 chrysotiles, 3 amosites, 1 crocidolite, and 1 tremolite asbestos) to assess fiber dimension and Discussions of thresholds for adverse health mineralogy as predictors of lung tumor and effects associated with exposure to asbestos mesothelioma risks. Archived samples from the fibers and related EMPs have focused on the studies were reanalyzed to provide detailed in- characteristics of dimension, including length, formation on each asbestos structure, including width, and the derived aspect ratio, as well as mineralogy (chrysotile, amosite, crocidolite, or concentration. Although other particle char- tremolite), size (length and width, each in 5 cat- acteristics discussed above may impact these egories), type (fiber, bundle, cluster, or matrix), thresholds or may have thresholds of their own and complexity (number of identifiable com- that impact the toxicity of EMPs, they are not ponents of a cluster or matrix). Multiple con- well discussed in the literature. The following centrations (each for asbestos structures with discussion is focused on thresholds for dimen- different specified characteristics) were calcu- sion and concentration. lated for the experimental exposures. Although no univariate index of exposure adequately de- The seminal work of Stanton et al. [1981] laid scribed lung tumor incidence observed across all the foundation for much of the information on inhalation studies, certain multivariate indices of dimensional thresholds. Their analyses showed exposure did adequately describe outcomes. Fi- that malignant neoplasms in exposed rats were bers and bundles longer than 5 µm and thinner best predicted by the number of EMPs longer than 0.4 µm contributed to lung tumor risk; very than 8 µm and thinner than 0.25 µm. How- long (>40 µm) and very thick (>5 µm) complex ever, the number of EMPs in other size cate- clusters and matrices possibly contributed. Al- gories, having lengths greater than 4 µm and though structures <5 µm long did not contrib- widths up to 1.5 µm, were also highly correlat- ute to lung tumor risk, potency of thin (<0.4 µm) ed with malignant neoplasms. Also, some sam- structures increased with increasing length above ples with relatively larger proportions of short- 5 µm, and structures >40 µm long were estimat- er particles, such as the tremolites, produced ed to be about 500 times more potent than structures between 5 and 40 µm long. With respect to high rates of tumors. Lippmann [1988, 1990] lung tumor risk, no difference was observed be- reviewed the literature and suggested that lung tween chrysotile and amphibole asbestos. With cancer is most closely associated with asbes- respect to mesothelioma risk, chrysotile was tos fibers longer than 10 µm and thicker than found to be less potent than amphibole asbestos. 0.15 µm, whereas mesothelioma is most close- Although the analysis of Berman et al. [1995] ly associated with asbestos fibers longer than was limited to studies of asbestos exposure, sim- 5 µm and thinner than 0.1 µm. Evidence from ilar statistical approaches may be adaptable to as- animal studies and some in vitro studies sug- sess study outcomes from exposures to a broader gests that short asbestos fibers (e.g., <5 µm range of EMPs, beyond asbestos. long) may play a role in fibrosis but are of less- er concern than longer asbestos fibers for can- In addressing the issue of a length thresh- cer development. old, the Health Effects Institute [HEI 1991]

58 NIOSH CIB 62 • Asbestos concluded that asbestos fibers <5 µm long ap- chrysotile-exposed textile workers previous- pear to have much less carcinogenic activity ly studied by Dement et al. [1994], Stayner et than longer fibers and may be relatively inac- al. [1997], and Hein et al. [2007]. Archived air tive. A panel convened by ATSDR [2003] con- samples collected at this chrysotile textile plant cluded that “given findings from epidemiolog- were reanalyzed by TEM to generate exposure ical studies, laboratory animal studies, and in estimates based on bivariate fiber-size distri- vitro genotoxicity studies, combined with the bution [Dement et al. 2008]. TEM analysis of lung’s ability to clear short fibers, the panelists sampled fibers found all size-specific categories agreed that there is a strong weight of evidence (35 categories were assigned, based on combi- that asbestos and SVFs shorter than 5 µm are nations of fiber width and length) to be highly unlikely to cause cancer in humans.” Also, an statistically significant predictors of lung can- EPA [2003] peer consultant panel “agreed that cer and asbestosis [Stayner et al. 2007]. The the available data suggest that the risk for fibers smallest fiber size–specific category was thin- <5 µm long is very low and could be zero.” They ner than 0.25 µm and <1.5 µm long. The largest generally agreed that the width cutoff should size-specific category was thicker than 3.0 µm be between 0.5 and 1.5 µm but deserved fur- and >40 µm long. Both lung cancer and asbes- ther analysis. tosis were most strongly associated with exposures to thin fibers (<0.25 µm), and longer -fi However, Dodson et al. [2003] have argued bers (>10 µm) were found to be the strongest that it is difficult to rule out the involvement predictors of lung cancer. A limitation of the of short (<5 µm) asbestos fibers in causing study is that cumulative exposures for the co- disease, because exposures to asbestos fibers hort were highly correlated across all fiber-size overwhelmingly involve fibers shorter than categories, which complicates the interpreta- 5 µm, and fibers observed in the lung and in tion of the study results. extrapulmonary locations are also overwhelmingly shorter than 5 µm. For example, in a In addition to length and width, an impor- study of malignant mesothelioma cases, Suzuki tant parameter used to define EMPs is the as- and Yuen [2002] and Suzuki et al. [2005] found pect ratio. The use of the 3:1 length:width as- that the majority of asbestos fibers in lung and pect ratio as the minimum to define an EMP mesothelial tissues were shorter than 5 µm. was not established on scientific bases such as Another study [Berman and Crump 2008a] toxicity or exposure potential. Rather, the deci- showed that the best estimate for the potency sion was based on the ability of the microsco- of asbestos fibers between 5 and 10 µm is zero, pist to determine the elongate nature of a par- but the hypothesis that these shorter fibers are ticle [Holmes 1965], and the practice has been not potent could not be rejected. Likewise, in carried through to this day. As bivariate analy- no case could the hypothesis be rejected that fi- ses are conducted, the impact of aspect ratio, in bers shorter than 5 µm are not potent. addition to length and width, on toxicity and health outcomes needs to be addressed. NIOSH investigators have recently evaluated the relationship between the dimensions As discussed in Section 2.4.2, the nature of oc- (i.e., length and width) of airborne chrysotile cupational exposures to asbestos has changed fibers and risks for developing lung can- over the last several decades. Once dominated cer or asbestosis, by updating the cohort of by chronic exposures in textile mills, friction

NIOSH CIB 62 • Asbestos 59 product manufacturing, and cement pipe fabri- same inflammatory processes that produce lung cation, current occupational exposures to asbes- fibrosis. Some evidence for a threshold is pro- tos in the United States are primarily occurring vided by an analysis of a chrysotile-exposed co- during maintenance activities or remediation hort, which suggests a potential threshold dose of buildings containing asbestos. These current of about 30 f/mL-yr to produce radiologically occupational exposure scenarios frequently in- evident fibrosis [Weill 1994]. Another study of volve short-term, intermittent exposures. The necropsy material from textile workers exposed generally lower current exposures give added to chrysotile shows a distinct step increase in fi- significance to the question of whether or not brosis for exposures in the 20–30 f/mL-yr range there is an asbestos exposure threshold below [Green et al. 1997]. However, a study of textile which workers would incur no risk of adverse mill workers exposed to chrysotile did not reveal health outcomes. evidence of significant concentration thresholds for either asbestosis or lung cancer [Stayner et Risk assessments of workers occupationally ex- al. 1997]. Hodgson and Darnton [2000] pointed posed to asbestos were reviewed by investiga- out that any evidence suggesting a threshold for tors sponsored by the Health Effects Institute chrysotile would likely not apply to amphibole [1991]. They found that dose-specific risk is asbestos because radiologically evident fibrosis highly dependent on how the measurement of has been documented among workers exposed dose (exposure) was determined. A common to amphibole asbestos at low levels (<5 f/mL-yr). problem with many of the epidemiological They concluded that if a concentration threshold studies of workers exposed to asbestos is the exists for amphiboles, it is very low. quality of the exposure data. Few studies have good historical exposure data, and the avail- For mesothelioma, Hodgson and Darnton [2000] able data are mostly area samples with concen- identified cohorts with high rates of mesotheli- trations reported as millions of particles per oma at levels of exposure below those at which in- cubic foot of air (mppcf). Although correction creased lung cancer has been identified; in some factors have been used to convert exposures studies, the proportion of mesothelioma cases measured in mppcf to f/cm3, the conversions with no likely asbestos exposure is much high- were often based on more recent exposure er than expected. Hodgson and Darnton [2000] measurements collected at concentrations low- concluded that these studies support a nonzero er than those prevalent in earlier years. In ad- risk, even from brief, low-level exposures. dition, a single conversion factor was typically used to estimate exposures throughout a facil- Animal studies using intraperitoneal and intra ity, which may not accurately represent differ- pleural injection of asbestos fibers cited by Ilgren ences in particle sizes and counts at different and Browne [1991] suggest a possible threshold processes in the facility. concentration for mesothelioma. However, it is not clear how this would be useful to determine More recently, the concept of a concentration a threshold for inhalation exposure in humans. threshold has been reviewed by Hodgson and Darnton [2000]. It is generally accepted that 2.10 Analytical Methods lung fibrosis requires relatively heavy exposure to asbestos and that the carcinogenic re- Available analytical methods can characterize sponse of the lung may be an extension of the the size, morphology, elemental composition,

60 NIOSH CIB 62 • Asbestos crystal structure, and surface composition of to determine the actual proportion of the total bulk materials and individual airborne parti- particles that are covered by the airborne asbes- cles. There are two separate paradigms for se- tos fiber REL, and this proportion can be used lecting among these methods for their use or to adjust the count from PCM (NIOSH Method further development for application to EMPs: 7402) [NIOSH 1994b]. Such counts are known one is for their support of standardized surveys as PCM-equivalents, or PCMe. Note that this or compliance assessments of workplace expo- is not the same procedure as counting parti- sures to EMPs; another is for their support of cles that would meet the PCM criteria under the research to identify physicochemical proper- electron microscope. Methods have been devel- ties of EMPs that are critical to predicting tox- oped for performing counts under both scan- icity or pathogenic potential for lung fibrosis, ning electron microscopy (SEM) [ISO 2002] lung cancer, or mesothelioma. The former re- and TEM [40 CFR§§ 763.A.E (2001)]. Howev- fers to analytical methods that can be applied er, only a few countries (e.g., Germany, Austria, to samples of airborne particles, whereas the Netherlands, and Switzerland) use SEM rou- latter can be used to characterize airborne par- tinely for counting. ticles and bulk materials. Characterization of bulk minerals is a process Cost, time, availability, standardization require- known as petrographic analysis. Petrograph- ments, and other pragmatic factors limit the se- ic analysis includes a number of techniques, lection of analytical methods for standard- including polarized light microscopy (PLM), ized analysis of field samples for the first set of electron microscopy (SEM or TEM), X-ray dif- uses. Additionally, those uses require meth- fraction (XRD), X-ray fluorescence (XRF), and ods employed historically to establish exposure- electron microprobe analysis. Other techniques, response relationships. Principal among these such as infrared and Raman spectroscopy and analyses for standardized industrial hygiene use surface area measurements, can also be used. is an optical microscopy method, PCM (e.g., Some of these techniques can also be applied to NIOSH Method 7400 or equivalent) [NIOSH individual airborne particles. If it is determined 1994a]. Under the current NIOSH REL for air- that the toxicity of EMPs has a basis in prop- borne asbestos fibers, particles are counted erties that can be measured by one or more of if they are EMPs (i.e., mineral particles with these techniques, then it may be possible to tai- an aspect ratio [length:width] of 3:1 or great- lor analytical procedures in the future to more er) of the covered minerals and they are lon- precisely estimate risk. ger than 5 µm when viewed microscopically according to NIOSH Method 7400 or its equiv- Care should be taken in developing or applying alent. The assumption when using this meth- new analytical methods to the analysis of as- od is that all particles meeting the dimension- bestos for standardized and compliance assess- al criteria are airborne asbestos fibers, because ments. The use of new or different analytical PCM cannot identify the chemistry or crystal- methods to assess exposures must be careful- line structure of a particle. This assumption may ly evaluated and validated to ensure that they be appropriate in situations where the majori- measure exposures covered by the health pro- ty of particles are reasonably assumed to be one tection standard. of the minerals covered by the airborne asbestos fiber REL. Electron microscopy can be used §§Code of Federal Regulations. See CFR in references.

NIOSH CIB 62 • Asbestos 61 One consideration in developing new methods of occupational cancer among asbestos-exposed for assessing workplace exposures is that silicate workers. With advances in sampling pump ca- mineral particles thinner than the resolution of pabilities—and if interference from other dust is PCM in NIOSH Method 7400 are in the same not excessive—a lower limit of quantitation and size range as the deposition minimum observed thus a shorter averaging time for the REL may for small particles in human respirable particle be possible. studies. Current standards for assessing particle dose are based on particle penetration into the PCM was designated as the principal analyt- human respiratory system, which may overes- ical method for applying the REL because it timate deposition [ISO 1995a]. More recent- was thought to be the most practical and reli- ly, proposals have been developed to account able available method, particularly for field assessments. The particle counting rules speci- for deposition [Vincent 2005]. In addition, af- fied for PCM analysis of air samples result in ter depositing in the lung, a single asbestos fiber an index of exposure that has been used with bundle can split into a great many individual fi- human health data for risk assessment. PCM- brils. Accounting for this behavior may be im- based counts do not enumerate all EMPs be- portant in developing methods that accurately cause very thin particles, such as asbestos fi- represent risk from exposure. brils, are typically not visible by PCM when It is also important to recognize that the sampling using NIOSH Method 7400. The ratio of and analytical methods for assessing workplace countable EPs to the total number of EPs col- exposures to EMPs have different constraints lected on air samples can therefore vary for from methods used to assess environmental ex- samples collected within the same workplace, posures. NIOSH is focused on developing and as well as between different workplaces where validating methods for assessing workplace ex- the same or different asbestos materials are posures to EMPs and provides assistance in de- handled [Dement and Wallingford 1990]. The veloping environmental exposure methods, where result of this is that equivalent PCM asbestos possible and appropriate, through its relation- exposure concentrations determined at differ- ships with other federal agencies. ent workplaces would be considered to pose the same health risk, when, in fact, those risks may be different because of unknown amounts 2.10.1 NIOSH Sampling and of unobserved fibers on the samples. It is com- Analytical Methods for monly stated that particles thinner than about Standardized Industrial 0.2–0.25 µm typically cannot be observed with Hygiene Surveys PCM because they are below the resolution limits of the microscope. However, the results The analytical components of NIOSH’s REL for for PCM counts may also vary according to the asbestos exposure take on substantial signifi- index of refraction of the material being exam- cance because the current REL was set on the ined. When the index of refraction of the par- basis of the limit of quantification (LOQ) of the ticle is similar to that of the filter substrate or PCM method with use of a 400-L sample, rather mounting medium, the ability to resolve par- than solely on estimates of the health risk. Had ticles is less than when the refractive index of a lower LOQ been possible, a lower REL may the particle differs from that of the substrate have been proposed to further reduce the risk [Kenny and Rood 1987]. When a microscope

62 NIOSH CIB 62 • Asbestos is calibrated appropriately for NIOSH Meth- lung when inhaled. The “B” counting rules, od 7400 and triacetin is used as the mounting which are used to evaluate airborne exposure medium, calculation and experiment have in- to other EPs, specify that only EPs thinner than dicated that chrysotile fibers as thin as 0.15 µm 3 µm and longer than 5 µm should be count- can be resolved [Rooker et al. 1982], which im- ed [NIOSH 1994a]. The European Union is plies that amphibole fibers thinner than 0.2 µm moving toward a standardized PCM method and with higher refractive index may actually for evaluating asbestos exposures with count- be visible and potentially counted. ing rules recommended by the World Health Organization (WHO), which specify counting Individual asbestos fibrils range in width from only EPs thinner than 3 µm and with a 3:1 or <10 nm (0.01 µm) for chrysotile up to 40 nm larger aspect ratio [WHO 1997; European Par- (0.04 µm) or more for amosite. Thus, indi- liament and Council 2003]. vidual asbestos fibrils are not likely to be visible by PCM. Early studies suggested that asbestos particles of 3:1 aspect ratio and longer 2.10.2 Analytical Methods than 5 µm are not usually individual fibrils but for Research fibrillar bundles that are much wider than fi- For research purposes, it may be important for brils [Hwang and Gibbs 1981; further data cited in Walton 1982], so that the number of par- a more expansive set of analyses to be consid- ticles meeting these criteria counted under ered. However, EMPs thinner than the limit of PCM were not generally found to differ greatly spatial resolution of the optical microscope are from the number of particles meeting the same thought to be important etiologic agents for criteria counted under the electron microscope disease, so other detection and measurement [Lynch et al. 1970; Hwang and Gibbs 1981; methods may be needed for improved inves- Marconi et al. 1984; Dement and Wallingford tigations of the relationship between fiber di- 1990]. However, more recent studies suggest mension and disease outcomes. there is a substantial difference between counts TEM has much greater resolving power than of particles seen by PCM and TEM [Dement et optical microscopy, on the order of 0.001 µm. al. 2009], and the importance of these differ- Additionally, TEM has the ability to semiquan- ences in developing new methods to be used titatively determine elemental composition by routinely for industrial hygiene surveys will be means of EDS. Incident electrons excite elec- important to reconcile with the particle char- tronic states of atoms of the sample, and the at- acteristics important in disease causation. oms decay that excess energy either by emitting Another aspect of NIOSH Method 7400 is that an X-ray of frequency specific to the element two sets of counting rules are specified, de- (X-ray spectroscopy) or by releasing a second- pending on the type of fiber analysis. The rules ary electron with equivalent kinetic energy for counting particles for asbestos determina- (an Auger electron). Furthermore, TEM can tion, referred to as the “A” rules, instruct the provide some level of electron diffraction (ED) microscopist to count EPs of any width that are analysis of particle mineralogy by producing a longer than 5 µm and have an aspect ratio of mineral-specific diffraction pattern based on at least 3:1. However, EPs wider than 3 µm are the regular arrangement of the particle’s crys- not likely to reach the thoracic region of the tal structure [Egerton 2005].

NIOSH CIB 62 • Asbestos 63 The greater spatial resolving power and the analyses, both of field samples and for research crystallographic analysis abilities of TEM and [Goldstein 2003]. TEM-ED are used in some cases for standardized workplace industrial hygiene character- Research on mechanisms of EMP toxicity in- izations. TEM methods (e.g., NIOSH 7402) cludes concerns for surface-associated factors. are used to complement PCM in cases where To support this research, elemental surface there is apparent ambiguity in EMP identifi- analyses can be performed by scanning Au- cation [NIOSH 1994b] and, under the Asbes- ger spectroscopy on individual particles with tos Hazardous Emergency Response Act of widths near the upper end of SEM resolution. In 1986, the EPA requires that TEM analysis be scanning Auger spectroscopy, the Auger elec- used to ensure the effective removal of asbestos trons stimulated by an incident electron beam from schools [EPA 1987]. Each of these meth- are detected; the energy of these secondary ods employs specific criteria for defining and electrons is low, which permits only secondary counting visualized fibers and reporting differ- electrons from near-surface atoms to escape ent fiber counts for a given sample. These data and be analyzed, thus analyzing the particle el- subsequently can be independently interpret- emental composition to a depth of only one or a ed according to different definitional criteria, few atomic layers [Egerton 2005]. This method such as those developed by the International has been used in some pertinent research stud- Organization for Standardization (ISO), which ies (e.g., assessing effects on toxicity of leaching provides methods ISO 10312 and ISO 13794 Mg from chrysotile fiber surfaces) [Keane et al. [ISO 1995b, 1999]. 1999]. Currently, this form of analysis is time- consuming and not ideal for the routine analy- Improved analytical methods that have become sis of samples collected in field studies. widely available should be reevaluated for complementary research applications or for ease of Surface elemental composition and limited va- applicability to field samples. SEM is now gen- lence state information on surface-borne ele- erally available in research laboratories and ments can be obtained by X-ray photoelectron commercial analytical service laboratories. SEM spectroscopy (XPS or ESCA), albeit not for in- resolution is on the order of ten times that of dividual particles. XPS uses X-ray excitation of optical microscopy, and newly commercial field the sample, rather than electron excitation as emission SEM (FESEM) can improve this res- used in SEM-EDS or TEM-EDS. The X-rays olution to about 0.01 µm or better, near that of excite sample atom electrons to higher ener- TEM. SEM-EDS and SEM- wavelength disper- gy states, which then can decay by emission of sive spectrometers (WDS) can identify the ele- photoelectrons. XPS detects these element-spe- mental composition of particles. It is not clear cific photoelectron energies, which are weak that SEM-backscatter electron diffraction anal- and therefore emitted only near the sample sur- ysis can be adapted to crystallographic analy- face, similar to the case of Auger electron sur- ses equivalent to TEM-ED capability. The ease face spectroscopy. In contrast to scanning Au- of sample collection and preparation for SEM ger spectroscopy, XPS can in some cases provide analysis in comparison with TEM and some not only elemental but also valence state infor- of the advantages of SEM in visualizing fields mation on atoms near the sample surface. How- of EMPs and EMP morphology suggest that ever, in XPS the exciting X-rays cannot be fine- SEM methods should be reevaluated for EMP ly focused on individual particles, so analysis

64 NIOSH CIB 62 • Asbestos is made of an area larger than a single particle are to be counted as asbestos fibers. One effect [Watts and Wolstenholme 2003]. Thus, analysis of using differential counting is to introduce an of a mixed-composition dust sample would be additional source of variability in the particle confounded, so XPS is applicable only to some counts, caused by different “reading” tenden- selected or prepared homogeneous materials or cies between microscopists. The technique has to pure field samples. not been formally validated and has not been recommended by NIOSH.

2.10.3 Differential Counting For counting airborne asbestos fibers in mines and Other Proposed and quarries, ASTM has proposed “discrimina- Analytical Approaches for tory counting” that incorporates the concepts Differentiating EMPs of differential counting. The proposed method uses PCM and TEM in a tiered scheme. Air In assessments of asbestos fiber counts in samples are first analyzed by PCM. If the initial mixed exposures, the use of PCM to deter- PCM fiber count exceeds the MSHA permis- mine concentrations of airborne fibers from sible exposure limit (PEL), TEM is performed asbestos minerals cannot ensure that EMPs to determine an equivalent PCM count of reg- from nonasbestiform minerals are excluded. ulated asbestos fibers only. If the initial PCM No reliable, reproducible methods are available count is greater than one-half the PEL but less for analysis of air samples that would distin- than the PEL, discriminatory counting is then guish between asbestos fibers and EMPs from performed. Discriminatory counts are restrict- nonasbestiform analogs of the asbestos miner- ed to fiber bundles, fibers longer than 10 µm, als. The lack of such validated analytical meth- and fibers thinner than 1.0 μm. If the discrim- ods is clearly a major limitation in applying inatory count is at least 50% of the initial PCM federal agencies’ definitions of airborne asbes- fiber count, TEM is performed to determine an tos fibers. equivalent PCM count of regulated asbestos fibers only. These results are then compared to A technique referred to as differential count- regulatory limits [ASTM 2006]. ing, suggested as an approach to differentiate between asbestiform and nonasbestiform ASTM has begun an interlaboratory study (ILS EMPs, is mentioned in a nonmandatory ap- #282) to determine the interlaboratory preci- pendix to the OSHA asbestos standard. That sion of “binning” fibers into different classes appendix points out that the differential count- based on morphology [Harper et al. 2007]. The ing technique requires “a great deal of experi- first part of the validation process was to evalu- ence” and is “discouraged unless legally neces- ate samples of ground massive or coarsely crys- sary.” It relies heavily on subjective judgment talline amphiboles and air samples from a taco- and does not appear to be commonly used nite mine that have amphibole particulates, of except for samples from mines. In this tech- which the majority are characterized as cleav- nique, EMPs that the microscopist judges to be age fragments. Almost none of the observed nonasbestiform (e.g., having the appearance particles met the Class 1 criteria (i.e., potential- of cleavage fragments) are not counted; any ly asbestiform on the basis of curved particles EMPs not clearly distinguishable as either as- and/or fibril bundles). Many particles were clas- bestos or not asbestos in differential counting sified as Class 2 (i.e., potentially asbestiform on

NIOSH CIB 62 • Asbestos 65 the basis of length >10 μm or width <1 μm), al- 2.11 Summary of Key Issues though their morphology suggested they were For asbestos fibers and other EMPs, an im- more likely cleavage fragments. With use of al- portant question that remains unanswered ternate criteria for Class 2 (length >10 µm plus is “What are the important dimensional and width <1 µm), the number of Class 2 particles physicochemical determinants of pathogenic- was greatly reduced. However, evidence from ity?” Evidence from epidemiological and an- the literature [Dement et al. 1976; Griffis et al. imal studies indicates that risks for asbesto- 1983; Wylie et al. 1985; Siegrist and Wylie 1980; sis and lung cancer decrease with decreasing Beckett and Jarvis 1979; Myojo 1999] indicates exposure concentration and that the potency that as many as 50% of airborne asbestos fibers of asbestos is reduced as the fiber length de- are <10 µm long. The proportion of asbestos fi- creases. However, the results from lung burden bers in the length “bin” bracketed by 5 µm and studies indicate the presence of short asbestos 10 µm was also quite large (about 30%), and fibers at disease sites, and positive correlations the adoption of the alternate Class 2 criteria as between lung cancer and exposure to short as- length >10 µm and width <1 µm would cause bestos fibers make it difficult to rule out a role this proportion of asbestos fibers to be classified for short asbestos fibers in causing disease. as nonasbestiform and excluded from counts of asbestos fibers [Harper et al. 2008]. Other areas of debate remain. For example, there is a continuing debate as to whether or Other procedures have been suggested with not amphibole asbestos fibers are more potent the intent of ensuring that the counts on air lung carcinogens than chrysotile fibers. This samples do not include cleavage fragments possible greater potency has been postulated to [IMA-NA 2005; NSSGA 2005]. These proce- result from slower dissolution (in lung, inter- dures include reviewing available geological stitial, and phagolysosomal fluids) of amphi- information and/or results from analysis of bole asbestos fibers compared to chrysotile fi- bulk materials to establish that asbestos is pres- bers. Thus, amphibole asbestos fibers may tend to persist for longer periods in the lungs and ent in the sampled environment, or specifying other tissues, thereby imparting a greater po- dimensional criteria to establish that airborne tential to trigger carcinogenesis. A related issue particulates have population characteristics that continues to be debated is the magnitude typical of asbestos fibers (e.g., mean particle of the difference in potency for mesothelioma aspect ratios exceeding 20:1). associated with types of asbestos fiber.

For research purposes, it is critically important Understanding the determinants of toxicity of that an analytical method that clearly distin- asbestos fibers and other EMPs, as well as of guishes between asbestiform and nonasbestiform nonelongate mineral particles such as quartz, EMPs be developed, validated, and used. Wheth- may help to elucidate some of these issues. The er any of these suggested procedures would human, animal, and in vitro studies performed ensure adequate health protection for exposed to date have been on asbestos fibers and a limit- workers is unclear, and the practical issues associ- ed number of nonasbestiform EMPs relative to ated with implementing these supplemental pro- the large and highly variable group of minerals cedures are also undetermined. to which there is potential exposure. Additional

66 NIOSH CIB 62 • Asbestos data are needed to more fully assess the parti- which humans are or could be exposed and the cle characteristics that cause adverse health out- exposures in occupational and other settings. comes and to develop risk assessments. An important need is to identify and develop Information on occupational exposures to non- analytical methods that can be used or mod- asbestiform EMPs is limited, as is information ified to quantify occupational exposures to on exposure to asbestos fibers and other EMPs EMPs of toxicological importance and that are in mixed-dust environments, making it difficult capable of differentiating EMPs on the basis of particle characteristics demonstrated to be im- to assess the range of particle characteristics, portant in causing disease. The current PCM including dimension, in occupational settings method is inadequate for assessing exposures with exposures to nonasbestiform EMPs. The to fibers in mixed-dust environments, and few studies that have assessed biopersistence or it lacks the capability to measure all the im- durability suggest that nonasbestiform EMPs are portant physical and chemical parameters of not as biopersistent as asbestiform fibers of the EMPs thought to be associated with toxicity. same length, but more information is needed The feasibility of using EM methods will need to systematically assess the ranges and impor- to be addressed if they are to replace the PCM tance of biopersistence in determining toxicity. method. Until these issues are addressed, im- Any assessment of risk needs to address the in- provements in PCM methodologies should be fluence of EMP dimensions, so studies that sys- pursued. In epidemiological and toxicological tematically compare, to the extent possible, the research, EM methods will need to be used to effects of asbestiform and nonasbestiform par- carefully characterize the exposure materials. ticles of similar dimensions and dosimetrics— Also, the results of toxicological and epidemio- such as particle count, disaggregation, and logical studies may identify additional particle surface area—from the same mineral (e.g., characteristics that warrant further evaluation crocidolite and nonasbestiform riebeckite) are to determine whether they can be incorporated into sampling and analytical methods used needed for a variety of mineral types. Ulti- to assess worker exposures. mately, management of risk needs to be based on an understanding of the estimated quantita- Section 3 of this Roadmap presents a frame- tive risk from exposures to various EMPs and work for proposed research intended to ad- on an understanding of the concentrations and dress these scientific issues and inform future particle characteristics of the various EMPs to public health policies and practices.

NIOSH CIB 62 • Asbestos 67

3 Framework for Research

3.1 Strategic Research Goals and Objectives Strategic goals and objectives for a multidisci brackets following each goal and objective is the plinary research program on mineral fibers number of the section of this Roadmap in which and other EMPs are identified below. Shown in the goal or objective is subsequently discussed.

I. Develop a broader understanding of the important determinants of toxicity for asbestos fibers and other EMPs [3.2].

•• Conduct in vitro studies to ascertain what physical, chemical, surface properties, and other particle characteristics influence the toxicity of asbestos fibers and other EMPs [3.2.1]; and •• Conduct animal studies to ascertain what physical and chemical properties, surface properties, and other particle characteristics influence the toxicity of asbestos fibers and other EMPs [3.2.2].

II. Develop information and knowledge on occupational exposures to asbestos fibers and other EMPs and related health outcomes [3.3].

•• Assess available occupational exposure information relating to various types of asbestos fibers and other EMPs [3.3.1]; •• Collect and analyze available information on health outcomes associated with exposures to various types of asbestos fibers and other EMPs [3.3.2]; •• Conduct selective epidemiologic studies of workers exposed to various types of asbestos fibers and other EMPs [3.3.3]; and •• Improve clinical tools and practices for screening, diagnosis, treatment, and secondary prevention of diseases caused by asbestos fibers and other EMPs [3.3.4].

NIOSH CIB 62 • Asbestos 69 III. Develop improved sampling and analytical methods for asbestos fibers and other EMPs [3.4].

•• Reduce inter-operator and inter-laboratory variability of the current analytical methods used for asbestos fibers [3.4.1]; •• Develop analytical methods with improved sensitivity to visualize thinner EMPs to ensure a more complete evaluation of airborne exposures [3.4.2]; •• Develop a practical analytical method for air samples to differentiate between exposures to asbestiform fibers from the asbestos minerals and exposures to EMPs from their nonasbestiform analogs [3.4.3]; •• Develop analytical methods to assess durability of EMPs [3.4.4]; and •• Develop and validate size-selective sampling methods for EMPs [3.4.5].

3.2 An Approach to Conducting exposure and health. Much of this research may Interdisciplinary Research be accomplished by NIOSH, other federal agencies, or other stakeholders. Any individual re- Within each of the goals and objectives laid out search project undertaken should be designed in this framework, a more detailed research to ensure that the results can be interpreted and program will have to be developed. Research to applied within the context of other studies in the support these three goals must be planned and overall program and lead to outcomes useful for conducted by means of an interdisciplinary ap- decision-making and policy-setting. proach, incorporating toxicological, epidemiological, exposure assessment, medical, analyti- 3.3 National Reference cal, and mineralogical methods. The research must also be integrated to optimize resources, Repository of Minerals and facilitate the simultaneous collection of data, Information System and ensure, to the extent feasible, that the research builds toward a resolution of the key is- To support the needed research, a national ref- sues. An aim of the research is to acquire a level erence repository of samples of asbestos and re- of mechanistic understanding that can provide lated minerals will be required, and a database the basis for developing biologically-based of relevant information should be developed. models for extrapolating results of animal inha- Minerals vary in composition and morphology lation and other types of in vivo studies to ex- by location and origin, and differences within the posure conditions typically encountered in the same mineral type can be significant. Currently, workplace. The information gained from such no national repository exists to retain, docu- research can then be used by regulatory agen- ment, and distribute samples of asbestiform and cies and occupational health professionals to nonasbestiform reference minerals for research implement appropriate exposure limits and risk and testing. These reference samples should be management programs for monitoring worker well-characterized research-grade materials that

70 NIOSH CIB 62 • Asbestos are made available to the research community 3.4 Develop a Broader for testing and standardization. This will allow Understanding of the minerals with matching properties (e.g., morphology, dimension) to be chosen for study. To Important Determinants of accomplish this research, exhaustive character- Toxicity for Asbestos Fibers ization of the samples, including contaminants, and Other EMPs is necessary. Detailed characterizations of minerals should include their ability to affect biologi- To address this objective, one of the first steps cal activities and properties such as (1) purity, will be to identify the range of minerals and min- (2) particle morphology (range of dimensions eral habits needed to systematically address the and sizes), (3) surface area, (4) surface chemis- mineral characteristics that may determine par- try, and (5) surface reactivity. The particle char- ticle toxicity. Care must be taken to ensure that acteristics identified by Hochella [1993] should mineralogical issues in a study are adequately ad- be considered for particle characterization. The dressed. Information on both crystalline lattice use of these samples in research would facilitate structure and composition is needed to define a meaningful comparisons and reduce uncertain- mineral species, because information on either ties in the interpretation of results between and alone is insufficient to describe the properties of among studies. a mineral. For example, nonasbestiform riebeck- Care must be taken to ensure that a sufficient ite and asbestiform riebeckite (crocidolite) share amount of the studied material is available, not the same elemental composition but have differ- only for current studies, but also as reference ma- ent expressions of their crystalline lattices. EMPs terial for possible future studies. The repository from nonasbestiform riebeckite are not flexible. should accept and store samples from research- Crocidolite fibers generally have chain-width de- ers conducting EMP studies so that further test- fects, which explain their flexibility. These chain- ing and characterizations can be performed. The width defects also affect diffusion of cations and information developed from all of these efforts dissolution properties, both of which can explain should be entered into a database, which can greater release of iron into surrounding fluid by serve as a tool for selection of minerals for test- crocidolite than by nonasbestiform riebeckite ing and validation of toxicological tests, as well [Guthrie 1997]. as to assist in identification of worker popula- In addition to elemental content and crystal- tions for possible epidemiological studies. line habit, the particle characteristics identi- The development of a comprehensive, publicly fied by Hochella [1993] should be considered available information system incorporating all for particle characterization. For example, the studies of the toxicity, exposures, and health current paradigm for fiber pathogenicity does effects of asbestos and related minerals could not discriminate between different composi- help enhance the development of the research tions of biopersistent fibers, except insofar as programs, avoid duplication of effort, and en- composition determines biopersistence. Two hance interpretation of the data generated. The biopersistent fiber types, erionite [Wagner et system should include all pertinent informa- al. 1985] and silicon carbide [Davis et al. 1996], tion about methods, doses or exposures, min- show a special proclivity to cause mesothelio- erals, particle characteristics, and other topics. ma, for reasons that are not easily explained by

NIOSH CIB 62 • Asbestos 71 the current paradigm because their biopersis- vivo studies may be useful to assess the relative tence and distributions of fiber lengths are not potential of various EMPs to cause lung toxicity substantially different from those of the amphi- or carcinogenicity [Vu et al. 1996]. boles. The biochemical basis of the enhanced pathogenicity of these two fiber types has not Such short-term assays and strategies were con- been elucidated. This suggests that some fiber sidered by an expert working group assembled types may possess surface or chemical reactiv- by the International Life Sciences Institute’s ity that imparts added pathogenicity over and Risk Science Institute to arrive at a consensus above what would be anticipated for long biop- on current assays useful for screening EMPs ersistent fibers. Because of the many variations for potential toxicity and carcinogenicity [ILSI in elemental composition, crystalline struc- 2005]. Dose, dimension, durability, and pos- ture, and other characteristics of these miner- sible surface reactivities were identified as criti- als, it will be impossible to study all variants. cal parameters for study, although it was noted Therefore, a strategy will need to be developed that no single physicochemical property or for selecting minerals for testing. This strategy mechanism can now be used to predict carci- should include consideration of occupationally nogenicity of all EMPs. The strategy for short- relevant minerals and habits in order to com- term (i.e., 3 months or less) testing in animal plement available information, availability of models included sample preparation and char- appropriate and well-characterized specimens acterization (composition, crystallinity, habit, for testing, and practical relevance of the results size distribution); testing for biopersistence in to be achieved through testing. vivo with use of a standard protocol such as that of the European Union [European Com- EPA’s Office of Pollution Prevention and Tox- mission 1999]; and a subchronic inhalation or ics, NIEHS, NIOSH, and OSHA assembled an instillation challenge of the rat, with evaluation expert panel in the 1990s to consider major is- of lung weight and fiber burden, bronchoalveo- sues in the use of animal models for chronic lar lavage profile, cell proliferation, fibrosis, and inhalation toxicity and carcinogenicity testing histopathology. Additionally, other nonroutine of thoracic-size elongate particles. Issues con- analyses for particle surface area and surface re- sidered included the design of animal tests of activities and short-term in vitro cellular toxico- chronic inhalation exposure to EMPs; prelimi- logical assays might be evaluated. The use ofin nary studies to guide them; parallel mechanis- vitro tests should be tempered by the observa- tic studies to help interpret study results and tions that standard protocols fail to distinguish to extrapolate findings with regard to potential relative pathogenic potentials of even nonelon- health effects in humans; and available screen- gate silicates (such as quartz versus clay dusts) ing tests for identifying and assigning a priority and that treatment of particle surfaces (such as for chronic inhalation study. There was general modeling their conditioning upon deposition agreement that (1) chronic inhalation studies of on the lipoprotein-rich aqueous hypophase EMPs in the rat are the most appropriate tests surface of the deep lung) can greatly affect their for predicting inhalation hazard and risk of expression of toxicities [ATSDR 2003]. EMPs to humans; (2) no single assay or battery of short-term assays could predict the outcome EMPs encountered in any particular work envi- of a chronic inhalation bioassay for carcinoge- ronment are frequently heterogeneous, which nicity; and (3) several short-term in vitro and in limits the ability of epidemiological and other

72 NIOSH CIB 62 • Asbestos types of health assessment studies to evaluate exogenous and endogenous factors, but few the influence on toxicity of EMP dimensions experiments have been attempted to evalu- (length and width), chemical composition, biop- ate these variables in animal or human model ersistence, and other characteristics. Toxico- systems. Kane [1996] has suggested that the logical testing is needed to address some of the mechanisms responsible for the genotoxic ef- fundamental questions about EMP toxicity that fects of asbestos fibers are due to indirect DNA cannot be determined through epidemiology or damage mediated by free radicals and direct other types of health assessment studies. Irre- physical interference with the mitotic appara- spective of study type or design, the full char- tus by the fibers themselves. Research to ad- acterization of all particulate material in a test dress the following questions would assist in sample is an essential step in understanding validating these proposed mechanisms: the mechanisms of EMP toxicity. The determi- •• Are in vitro genotoxicity assays relevant nation of EMP dimensions is important, and to carcinogenesis of asbestos fibers and they are best expressed as bivariate size distri- other EMPs? butions (i.e., width and length). Such deter- •• Are in vitro doses relevant for in vivo ex- minations should be made by using both rela- posures? tively simple procedures (optical microscopy) and highly specialized techniques (e.g., TEM •• Can genotoxic effects of asbestos fibers or SEM with EDS), because size-specific frac- and other EMPs be assessed in vivo? tions of EMP exposures have both biological Macrophages are the initial target cells of EMPs and regulatory significance. and other particulates deposited in the lungs The chemical composition (e.g., intrinsic chem- or pleural and peritoneal spaces. Phagocyto- ical constituents and surface chemistry) of as- sis of asbestos fibers has been shown to be ac- bestos fibers and other EMPs has been shown companied by the activation of macrophages, to have a direct effect on their ability to persist which results in the generation of ROS as well in the lung and to interact with surrounding as a variety of chemical mediators and cyto- tissue to cause DNA damage. For example, fer- kines [Kane 1996]. These mediators amplify ric and ferrous cations are major components the local inflammatory reaction. Persistence of the crystalline structure of amphibole asbes- of asbestos fibers in the lung interstitium or tos fibers; iron may also be present as a surface in the subpleural connective tissue may lead impurity on chrysotile asbestos fibers and oth- to a sustained chronic inflammatory reaction er EMPs. The availability of iron at the surface accompanied by fibrosis [Oberdorster 1994]. of asbestos fibers and other EMPs has been The unregulated or persistent release of these shown to be a critical parameter in catalyz- inflammatory mediators may lead to tissue ing the generation of ROS that may indirectly injury, scarring by fibrosis, and proliferation cause genetic damage [Kane 1996]. Also, at- of epithelial and mesenchymal cells. This re- tempted clearance of long asbestos fibers from sponse appears to occur independently of fiber the lung causes frustrated phagocytosis, which length. In the lungs and pleural linings, chron- stimulates the release of ROS [Mossman and ic inflammation and fibrosis are common reac- Marsh 1989]. Individual adaptive responses tions following exposure to asbestos fibers, but to oxidant stress and the body’s ability to re- research is needed to understand the effects of pair damaged DNA are dependent on multiple fiber dimension, loading, and surface reactivity

NIOSH CIB 62 • Asbestos 73 on the development of disease endpoints such that EMPs from some minerals have low po- as inflammation, fibrosis, and cancer. tency for causing cancer, additional studies may be needed to investigate their potential for It has been suggested that asbestos fibers and causing inflammation, fibrosis, and other non- other EMPs may contribute to carcinogenesis malignant respiratory effects. Also, the rela- by multiple mechanisms and that EMPs may act tionship between EMP dimension and fibrosis at multiple stages in neoplastic development, should be more fully investigated. The results depending on their physicochemical composi- of such research may allow currently used stan- tion, surface reactivity, and biopersistence in the dard exposure indices to be modified by speci- lung [Barrett 1994]. Animal inhalation studies fying different dimensional criteria (lengths are needed to investigate the biopersistence and and widths) relevant to each of the disease out- toxicity of asbestos fibers and other EMPs rep- comes associated with EMP exposures, and by resenting a range of chemical compositions and determining whether biopersistence should be morphological characteristics (including crys- included as an additional criterion. However, talline habits) and representing a range of dis- this research may be dependent on the devel- crete lengths and widths. An additional factor opment of new technology that can generate that should be considered and evaluated is the mineral fibers and other EMPs of specific -di influence of concurrent exposure to other par- mensions in sufficient quantities to conduct ticles and contaminants on the biopersistence animal inhalation experiments. Consequently, and toxicity of EMPs. In a recently reported the development of revised exposure indices short-term (5-day) animal inhalation study to based on EMP dimension may not be possible evaluate the biopersistence of chrysotile fibers in the short term. with and without concurrent exposure to joint compound particles (1–4 µm MMAD), the The research strategy described above should clearance half-time of all fiber sizes was approx- conform with the general strategies and tactics imately an order of magnitude less for the group that have been recommended by several expert exposed to chrysotile and joint-compound par- panels for clarifying the risks and causes of as- ticles [Bernstein et al. 2008]. Histopathological bestos exposure–associated diseases and with the examination indicated that the combination of current effort of the U.S. Federal Government In- chrysotile and fine particles accelerated the re- teragency Asbestos Working Group (IAWG), in- cruitment of alveolar macrophages, resulting in volving participation of the EPA, USGS, NIOSH, a 10-fold decrease in the number of fibers re- ATSDR, CPSC, OSHA, MSHA, and NIEHS/ maining in the lung. Although no mention was NTP, to identify federal research needs and pos- made of any pathological changes in the lungs of sible actions regarding asbestos fibers and other the chrysotile/particulate-exposed group, other durable EMPs of public health concern [Vu et al. studies have shown that the recruitment of mac- 1996; ILSI 2005; Schins 2002; Greim 2004; Moss- rophages then increases the production and re- man et al. 2007]. cruitment of polymorphonuclear leukocytes, which themselves can generate ROS [Driscoll et An ILSI Risk Science Institute Working Group al. 2002; Donaldson and Tran 2002]. supported by EPA published a tiered testing strategy for fibrous particles in 2005 [ILSI 2005]. Much research has been focused on lung can- Consideration should be given to the following cer and mesothelioma. Even if it is determined slight modification of this published scheme.

74 NIOSH CIB 62 • Asbestos Noteworthy in the findings of the ILSI Work- EMP. This step is optional, as one could move ing Group report is the inadequacy of in vitro directly to Step 3. test models to predict the in vivo toxicity of EMPs. Indeed, many man-made mineral fibers Step 3. Short-term in vivo biopersistence test are positive in cell test systems but do not cause Biopersistence of fibers longer than 20 µm has fibrosis or cancer in chronic animal models. been found to be an excellent predictor of col- The in vitro test systems lack predictive ability lagen deposition in chronic inhalation studies because they do not incorporate biopersistence. [Bernstein et al. 2001]. Two alternative meth- For this reason, in vitro tests, other than assays ods are accepted by the European Commission for durability, are not included in the tiered test- [1997]: intratracheal instillation and 5-day ing strategy given below. inhalation by rats. It is recommended that fiber burden be measured at time points up to Step 1. Preparation and characterization 3 months post-exposure. Biopersistence would of test EMPs be an indication of concern and would indicate This is the initial, required step for any toxico- the need for further testing of the pathogenic logical evaluation. It should include potential of the EMP. •• comprehensive chemical and mineralogical characterization, including crystallin- Step 4. Subchronic inhalation study ity and EMP habit. Parameters that should be measured in such •• size distribution of the EMPs found in the an inhalation study are noted by EPA [2001]. workplace (total particulate sample), as The test should involve inhalation exposure well as dimensional characteristics of size- for 3 months and should evaluate pulmonary selected fraction(s) to be used for hazard responses over 6 months post-exposure. Re- evaluation. A limiting step for detailed tox- sponses to be measured should include bio- icological evaluation is the availability of persistence, persistent inflammation, cell pro- sufficient quantities of size-selected EMPs liferation (bromodeoxyuradine [BrdU] assay), of known chemistry and mineralogy. fibrosis, epithelial cell hyperplasia, lung weight, and fiber burden. Biopersistence and persistent Step 2. Assessment of in vitro durability inflammation are notable markers of concern. Evidence indicates that highly soluble fibrous If the subchronic study is positive, a long-term particles do not exhibit fibrotic or carcinogenic inhalation study is necessary to conduct a full- potential in animal studies. Rate of dissolution in risk assessment. simulated body fluids should be measured with a dynamic flow-through system, as outlined by Step 5. Long-term inhalation study Potter et al. [2000]. In brief, EMPs are exposed The test would include a 2-year inhalation by continuous flow to a modified Gamble’s solu- study in rats, with lifelong follow-up. Fibro- tion, and fiber diameter is monitored optically sis, lung tumors, and mesothelioma should be over time. Biopersistence would be an indica- measured according to EPA guidelines [EPA tion of concern and would indicate the need for 2001] for long-term inhalation studies of fi- further testing of the pathogenic potential of the bers. Obtainment of lung burden, dose-related

NIOSH CIB 62 • Asbestos 75 response, and time-course data would enable With the exception of in vitro genotoxicity risk assessment. testing of asbestos fibers, little testing information is available on the potential genotoxicity Implicit in any new or revised occupational of EMPs. In contrast to standard genotoxicity health policy for EMPs would be the need to testing of soluble substances, the results from conduct appropriate assessments of risk. Risk testing EMPs can be influenced by dimen- assessments for lung cancer, mesothelioma, sion, surface properties, and biopersistence. The and asbestosis have been conducted on worker mechanisms of asbestos-induced genotoxicity populations exposed to various asbestos min- are not clear, but direct interaction with the erals. These risks have been qualitatively con- genetic material and indirect effects via pro- firmed in animals, but no adequate quantitative duction of ROS have been proposed. A combi- multidose inhalation studies with asbestos have nation of the micronucleus test and the comet been conducted in rodents that would permit assay with continuous treatment (without exog- direct comparisons to lung cancer and meso- enous metabolic activation) has been reported thelioma risks determined from exposed hu- to detect genotoxic activity of asbestos fibers man populations. Given the availability of risk [Speit 2002]. However, further research is need- estimates for lung cancer in asbestos-exposed ed to determine whether this approach is ap- humans, chronic studies with rats exposed to plicable for genotoxicity testing of other EMPs. asbestos (e.g., chrysotile) fibers would provide Before conducting such studies, the following an assessment of the rat as a valid “predictor” EMP interactions should be addressed: of human lung cancer risks associated with exposure to asbestos fibers and other EMPs. •• initial lesions evoking cell damage or response (e.g., direct or indirect cytotoxic 3.4.1 Conduct In Vitro Studies to or genotoxic events or induction of toxic Ascertain the Physical and reactive intermediate materials); Chemical Properties that •• subsequent multistage cellular response Influence the Toxicity of (e.g., intracellular signaling through a kinase cascade to nuclear transcription of Asbestos Fibers and Other EMPs factors for apoptosis, cell transformation, Although in vitro studies may not be appropri- and cell or cell system proliferation or re- ate for toxicology screening tests of EMPs, they modeling and initiation or promotion of can help clarify the mechanisms by which some neoplasia or fibrosis); and EMPs induce cancer, mesothelioma, or fibrosis, •• critical time-course events in those pro- as well as the properties of EMPs and condi- cesses (e.g., cell-cycle-dependent EMP in- tions of exposure that determine pathogenic- teractions or EMP durability under differ- ity. In vitro studies allow specific biological and ent phagocytic conditions). mechanistic pathways to be isolated and tested under controlled conditions that are not feasible Capabilities for conducting these studies im- in animal studies. In vitro studies can yield data proved during the 2000s, including rapidly and provide important insights and con- •• advancement in analytical methods for firmations of mechanisms, which can be con- physicochemical characterization of firmed with specifically designed in vivo studies. EMP properties (e.g., for resolving small

76 NIOSH CIB 62 • Asbestos dimensions and nanoscale surface proper- system may occur in frustrated phagocytosis ties); and of long EMPs. The hypothesis of frustrated •• ability to prepare EMP samples that are phagocytosis suggests that EMPs that are too “monochromatic” in size or surface prop- long to permit full invagination may stimulate erties in quantities sufficient for well-con- cells to generate ROS or anomalously release trolled in vitro assays. lytic factors into the extracellular annulus rather than into a closed intracellular phagosome. Identification of the initiating EMP-cell interactions calls for research on the mechanisms of EMP surfaces may be tested for direct membra- •• cell-free generation of toxic ROS by EMPs nolytic or cytotoxic activities that are dependent or EMP-induced cellular generation of on surface composition or structure. As a guide, toxic ROS; and membranolytic or cytotoxic activities of non- •• direct membranolytic, cytotoxic, or geno- elongate particulate silicates are dependent on toxic activities of the EMP surface in contact surface properties. Nonelongate particulate sili- with cellular membranes or genetic material. cates also provide an example of failure of in vitro cytotoxicity to relate with pathogenicity (e.g., These investigations will require attention to the respirable particles of quartz or kaolin clay sig- following: nificantly differ in disease risk for fibrosis, but •• effects of EMP surface composition (e.g., are comparably cytotoxic in vitro unless they are surface-borne iron species); preconditioned with pulmonary surfactants and •• effects of normal physiological condition- then subjected to phagolysosomal digestion). In ing of respired particles (e.g., in vitro mod- vitro studies of direct versus indirect induction eling of in vivo initial conditioning of EMP of genotoxic activities may consider factors af- surfaces by pulmonary surfactant); fecting the bioavailability of the nuclear genetic material (e.g., the state of phagocytic activity of •• nonphysiological conditioning of EMP un- the cell or the stages in the cell cycle with col- der in vitro test conditions (e.g., by compo- lapse of the nuclear membrane in mitosis). nents of nutrient medium); These again suggest care in the preparation of •• cell type (e.g., phagocytic inflammatory EMPs and the manner of challenge with EMPs cell or phagocytic versus nonphagocytic employed in in vitro experiments. target cell); and The two modes of primary damage, a release •• EMP dimensions in relation to cell size (e.g., of reactive toxic agents induced by long par- as a factor distinguishing total phagocytosis ticulates or a surface-based membranolytic or and partial frustrated phagocytosis). genotoxic mechanism, may be involved singly Cell generation of ROS is seen generally in or jointly in primary cell responses to EMPs. phagocytic uptake of elongate or nonelongate These may be investigated by comparing the particles (e.g., as a respiratory burst). In nor- effects of different types of EMPs (e.g., rela- mal phagocytosis, there is a maturation of the tive potencies of erionite fibers and amphibole phagosomal membrane, with progression to a asbestos fibers inin vitro cell transformation phagolysosomal structure for attempted lyso- studies are different than their potencies inin somal digestion. Anomalous behavior of this vivo induction of mesothelioma).

NIOSH CIB 62 • Asbestos 77 In the second phase of cellular response to EMPs, and chronic inhalation studies [EPA 2000] the central dogma of intracellular response is that would provide solid scientific evidence being intensively researched. The initial extra- on which to base human risk assessments for a cellular primary damage induces intracellular variety of EMPs. To date, the most substantial signaling (e.g., by MAPK), which causes a cas- base of human health data for estimating lung cade of kinase activities that stimulate selective cancer risk is for workers exposed to fibers nuclear transcription of mRNAs, leading to from different varieties of asbestos minerals. production of TNF-α or other cytokines for extracellular signaling of target cells. Those other There are similarities between animal species cytokines may induce cell proliferation toward and humans in deposition, clearance, and re- cancer or collagen synthesis toward fibrosis. tention of inhaled particles in the lungs. For Further definition of signaling mechanisms and example, peak alveolar deposition fraction is analyses of their induction by different primary greatest for particles at an AED of about 2 µm in EMP-cellular interactions may better define the humans and about 1 µm for rodents. However, ultimate role of EMP properties in the overall some interspecies differences have been identi- process. That research, again, may be facilitated fied. Variations in ventilation, airway anatomy, by using different specific types of EMPs, each and airway cell morphology and distribution ac- with relatively homogeneous morphology and count for quantitative differences in deposition surface properties. pattern and rate of clearance among species. In addition, the efficacy of pulmonary macrophage Although full investigation of biopersistence function differs among species. All these differ- of EMPs may require long-term animal model ences could affect particle clearance and reten- studies, in vitro systems coupled with advanced tion. It has been suggested that the following surface analytical tools (e.g., field emission species differences should be considered in the SEM–energy dispersive X-ray spectroscopy or design of experimental animal inhalation stud- scanning Auger spectroscopy) may help guide ies of elongate particles [Dai and Yu 1988; War- in vivo studies. This could be done by detailing specific surface properties of EMPs and their heit et al. 1988; Warheit 1989]. modifications under cell-free orin vitro con- •• Due to differences in airway structure, ditions representing the local pH and reactive airway size, and ventilation parameters, a species at the EMP surface under conditions greater fraction with large AED particles of extracellular, intra-phagolysosomal, or frus- are deposited in humans than in rodents. trated annular phagocytic environments. •• Alveolar deposition fraction in humans varies with workload. An increase in the 3.4.2 Conduct Animal Studies to workload reduces the deposition fraction Ascertain the Physical and in the alveolar region because more of Chemical Properties that the inhaled particulate is deposited in the extra-thoracic and bronchial regions. Influence the Toxicity of Asbestos Fibers and Other EMPs •• Mouth breathing by humans results in a greater upper bronchial deposition and A multispecies testing approach has been rec- enhanced particle penetration to the pe- ommended for short-term assays [ILSI 2005] ripheral lung.

78 NIOSH CIB 62 • Asbestos •• For rats and hamsters, alveolar deposition in deposition and clearance characteristics becomes practically zero when particle between rodents and humans. EMPs that are AED exceeds 3.0 µm and aspect ratio ex- capable of being deposited in the bronchoal- ceeds 10. In contrast, considerable alveolar veolar region of humans cannot be completely deposition is found for humans breathing evaluated in animal inhalation studies because at rest, even for EPs with AEDs approach- the maximum thoracic size for particles in ro- ing 5 µm and aspect ratio exceeding 10. dents is approximately 2 µm AED, which is •• Rodents have smaller-diameter airways less than the maximum thoracic size of about than humans, a characteristic which in- 3 µm AED for humans [Timbrell 1982; Su and creases the chance for particle deposition Cheng 2005]. via contact with airway surfaces. •• Turbulent air flow, which enhances particle 3.4.2.1 Short-Term Animal Studies deposition via impaction, is common in There are several advantages to conducting human airways but rare in rodent airways. short-term animal studies in rats; one is that •• Variations in airway branching patterns the information gained (e.g., regarding over- may account for significant differences load and maximum tolerated dose [MTD]) in deposition between humans and ro- can be used to more effectively design chronic dents. Human airways are characterized inhalation studies [ILSI 2005]. The objectives by symmetrical branching, wherein each of these studies would be to bifurcation is located near the centerline of the parent airway. This symmetry fa- •• Evaluate EMP deposition, translocation, vors deposition “hotspots” on carinal and clearance mechanisms; ridges at the bifurcations due to disrupted •• Compare the biopersistence of EMPs re- airstreams and local turbulence. Rodent tained in the lung with results from in vi- airways are characterized by asymmetric tro durability assays; branching, which results in a more diffuse •• Compare in vivo pulmonary responses to deposition pattern because the bulk flow in vitro bioactivity for EMPs of different of inspired air follows the major airways dimensions; and with little change in velocity or direction. •• Compare cancer and noncancer toxicities •• Alveolar clearance is slower in humans for EMPs from asbestiform and nonas- than in rats. Human dosimetry models bestiform amphibole mineral varieties of predict that, at nonoverloading exposure concentrations, a greater proportion of varying shapes, as well as within narrow particles deposited in the alveolar region ranges of length and width. will be interstitialized and sequestered in More fundamental studies should also be per- humans than in rats. formed to An important consideration in the conduct and •• Identify biomarkers or tracer/imaging interpretation of animal studies is the selection methods that could be used to predict or of well characterized (with respect to chemi- monitor active pulmonary inflammation, cal and physical parameters) and appropriately pulmonary fibrosis, and malignant trans- sized EMPs that take into account differences formation;

NIOSH CIB 62 • Asbestos 79 •• Investigate mechanisms of EMP-induced proposed testing guidelines should be consid- pulmonary disease; and ered as the criteria for establishing the testing •• Determine whether cell proliferation in parameters for chronic studies [EPA 2001]. the lungs (terminal bronchioles and alveo- To date, chronic inhalation studies have been lar ducts) can be a predictive measure of conducted with different animal species and dif- pathogenicity following brief inhalation ex- ferent types of EPs. However, it remains uncer- posure and use of the BrdU assay [Cullen et tain which species of animal(s) best predict(s) al. 1997]. the risk of respiratory disease(s) for workers Exposure protocols for tracheal inhalation or exposed to different EPs. Chronic inhalation instillation in an animal model for short-term studies should be initiated to establish exposure/ in vivo studies using field-collected or labora- dose-response relationships for at least two ani- tory-generated EMPs should address possible mal species. The rat has historically been the adulteration of EMP morphology (e.g., anom- animal of choice for chronic inhalation studies alous agglomeration of particles). This might with EPs, but the low incidence of lung tumors be addressed in part by preconditioning EMPs and mesotheliomas in rats exposed to asbestos in a delivery vehicle containing representative fibers suggests that rats may be less sensitive than components of pulmonary hypophase fluids. humans. Therefore, any future consideration for Exposure protocols using pharyngeal aspira- conducting long-term animal inhalation studies tion as a delivery system should be considered, should address the need for using a multispecies given the observations in studies with single- testing approach to help provide solid scientific walled carbon nanotubes that such a delivery evidence on which to base human risk assess- system closely mimics animal inhalation stud- ments for a variety of EMPs of different durabil- ies [Shvedova et al. 2005, 2008]. ities and dimensions. For example, some recent studies suggest that the hamster may be a more Studies evaluating the roles of biopersistence sensitive model for mesothelioma than the rat. and dimension in the development of noncancer Validation of appropriate animal models could and cancer endpoints from exposure to EMPs reduce the resources needed to perform long- are also needed. These studies should attempt to term experimental studies on other EMP types elucidate the physicochemical parameters that [EPA 2001]. might affect bio-durability of EMPs of specific dimensions. Although short-term animal inha- Multidose animal inhalation studies with as- lation studies would be informative, companion bestos (probably a carefully selected and well- in vitro assays should also be conducted to as- characterized chrysotile, because most of the sess their validity for screening EMPs. estimates of human risk have been established from epidemiological studies of chrysotile- exposed workers) are needed to provide an im- 3.4.2.2 Long-Term Animal Studies proved basis for comparing the potential can- Chronic animal inhalation studies are required cer and noncancer risks associated with other to address the impacts of dimension, morphol- types of EMPs and various types of synthetic ogy, chemistry, and biopersistence on critical EPs. The asbestos fibers administered in these disease endpoints of cancer induction and animal studies should be comparable in dimen- nonmalignant respiratory disease. The EPA’s sion to those fibers found in the occupational

80 NIOSH CIB 62 • Asbestos environment. The results from these studies •• effects on mitosis and aneuploidy, deter- with asbestos (e.g., chrysotile) would provide mined by confocal fluorescent micros- a “gold standard” that could be used to validate copy; and the utility of long-term inhalation studies (in •• signal transduction pathways, such as rats or other species) for predicting human risks MAPK, and phosphoinositide-3 (PI3) ki- of exposure to various types of EMPs. nase pathways.

3.4.3 Evaluate Toxicological In vivo tests would measure markers of inflammation (e.g., BAL neutrophils, inflammatory Mechanisms to Develop cytokines and chemokines), fibrosis (colla- Early Biomarkers of Human gen, hydroxyproline), and proliferation (BrdU Health Effects assay, hyperplasia) that precede pathology. Knockout mice or pathway inhibitors in rats The following scheme using acellular and cel- may be used to confirm mechanistic pathways lular tests can be conducted to develop a mech- identified in vitro and develop biomarkers for anistic understanding of fiber toxicity and to disease initiation and progression. Potential support the development of in vivo biomark- biomarkers identified inin vitro and in vivo ers of effect in humans. These studies must use studies would be evaluated in human popula- well-characterized EMP samples as described tions with known exposure to EMPs, and the in the tiered testing strategy presented in Sec- type and extent of the relationships between tion 3.4. The use of size-selected fractions of the marker and clinical signs of disease could EMPs could provide information needed to be determined. understand the relationships between dimension and bioactivity. 3.5 Develop Information and Acellular assays could include measurement of Knowledge on Occupational the generation of ROS employing electron spin Exposures to Asbestos resonance (ESR) or oxidant sensitive fluorescent dyes. Evaluation of the mobilization of metal ions Fibers and Other EMPs and from EMPs could indicate cytotoxic potential. Related Health Outcomes

The in vitro cellular tests could include the fol- Many studies have been published concerning lowing: occupational exposures to asbestos fibers and as- •• generation of reactive species measured sociated health effects. These studies have formed by ESR or fluorescent dyes; a knowledge base that has supported increased regulation of occupational asbestos exposures •• generation of inflammatory, fibrogenic, and substantial reductions in asbestos use and and proliferative mediators, such as TNF- asbestos exposures in the United States over the alpha, IL-1, and TGF; past several decades. But, as this Roadmap makes •• DNA damage by comet assay; clear, much less is known about other types of •• effects on cell growth regulation by mea- mineral fibers and EMPs in terms of occupation- suring cell proliferation; al exposures and potential health effects.

NIOSH CIB 62 • Asbestos 81 Research is needed to produce information on EMPs currently, in the past, and project- •• current estimates and, where possible, fu- ed in the future; and ture projections of numbers of U.S. work- •• the specific distributions and levels of ex- ers exposed to asbestos fibers; posures to each particular type of EMP, •• levels of current exposures and nature of as well as numbers of workers exposed to the exposures (e.g., continuous, short-term, each type of EMP currently, in the past, or intermittent); and and projected in the future. •• the nature of any concomitant dust expo- To complement readily available information sures. disseminated by the USGS on annual domestic production and importation of raw asbestos, Similar research is needed to produce analo- data on the annual amounts of asbestos im- gous information about occupational expo- ported into the United States in the form of any sures to other EMPs. Research is needed to asbestos-containing products should be aggre- assess and quantify potential human health gated and made easily accessible. risks associated with occupational exposures to other EMPs, as well as to better understand Additional efforts should be made to collect, re- and quantify the epidemiology of asbestos- view, and summarize available occupational ex- related diseases by using more refined indices posure information and to collect and analyze of exposure. Research is also needed to pro- representative air samples relating to various duce improved methods and clinical guidance types of EMPs. For example, systematic com- for screening, diagnosis, secondary prevention, pilation of exposure data collected by OSHA, and treatment of diseases caused by asbestos fi- MSHA, NIOSH, state agencies, and private bers and other hazardous EMPs. industry could contribute to an improved understanding of current occupational exposures 3.5.1 Assess Available Information to EMPs, particularly if there are opportunities to (re)analyze collected samples with use of en- on Occupational Exposures to hanced analytical methods to better character- Asbestos Fibers and Other EMPs ize the exposures (see Section 3.6). To help limit A fully informed strategy for prioritizing re- potential impact of sampling bias that may be search on EMPs should be based on preliminary inherent in the available EMP exposure data, systematic collection and evaluation of available these initial efforts should be supplemented information on (1) industries/occupations/job with efforts to systematically identify, sample, and characterize EMP exposures through- tasks/processes with exposure to various types out U.S. industry. These exposure assessments of asbestos fibers and other EMPs; (2) numbers should include workplaces in which a fraction of workers exposed; (3) characteristics and lev- of the dust comprises EMPs (i.e., mixed-dust els of exposures; and (4) associated concomitant environments), and occupational environments particulate exposures. Such information could in which EMPs may not meet the current regu- enable estimations of latory criteria to be counted (i.e., “short” fibers). •• the overall distribution and levels of oc- With appropriate planning and resources, such cupational exposures and an estimate of efforts could be designed and implemented as the total number of workers exposed to ongoing surveillance of occupational exposures

82 NIOSH CIB 62 • Asbestos to EMPs, with periodic summary reporting of Libby, MT, vermiculite” [NIOSH 2005]. To en- findings. Representative EMP exposure data sure a clear science base that might support a could help identify worker populations or par- formal recommendation for control of occupa- ticular types of EMPs warranting further study tional exposures to all asbestiform amphibole (i.e., more in-depth exposure assessment; medi- fibers, it would be reasonable to thoroughly cal surveillance; epidemiologic studies of par- review, assess, and summarize the available ticular types of EMPs, processes, job tasks, oc- information on asbestiform amphiboles such cupations, or industries; and toxicity studies of as winchite, richterite, and fluoro-edenite that particular EMPs). Occupational exposure data have not been commercially exploited. should be collected and stored in a comprehensive database. Information similar to that It will also be important to quantitatively de- described by Marchant et al. [2002] should be termine the health risks posed by EMPs from incorporated into the database to support these nonasbestiform amphiboles and to compare efforts. This could be accomplished in parallel them to the risks posed by fibers from asbesti- with efforts to develop an occupational exposure form amphiboles. If nonasbestiform amphibole database for nanotechnology [Miller et al. 2007] EMPs are, in fact, associated with some risk, a or efforts to develop a national occupational ex- quantitative risk assessment would be needed posure database [Middendorf et al. 2007]. to understand the risks relative to those associated with exposures to asbestos fibers. If new 3.5.2 Collect and Analyze Available epidemiological and other evidence is sufficient to support such a risk estimate, that could lead Information on Health to the development of risk management policies Outcomes Associated with for nonasbestiform amphibole EMPs distinct Exposures to Asbestos Fibers from risk management policies for asbestos fi- and Other EMPs bers. Risk management policies that differ for asbestiform and nonasbestiform amphiboles The body of knowledge concerning human would motivate the development and routine health effects from exposure to EMPs consists use of new analytical methods that differentiate primarily of findings from epidemiological asbestiform from nonasbestiform particles. studies of workers exposed to asbestos fibers. There is general agreement that workers ex- In addition to collecting and analyzing infor- posed to fibers from any asbestiform amphi- mation on health outcomes associated with ex- bole mineral would be at risk of serious ad- posures to asbestiform EMPs and EMPs from verse health outcomes of the type caused by nonasbestiform amphiboles, similar information exposure to fibers from the six commercially related to other EMPs (e.g., erionite, wollastonite, exploited asbestos minerals. NIOSH com- attapulgite, and fibrous talc) should be collected mented on the most recently proposed MSHA for systematic analysis. Additional relevant in- rule on asbestos (subsequently promulgated as formation may be gleaned from epidemiological a final rule), stating that “NIOSH remains con- studies conducted on some SVFs (e.g., glass and cerned that the regulatory definition of asbes- mineral wool fibers, ceramic fibers). tos should include asbestiform mineral fibers such as winchite and richterite, which were Surveillance and epidemiological studies gener- of major importance as contaminants in the ally have been circumscribed by the long latency

NIOSH CIB 62 • Asbestos 83 periods that characterize manifestations of either after having more thoroughly characterized pulmonary fibrosis (e.g., as detected by chest ra- exposures with use of sample filters archived diography or pulmonary function tests) or can- from that study [Kuempel et al. 2006]. Out- cer caused by asbestos exposures. Modern medi- comes from the approaches outlined above in cal pulmonary imaging techniques or bioassays Section 3.3.2 might also potentially identify of circulating levels of cytokines or other bio- opportunities for aggregate meta-analyses of chemical factors associated with disease process- data from multiple prior epidemiological stud- es might be adaptable to better define early stages ies, allowing an assessment of risks across vari- of asbestosis, and might provide a new paradigm ous types of EMPs. Recently published research for early detection of the active disease process. illustrates the potential of such meta-analyses For example, positron emission tomographic im- to contribute to an understanding of determi- aging with use of tracers indicative of active col- nants of disease caused by exposure to asbestos lagen synthesis can detect fibrogenic response in and related EMPs [Berman et al. 1995; Berman a matter of weeks after quartz dust challenge in a and Crump 2008b; Berman 2010]. rabbit animal model [Jones et al. 1997; Wallace et al. 2002]. Given the ongoing and widespread occupational and environmental exposure to Libby vermiculite, a more complete understanding of 3.5.3 Conduct Selective the mortality experience of the Libby occupa- Epidemiological Studies of tional cohort could shed light on risks associ- Workers Exposed to Asbestos ated with exposure to the Libby amphibole, Fibers and Other EMPs such as exposures at the World Trade Center disaster, as well as the health effects among the Statistically powerful and well designed epi- Libby community. Analyses of the Libby work- demiological studies are typically very expen- er cohort continue and future analyses are en- sive and time consuming, but they have been visioned, with the following aims: invaluable for defining associations between •• complete exposure-response modeling and human health outcomes and occupational ex- occupational risk assessment for mesothe- posures. In fact, the strongest human evidence lioma and asbestosis, and indicating that, at a sufficient dose and with a sufficient latency, certain EMPs of thoracic •• description of nonrespiratory outcomes dimension and high durability pose risks for (e.g., mortality with rheumatoid arthri- malignant and nonmalignant respiratory dis- tis and mortality from extrapulmonary ease has come from epidemiological studies of cancers). workers exposed to asbestos fibers. Other research relating to Libby amphibole Outcomes from proposed research efforts also continues. EPA and ATSDR have been en- outlined above in Section 3.5.2 may identify gaged in a program of research involving sev- additional opportunities for informative epi- eral recent projects, including evaluation of demiological studies following the example •• the relationship between radiographic ab- of NIOSH researchers who have recently un- normalities and lung function in Libby dertaken a reanalysis of data from a prior epi- community residents, finding that diffuse demiological study of asbestos textile workers, pleural thickening on radiography was a

84 NIOSH CIB 62 • Asbestos significant predictor of both restrictive and Large unstudied populations with sufficiently obstructive patterns on spirometry. high exposure to commercial asbestos fibers •• the natural history of radiographic dis- are unlikely to be identified in developed coun- ease progression, observing an exposure- tries such as the United States, where asbestos response relationship between cumulative use has been markedly curtailed and where occupational exposures have been strictly regu- fiber exposure and small opacity profu- lated in recent decades. Nevertheless, some sion level on chest radiographs of Libby developing countries (where asbestos use con- workers. tinues on a large scale and where exposures •• the effect of exposure to asbestos-containing may be less regulated) may offer opportunities Libby vermiculite at 28 processing sites in for de novo epidemiological studies that could the United States. Activities included con- contribute to a more refined understanding ducting medical screening of former work- of the association of human health outcomes ers and household contacts at six sites; a with occupational exposures to asbestos fibers summary report is available at www.atsdr. and other EMPs. cdc.gov/asbestos/sites/national_map. Opportunities for epidemiological studies of ex- •• cases of mesothelioma, asbestosis, and posed workers might be sought in other coun- lung cancer among former workers and tries where medical registry data and historical others with nonoccupational exposure or current workplace sampling data are available associated with a vermiculite processing (e.g., in China, where epidemiological studies facility in northeast Minneapolis. of another occupational dust disease, silicosis, •• disease progression in workers exposed have been collaboratively conducted by Chinese to asbestos-containing vermiculite ore at and NIOSH researchers [Chen et al. 2005]). a fertilizer plant in Marysville, Ohio. Opportunities may also exist in other coun- •• autoimmune conditions not classically tries for epidemiological studies of nonworker associated with asbestos exposure and populations exposed to asbestos in ways not health effects associated with low-level encountered in more developed countries. For exposure and childhood exposure. example, regular whitewashing of the interiors of homes has, in more than one country, been In addition, ATSDR continues to update its shown to be fraught with hazard. In parts of Tremolite Asbestos Registry (TAR) of individ- Greece and Turkey and in New Caledonia, the uals exposed to vermiculite-associated asbes- local earthen material traditionally used for tiform amphibole in Libby. Opportunities for whitewashing homes was predominantly com- additional informative epidemiological studies posed of tremolite asbestos, resulting in high relating to Libby amphibole could be pursued rates of nonmalignant pleural plaques [Con- in the future, particularly if an EM-based job- stantopoulos et al. 1987], lung cancer [Luce et exposure matrix for workers exposed to the al 2000; Menvielle et al. 2003], and malignant Libby amphiboles is developed, or if amphi- mesothelioma [Sakellariou et al. 1996; Senyiğit bole exposures during commercial building et al. 2000]. The whitewashing work, including and household construction renovation tasks crushing of the dry material before addition of were well-characterized. water, was typically done by women with small

NIOSH CIB 62 • Asbestos 85 children in tow, placing both sexes at risk of Other studies worthy of consideration include intermittent heavy exposures very early in life these: [Sakellariou et al. 1996]. This, along with the •• Epidemiological studies of worker pop- longer-term and lower-level exposures associ- ulations incidentally exposed to EMPs ated with inhabiting homes whitewashed with from fibrous minerals, including asbesti- this asbestos-containing material, represents form minerals (e.g., those associated with an exposure pattern very different from the oc- Libby vermiculite); cupational exposures to asbestos studied in the •• Epidemiological studies of populations ex- Unites States and other industrialized countries. posed to other less-well-studied EMPs (e.g., wollastonite, attapulgite, and erionite); and Results of epidemiological studies of workers exposed to EMPs, such as from nonasbesti- •• Meta-analyses of data from multiple epidemiological studies of various worker form amphibole minerals or minerals in talc populations, each exposed to EMPs with deposits, have provided limited evidence of somewhat different attributes (such as an association between occupational exposure EMP type or dimensions), to better define and lung cancer or mesothelioma. It will be specific determinants of EMP-associated important to establish a priori criteria to en- adverse health outcomes for purposes of able results of epidemiological studies or meta- risk assessment. analyses to be used to indicate whether or not occupational exposure to EMPs from nonas- The following criteria should be considered in bestiform amphibole minerals or minerals in selecting and prioritizing possible populations talc deposits is associated with a risk level that for epidemiological study: (1) type of EMP ex- warrants preventive intervention. Clearly lay- posure (e.g., mineral source, chemical compo- ing out these criteria and assessing the feasi- sition, crystalline structure, surface character- bility of conducting necessary studies should istics, and durability); (2) adequate exposure be done by a panel of knowledgeable experts. information (e.g., EMP concentrations and Laboratory research will undoubtedly shed [bivariate] EMP dimensions); (3) good work much light on the issue of potential human histories; (4) sufficient latency; (5) number of workers needed to provide adequate statisti- health risks associated with specific physico- cal power for the health outcome(s) of interest; chemical characteristics of EMPs. Still, where and (6) availability of data on other potentially such studies are not only feasible but also likely confounding risk factors. Priority should be informative, there is reason to consider further placed on epidemiological studies with poten- epidemiological studies of worker populations tial to contribute to the understanding of EMP exposed to EMPs from nonasbestiform amphi- characteristics that determine toxicity, includ- boles. These may be conducted either de novo ing type of mineral source (e.g., asbestiform or through updating of prior studies for more mineral habit vs. other fibrous mineral habit complete follow-up of health outcomes and/or vs. blocky mineral habit) and morphology and through reanalyzing archived exposure sam- other aspects of the airborne EMPs (e.g., di- ples for development of more specific knowl- mensions [length and width], chemical com- edge concerning etiologic determinants and position, crystalline structure, surface charac- quantitative risk. teristics, and durability).

86 NIOSH CIB 62 • Asbestos In addition to epidemiological studies that of pursuit by NIOSH and other federal agen- address etiology and that quantify exposure- cies, along with their partners, to improve related risk, epidemiological studies can be screening, diagnosis, secondary prevention, and used to better understand the pathogenesis of treatment. These include but are not limited to lung diseases caused by asbestos fibers and oth- the following objectives: er EMPs. For example, appropriately designed •• Continue to develop and validate techni- or reconstructed epidemiological studies could be used to assess the relationship between the cal standards for the assessment of digital physicochemical properties of EMPs, lung fi- chest radiographs with the ILO classifica- brosis, and lung cancer. tion system. The ILO system for classifying chest radiographs of the pneumoconioses 3.5.4 Improve Clinical Tools and is widely used as a standard throughout the world. Although initially intended for use Practices for Screening, in epidemiological studies, the ILO system Diagnosis, Treatment, and is now also commonly used as a basis for Secondary Prevention of describing severity of disease in clinical Diseases Caused by Asbestos care and for awarding compensation to Fibers and Other EMPs individuals affected by nonmalignant diseases of the chest caused by asbestos and Given the huge human and economic impact of other airborne dusts. To ensure that digital asbestos-related disease and litigation, Congress chest radiographic methods used in future has considered asbestos-related legislation on clinical and epidemiological studies can several occasions in recent years. To date, bills be compared with past studies based on with provisions to require private industry to fund an asbestos victims’ trust fund have not conventional film radiography, there is a succeeded in Congress. Most recently, the Ban critical need to continue ongoing research Asbestos in America Act, which was passed by to validate use of the ILO system for clas- the U.S. Senate in 2007 but was not acted on sification of digital chest images. in the House of Representatives, would have •• Develop and promote standardized as- authorized and funded a network of asbestos- sessment of nonmalignant dust-induced related disease research and treatment centers diseases, including asbestos-related pleu- to conduct studies, including clinical trials, on ral and parenchymal disease, on comput- effective treatment, early detection, and preven- ed tomography (CT) images of the chest. tion [U.S. Senate 2007]. This bill also called for Over the past several decades, CT scan- the establishment of a mechanism for coordi- ning of the chest has been increasingly nating and providing data and specimens re- used for assessing chest disease, and high- lating to asbestos-caused diseases from cancer resolution CT scanning is often done in registries and other centers, including a recently clinical settings. Although approaches for funded virtual biospecimen bank for mesothelioma [Mesothelioma Virtual Bank 2007]. standardizing classifications of CT images for dust-related diseases have been Various research objectives relevant to clinical proposed, none have yet been widely ad- aspects of asbestos-related diseases are worthy opted or authoritatively promoted.

NIOSH CIB 62 • Asbestos 87 •• Develop, validate, and promote standard- •• Develop new treatment options to reduce ization of approaches for assessment of risk of malignant and nonmalignant disease past asbestos exposures by measurement among those exposed to asbestos and to ef- of asbestos bodies and uncoated fibers, fectively treat established asbestos-induced particularly in samples collected noninva- disease. For example, many widely used sively (e.g., sputum). Various approaches anti-inflammatory drugs exert their effect for quantifying fiber burden have been by inhibiting cyclooxygenase-2 (COX-2), used for research and clinical purposes, but an enzyme that is induced in inflammatory results are often difficult or impossible to and malignant (including premalignant) compare across different studies because of processes. Promising results of laboratory lack of standardization and the differential and case-control epidemiological studies rates of biopersistence and translocation of have led to clinical trials of COX-2 inhibi- various types of asbestos fibers. tors as adjuvant therapy to enhance treat- ments for various types of cancer. Research •• Develop and validate biomarkers for as- is warranted to determine whether these bestosis, lung cancer, and mesothelioma drugs can reduce the risk of asbestos-relat- to enable more specific identification of ed malignancies in exposed individuals. those at risk or early detection of disease in those previously exposed to asbestos. •• Authoritatively and regularly update and For example, noninvasive bioassays for disseminate clear clinical guidance for mesothelioma warrant further research practitioners, based on expert synthesis before they can be considered ready for of the available literature. routine application in clinical practice. •• Develop and/or adapt emerging medi- 3.6 Develop Improved cal imaging techniques to better define Sampling and Analytical stages of asbestosis, or to provide a new Methods for Asbestos paradigm for early detection or grading of the active disease process. For example, Fibers and Other EMPs positron emission tomographic (PET) There are important scientific gaps in under- imaging using tracers indicative of active standing the health impacts of exposure to collagen synthesis can detect pulmonary EMPs. Changes in how EMPs are defined for fibrogenic response in a matter of weeks regulatory purposes will likely have to be ac- after quartz dust challenge in a rabbit ani- companied by improvements to currently used mal model [Jones et al. 1997; Wallace et al. analytical methods or development and appli- 2002]. This holds promise for noninvasive cation of new analytical methods. An ability to approaches for earlier clinical detection differentiate between fibers from the asbestos and more sensitive surveillance and epide- minerals and EMPs from their nonasbestiform miological studies, that to date have been analogs in air samples is an important need, es- circumscribed by the long latency periods pecially for mineral-specific recommendations that characterize pulmonary fibrosis asso- (e.g., occupational exposure limits). However, ciated with asbestos exposure (e.g., as de- overcoming this obstacle may be difficult -be tected by conventional chest radiography). cause of (1) the lack of standard criteria for the

88 NIOSH CIB 62 • Asbestos mineralogical identification of airborne EMPs However, the routine use of EM would and (2) technical difficulties in generating test •• require the development of standardized aerosols of size-specific EMPs representative of analytical criteria for the identification of worker exposures so that sampling and analyt- various EMPs; ical methods can be tested and validated. •• require specialized experience in micros- Improvements in exposure assessment meth- copy and mineral identification; ods are needed to increase the accuracy of the •• increase analytical costs; and methods used to identify, differentiate, and count •• potentially increase the lag time between EMPs captured in air-sampling filter media. Un- collecting the sample and obtaining results. til new analytical methods are developed and validated, it will be necessary to investigate the In some workplace situations, such as in con- various proposals that have been made to modify struction, increases in the time needed to ana- current analytical methods, such as those dis- lyze samples and identify EMPs could poten- cussed in Section 3.6.2, and additional modifica- tially delay the implementation of appropriate tions to the current analytical methods. control measures to reduce exposures.

Manual microscopy methods are labor-intensive Several potential sampling and analytical im- and error-prone. Automated analyses would provements are currently under study. Some permit examination of larger sample fractions of the studies are aimed at improving the ac- and improve the accuracy of particle classifica- curacy of current techniques used for moni- tion. Developing a practical method that accu- toring exposures to asbestos. One such study rately counts and sizes all EMPs could improve is evaluating the use of thoracic samplers for risk assessments and exposure assessments done the collection of airborne EPs, and another in support of risk management. Automated concerns the use of gridded coverslips for methods could reduce operator bias and inter- PCM analyses. The proposed use of gridded laboratory variability, providing more consis- coverslips for sample evaluation can aid in the tent results for risk assessments. counting of asbestos and other EMPs and can provide a means for “recounting” fibers at spe- Some barriers to improving current analytical cific locations on a filter sample. Another study methods have been identified. Increasing the is evaluating the proposed ASTM method to optical resolution of PCM analysis may help determine whether interoperator variability of to increase counts of thinner asbestos fibers. differential counting (to distinguish fibers of However, any increases in optical microscopy asbestos minerals from other EMPs) is within resolution will not be sufficient to detect all asan acceptable range. bestos fibers. In addition, any improvements in counting EMPs (e.g., an increase in the number Research to develop new methods is warranted. of EMPs observed and counted) will need to One such research area could be development be evaluated by comparing them with counts of methods that would permit assessment of made by the current PCM method. The use of the potential biopersistence (e.g., durability) of electron microscopy (EM) would improve the EMPs collected on air sampling filters prior to capability to detect thin fibers and also provide their evaluation by PCM or other microscopic a means to identify many types of minerals. methods. If durability is deemed biologically

NIOSH CIB 62 • Asbestos 89 relevant, then an exposure assessment limited procedures require the analyst to make deci- to the durable EMPs collected on a sample sions on whether each observed particle meets would help to reduce possible analytical in- specified criteria for counting. Interlaboratory terferences caused by other, nondurable EMPs sample exchange programs have been shown to and may eliminate the need for mineral identi- be important for ensuring agreement in asbes- fication. Another such area would be improve- tos fiber counts between laboratories [Crawford ment in EM particle identification techniques, et al. 1982]. Unfortunately, microscopists from such as field emission SEM and the capabil- different laboratories are unlikely to view exact- ity to determine the elemental composition ly the same fields, and this alone accounts for of EMPs with an SEM equipped with EDS. A some of the observed variation in fiber counts third research area, largely conceptual at this between microscopists. A mechanism to allow time, would be development of techniques to recounts of fibers from the exact same field -ar more accurately reflect internal dose by quan- eas would remove this variable and allow a bet- tifying or estimating the number of particles ter assessment of the variation attributable to likely to be produced by splitting of asbestos- microscopists in analyzing samples. fiber bundles deposited in the lung. A technique is under development for improv- Modifications of current analytical methods ing the accuracy of PCM-based fiber-counting and development of new analytical methods by allowing the same sample fields to be ex- will require an assessment of their implica- amined by multiple microscopists or by the tions for worker health protection (e.g., how same microscopist on different occasions [Pang do the results using improved or new methods et al. 1984, 1989; Pang 2000]. The method in- relate to human risk estimates based on counts volves the deposition of an almost transparent of EMPs made by PCM?). To ensure that rel- TEM grid onto the sample. Included with the evant toxicological parameters (e.g., dose, di- grid are coordinates that allow relocation of mension, durability, and physicochemical pa- each grid opening. Photomicrographs of typical rameters) are incorporated in the analysis and grid openings superimposed on chrysotile and measurement, any changes in analytical meth- amosite samples have been published [Pang et al. 1989]. Slides prepared in this manner have ods should be made in concert with changes in been used in a Canadian proficiency test pro- how asbestos fibers or other EMPs are defined. gram for many years. The main errors affecting the counts of various types of fibers (e.g., chrys- 3.6.1 Reduce Interoperator and otile, amosite, and SVF) have been evaluated Interlaboratory Variability of by examining large numbers of slides by large the Current Analytical Methods numbers of participants in this program. A re- Used for Asbestos Fibers cently developed scoring system for evaluating the performance of microscopists is based on To ensure the validity of EMP counts on air errors compared with a reference value defined samples, it is important to ensure consistency for each slide by the laboratory in which they in EMP counts between and among analysts. were produced [Pang 2002]. A statistical analy- Microscopy counts of EMPs on air sample fil- sis of the intragroup precision in this study was ters are based on only a small percentage of able to identify those analysts who were outliers the surface area of the filters, and the counting [Harper and Bartolucci 2003]. In a pilot study,

90 NIOSH CIB 62 • Asbestos the pooled relative standard deviations, without the use of 15× eyepiece oculars would help im- the outliers, met the requirements for an un- prove the visibility of small particles and thin biased air-sampling method. Further study is EMPs in samples. However, using oil immer- needed to validate these findings and to identify sion has several drawbacks. When exposed to other techniques that can reduce interlabora- air for more than a few hours, the oil on the tory and interoperator variability in counting slide dries and its optical properties change. asbestos fibers and other EMPs by PCM. Also, the oil cannot be wiped off because the cover slip is likely to be moved and thus ruin Reference slides made from proficiency test the sample. For these reasons, using oil immer- filters from the American Industrial Hygiene sion does not permit recounts or further analy- Association (AIHA) have been created and cir- sis for quality control purposes and is not an culated to laboratories and individual micros- attractive alternative. copists recruited from AIHA laboratory quality programs [Pang and Harper 2008; Harper Other methods may also allow for increased et al. 2009]. The results illustrate an improved resolution with optical microscopes. Anecdotal discrimination of fiber counts when the pro- information on the use of PCM with dark- ficiency test materials have a more controlled medium (DM) objectives, presented at a meet- composition. These reference slides have also ing in November 2007, suggests that analysts been evaluated in Japan, the United Kingdom, using DM objectives could resolve more blocks and elsewhere in Europe. Further research will of the Health and Safety Executive/National be useful in determining the value of these Physical Laboratory (HSL/ULO) test slide‡‡ slides for training purposes. than are allowable for the method and produced higher counts of chrysotile fibers than 3.6.2 Develop Analytical Methods expected [Harper et al. 2009]. The implication is that using DM objectives can resolve thinner with Improved Sensitivity chrysotile fibers than the accepted method. This to Visualize Thinner EMPs methodology should be explored further to de- to Ensure a More Complete termine its resolution and potential application Evaluation of Airborne in asbestos exposure assessment. Exposures As stated previously, because risk estimates for Most PCMs can visualize EMPs with widths workers exposed to asbestos fibers have been >0.25 µm, which is the approximate lower ‡‡ resolution limit when the microscope is oper- The HSE/NPL Mark II or HSL/ULO Mark III Phase Shift Test Slide checks or standardizes the visual de- ated at a magnification of 400× and calibrated tection limits of the PCM. The HSL/ULO Test Slide to NIOSH 7400 specifications [NIOSH 1994a]. consists of a conventional glass microscope slide with However, higher-end optical microscopes can seven sets of parallel line pairs of decreasing widths. resolve thinner widths, and, for crocidolite, The microscope must be able to resolve the blocks of they may resolve widths as thin as 0.1 µm. lines in accordance with the certificate accompanying the slide. Only slides where at least one block of lines is intended to be invisible should be used. Microscopes Improvement in the optical resolution may be that resolve fewer or greater numbers of blocks than possible with use of an oil-immersion 100× ob- stated on the certificate cannot be used in NIOSH jective with a numerical aperture of 1.49. Also, Method 7400.

NIOSH CIB 62 • Asbestos 91 based on counts made by the current PCM SEM-backscatter electron diffraction analysis method, counts made with improved optical can be adapted to EMP crystallographic analy- microscope resolution capabilities would not ses equivalent to TEM-SAED capability. The be directly comparable to current occupational ease of sample preparation and data collection exposure limits for airborne asbestos fibers. for SEM analysis in comparison with TEM anal- Additionally, the findings that asbestos fibers ysis, along with an SEM advantage in visualizing thinner than 0.1 µm are most associated with EMP and EMP morphology (e.g., surface char- mesothelioma and that optical microscopes acteristics), provides reason to reevaluate SEM cannot resolve fibers <0.1 µm in width suggest methods for EMP characterization and mineral that alternatives to PCM should be researched. identification for field and laboratory sample analysis. TEM can resolve asbestos fibers with widths less than ~0.01 µm, which effectively detects the presence of all asbestos fibers and other EMPs 3.6.3 Develop a Practical Analytical collected on airborne samples. Both TEM and Method for Air Samples to SEM provide greater resolution for detecting Differentiate Asbestiform and sizing EMPs. Both methods also provide Fibers from the Asbestos capability for mineral identification (TEM us- Minerals and EMPs from Their ing selected area X-ray diffraction [SAED], and TEM and SEM using EDS or WDS for elemen- Nonasbestiform Analogs tal analysis). The cost of using TEM and/or SEM A recently published ASTM method for dis- for routine analysis of all samples would be con- tinguishing other EMPs from probable as- siderably higher than PCM analysis and the bestos fibers uses PCM-determined morpho- turnaround time for analysis would be substan- logic features to differentiate asbestos fibers tially longer. In addition, any routine use of EM from other EMPs [ASTM 2006]. The proposed methods for counting and sizing asbestos fibers method has several points of deviation from or other EMPs would require formal evaluation existing PCM methods. It uses a new grati- of interoperator and interlaboratory variability. cule that has not been tested for conformance with the traditional graticule used in standard SEM is now a generally available method that PCM analysis of asbestos air samples. It speci- can routinely resolve features down to ~0.05 fies additional counting rules to classify par- µm, an order of magnitude better than optical microscopes. Field emission SEM is now com- ticles, and there are few data to show these mercially available and further increases this rules provide consistently achievable or mean- resolution. In vitro or short-term or long-term ingful results. Also, only limited data are avail- animal model studies can now utilize these EM able to show interoperator, intraoperator, or imaging technologies to characterize EMPs interlaboratory variation. These issues must be for studies of etiology and disease mechanism. addressed before the method can be consid- EM analyses of EMP size and composition can ered acceptable. NIOSH researchers are cur- be supplemented with analysis of surface el- rently addressing these issues. Specific aims of emental composition by scanning Auger spec- the project are troscopy or X-ray photoelectron spectroscopy. •• to determine the effect of using the tradi- Investigation is needed to determine whether tional Walton-Beckett graticule and the

92 NIOSH CIB 62 • Asbestos new RIB graticule on the precision of mea- EMPs appears to be strongly dependent on their suring fiber dimensions; and chemical composition, surface characteristics, •• to determine the interlaboratory variation and dimension. of the proposed method for determining The selective dissolution of EMPs might be a particle identities by observing morpho- useful approach for eliminating specific types logical features of individual particles. of EMPs or other particles collected on air sam- Anticipated outcomes of these ongoing re- ples prior to analysis (e.g., microscopic count- search projects include a measure of method ing). The removal of interfering EMPs prior to precision, which will help to determine wheth- counting could potentially eliminate the need er the method meets the requirements of regu- for additional analysis to identify EMPs on the latory and other agencies. sample. Selective dissolution of samples to remove interferences is well established in NIOSH Although EM may currently not be suitable for practice for other analytes. NIOSH Method 5040 routine analysis of samples of airborne EMPs, for diesel exhaust has an option for using acidi- EM techniques used to characterize and iden- fication of the filter sample with hydrochloric tify minerals (e.g., differentiating between as- acid to remove carbonate interference [NIOSH bestos fibers and other EMPs) should be fur- 2003a]. Silicate interferences for quartz by in- ther investigated and evaluated to determine frared spectroscopic detection are removed by whether results are reproducible by multiple phosphoric acid digestion in NIOSH Method microscopists and laboratories. 7603 [NIOSH 2003b]. Although selective dissolution might be accomplished for some EMPs, 3.6.4 Develop Analytical Methods to research will be necessary to develop and char- Assess Durability of EMPs acterize a procedure that would correlate residual EMP counts to the results of toxicity studies. Although research has been conducted to determine the ability of biological assays to evaluate the biopersistence of EMPs in the lung, there is 3.6.5 Develop and Validate Size- a need to consider how the assessment of EMP selective Sampling Methods durability might be incorporated into the evalu- for EMPs ation of air samples containing a heterogeneous mix of EMPs. Research with several types of For measuring airborne concentrations of non- glass fibers and some other SVFs indicate that elongate particles in the workplace, conventions they dissolve in media at different rates de- have been developed for sampling the aerosol pending on the pH and that they dissolve more fractions that penetrate to certain regions of the rapidly than chrysotile and amphibole asbes- respiratory tract upon inhalation: the inhalable tos fibers [Leineweber 1984]. Chrysotile fibers fraction of particulate that enters into the nose have been shown to dissolve at a rate that varies or the mouth; the thoracic fraction that pene- not only with the strength of the acid, but also trates into the thorax (i.e., beyond the larynx); with the type of acid. Amphibole asbestos fibers and the respirable fraction that reaches the al- have been shown to be more resistant to disso- veoli of the lung. The thoracic convention is rec- lution than chrysotile fibers. Research suggests ognized by NIOSH and other organizations that that the rate of dissolution in the lungs for most recommend exposure limits, and NIOSH has

NIOSH CIB 62 • Asbestos 93 established precedence in applying it in RELs Thoracic samplers allow the collection of air- (e.g., the REL for metalworking fluid aerosols borne particles that meet the aerodynamic defi- [NIOSH 1998]). nition of thoracic-size EMPs (i.e., with physical widths equal to or less than 3 µm for the typical Asbestos fibers currently are collected for mea- length distributions of fibers of silicate compo- surement by standard sampling and analytical sition), collecting only those EMPs considered methods (e.g., NIOSH Method 7400 [NIOSH most pathogenic. The results of studies have in- 1994a], in OSHA ID–160 [OSHA 1998], in dicated that penetration of some thoracic sam- Methods for the Determination of Hazardous plers is independent of EMP length, at least up to Substances (MDHS) 39/4 [HSE 1995], and in 60 µm, indicating that the samplers’ penetration ISO 8672 [ISO 1993]). In these methods, air characteristics for an EP aerosol should be no dif- samples are taken by means of a membrane fil- ferent than that of an isometric aerosol. In a study ter housed in a cassette with a cowled sampling be Jones et al. [2005], the relative ability of the head. Early studies [Walton 1954] showed that thoracic samplers to produce adequately uniform the vertical cowl excludes some very coarse distributions of EPs on the surface of the mem- particles because of elutriation, but its selection brane filter was also tested. On the basis of results characteristics should have little effect on the of these studies, two samplers appeared to meet collection efficiency for asbestos fibers. Howev- the criteria of minimal selection bias with respect er, when Chen and Baron [1996] evaluated the to EP length and uniform distribution on the col- sampling cassette with a conductive cowl used lection filters. However, neither of these samplers in sampling for asbestos fibers, they found in- has been tested under conditions of field use. let deposition was higher in field measurements NIOSH is currently evaluating these two thoracic than predicted by models. samplers and the traditional cowled sampler in three different mining environments. The results Unlike the WHO [1997], NIOSH has not rec- from these studies have been published [Lee et al. ommended an upper limit for width of asbestos 2008; Lee et al. 2010], and each of the samplers fibers to be counted because airborne asbestos gave fiber concentrations in proportion to their fibers typically have widths <3 µm. The absence fiber loading rates, which is consistent with pre- of an upper width criterion for the NIOSH vious reports [Cherrie et al. 1986]. Thus, alterna- Method 7400 A rules has generated criticism tive samplers cannot be recommended until the that some EMPs counted by this method may impact of this effect on the established risk analy- not be of thoracic size. Others have recom- sis has been evaluated. mended NIOSH Method 7400 B rules for the sampling and analysis of various types of fibers and EPs, including asbestos fibers [Baron 1996], 3.7 From Research to because the B rules specify an upper limit of Improved Public Health 3 µm for EP width. However, Method 7400 B rules have not been field-tested for occupational Policies for Asbestos Fibers exposures to asbestos and many types of EPs. and Other EMPs

Two separate but complementary investigations Section 3 of this Roadmap proposes several have examined the performance of thoracic sam- strategic goals and associated objectives for a plers for EMPs [Jones et al. 2005; Maynard 2002]. multidisciplinary research program on asbestos

94 NIOSH CIB 62 • Asbestos fibers and other EMPs. In summary, accom- a biological response. However, uncertainty plishing these goals is intended to (1) further remains as to whether the respiratory disease elucidate the physicochemical properties that outcomes for workers exposed to asbestos fi- contribute to their pathogenicity; (2) improve bers can be anticipated for workers exposed to existing analytical tools and develop new ana- other EMPs of thoracic size and with elemental lytical tools for identifying and measuring ex- compositions similar to asbestos. posures to EMPs with use of metrics that reflect the important determinants of toxicity (e.g., Another important effort that can inform devel- dimension and composition); (3) better define opment of the research program will involve a the nature and extent of occupational expo- systematic collection and review of available in- sures to EMPs and their relationships to EMP- formation on (1) industries and occupations with related health outcomes among exposed worker exposure to EMPs; (2) airborne exposure in these populations; and (4) improve clinical tools for industries and occupations; and (3) numbers of screening, diagnosis, secondary prevention, and workers potentially exposed in these industries treatment of EMP-related diseases. and occupations. Additional relevant minerals and mineral habits identified should also be con- Results of much of the research to date (e.g., sidered for study. The minerals identified through animal and human studies with asbestos and these efforts should be carefully and comprehen- other EMPs) are readily available and should sively characterized with respect to both struc- be considered in developing the research pro- ture and elemental composition. In the charac- gram, including the specification of minerals terization of minerals, consideration should also to be studied. Much of this evidence supports be given to (1) purity, (2) particle morphology the important role of particle dimension as a (range of dimensions and sizes), (3) surface area, determinant of lung deposition and retention (4) surface chemistry, and (5) surface reactivity. and the concomitant role of particle composi- Care must be taken to ensure that a sufficient tion and crystalline structure as a determinant amount of the studied material is available, not of durability and biopersistence. Despite this only for current studies but also as reference ma- body of research, several fundamental issues terial for possible future studies. The information are not clearly understood, and a broad sys- developed from all of these efforts should be en- tematic approach to further toxicological and tered into a database, which can serve as a tool epidemiological research would help to reduce for selection of minerals for testing and valida- remaining uncertainties. Although long, thin tion of toxicological tests, as well as to assist in asbestos fibers clearly cause respiratory dis- identification of worker populations for possible ease, the role of unregulated short (i.e., <5 μm) epidemiological studies. asbestos fibers is not entirely clear. It also remains unclear to what extent each of the vari- An objective of the proposed research is to ous physicochemical parameters of asbestos achieve a level of mechanistic understanding fibers is responsible for respiratory disease out- that can provide a basis for developing biologi- comes (e.g., asbestosis, lung cancer, and meso- cally based models for extrapolating results of thelioma) observed in asbestos-exposed indi- animal inhalation and other types of in vivo viduals. Limited evidence from studies with studies to predict risks to worker health asso- other EMPs confirms the importance of par- ciated with exposure conditions typically en- ticle dimension and biopersistence in causing countered in workplaces. Little is known about

NIOSH CIB 62 • Asbestos 95 the mechanisms by which asbestos fibers and (e.g., particle dimension) relate to disease out- some other EMPs cause lung cancer, mesothe- comes. New epidemiological (retrospective and lioma, and nonmalignant respiratory diseases. prospective) studies should not be undertaken As these mechanisms become understood, unless feasibility studies (e.g., preliminary assess- biologically based models can be developed to ments of study population size, exposure laten- extrapolate from exposure-dose-response rela- cies, records of exposure, and confounders) have tionships observed in animals to estimates of been appropriately considered. disease risk in exposed humans. In addition, such studies would provide (1) an opportunity Because the opportunities for informative epi- to measure molecular and cellular outcomes demiological studies are likely to be limited, that can be used to determine why one animal it will be necessary to complement them with species responds differently from another and toxicological testing, and an integrated ap- (2) information on EMP characteristics associ- proach to toxicological research will be needed ated with eliciting or potentiating various bio- to understand how various types of EMPs in- logical effects. The outcomes of these studies can duce disease. Where epidemiological studies of then be evaluated in subsequent experiments to new cohorts are possible, or where epidemio- provide (1) risk assessors with a useful under- logical studies of previously studied cohorts standing of the various disease mechanisms by can be updated, attempts should be made to which animals respond to EMP exposures; and link their results with those of toxicological (2) regulatory agencies and industrial hygiene studies to assess the ability of various types and occupational health professionals with in- of toxicological testing to predict health out- formation needed to implement appropriate comes in humans. Toxicological testing should exposure limits and risk management programs be done with attention to collecting more spe- for monitoring worker exposure and health. cific information, including: (1) physical characteristics (e.g., dimension); (2) chemical com- It is anticipated that it may be difficult to find position; (3) in vitro acellular data (dissolution, populations of workers that are exposed to EMPs durability); and (4) in vitro/in vivo cellular data with characteristics (e.g., dimension, composi- (e.g., cytotoxicity, phagocytosis, chromosomal tion) of interest that are sufficiently large to pro- damage, mediator release). vide adequate statistical power, and where exposures are not confounded or where confounding To help elucidate which physicochemical prop- can be effectively controlled in the analysis. erties are important for inducing a biological ef- NIOSH retains exposure information and, in fect, it may be necessary to generate exposures some cases, personal air sample filters collected to EMPs of specific dimensions and composi- and archived from past epidemiological studies tion. Several approaches are being pursued by of workers exposed to asbestos. Such existing NIOSH to overcome technological difficulties data might be used to update and extend find- in generating sufficient quantities of well-char- ings from these studies. Where appropriately bal- acterized and dimensionally restricted EMPs. anced epidemiological studies can be identified, Efforts to generate mineral samples of appropri- it may be possible to conduct meta-analyses to ate particle-size dimensions by grinding tech- investigate important EMP characteristics. The niques have met with some success but have analysis of archived samples may help to elucidate not consistently generated EMPs in restricted how more detailed characteristics of exposure size ranges of interest or in sufficient quantity

96 NIOSH CIB 62 • Asbestos to enable toxicity testing. Another approach has incorporate the exposure metrics used in deter- used a fiber size classifier [Deye et al. 1999], but mining the dose-response effect found in animal this has not provided large enough quantities of studies. The development of such exposure mea- EMPs for long-term inhalational exposure stud- surement techniques should (1) reduce the sub- ies in animals. NIOSH researchers are currently jectivity inherent in current methods of particle evaluating the possibility of developing a fiber identification and counting, (2) closely quantify size classifier with increased output to generate EMPs on the basis of characteristics that are im- much larger quantities of particles in restricted portant to toxicity, and (3) reduce cost and short- size ranges for toxicological testing. en turnaround times in comparison with current EM methods. An outcome of the proposed research programs should be an understanding of the relationships Toxicological, exposure assessment, and epide- between and among the results of human obser- miological research should be conducted with vational studies and in vitro, short-term in vivo, the overarching goal of developing informa- and long-term in vivo experimental studies. tion necessary for risk assessments. Although Any research undertaken should be designed a framework for mineralogical research is not to ensure that results can be interpreted and provided in this Roadmap, research provid- applied within the context of other studies. For ing a better understanding of mineralogical example, EMPs used in long-term animal inha- physicochemical properties will help inform the lation studies should also be tested in in vitro/in risk assessment process. Improved risk assess- vivo assay systems so that findings can be comments and analytical methodology are needed pared. The results of such experiments can help to inform the development of new and revised to develop and standardize in vitro/in vivo assay occupational exposure limits for control of ex- systems for use in predicting the potential toxic- posures associated with the production of EMP- ity of various types of EMPs. caused disease.

Government agencies, other organizations, For those individuals who have an asbestos- and individual researchers have already recom- related disease or are at high risk of developing mended similar research strategies for evaluat- an asbestos-related disease, research is needed ing the toxicity of mineral and synthetic fibers to improve methods and clinical guidance for [Greim 2004; ILSI 2005; Mossman et al. 2007; screening, diagnosis, secondary prevention, and Schins 2002; Vu et al. 1996]. These published treatment of EMP-caused diseases. The devel- strategies should be used as a foundation for opment and validation of biomarkers of disease developing a research program. and improved lung-imaging technologies can lead to earlier diagnosis of asbestos-related dis- Some research and improvements in sampling ease. It will also be important to advance knowl- and analytical methods used to routinely assess edge on how to effectively treat EMP-caused exposures to EMPs can be done in the short diseases, especially malignant mesothelioma, term, and because the results of the toxicological which is fatal in most cases. Accomplishing the studies provide a clearer understanding of EMP goals of early diagnosis and development of characteristics that determine toxicity, it will be treatment options can improve the quality and necessary to ensure that the measurement tech- quantity of life for those who develop asbestos- niques used in evaluating workplace exposures related disease.

NIOSH CIB 62 • Asbestos 97

4 The Path Forward

Developing an interdisciplinary research pro- will be used to help focus the scope of the re- gram and prioritizing research projects to search to be undertaken, enhance extramural implement the research agenda envisioned in research activities, and assist in the develop- this Roadmap will require a substantial investment and dissemination of educational materi- ment of time, scientific talent, and resources als describing the outcomes of the research and by NIOSH and its partners. However, achiev- their implications for occupational and public ing the proposed goals will be well worth the health policies and practices. investment because it will improve the quality of life of U.S. workers by preventing workplace Some of the next steps in development will in- exposure to potentially hazardous EMPs, and it volve organizing study groups with representa- will reduce future healthcare costs. As with any tives from federal agencies, industry, academia, strategic approach, unintended and unforeseen and workers’ organizations to identify specific results and consequences will require program priorities for the programs developed within adjustments as available resources change, in- the overarching research framework. Study formation is produced, and time goes on. groups should be assembled from among the partners to identify specific research elements 4.1 Organization of the needed to address the information gaps and data needs outlined in this Roadmap. Although Research Program it may be appropriate to organize separate To ensure that the scientific knowledge created study groups around the scientific disciplines from implementation of this Roadmap is ap- needed to conduct the research—such as epi- plied as broadly as possible, NIOSH plans to demiology, toxicology, exposure assessment, partner with other federal agencies, such as the mineralogy, and particle characterization and Agency for Toxic Substances and Disease Reg- analysis—and to conduct the risk assessments, istry (ATSDR), the Consumer Product Safety each of the study groups will need to include Commission (CPSC), the Environmental Pro- members from other disciplines to ensure the tection Agency (EPA), the Mine Safety and multidisciplinary nature of the research is con- Health Administration (MSHA), the National sidered and addressed. Also important will be Institute of Standards and Technology (NIST), coordination between and among study groups the National Institute of Environmental Health to ensure the efforts in the various research Sciences (NIEHS), the National Toxicology areas are complementary and move toward Program (NTP), the Occupational Safety and common goals and the eventual development Health Administration (OSHA), and the Unit- of sufficient information for risk assessment. ed States Geological Survey (USGS), as well as These study groups should be maintained over with labor, industry, academia, practitioners, the lifetime of the research program to oversee and other interested parties including interna- and help guide the research. An independent tional groups. Partnerships and collaborations group could provide oversight of the overall

NIOSH CIB 62 • Asbestos 99 research effort, periodically reviewing the vari- this characterization effort should be the devel- ous discipline-specific research programs to opment of a mineralogical research effort ad- help ensure that the most appropriate research dressing issues pertaining to the identification is accomplished in a timely and coordinated of minerals that might be found on airborne manner and to help maintain the scientific samples collected at various workplace environ- quality of the research. ments and to develop further and deeper understanding of mineralogical properties that may 4.2 Research Priorities contribute to the toxicity of particles. The key issues discussed in Section 2.10 include One of the earliest research efforts will be pre- several research needs: (1) for the asbestos min- liminary systematic collection and evaluation erals, development of a clearer understanding of of available information on (1) industries/oc- the important dimensional and physicochemi- cupations/job tasks/processes with exposure to cal determinants of pathogenicity; (2) for other various types of asbestos fibers and other EMPs, EMPs, such as those from nonasbestiform hab- (2) numbers of workers exposed, (3) character- its of the asbestos minerals and erionite, devel- istics and levels of exposures, and (4) associated opment of a deeper understanding of the de- particulate exposures. The knowledge generated terminants of toxicity; and (3) development of from these efforts will be needed to identify the analytical methods that can differentiate EMPs EMPs that workers are exposed to and worker and quantify airborne exposures to EMPs. To populations that have the potential to be includ- begin addressing these issues, infrastructure ed in epidemiological studies. In addition to as- projects should be developed and initiated with certaining EMP exposures and EMP-exposed input from the study groups. populations in the United States, networking One such infrastructure project is the develop- and other tools should be used to identify po- ment of a standardized set of terms that can be tential international populations for epidemio- used to clearly and precisely describe minerals logical studies. Representative samples of the and other scientific concepts. This is needed to EMPs identified through these efforts should help with the planning of research projects and be procured, characterized, and included in the to effectively communicate research results. mineralogical reference repository. After thor- This effort should involve representatives from ough characterization, these samples can be each of the relevant scientific disciplines. classified and prioritized for use in the toxicological studies. Another infrastructure project that should be considered at the onset of prioritizing research A part of this early effort should be the devel- is the development of criteria and logistics for opment of a comprehensive and integrated establishing a mineral reference repository. Ini- public-use information management system to tially, representative samples from the known warehouse (1) the mineral characterization in- asbestos deposits should be procured and care- formation generated on the reference samples; fully and comprehensively characterized. If (2) data generated from hazard and health sur- samples of these repository minerals are fur- veillance activities; (3) information on the min- ther processed in the course of conducting re- erals tested and the methods used, as well as search, the processed materials will need to be the results of toxicological studies; and (4) the fully characterized as well. Concomitant with data gathered from epidemiological and other

100 NIOSH CIB 62 • Asbestos surveillance investigations. By having the re- The goals and objectives of this Roadmap sults of previous studies available in the infor- can be substantially advanced through robust mation management system, it could be used to public-private sector partnership. promote the development of an efficient, non- duplicative research program. It could also be The ideal outcome of a comprehensive research a resource for data exploration and additional program for asbestos fibers and other EMPs analyses of accumulated results. would be to use the results to develop recommendations to protect workers’ health that are After comprehensive review of current knowl- based on unambiguous science. Optimally, such edge and the available data in the above- recommendations may specify criteria, such as described information management system, a range of chemical composition, dimensional the study groups should identify specific aims attributes (e.g., ranges of length, width, and as- and plan, prioritize, and conduct mineralogi- pect ratio), dissolution rate/fragility parameters, cal, toxicological, epidemiological, and clinical and other factors that can be used to indirectly research within the general framework laid out assess the toxicity of EMPs. It would be particu- in this Roadmap. Early results will inform the larly advantageous if the results of the research need for later research and will dictate changes could be used to devise a battery of validated in priorities and directions needed to accom- in vitro or short-term in vivo assays with suf- plish the overall goals of the research program. ficient predictive value to identify EMPs warranting concern on the basis of their physical Ongoing research and study on improvements and chemical properties, without the need for of the analytical methods currently used for comprehensive toxicity testing and/or epide- regulatory purposes should be independent of miological evaluation of each individual EMP. other research. However, as surveillance and Newly identified EMPs could be compared to exposure assessment efforts proceed, research the criteria to determine a likelihood of toxic- on analytical methods should advance the ca- ity. Coherent risk management approaches for pability to identify and characterize worker ex- EMPs that fully incorporate a clear understand- posures and to measure relevant exposure pa- ing of the toxicity could then be developed to rameters identified by toxicological research. minimize the potential for EMP-related disease Eventually, after determinants of EMP toxic- outcomes among exposed workers. ity are more fully elucidated, research should increasingly focus on sampling and analytical Although it is beyond the scope of this Road- methods that can be routinely used in compli- map, exploration of the extent to which a ance exposure assessment. health-protective policy for EMPs could be extended to SVFs and other manufactured ma- 4.3 Outcomes terials, such as engineered carbon nanotubes and nanofibers, is warranted. It has been noted NIOSH will promote integration of the re- that elongate nanoscale particles (e.g., single- search goals set forth in this Roadmap into walled and multiwalled carbon nanotubes) the industry sector–based and research-to- cause interstitial fibrosis in mice [Shvedova et practice-focused National Occupational Re- al. 2005; Porter et al. 2009] and that peritone- search Agenda (NORA), a national program al exposure of mice to carbon nanotubes has involving both the public and private sectors. been reported to induce pathological responses

NIOSH CIB 62 • Asbestos 101 similar to those caused by asbestos, suggesting relevant for use in protecting workers from potential for induction of mesothelioma [Po- adverse health effects arising from exposure land et al. 2008]. Recommendations have been to asbestos fibers and other EMPs is the ulti- made elsewhere to systematically investigate mate goal. Though further scientific research the health effects of these manufactured nano- conducted by NIOSH will continue to focus on materials within the next five years [Maynard the occupational environment, NIOSH intends et al. 2006; NIOSH 2008b]. Integrating results to pursue partnerships to ensure that scientific of nanoparticle toxicity investigations with the research arising from this Roadmap will com- results of the research program developed as a prise an integrated approach to understanding result of this Roadmap may lead to a broader and limiting EMP hazards incurred not only in and more fundamental understanding of the work settings, but also in the general commu- determinants of toxicity of EPs. nity and the general environment.

Working toward achieving the goals delineated As information becomes available from re- in this Roadmap is consonant with NIOSH’s search activities, NIOSH plans to assist in the statutory mission to generate new knowledge development and dissemination of educational in the field of occupational safety and health materials describing the outcomes of the re- and to transfer that knowledge into practice for search and their implications for occupational the benefit of workers. Advancing knowledge and public health policies and practices.

102 NIOSH CIB 62 • Asbestos 5 References

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NIOSH CIB 62 • Asbestos 129

6 Glossary

6.1 NIOSH Definition of Under the NIOSH REL for Airborne Asbestos Potential Occupational Fibers and Related Elongate Mineral Particles, covered minerals include those minerals hav- Carcinogen ing the crystal structure and elemental com- Potential Occupational Carcinogen means any position of the asbestos varieties (chrysotile, substance, or combination or mixture of sub- riebeckite asbestos [crocidolite], cummingtonite- stances, which causes an increased incidence of grunerite asbestos [amosite], anthophyllite benign and/or malignant neoplasms, or a sub- asbestos, tremolite asbestos, and actinolite as- stantial decrease in the latency period between bestos) or their nonasbestiform analogs (the exposure and onset of neoplasms in humans serpentine minerals antigorite and lizardite or in one or more experimental mammalian and the amphibole minerals contained in the species as the result of any oral, respiratory or cummingtonite-grunerite mineral series, the dermal exposure, or any other exposure which tremolite-ferroactinolite mineral series, and the results in the induction of tumors at a site other glaucophane-riebeckite mineral series). than the site of administration. This definition also includes any substance which is metabo- Elongate mineral particle (EMP): Any min- lized into one or more potential occupational eral particle with a minimum aspect ratio of carcinogens by mammals. 3:1. This Roadmap is focused on EMPs that are of inhalable, thoracic, or respirable size, as de- 6.2 Definitions of New Terms scribed below in Section 6.2. Used in this Roadmap Elongate particle (EP): Any particle with a minimum aspect ratio of 3:1. The research de- Countable elongate mineral particle: A particle scribed in this Roadmap is focused on EPs that that meets specified dimensional criteria and is to are of inhalable, thoracic, or respirable size, as be counted according to an established protocol. described below in Section 6.2. A countable elongate mineral particle under the NIOSH REL for Airborne Asbestos Fibers and Re- lated Elongate Mineral Particles is any asbestiform 6.3 Definitions of fiber, acicular or prismatic crystal, or cleavage frag- Inhalational Terms ment of a covered mineral that is longer than 5 µm and has a minimum aspect ratio of 3:1 on the basis Inhalable particulate matter: Particles that of a microscopic analysis of an air sample using deposit anywhere in the respiratory tract. NIOSH Method 7400 or an equivalent method. This varies by species, but for humans such Covered mineral: A mineral encompassed by a matter can be approximated as those particles specified regulation or recommended standard. captured according to the following collection

NIOSH CIB 62 • Asbestos 131 efficiency, regardless of sampler orientation with terms used in this Roadmap. Definitions of respect to wind direction: some terms in this table differ. Also, definitions of these same terms, as used by various authors IPM(dae) = 0.5 (1 + exp[−0.06 dae]) ± 10; for 0 < d ≤ 100 µm whose work has been cited in this Roadmap, ae may vary from those provided here. It is not Where IPM(dae) = the collection efficiency possible to know and/or provide each of the and dae is the aerody- variant definitions. namic diameter in µm. [ACGIH 1999] Respirable particulate matter: Particles that 6.5 References for Definitions deposit anywhere in the gas-exchange re- of General Mineralogical gion of the lung. This varies by species, but Terms, Specific Minerals, for humans such matter can be approximated as those particles captured according to the and Inhalational Terms following collection efficiency: RPM(d ) = ae ACGIH (American Conference of Governmental IPM(d )[1−F(x)] ae Industrial Hygienists) [1999]. Particle size–selective Where F(x) = cumulative probability func- sampling for particulate air contaminants. Vincent tion of the standardized nor- JH, ed. Cincinnati, OH: ACGIH. mal variable, x. American Geological Institute [2005]. Glos- x = ln(d /4.25 µm)/ln(1.5) [ACGIH 1999] ae sary of Geology, 5th ed. Neuendorf KKE, Mehl Thoracic particulate matter: Particles that JP, Jackson JA, eds. Alexandria, VA: American deposit anywhere within the lung airways and Geological Institute. the gas-exchange region. This varies by species, Leake BE, Woolley AR, Arps CES, Birch WD, but for humans such matter can be approxi- Gilbert CM, Grice JD, Hawthorne FC, Kato A, mated as those particles captured according to Kisch HF, Krivovichev VG, Linthout K, Laird J, the following capture efficiency: TPM(d ) = ae Mandarino JA, Maresch WV, Nickel EH, Rock IPM(d )[1−F(x)] ae NMS, Schumacher JC, Smith DC, Stephenson Where F(x) = cumulative probability func- NCN, Ungaretti L, Whittaker EJW, Youzhi G tion of the standardized nor- [1997]. Nomenclature of the amphiboles: re- mal variable, x port of the Subcommittee on Amphiboles of the International Mineralogical Association x = ln(dae/11.64 µm)/ln(1.5) [ACGIH 1999] Commission on new minerals and mineral names. Can Mineral 35:219–246.

6.4 Definitions of General NIOSH [1990a]. Comments of the National Mineralogical Terms Institute for Occupational Safety and Health and Specific Minerals on the Occupational Safety and Health Admin- istration’s Notice of Proposed Rulemaking on Definitions from several sources are provided in Occupational Exposure to Asbestos, Tremolite, the following tables for many of the mineralogical Anthophyllite, and Actinolite. OSHA Docket

132 NIOSH CIB 62 • Asbestos No. H-033d, April 9, 1990 [http://www.cdc. U.S. Bureau of Mines [1996]. Dictionary of gov/niosh/review/public/099/pdfs/Asbestos- mining, mineral, and related terms. 2nd ed Testimony_April%209_1990.pdf]. Date ac- [http://xmlwords.infomine.com/USBM.htm]. cessed: December 17, 2009. Date accessed: December 18, 2009.

NIOSH CIB 62 • Asbestos 133 (Continued) NIOSH [1990a] Minerals in the amphibole group are are group in the amphibole Minerals crust in the earth’s distributed widely metamorphic or igneous in many the mineral instances, some In rocks. quantities sufficient contain deposits be to minerals the asbestiform of commercial for minable economically mineral and series minerals The use. variable have group the amphibole of elemental extensive with compositions forms in found are They substitutions. fibrous. to massive from ranging commercially common most The varieties of asbestiform exploited include this mineralogical group anthophyllite, amosite, crocidolite, Crocidolite, actinolite. and tremolite, are anthophyllite and amosite, use, commercial mined for selectively are actinolite and tremolite whereas as a contaminant found often most as such mined commodities in other amphiboles The vermiculite. talc and good electrical thermal and have they have and properties, insulation acids. to good to resistance moderate

4+ ; , B , Zr C , T and, two B or 3+ only; , with a B 2 C or , Li and , Li and only; B A sites. sites. C 2+ C C , Fe C T at at (OH) 4+ 3+ 22 , Mn or ; Ca at ; Ca at 2+ O B C 3 sites per formula per formula 3 sites 8 , Cr T -type ions normally normally -type ions M only; anions: OH, F, F, OH, only; anions: 3+ IV or 5 T M A C VI 2 2 sites and so are normally normally so are and 2 sites 2 and 1 2 and AB Leake et al. [1997] et al. Leake M eight sites, in two sets of sets in two of sites, eight M T only, Si at at Si only, C -type ions: Al at Al at -type ions: 4 sites per formula unit; unit; per formula 4 sites 1, 2 one site per formula unit; unit; per formula site one at only; Na and “OH” corresponding to the to corresponding “OH” and -type ions: Mg, Fe -type ions: M Mn rarely more high-valency Ti ions: at “OH”. O at Cl, occupy the five of two to limited A mineral comprising a double a double A mineral comprising the general with chain silicate formula the formula of the components described as conventionally L at size, similar of ions rarer T crystallographic sites: following A M of 2 up made sites five of composite M unit; be needdistinguished; not that four, unit. per formula sites two “OH” to normally considered ions The in the following are these sites occupy K at and site) (empty categories: A

, 3+ , Fe 2+ , where A = Mg, , where 2 (OH) 22 O 8 Institute 2005] Institute [American Geological [American (Si,Al) 5 Glossary of Geology, 5th ed. Glossary of Geology, , Ca, or Na, and B = Mg, Fe and Na, , Ca, or B 2+ 2-3 [crystal]: a crystal of Said that needlelike is in form. [sic] rock-forming dark of 1. A group closely minerals, silicate ferromagnesian in crystal composition and related form formula: the general having and A Fe a by characterized is It Al. or Li, Mn, tetrahedral of chain double cross-linked 4:11, by of ratio silicon:oxygen with crystals,prismatic fibrous or columnar in two cleavage good prismatic by and the crystal parallel to directions faces and 124°; 56° and of angles at intersecting Most black. to white from range colors crystallize amphiboles in the monoclinic in the orthorhombic. some system, widely and abundant an They constitute and in igneous constituent distributed wholly are (some rocks metamorphic in analogous they are and metamorphic), the pyroxenes. to composition chemical group, the amphibole 2. A mineral of anthophyllite, hornblende, as such actinolite, tremolite, cummingtonite, etc. arfvedsonite, glaucophane, riebeckite, Table 1. Definitions of general mineralogical terms mineralogical 1. Definitions of general Table 2 - - -

(OH,F,Cl) , where , where (OH,F,Cl) 22 O 8 Z 5 of Mines 1996] Y 2 Terms [U.S. Bureau Bureau [U.S. Terms B Mineral, and Related and Related Mineral, Dictionary of Mining, 0-1 [Note: Footnotes identify the Primary Footnotes [Note: the definition] for Citation Source of 1. A mineral consisting needlelike crystals,fine natrolite. e.g., needlelike crystal.2. Slender needlelike crystals. to 3. Refers characterized A mineral group; silica tetra of chains double by the composition hedra having A (A = Ca,Na,K,Pb,B), (B = Ca,Fe,Li,Mg,Mn,Na), and (Y = Al,Cr,Fe,Mg,Mn,Ti), in the ortho (Z = Al,Be,Si,Ti); crystal monoclinic or rhombic actinolite, including systems, anthophyllite, arfvedsonite, hornblende, cummingtonite, grune glaucophane, richterite, rite, anthophyllite, riebeckite, All others. and tremolite, prismatic a diagnostic display directions in two cleavage crystalparallel to faces and about of angles at intersecting mem 124°. Some 54° and be asbestiform. bers may 1 Term Acicular Amphibole See footnotes at end of table. of end at See footnotes

134 NIOSH CIB 62 • Asbestos (Continued) NIOSH [1990a] A specific type of mineral fibrosity A specificfibrosity of mineral type primarily is in which the growth the crystals and dimension in one fibers. flexible long, as naturally form that in bundles be can Fibers found smaller into becan easily separated fibrils. into ultimately or bundles sites: Mg-Fe-Mn- sites: B Leake et al. [1997] et al. Leake Exceptions may occur to the above occur the above to may Exceptions groups Four behavior. “normal” on the depending classified are occupancy the of sodic-calcic calcic group; Li group; Asbestiform sodic and group. group; be named should amphiboles mineral their precise to according the by followed (when known) name anthophyllite- e.g., suffix—asbestos, tremolite-asbestos. asbestos,

Institute 2005] Institute [American Geological [American Glossary of Geology, 5th ed. Glossary of Geology, 3. A term sometimes used a synonym used3. A term sometimes a synonym Greek Etymol: hornblende. for doubtful”, “ambiguous, “amphibolos”, varieties. many its to in reference composed is a mineral that of Said fibers. separable of Table 1. Definitions of general mineralogical terms (Continued) terms mineralogical 1. Definitions of general Table of Mines 1996] Terms [U.S. Bureau Bureau [U.S. Terms Mineral, and Related and Related Mineral, Dictionary of Mining, [Note: Footnotes identify the Primary Footnotes [Note: the definition] for Citation Source is a mineral that of 1. Said asbestos. like i.e., fibrous, 1

Term Amphibole (Continued) Asbestiform See footnotes at end of table. of end at See footnotes

NIOSH CIB 62 • Asbestos 135 (Continued) NIOSH [1990a] Asbestos is a generic term for a term for a generic is Asbestos with minerals silicate of number crystalline structure. a fibrous used of commercially quality The the mineralogy depends on asbestos the variety, the asbestiform of the fiber development, of degree to acicular crystals fibers of ratio the length and impurities, other or The fibers. of the flexibility and these varieties of asbestiform in both the be can minerals found serpentine mineral and amphibole varieties asbestiform The groups. small veinlets occur or in veins composed or containing rock within (nonasbestiform) the common of mineral. the same variety of varieties asbestiform major The used minerals commercially of chrysotile,are tremolite-actinolite cummingtonite-grunerite asbestos, and asbestos, anthophyllite asbestos, by marketed is Asbestos crocidolite. anthophyllite (e.g., mineral name its (e.g., variety name its asbestos), its or chrysotile crocidolite), or Amosite). (e.g., trade name Leake et al. [1997] et al. Leake

Institute 2005] Institute [American Geological [American Glossary of Geology, 5th ed. Glossary of Geology, 1. A commercial term applied to a group a group to term applied 1. A commercial separate readily that minerals silicate of flexible, are fibers that thin, strong into inert, chemically and and resistant, heat uses in yarn, (as for suitable therefore are tiles, linings, brake paint, paper, cloth, and filters) fillers, cement, insulation, or nonconducting, incombustible, where required. is material resistant chemically [sic], group the asbestos 2. A mineral of chrysotile principally (best adapted certain fibrous and spinning) for amosite, (esp. amphibole varieties of crocidolite). and anthophyllite, the to 3. A term strictly applied Certain of actinolite. variety fibrous health. to deleterious varieties are Table 1. Definitions of general mineralogical terms (Continued) terms mineralogical 1. Definitions of general Table of Mines 1996] Terms [U.S. Bureau Bureau [U.S. Terms Mineral, and Related and Related Mineral, Dictionary of Mining, [Note: Footnotes identify the Primary Footnotes [Note: the definition] for Citation Source term 1. A commercial minerals silicate to applied into readily separate that fibers that thin, strong resistant, heat flexible, are inert, chemically thus and for them making suitable paper, cloth, uses in yarn, (as tiles, linings, brake paint, and fillers, cement, insulation, incombustible, where filters) chemically or nonconducting, required. is material resistant 1970’s, the early Since been serious have there concerns environmental health the potential about products, asbestos of hazards in strong resulted which has regulations. environmental asbestiform 2. Any the serpentine mineral of (chrysotile, best group and spinning for adapted variety in the principal amphibole or commerce) actinolite, (esp. group anthophyllite, gedrite, grunerite, cummingtonite, tremolite). and riebeckite, 3. A term strictly applied actinolite. asbestiform to 1 Term Asbestos See footnotes at end of table. of end at See footnotes

136 NIOSH CIB 62 • Asbestos (Continued) NIOSH [1990a] These fragments can can These fragments A fragment produced by the breaking the breaking by produced A fragment crystalsare of that in directions the crystal to structure related possible parallel to always are and crystal perfect with faces. Minerals perfect produce can cleavage Amphiboles fragments. regular will cleavage prismatic with fragments. prismatic produce Note: meet may and be elongated fiber of a upon the definition examination. microscopic Leake et al. [1997] et al. Leake

Institute 2005] Institute [American Geological [American Glossary of Geology, 5th ed. Glossary of Geology, A fragment of a crystal of is A fragment that faces. cleavage by bounded of crystals, shape e.g.general The a given For fibrous. prismatic, cubic, vary may type crystal, of the habit locality locality to depending from growth. of environment on Table 1. Definitions of general mineralogical terms (Continued) terms mineralogical 1. Definitions of general Table 3 of Mines 1996] Terms [U.S. Bureau Bureau [U.S. Terms Mineral, and Related and Related Mineral, Dictionary of Mining, [Note: Footnotes identify the Primary Footnotes [Note: the definition] for Citation Source appearing typically forms The a mineral of specimens on all the rarely group, species or point its by permitted forms Crystalrange habits group. e.g., highly diverse, from showing never almost to calcite, crystal turquoise. faces, e.g. describing to addition In form with mineral habits prismatic, e.g. names, tetrahedral, or pyramidal, appearances for names other used, fibrous, e.g. are botryoidal. or platy, columnar, by given are Intergrowths specific description.

1 Term Cleavage Cleavage fragment Crystal habit See footnotes at end of table. of end at See footnotes

NIOSH CIB 62 • Asbestos 137 (Continued) Upon microscopic microscopic Upon Note: Note: NIOSH [1990a] An acicularAn crystal single or polycrystalline elongated similarly particles particles. Such aggregate such properties macroscopic have silky high aspect ratio, flexibility, as These axial lineation. and luster, their shape attained particles have manifold because of primarily randomly are that planes dislocation parallel in but axes in two oriented the third. particles that only examination, are aspect ratio greater a 3:l or have fibers.as defined macroscopic Other fibers used define to properties be individual ascertainedcannot for microscopically. particles examined be cannot fiberA single that smaller components into separated fibrous its losing without appearances. or properties Leake et al. [1997] et al. Leake

Institute 2005] Institute [American Geological [American Glossary of Geology, 5th ed. Glossary of Geology, A strengthening cell, usually elongated, elongated, usually cell, A strengthening thick-walled, occurring and tapering, vascular parts plants. of in various does provided definition The [Note: fibers.] mineral to refer not 5 Table 1. Definitions of general mineralogical terms (Continued) terms mineralogical 1. Definitions of general Table 4 of Mines 1996] Terms [U.S. Bureau Bureau [U.S. Terms Mineral, and Related and Related Mineral, Dictionary of Mining, [Note: Footnotes identify the Primary Footnotes [Note: the definition] for Citation Source strand smallest single The other or asbestos of material.fibrous fiber1. A single which into be separated cannot smaller components fibrous its losing without appearance. or properties minerals to 1. Applied occur fibers, that as asbestos. as such asbestiform Syn: fine of 2. Consisting satin e.g., threadlike strands, gypsum. variety of spar 1 1 1 Term Fiber Fibril Fibrous See footnotes at end of table. of end at See footnotes

138 NIOSH CIB 62 • Asbestos (Continued) NIOSH [1990a] Leake et al. [1997] et al. Leake

Institute 2005] Institute [American Geological [American Glossary of Geology, 5th ed. Glossary of Geology, The tendency of certaintendency minerals, The crystallize to asbestos, e.g., in fibers. or needlelike grains A structure: prismatic Fibrous in which each first- structure prismatic in prism a simple like is prism order and prismatic nonspherulitic showing substructure, prismatic noncomposite higher much have the prisms but simple typical than ratios length/width fibers. occurringprisms, long as finely of a pattern mineral deposits, In crystals, rod-like in e.g., acicular, asbestos. chrysotile amphibole and 6 7 Table 1. Definitions of general mineralogical terms (Continued) terms mineralogical 1. Definitions of general Table of Mines 1996] Terms [U.S. Bureau Bureau [U.S. Terms Mineral, and Related and Related Mineral, Dictionary of Mining, [Note: Footnotes identify the Primary Footnotes [Note: the definition] for Citation Source the crystalsIf in a mineral elongated greatly are aggregate small a relatively have and the structure cross-section, The fibrous. is texture or as in be parallel, may fibers in sometimes and crocidolite When cerussite. and calcite very are they the fine, fibers to a silky luster impart may in crocidolite as the aggregate, gypsum. satin-spar There or type. Fibrous alsois a feltlike a from crystals radiate may or asteriated forming center, or coarse either groups, starlike observed as in frequently fine, natrolite wavellite, pyrolusite, sometimes and tourmaline, and minerals. other and in stibnite texture. Also called fibrous a pattern mineral deposits, In rod-like acicular, finely of crystals, in chrysotile e.g., asbestos. amphibole and Term Fibrous habit structure Fibrous texture Fibrous See footnotes at end of table. of end at See footnotes

NIOSH CIB 62 • Asbestos 139 (Continued) NIOSH [1990a] A homogeneous, naturally naturally A homogeneous, crystallineoccurring, inorganic distinct have Minerals substance. crystal variation and structures and composition, in chemical names. individual given are Leake et al. [1997] et al. Leake

Institute 2005] Institute [American Geological [American Glossary of Geology, 5th ed. Glossary of Geology, 1. A naturally occurring inorganic element element occurring inorganic 1. A naturally a periodically having compound or and atoms of arrangement repeating composition, chemical characteristic properties. physical in distinctive resulting compound chemical or element 2. An crystalline is a as that formed and Materials processes. geologic of result geological processes by formed no are artificialsubstances from newas 1995) (after accepted longer a 1995). Mercury, (Nickel, minerals to exception a traditional is liquid, a not is the crystallinity rule. Water crystalline and ice is), mineral (although artificialmaterials and biological mineraloid). (cf. minerals not are inorganic formed naturally 3. Any the of a member i.e., material, opposed to as mineral kingdom kingdom. animal or the plant 7 Table 1. Definitions of general mineralogical terms (Continued) terms mineralogical 1. Definitions of general Table of Mines 1996] Terms [U.S. Bureau Bureau [U.S. Terms Mineral, and Related and Related Mineral, Dictionary of Mining, [Note: Footnotes identify the Primary Footnotes [Note: the definition] for Citation Source occurring 1. A naturally or element inorganic an having compound structure internal orderly characteristic and composition, chemical crystal physical and form, metallic. CF: properties. phraseology, miner’s 2. In See also: ore. ore. 3. See: mineral species; mineral series; mineral group. resource natural 4. Any the earthextracted from use; ores, e.g., human for petroleum. coal,salts, or valuable flotation, 5. In as ore of mineral constituents minerals. gangue opposed to plant inorganic 6. Any nutrient. animal or the mineral of member 7. Any the opposed to as kingdom kingdoms. plant and animal Term Mineral See footnotes at end of table. of end at See footnotes

140 NIOSH CIB 62 • Asbestos (Continued) NIOSH [1990a] A mineral series includes two or or two A mineral series includes a mineral group of members more in secondary in which the cations in similar structural are position be can and properties chemical frequently but in variable present cummingtonite- (e.g., ratios limited in trend The current actinolite). a mineral series to to is referring using by series names long simplify (end one only of the mineral name (i.e., member intermediate) or tremolite-actinolite-ferroactinolite). minerals variety distinguishes The different conspicuously are that normal (1) those considered from crystallization the common within other polytypes, and I habits, (2) those and structural variants, properties physical different with by named are Varieties color. as such gemologists, miners, mineralogists, industrial of manufacturers mineral collectors. and products, Leake et al. [1997] et al. Leake

Institute 2005] Institute [American Geological [American Glossary of Geology, 5th ed. Glossary of Geology, [crystal]: or A needle-shaped acicular mineral crystal. Table 1. Definitions of general mineralogical terms (Continued) terms mineralogical 1. Definitions of general Table of Mines 1996] Terms [U.S. Bureau Bureau [U.S. Terms Mineral, and Related and Related Mineral, Dictionary of Mining, [Note: Footnotes identify the Primary Footnotes [Note: the definition] for Citation Source or 5. A needle-shaped acicular mineral crystal. Term Mineral seriesMineral variety Mineral Needle See footnotes at end of table. of end at See footnotes

NIOSH CIB 62 • Asbestos 141 (Continued) NIOSH [1990a] Each of the six commercially exploited exploited the six commercially Each of also minerals occursasbestiform in a These mineral habit. nonasbestiform chemical the same have minerals but variety, the asbestiform as formula growth crystalwhere they have habits dimensions three or in two proceeds When dimension. one of instead milled, break these do not minerals fragments into rather but fibrils into the two along cleavage from resulting thus Particles planes. growth three or cleavage as to referred are formed meet the definition can and fragments purposes.regulatory for a fiber of Leake et al. [1997] et al. Leake

Institute 2005] Institute [American Geological [American Glossary of Geology, 5th ed. Glossary of Geology, [crystal] A crystal form having three, four, [crystal] four, three, A crystal having form parallel faces, with twelve or six, eight, open which is and edges, intersection parallel the axis of ends the two at only the faces. of edges the intersection to Table 1. Definitions of general mineralogical terms (Continued) terms mineralogical 1. Definitions of general Table of Mines 1996] Terms [U.S. Bureau Bureau [U.S. Terms Mineral, and Related and Related Mineral, Dictionary of Mining, [Note: Footnotes identify the Primary Footnotes [Note: the definition] for Citation Source crystal open 1. An with form their intersecting faces and the principle parallel to edges crystallographic Prisms axis. four (trigonal), three have six (ditrigonal (tetragonal), eight hexagonal), or twelve or (ditetragonal), nine- faces. The (dihexagonal) tourmaline of sided prisms trigonal of a combination are prisms. hexagonal and Term Nonasbestiform Nonasbestiform habit Prism See footnotes at end of table. of end at See footnotes

142 NIOSH CIB 62 • Asbestos (Continued) NIOSH [1990a] The serpentine minerals belong to The serpentine minerals belong minerals. of group the phyllosilicate variety important commercially The in chrysotile,is which originates Antigorite habit. the asbestiform types other two are lizardite and are serpentine that minerals of structurallyfibrous distinct. The called is picrolite. antigorite of form Leake et al. [1997] et al. Leake

Institute 2005] Institute [American Geological [American Glossary of Geology, 5th ed. Glossary of Geology, [crystal] a crystal of Said that markedly dimension one shows two. the other than longer wholly almost consisting A rock e.g., minerals, serpentine-group of derived chrysotile, lizardite, or antigorite, ferromagnesian of the hydration from and olivine as such minerals silicate talc, chlorite, Accessory pyroxene. be present. may magnetite and Table 1. Definitions of general mineralogical terms (Continued) terms mineralogical 1. Definitions of general Table of Mines 1996] Terms [U.S. Bureau Bureau [U.S. Terms Mineral, and Related and Related Mineral, Dictionary of Mining, [Note: Footnotes identify the Primary Footnotes [Note: the definition] for Citation Source a to 2. Pertaining crystallographic prism. a crystal of 3. Descriptive markedly dimension one with two. the other than longer two of 4. Descriptive cleavage. of directions Term Prismatic Serpentine Minerals See footnotes at end of table. of end at See footnotes

NIOSH CIB 62 • Asbestos 143 (Continued) NIOSH [1990a] Leake et al. [1997] et al. Leake

8 O molecules 2 tetrahedra with 4 Institute 2005] Institute [American Geological [American Glossary of Geology, 5th ed. Glossary of Geology, a generic term for a large group of of group a large term for a generic tinted (sometimes colorless or white hydrous impurities) by yellow or red have that minerals aluminosilicate of structure framework open an (Si,Al)O interconnected H and cations exchangeable a ratio Theyhave in structural cavities. 1:2, of oxygen nonhydrous to (Al + Si) of their easy and by characterized are and and hydration of water of loss reversible when swelling and fusion their ready by the blowpipe. under heated strongly occur been to as known long have Zeolites crystals in basalt. formed well in cavities is their significance occurrence Of more in the minerals sediments authigenic as the deep saline sea esp. lades and of and and “during form They tuff. in beds of of reaction by burial,generally after solid aluminosilicate with waters pore glass, feldspar, volcanic (e.g., materials minerals).” clay silica, and biogenic - O. Table 1. Definitions of general mineralogical terms (Continued) terms mineralogical 1. Definitions of general Table 2 O. The term The O. 2 xH • 2 of Mines 1996] .nSiO 3 Terms [U.S. Bureau Bureau [U.S. Terms Mineral, and Related and Related Mineral, O Dictionary of Mining, 2 [Note: Footnotes identify the Primary Footnotes [Note: the definition] for Citation Source of class term for 1. A generic aluminum of silicates hydrated calcium sodium or either and the type both, of Na or Al of describedoriginally a group occurring minerals. naturally analcite, are zeolites natural The natro heulandite, chabazite, lite, stilbite, and thomsonite. made are Artificial zeolites ranging forms, in a variety of and porous to gelatinous from used gas as are and sandlike, drying and agents adsorbents softeners. Both water as well as artificial and zeolites natural water for used extensively are now term The zeolite softening. groups diverse such includes sulfonated as compounds of which basic resins, or organics effect to act manner in a similar exchange. anion or cation either Term Zeolite See footnotes at end of table. of end at See footnotes

144 NIOSH CIB 62 • Asbestos NIOSH [1990a] Leake et al. [1997] et al. Leake

Institute 2005] Institute [American Geological [American Glossary of Geology, 5th ed. Glossary of Geology, - - Table 1. Definitions of general mineralogical terms (Continued) terms mineralogical 1. Definitions of general Table of Mines 1996] Terms [U.S. Bureau Bureau [U.S. Terms Mineral, and Related and Related Mineral, Dictionary of Mining, [Note: Footnotes identify the Primary Footnotes [Note: the definition] for Citation Source alumino hydrous of 2. A group the to similar are that silicates re They and loseeasily feldspars. and hydration of their water gain they when heated. swell fuse and used in frequently are Zeolites exchange ion softening, water applications. absorbent and

Term 458/], pp. 70. Date accessed: December 21, 2009. 70. Date 458/], pp. 72. [1969], pp. 325; supplement sciences [1957], pp. Additional definitions can be found in Lowers H, Meeker G [2002]. Tabulation of asbestos-related terminology. Open-file report 02-458 [http://pubs.usgs.gov/of/2002/ofr-02- Open-file report 02-458 terminology. asbestos-related of Tabulation G [2002]. Meeker H, in Lowers found can be definitions Additional 523. pp. Library, Philosophical York: A [1965]. DictionaryNew mining. of Nelson 437. pp. Ltd., Publications, Mining London: Pryor EJ [1963]. Dictionary mineral technology. of 623. pp. McGraw-Hill, York: 4th New ed. industry, of [1947]. Materials SF Mersereau Mines. of Bureau the Interior, of Department DC: U.S. 8751. Washington, Circular varieties. USBM their asbestiform Selected WJ et al. and minerals Campbell, silicate 47. pp. Co., Chemical Publishing mineralogical dictionaryYork: [1948]. New Chamber’s Glossary geology related of and Geological the American also Institute: by addition, 788. In pp. VA; Alexandria, ed. 3rd [1987]. Glossary geology, of GeologicalAmerican Institute 135–143. pp. Pergamon, York: New zeolites. eds. Natural FA, Mumpton LB, Sand In: RL [1978]. Geologic zeolites. occurrence of Hay Zeolite (Continued) 1 2 3 4 5 6 7 8

NIOSH CIB 62 • Asbestos 145

1 in 1 (Continued) NIOSH [1990a] Actinolite can occur can in both the Actinolite nonasbestiform and asbestiform in the mineral is and mineral habits series tremolite-ferroactinolite. often is variety asbestiform The asbestos. actinolite as to referred the commercial is Amosite the acronym from term derived Africa.” South of Mines “Asbestos in the mineral is series Amosite cummingtonite-grunerite, and which both asbestiform the of habits nonasbestiform mineral This occur. mineral can referred type commonly is asbestos.” “brown as to - ; 2 ) between (OH) 2+ 22 O 8 Si 5 Leake et al. [1997] et al. Leake (Fe,Mg) 2 with Mg/(Mg+Fe with A monoclinic calcic amphi A monoclinic between bole intermediate tremolite: and ferroactinolite Ca 0.9 (otherwise0.5 and if ≤ and ferroactinolite, is 0.5 it tremolite). is if ≥ 0.9 it -

- . 4 (OH) 3 O 2 Si 3 ) ]. It may contain contain may ]. It 2+ 22 O 8 [Si 2 (OH) 5 Table 2. Definitions of specific minerals Table Glossary of Geology, 5th ed. Glossary of Geology, (Fe,Mg) 2 [American Geological 2005] Institute [American A bright-green or grayish-green monoclinic monoclinic grayish-green or A bright-green group: the amphibole mineral of Ca occurs sometimes in the form It manganese. or radiated, also in fibrous, and asbestos, of (such rocks in metamorphic forms columnar rocks. igneous in altered and schists) as iron-rich, an term for A commercial occurring amphibole variety of asbestiform an of consist may It fibers. in long (anthophyllite amphibole orthorhombic amphibole a monoclinic of or gedrite) or grunerite). or (cummingtonite green to brown lamellar A macroscopically serpentine which con mineral, monoclinic forms wave alternating structurallysists of sides reverses layer in which the 1:1 T-O null each wave at curvature of direction and dis the repeat specimens most In point. between measures pattern the wave of tance 51.0 Å: (Mg, Fe 25.5 and 2 - - - ]; 2 (OH) ; kaolinite- 4 22 O 8 Si (OH) 5 5 O 2 ) = 0.50 to 0.89 of the 0.89 of ) = 0.50 to Si 2+ 3 (Fe,Mg) 2 Dictionary of Mining, Mineral, and Related Terms Terms and Related Mineral, [U.S. Bureau of Mines 1996] Bureau [U.S. [Note: Footnotes identify the Primary Footnotes [Note: the definition] for Citation Source mineral, A monoclinic 2[Ca series Mg/ in the hornblende (Mg+Fe a series forms group; amphibole bladed, green, tremolite; with (byssolite fibrous acicular, (nephrite massive or asbestos), in cleavage; jade); prismatic rocks. metamorphic low-grade mineral in the 1. A monoclinic series. cummingtonite-grunerite asbestos 2. A commercial ge asbestiform of composed anthophyl or grunerite, drite, group; the amphibole of lite fibers. long typically has mineral, A monoclinic (Mg,Fe) polymorphous serpentine group; clinochrysotile,with lizardite, orthochrysotile, parachryso green; tile; variegated greasy stone. ornamental used an as Term Actinolite Amosite Antigorite See footnotes at end of table. of end at See footnotes

146 NIOSH CIB 62 • Asbestos - - (Continued) NIOSH [1990a] Anthophyllite can occur can in Anthophyllite and both the asbestiform mineral nonasbestiform asbestiform The habits. to referred often variety is asbestos. anthophyllite as Chrysotile occurs generally seg veins parallel in fibers as regated easily separate can and veinlets or bundles. or fibers individual into asbes “white as to referred Often its for used is commercially it tos,” in theof making good spinnability additive an as and textile products, friction or products. in cement’ ; 2 ) 2+ (OH) 22 O 8 Si 7 Leake et al. [1997] et al. Leake An orthorhombic Mg-Fe-Mn- orthorhombic An Mg Li amphibole: divalent also contain may Mg/(Mg+Fe with but iron ≥ 0.50 (otherwise ferro- > Si with and anthophyllite), 7.00 (otherwise gedrite). is it

. It is dimorphous dimorphous is . It 2 . It is a highly is . It 5 O, where A = Na, K, or Ca. K, or A = Na, where O, (OH) 2 O 22 2 O Si 8 4 11H Si • 5 36 ) 2+ O (OH) 3 18 Glossary of Geology, 5th ed. Glossary of Geology, (Mg,Fe 2 (Si,Al) ) 2-3 2+ [American Geological 2005] Institute [American A clove-brown to colorless orthorhombic orthorhombic colorless to A clove-brown (Mg, group: the amphibole mineral of Fe in aluminum increase with cummingtonite; with occurs Anthophyllite gedrite. grades into it typically rocks, ultrabasic in metamorphosed in monominerallic talc or or olivine with asbestiform radiating parallel or of aggregates asbestos. has It for been mined fibers. palygorskite variety asbestiform olive-green An tremolite-actinolite. of zeolite a monoclinic for name A group formula: the mineral general with A orthorhombic greenish or gray, A white, the serpentine mineral of monoclinic or Mg group: and of silkyserpentine, variety fibrous, type of important the most constitutes be to confused chrysolite. Not asbestos. - - Table 2. Definitions of specific minerals (Continued) 2. Definitions of specific minerals Table .12 36 ]; 2 O 13 Si ]; serpentine 2 (OH) 10 22 O 4 O 8 Si 8 Si (Al,Si) 7 3 Al 2 (OH) Dictionary of Mining, 6 O; of the zeolite group. the zeolite O; of 2 Mineral, and Related Terms Terms and Related Mineral, [U.S. Bureau of Mines 1996] Bureau [U.S. [Note: Footnotes identify the Primary Footnotes [Note: the definition] for Citation Source mineral, orthorhombic An 4[Mg,Fe) commonly group; amphibole to green fibrous, or lamellar from in schists clove-brown; rocks; ultramafic metamorphosed asbestos. grade of a nonspinning magnesium- A light-green, from named mineral, rich clay Attapulgus, occurrence at its quarried as is it GA, where earth. Crystallizes in fuller’s system. the monoclinic asbestiform olive-green An tremolite-actinolite. variety of (Na, mineral, A monoclinic K,Ca) H mineral (clinochrysA monoclinic mineral orthorhombic or otile), (orthochrysotile, parachrysotile), [Mg yel silky soft, white, forms group; fibers as flexible gray or green, low, rocks; ultramafic in altered veins (Not minerals. asbestos the chief beto confused chrysolite.) with Term Anthophyllite Attapulgite Byssolite Clinoptilolite Chrysotile See footnotes at end of table. of end at See footnotes

NIOSH CIB 62 • Asbestos 147 (Continued) NIOSH [1990a] Crocidolite is from the fibrous the fibrous from is Crocidolite the mineral riebeckite of habit in the mineral is seriesand in glaucophane-riebeckite, and which both asbestiform occur. can habits nonasbestiform mineral This typeis commonly asbestos.” “blue as to referred ; 2 ) ≥ 0.50 (OH) 2+ 22 ; may ; may 2 ) ≤ 0.5 O 8 2+ Si 7 (OH) 22 O 8 Si 5 2+ Leake et al. [1997] et al. Leake Fe 2 A monoclinic Mg-Fe-Mn-Li Mg-Fe-Mn-Li A monoclinic Mg amphibole: iron divalent also contain may Mg/(Mg+Fe with but (otherwise grunerite) is it calcic amphibole: A monoclinic Ca but magnesium also contain Mg/(Mg+Fe with (otherwise actinolite). is it -

- . It is dimorphous with dimorphous is . It 2 . Syn: ferrotremolite. . Syn: 2 (OH) 22 (OH) O 22 8 O Si 8 7 ) Si 5 2+ Glossary of Geology, 5th ed. Glossary of Geology, 2+ Fe 2 [American Geological 2005] Institute [American An asbestiform variety of riebeckite; riebeckite; variety of asbestiform An or indigo-blue, or lavender-blue, forms and massive and silkyleek-green fibers Also spelled krokidolit. forms. earthy beige mono or gray, brown, green, A dark group: the amphibole of member clinic (Mg,Fe and calcium contains typically and anthophyllite, occurs in metamor Cummingtonite manganese. rocks, and ultrabasic mafic phosed ironstone, a component as and rhyolites, and dacites some grunerite. variety is iron-rich Its uralite. of Note: [Ed. mineral. zeolite hexagonal A white depending (Ca,K,Na) Erionite as Designated substitution. cation the dominant on mineral monoclinic A green-black a theoretical representing component group: the amphibole of end-member Ca Table 2. Definitions of specific minerals (Continued) 2. Definitions of specific minerals Table ]; 2 ) = 0.30 2+ ; amphibole ; amphibole 2 (OH) 22 O 8 (OH) Si 22 5 O 8 ) = 0 to 0.50; ) = 0 to Si ,Mg) 2+ 7 2+ Dictionary of Mining, (Fe 2 Mineral, and Related Terms Terms and Related Mineral, [U.S. Bureau of Mines 1996] Bureau [U.S. [Note: Footnotes identify the Primary Footnotes [Note: the definition] for Citation Source variety of asbestiform An lavender-blue, forms riebeckite; silky leek-green or indigo-blue, or and earthy massive and fibers and spinning for suited forms; Also spelled krokitolit. weaving. mineral, A monoclinic (Fe,Mg) Mg/(Mg+Fe has group; be may cleavage; 0.69; prismatic to and in amphibolites asbestiform; varieties (amosite, fibrous dacites; montasite, rich, and magnesium used asbestos. as rich) are iron mineral, A monoclinic Ca Mg/ has group; amphibole (Mg+Fe a series tremolite with forms Formerly actinolite. and called ferrotremolite. Term Crocidolite Cummingtonite Erionite Ferroactinolite See footnotes at end of table. of end at See footnotes

148 NIOSH CIB 62 • Asbestos (Continued) NIOSH [1990a] ; 2 ) < 0.50 (OH) 2+ 22 O 8 Si 7 2+ Leake et al. [1997] et al. Leake A monoclinic Mg-Fe-Mn-Li Mg-Fe-Mn-Li A monoclinic Fe amphibole: magnesium also contain may Mg/(Mg+Fe with but (otherwise cummingtonite). is it

4 ; the term “endellite” ; the term “endellite” 3 (F,OH). It It (F,OH). 22 O) similar to kaolinite kaolinite to O) similar 2 Al)O 7 X(H • (Si 4 5 ) 2+ (OH) 5 Glossary of Geology, 5th ed. Glossary of Geology, O 2 (Mg,Fe Si 2 2 [American Geological 2005] Institute [American A vitreous dark brown monoclinic monoclinic brown dark A vitreous (Na,K) group: the amphibole mineral of Ca F>OH. with edenite represents mineral clay A 1:1 aluminosilicate Al Al(IV) and some with perhaps but the for compensate to cations interlayer Al(IV). able is this it because of Probably space in the interlayer water incorporate to and (7Å)” [Bailey “halloysite terms 1989]. The the for recommended (10Å)” were halloysite respectively forms, dihydrate and anhydrous 1976] Pegro [Brindley and be used not [Baileyshould 1980]. et al. Table 2. Definitions of specific minerals (Continued) 2. Definitions of specific minerals Table ; 2 ]; kaolinite- 10 (OH) O 8 22 O 8 ) = 0-0.30; forms ) = 0-0.30; forms Si 2+ 7 (OH) 4 Si 4 Dictionary of Mining, Mineral, and Related Terms Terms and Related Mineral, [U.S. Bureau of Mines 1996] Bureau [U.S. [Note: Footnotes identify the Primary Footnotes [Note: the definition] for Citation Source mineral, A monoclinic (Fe,Mg) Mg/ with group; amphibole (Mg+Fe and series cummingtonite with fibrous magnesiocummingtonite; in commonly needlelike, or characteristic radial aggregates; in the Lake formations iron of Trough Labrador and Superior Also spelled gruenerite. regions. mineral, 1. A monoclinic 2[Al up made serpentine group; shown as tubes slender of a microscopy; electron by mineral in veins. gangue include to name a group as 2. Used with minerals” “halloysite natural as hydration, of levels different artificially. those as well formed Term Fluoro-edenite Grunerite Halloysite See footnotes at end of table. of end at See footnotes

NIOSH CIB 62 • Asbestos 149 (Continued) NIOSH [1990a] Leake et al. [1997] et al. Leake O. 2

7H • 24 O O. 2 10 . 3+ Si 4H 2 • )Al 2 or Mn (OH) 3+ 10 ,Ca,K O 2 4 Si to create a better lateral a better create to 2 4 (OH) 5 O 2 Si Glossary of Geology, 5th ed. Glossary of Geology, 3 [American Geological 2005] Institute [American The most abundant form of the trioctahedral form abundant most The crystallizesserpentine flat It as minerals. for Al substitute of amounts Variable platelets. in the ideal Si serpentineboth Mg and formula Mg of octahedraland between component fit the and in antigorite tetrahedral found than sheets chrysotile. Several rhombohedral, polytypes exist: monoclinic. or hexagonal, trigonal, orthorhombic pinkish or yellowish, A white, mineral: (Na zeolite or yellowish, grayish, (a) A white, clay chain-structure grayish-green mineral: (Mg,Al) crystallizes It in several monoclinic polytypes. orthorhombic and monoclinic for name (b) A group composition, analogous an with minerals Na, or Mn by Mg replaced with but Fe by AL replaced and - - Table 2. Definitions of specific minerals (Continued) 2. Definitions of specific minerals Table - - O; - 2 8H O. • 2 20 O .7H 8 24 O 10 ; kaolinite-serpen 4 (Si,Al) Si 4 2 )Al 2 (OH) 5 K 2 O (Mg,Al) 2 2 Dictionary of Mining, Si 3 Mineral, and Related Terms Terms and Related Mineral, [U.S. Bureau of Mines 1996] Bureau [U.S. [Note: Footnotes identify the Primary Footnotes [Note: the definition] for Citation Source mineral, hexagonal and A trigonal Mg with polymorphous tine group; clinochrysotile, or antigorite, thochrysotile, parachrysotile; and in a series nepouite; with forms prod alteration an as masses platy rocks;most the ultramafic uct of serpentine mineral. abundant pinkish or yellowish, A white, group the zeolite of member the formula with minerals of (Ca,Na and 1. A monoclinic mineral, orthorhombic (OH) in desert soils. fibrous; lightweight for name 2. A general showing minerals clay fibrous of alumi substitution significant character magnesium; for num shapes rodlike distinctive ized by microscope. electron an under Term Lizardite Mordenite Palygorskite See footnotes at end of table. of end at See footnotes

150 NIOSH CIB 62 • Asbestos (Continued) NIOSH [1990a] ; 2 (OH) 22 ) ≥ 0.5 2+ O 8 ; may also ; may 2 otherwise is it 3+ )Si 2 3+ (OH) ) < 0.5 otherwise Fe < 0.50 otherwise it 22 3 2+ position but with with but position A 2+ O Al < Fe A 8 Leake et al. [1997] et al. Leake VI Si (Fe 5 2 may also contain aluminum aluminum also contain may but iron trivalent of in place with (Na+K) also may and arfvedsonite, is in place magnesium contain Mg/ with but iron divalent of (Mg+Fe magnesioriebeckite is it A monoclinic sodic-calcicA monoclinic Na(CaNa) amphibole: Mg but iron divalent contain Mg/(Mg+Fe with (otherwise ferrorichterite) is it sodic A monoclinic amphibole: Na also may and ferroglaucophane, potassium sodium and contain in the . It . It 2

(OH) 22 O 8 Si 2 3+ Fe O. 3 2 2+ . Cf: soda tremolite 6H Fe 2 • 2 16 O 8 (OH) 22 O 8 (Si,Al) Si 2 5 Glossary of Geology, 5th ed. Glossary of Geology, CaMg 2 [American Geological 2005] Institute [American A colorless or white monoclinic zeolite zeolite monoclinic white or A colorless phillipsite as designated Usually mineral. which on depending Na) – (Ca, K, or cation, exchangeable the dominant is (Ca,K,Na) monoclinic rose-red or yellow, A brown, group: the amphibole of member Na the mineral of monoclinic black or blue A dark Na group: amphibole acid or in some occurs a primary as constituent See rocks. sodium-rich igneous also: crocidolite 1- Table 2. Definitions of specific minerals (Continued) 2. Definitions of specific minerals Table / 3+ Ca 2 [sic]; 2 (OH) O; zeolite group; group; O; zeolite 2 22 O 8 .6H Si 16 ) = 0 to 0.49 and Fe 0.49 and ) = 0 to 5 ) 2+ O 2+ 8 +Al) = 0.7 to 1.0; forms a 1.0; forms +Al) = 0.7 to Dictionary of Mining, 3+ (Si,Al) Mineral, and Related Terms Terms and Related Mineral, [U.S. Bureau of Mines 1996] Bureau [U.S. [Note: Footnotes identify the Primary Footnotes [Note: the definition] for Citation Source (K,Na,Ca) mineral, A monoclinic 2 occurs in complex commonly twinned crystals; in basalt in in pelagicclays, red amydules, in alkaline tuffs, saline palagonite silicic vitric volcanic from lakes around in alkalineash, and soils, baths. in Roman springs hot Na mineral, A monoclinic (Mg,Fe Mg/ with group amphibole (Mg+Fe (Fe series magnesioriebeckite; with in soda-richrhyolites, fibrous; pegmatites; and granites, blue variety is crocidolite crocidolite eye is tiger asbestos; quartz. by replaced Term Phillipsite Richterite Riebeckite See footnotes at end of table. of end at See footnotes

NIOSH CIB 62 • Asbestos 151 (Continued) The asbestiform asbestiform The 1 NIOSH [1990a] Tremolite can occur can in both the Tremolite nonasbestiform and asbestiform in the is and mineral habits mineral series tremolite- ferroactinolite. to referred often variety is asbestos. tremolite as ) 3+ (Al,Fe ) ≥0.9 4 2+ ; may ; may 2 (OH) ; may also contain also contain ; may 22 2 O ) ≥ 0.5 (otherwise 8 2+ Si 5 (OH) Leake et al. [1997] et al. Leake 22 Mg 2 O 8 A monoclinic calcic amphibole: calcic amphibole: A monoclinic Ca iron divalent also contain Mg/(Mg+Fe with but (otherwise actinolite) is it sodic-calcicA monoclinic (CaNa)Mg amphibole: Si divalent iron but with Mg/ with but iron divalent (Mg+Fe ferrorichterite) is it - 2 - . 2

(OH) 22 (OH) O 22 8 O 8 Si Al)Si 5 4 O. It is a white to to a white is It O. Mg 2 2 6H • 2 (OH) 15 O 6 Si 4 Glossary of Geology, 5th ed. Glossary of Geology, [American Geological 2005] Institute [American An orthorhombic chain-structure clay min clay chain-structure orthorhombic An eral: Mg extremely material, yellow light or gray light is that compact, and absorbent, lightweight, usedis for and Minor Asia in chiefly found hold cigarette and cigar pipes, tobacco making occurs carvings. Sepiolite ornamental and ers in alluvial deposits and calcite, with in veins serpentine masses. of weathering from formed mineral of monoclinic dark-gray to A white Ca group: the amphibole may and iron, of varying has amounts It chromium. and manganese contain blade-shaped occurs in long Tremolite crystals prismatic and stout short or or granular fibrous, also in columnar, generally aggregates, compact or masses crystalline as such rocks in metamorphic is talc It schists. and limestones dolomitic talc. commercial much of a constituent the of member monoclinic gray or A blue NaCa(Mg group: amphibole - - Table 2. Definitions of specific minerals (Continued) 2. Definitions of specific minerals Table - - ]; amphibole ]; amphibole O; soft; sp O; soft; 2 2 .6H 2 (OH) 22 O 8 (OH) Si 5 15 O 6 Mg 2 Dictionary of Mining, Si 4 Mineral, and Related Terms Terms and Related Mineral, [U.S. Bureau of Mines 1996] Bureau [U.S. [Note: Footnotes identify the Primary Footnotes [Note: the definition] for Citation Source mineral, A monoclinic Mg drymasses fibrous 2, but gr, on water; veins occurs in float in alluvial depos and in calcite of weathering from formed its in serpentine chiefly masses, meerschaum; as Minor, Asia be used pipes, in making may carvings. ornamental mineral, A monoclinic 2[Ca replaced magnesium with group aluminum by silicon and iron, by green, to white actinolite; toward crys prismatic stout or long-bladed fibrous, columnar, show tals, may ag compact or masses granular or metamorphic in low-grade gregates; limestones dolomitic as such rocks va talc the nephrite schists; and jade; the riety the gemstone is byssolite. variety is asbestiform Term Sepiolite Tremolite Winchite See footnotes at end of table. of end at See footnotes

152 NIOSH CIB 62 • Asbestos - NIOSH [1990a] :5–6. 12 Leake et al. [1997] et al. Leake

. 3 Glossary of Geology, 5th ed. Glossary of Geology, dimorphous with parawollastonite. parawollastonite. with dimorphous [in the original source, a word is missing is missing a word source, original the [in [American Geological 2005] Institute [American A triclinic or monoclinic chain silicate silicate chain monoclinic A triclinic or type: CaSiO the pyroxenoid mineral of It here.] in contact- found is Wollastonite occurs usually and limestones, metamorphosed in tabular sometimes or masses in cleavable brown, gray, twinned be crystals; white, may it Several a pyroxene. not is It yellow. or red, Wo. been Symbol: characterized. polytypes have Table 2. Definitions of specific minerals (Continued) 2. Definitions of specific minerals Table - - . It is dimor is . It 3 Dictionary of Mining, Mineral, and Related Terms Terms and Related Mineral, [U.S. Bureau of Mines 1996] Bureau [U.S. [Note: Footnotes identify the Primary Footnotes [Note: the definition] for Citation Source the pyrox A triclinic mineral of CaSiO group: enoid parawollastonite. with phous in contact- found is Wollastonite limestones, metamorphosed occurs in cleavable usually and in tabular sometimes or masses twinned be crystals; white, may it is It yellow. or red, brown, gray, Wo. Symbol, a pyroxene. not Term ing the structure. There may be a gradation in the structure in some series, and minor changes in physical characteristics may occur with elemental substitution. Usually a series substitution. occurelemental may with characteristics physical in changes minor and in series,structure in some the be a gradation may There the structure. ing of the Members of the series. members as to referred by being qualified just or named, being separately compound substitutional intermediate an with members end two has this series actinolite. of member being named the intermediate with silicates, iron and magnesium-iron, calcium-magnesium, hydroxylated series are tremolite-ferroactinolite Mineral series such as cummingtonite-grunerite and tremolite-ferroactinolite are created when one cation is replaced by another in a crystal structure without significantly alter significantly in a crystal another without structure by replaced is cation when one created are tremolite-ferroactinolite and seriescummingtonite-grunerite as Mineral such 512. pp. Ltd. Publications, London: ed. 2nd Mining, utilization. and production origin, its WE [1959]. Asbestos: Sinclair Newsletter 12, 1975. AIPEA July City, Mexico AIPEA; of committee the nomenclature of G [1976]. Meeting Pedro Brindley GW, citation. this for reference the full provide doesoriginalnot The source Wollastonite 1 2 3 4

NIOSH CIB 62 • Asbestos 153 Delivering on the Nation’s promise: safety and health at work for all people through research and prevention

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